Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][N:30]=[C:31]=[O:32]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:30]([CH2:29][C:25]3[O:24][CH:28]=[CH:27][CH:26]=3)[C:31]2=[O:32])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: O=C=NCc1ccco1
Product: COc1cccc2c1ncc1c(=O)n(Cc3ccco3)c(=O)n(C3CCCC3)c12
Yield: 53.7 %

Procedure:
1-Cyclopentyl-3-furan-2-ylmethyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (21 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and (2-furyl)methyl isocyanate (0.4 mmol) following general procedure C. LCMS: m/z 392 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.45 (s, 1H), 7.78 (d, 1H), 7.57 (t, 1H), 7.32 (d, 1H), 7.24 (d, 1H), 6.30 (d, 1H), 6.18 (d, 1H), 5.04 (p, 1H), 4.33 (s, 2H), 4.12 (s, 3H), 2.40 (m, 2H), 2.11 (m, 4H), and 1.16 (m, 2H) ppm.
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CCO>[C:23]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:9]([OH:11])=[O:10])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)C(Cc1ccc2c(c1)OCO2)=C(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(Cc1ccc2c(c1)OCO2)=C(c1ccccc1)c1ccccc1
Yield: 79.4 %

Procedure:
Methyl 3,3-diphenyl-2-(3,4-methylenedioxybenzyl)prop-2-enoate (0.05 g, 0.13 mmol) was dissolved in EtOH (2 ml) and 3M aqueous NaOH added (2 mi, 6 mmol). After stirring at 80° C. for 15 h the EtOH was removed in vacuo and the residue partitioned between EtOAc and H2O. The aqueous layer was acidified to pH 2 with 1-M-aqueous HCl and extracted with EtOAc (3X). The combined organic extract was washed with brine, dried (MgSO4 anhydrous), filtered and evaporated to give a colorless solid. Recrystallization from EtOAc/hexane gave the title compound as a colorless solid (0.037 g, 77%).
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][NH2:7])([CH3:3])[CH3:2].[C:8](O)(=O)[CH3:9]>>[CH:1]([N:4]1[CH:5]=[CH:6][N:7]=[C:8]1[CH3:9])([CH3:3])[CH3:2]
Reactant: CC(C)NCCN
Reactant: CC(=O)O
Product: Cc1nccn1C(C)C

Procedure:
The procedure of Example 1 was followed except that 33.1 g (0.32 mol) of N-isopropylethylenediamine, 19.4 g (0.32 mole) of acetic acid and 5.9 g of Harshaw Ni-2715 catalyst were used. About 37.6 g of crude product was recovered. GLC analysis showed that the crude product contained 98% of 1-isopropyl-2-methylimidazole.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:21])([CH2:8][C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])([CH3:11])[CH3:10])[C:4]([F:7])([F:6])[F:5].Br[C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[F:39].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+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:5][C:4]([F:7])([F:6])[C:3]([CH2:2][NH:1][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[F:39])([OH:21])[CH2:8][C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])([CH3:11])[CH3:10]
Reactant: Cc1cc(Br)c2cnn(-c3ccccc3F)c2c1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CN)C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1F)C(F)(F)F
Temperature: 120 °C
Yield: 22.5 %

Procedure:
To a mixture of 2-(aminomethyl)-1,1,1-trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-pentanol (Intermediate 18, 49.5 mg, 0.16 mmol) and 4-bromo-1-(2-fluorophenyl)-6-methyl-1H-indazole (Intermediate 26, 45.8 mg, 0.15 mmol) in toluene (0.75 mL) were added tris(dibenzylideneacetone)dipalladium(0) (6.9 mg, 0.075 mmol), racemic-BINAP (9.3 mg, 0.015 mmol) and sodium tert-butoxide (18.5 mg, 0.192 mmol). The mixture was heated in a microwave at 120° C. for 30 min and then cooled and partitioned between water and dichloromethane. The organic layer was separated, dried and purified by silica gel chromatography using the Flashmaster II (20 g cartridge) eluting with a 0:100 cyclohexane:ethyl acetate gradient over 60 minutes to give crude product (43.6 mg) which was purified further by mass-directed autopreparation to give the title compound (18 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24](Cl)=[O:25])[CH:19]=1.ClC1N=CN=C(C(NC2C=CC(O)=CC=2)=O)C=1>ClCCl>[Cl:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=2[CH3:9])=[O:25])[CH:19]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: Cc1cc(O)ccc1N
Agent: O=C(Nc1ccc(O)cc1)c1cc(Cl)ncn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A cooled (0° C.) solution of 4-amino-m-cresol (Fluka, 4.17 g, 33.9 mmol) and triethylamine (23.6 mL, 0.170 mol) in dry dichloromethane (100 mL) was treated with 6-chloropyrimidine-4-carbonyl chloride, obtained as described above for Intermediate 7, step 1 (6.0 g, 34 mmol) and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic layers were dried on magnesium sulfate and evaporated in vacuo. The crude product was purified by column chromatography (silica) using as eluent petroleum ether/EtOAc to afford the title compound as yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14].[N-:15]=[N+:16]=[N-:17].[Na+].O>CN(C=O)C>[N:15]([C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14])=[N+:16]=[N-:17]
Reactant: COC(=O)c1nc(Br)cc(Br)c1OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(Br)cc(N=[N+]=[N-])c1OC
Temperature: 60 °C
Reaction time: 48 h
Yield: 57.7 %

Procedure:
Methyl 4,6-dibromo-3-methoxypyridine-2-carboxylate (0.980 g, 3.02 mmol) was dissolved in a minimum amount of DMF. Slowly sodium azide (0.216 g, 3.32 mmol) was added followed by H2O to form a homogeneous solution. The reaction mixture was heated to 60° C. and stirred for 2 days. Reaction mixture added to a flask filled with ice water and extracted with ethyl acetate (3×50 mL). Extracts were combined and back washed with H2O, dried (MgSO4) and concentrated to give 0.500 g of an orange oil. 1H NMR(CDCl3): δ 3.90 (s, 3H); 3.95 (s, 3H); 7.20 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:14][CH2:13][C@@H:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[N:11]2[C:24]2[CH:29]=[C:28]([F:30])[C:27]([N:31]3[CH2:36][CH2:35][CH:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:33][CH2:32]3)=[C:26]([F:43])[CH:25]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1.C(O)C.O.[Fe]>[F:43][C:26]1[CH:25]=[C:24]([N:11]2[C@H:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH2:14][CH2:13][C@H:12]2[C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH:29]=[C:28]([F:30])[C:27]=1[N:31]1[CH2:36][CH2:35][CH:34]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:33][CH2:32]1
Reactant: O=[N+]([O-])c1ccc([C@@H]2CC[C@@H](c3ccc([N+](=O)[O-])cc3)N2c2cc(F)c(N3CCC(c4ccccc4)CC3)c(F)c2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc([C@@H]2CC[C@@H](c3ccc(N)cc3)N2c2cc(F)c(N3CCC(c4ccccc4)CC3)c(F)c2)cc1
Temperature: 80 °C
Yield: 100.1 %

Procedure:
The product of Example 8A (197 mg, 0.337 mmol) was dissolved in a mixture of THF (3 mL), ethanol (3 mL) and water (0.5 mL), and then iron (95 mg, 1.69 mmol) and ammonium chloride (27 mg, 0.506 mmol) were added and the mixture heated at 80° C. for 3 hours. Afterwards ethyl acetate was added to the solution followed by extraction with sodium bicarbonate. The organic extract was dried, filtered and concentrated which afforded 177 mg (100%) of the title compound. MS (ESI) m/z 525 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1.[CH:34]([N:37]([CH2:41][CH2:42]Cl)[CH:38]([CH3:40])[CH3:39])([CH3:36])[CH3:35]>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][CH2:42][CH2:41][N:37]([CH:38]([CH3:40])[CH3:39])[CH:34]([CH3:36])[CH3:35])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC
Reactant: CC(C)N(CCCl)C(C)C
Product: COc1cc(-c2nc3ccc(OCCN(C(C)C)C(C)C)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 104 with 2-(N,N-diisopropylamino)ethyl chloride essentially as previously described. mp 184° C., MS 585, NMR, IR.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=[S:5])[NH2:4].Cl[CH:8]([C:14]([CH3:16])=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10]>CCO>[CH:2]([C:3]1[S:5][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:14]([CH3:16])[N:4]=1)([CH3:6])[CH3:1]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CC(C)C(N)=S
Solvent: CCO
Product: CCOC(=O)c1sc(C(C)C)nc1C
Yield: 77.5 %

Procedure:
To a solution of 2-methylpropanethioamide (1.51 g) in EtOH (40 mL) was added ethyl 2-chloroacetoacetate (2.409 g) at room temperature. The mixture was refluxed for 2 h. After cooling, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) to give the title compound (2.42 g).
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([OH:13])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:21]1([C:24]2[S:25][CH:26]=[C:27]([CH2:29][NH2:30])[N:28]=2)[CH2:23][CH2:22]1>>[CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([NH:30][CH2:29][C:27]2[N:28]=[C:24]([CH:21]3[CH2:23][CH2:22]3)[S:25][CH:26]=2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCc1csc(C2CC2)n1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Product: O=C(NCc1csc(C2CC2)n1)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 9c) (100 mg, 0.35 mmol) and 2-cyclopropyl-4-thiazolemethanamine (CAN 1083299-53-9, 54 mg, 0.35 mmol) as starting materials; off white solid (67 mg, 45.6%). MS (ESI): 426 (M+H)+.
Reaction SMILES: C([O:8][C:9](=[O:32])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:31])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21](=[O:30])[C@H:22]([CH3:29])[NH:23][S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])C1C=CC=CC=1.[H][H]>CO.O.[C].[Pd]>[CH2:27]([S:24]([NH:23][C@H:22]([C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:32])=[O:8])=[O:31])=[O:30])[CH3:29])(=[O:25])=[O:26])[CH3:28]
Reactant: [H][H]
Reactant: CCS(=O)(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CCS(=O)(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Yield: 72.5 %

Procedure:
N-ethanesulfonyl-L-alanyl-L-prolyl-L-proline benzylester (2.00 g, 4.29 m mole) was dissolved in a mixture of methanol (10 ml) and water (10 ml), and then hydrogen gas was passed through the solution in the presence of 5% palladium carbon for 1.5 hours at room temperature. Cellite was added to the reaction solution and the solution was filtered and this operation was repeated again. The catalyst was completely removed and the filtrate was concentrated under reduced pressure. The thus produced crystals were obtained by filtration, washed sufficiently with ethyl acetate, and then dried under reduced pressure to give white crystals of N-ethanesulfonyl-L-alanyl-L-prolyl-L-proline (1.17 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH2:12])[N:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:11][N:8]1[C:6]2=[N:7][C:2]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:3][C:4]([NH2:12])=[C:5]2[CH:10]=[N:9]1
Reactant: OB(O)c1ccccc1
Reactant: Cn1ncc2c(N)nc(Cl)nc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1ncc2c(N)nc(-c3ccccc3)nc21
Temperature: 170 °C

Procedure:
A suspension of 6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (68 mg, 0.37 mmol), phenyl boronic acid (68 mg, 0.56 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex (30 mg, 0.037 mmol), 1,4-dioxane (3 ml), water (0.2 ml), and aqueous sodium carbonate solution (2.0 M, 0.740 ml, 1.5 mmol) in a 5 mL microwave vial was deoxygenated using 10 alternate vacuum/argon flush cycles. The reaction mixture was then heated via microwave irradiation to 170° C. for 10 minutes. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (40 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The layers were separated and the organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0.5-6.5% methanol/dichloromethane, linear gradient) to afford 1-methyl-6-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine. MS ESI calc'd. for C12H12N5 [M+H]+ 226. found 226.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].C([O-])([O-])=O.[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:24]([F:27])([F:25])[F:26])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@H]2C[C@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@@H]2OC2CCOCC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCCO
Product: N#CC1(NC(=O)[C@H]2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@@H]2OC2CCOCC2)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Argon was bubbled through a mixture of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-(tetrahydro-pyran-4-yloxy)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (40 mg, 0.0707 mmol, example 169) and K2CO3 (20 mg, 0.1415 mmol) in n-butanol (2 ml) for 10 minutes. Then triphenyl-phosphine (1.48 mg, 0.00566 mmol) and palladium acetate (0.318 mg, 0.001415 mmol) were added and the reaction mixture was stirred at 100° C. for 2 h. The mixture was allowed to cool to room temperature, the solvent was removed and the remaining residue was diluted with water and extracted 3 times with EtOAc. The combined extracts were washed with brine, dried (Na2SO4) and evaporated. The remaining residue was purified by silica column chromatography (DCM/MeOH 98:2) to obtain the title compound contaminated with a small amount of triphenyl-phosphine oxide. This material was triturated with a small amount of ether to give the title compound (25 mg, 73%) as white solid. MS (EI): 487.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH2:27][C:28]2[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=2)=[C:6]([C:8]2[CH:25]=[CH:24][C:11]3[CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH2:16][C:10]=3[CH:9]=2)[CH:7]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH2:27][C:28]2[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=2)=[C:6]([C:8]2[CH:25]=[CH:24][C:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:10]=3[CH:9]=2)[CH:7]=1
Reactant: Cc1ccnc(COc2ccc(F)cc2-c2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccnc(COc2ccc(F)cc2-c2ccc3c(c2)CCNCC3)c1

Procedure:
1,1-dimethylethyl 7-(5-fluoro-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate, (0.304 g) was dissolved in a minimum amount of dioxane. The solution was cooled in ice and to this was added a solution of HCl in dioxane (2 ml). This was stirred until the reaction had gone to completion by tlc. The reaction mixture was concentrated in vacuo. The product salt was dissolved in water and backwashed with ethyl acetate. The aqueous was neutralised with aqueous sodium hydroxide (1M). This was extracted with ethyl acetate. The organics were dried over sodium sulphate and concentrated to give the title compound, 100 mg.
Reaction SMILES: [NH:1]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:2]1[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH:1]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4]
Reactant: O=C(OCc1ccccc1)C1CCCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@@H]1CCCCN1

Procedure:
Benzyl pipecolate was routinely generated by treating an ethyl acetate suspension of this salt with saturated sodium bicarbonate until dissolution of the organic material. The aqueous layer was extracted twicewith ethyl acetate and the combined organic extracts were dried with MgSO4 and evaporated to yield (S)-Benzyl pipecolate (133) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:31][CH3:32])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[NH:21][C:22]([CH:29]=O)=[C:23]2[C:28]=1[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:19])[CH3:13]>>[CH2:31]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[NH:21][C:22]([CH:29]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[C:23]2[C:28]=1[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:19])[CH3:32]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1[nH]c(C=O)c2c1CCCC2
Product: CCN(CC)CCNC(=O)c1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c2c1CCCC2
Yield: 67 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (1.43 g, 6.8 mmol) was condensed with 3-formyl-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic acid (2-diethylaminoethyl)amide (1.97 g) to give 2.2 g (67%) of the title compound as a yellow-orange solid.
Reaction SMILES: Br[CH2:2][C:3]1([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1.[N+:20]([C:23]1[NH:24][CH:25]=[CH:26][N:27]=1)([O-:22])=[O:21].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O.O>[O:12]([CH2:11][C:3]1([CH2:2][N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[N+:20]([O-:22])=[O:21])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1)[Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: CC1(C)OCC(CBr)(CO[Si](C)(C)C(C)(C)C)CO1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCC(CO[Si](C)(C)C(C)(C)C)(Cn2ccnc2[N+](=O)[O-])CO1
Temperature: 100 °C
Yield: 57.4 %

Procedure:
578 mg (1.64 mmol equivalents) of 5-bromomethyl-5-(t-butyldimethylsiloxymethyl)-2,2-dimethyl-1,3-dioxane was dissolved in 10 mL of dimethylformamide, 186 mg (1.64 mmol equivalents) of 2-nitroimidazole and 680 mg (4.92 mmol equivalents) of potassium carbonate were added thereto, and the mixture was heated to 100° C. for 18 hours. After completion of the reaction, the reaction liquid was cooled to room temperature (25° C.), a saturated aqueous solution of ammonium chloride and water were added thereto, and the mixture was extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, then dried with anhydrous magnesium sulfate and subsequently concentrated under vacuum, and the obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=3/1) to give 363 mg (0.942 mmol equivalents) of 5-(t-butyldimethylsiloxymethyl)-2,2-dimethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:5]=1[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O:32]=[C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](=[O:42])[N:34]1[CH2:43][CH2:44][CH2:45][C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][CH:53]=1)[CH:49]=O>>[CH3:31][O:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:4]([O:3][CH3:2])[C:5]=1/[CH:6]=[CH:49]/[C:48]1[CH:47]=[C:46]([CH2:45][CH2:44][CH2:43][N:34]2[C:35](=[O:42])[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:33]2=[O:32])[CH:53]=[CH:52][CH:51]=1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Reactant: COc1cccc(OC)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: COc1cccc(OC)c1/C=C/c1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,6-Dimethoxybenzyltriphenylphosphonium bromide was coupled with phthalimide 29 following the method used in Example 44, except that the reaction was stirred overnight after warming up to room temperature. After concentration under reduced pressure, the residue was partitioned between EtOAc and water. The combined organics were washed with brine, dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (7 to 60% EtOAc-hexanes gradient) gave (E)-2-(3-(3-(2,6-dimethoxystyryl)phenyl)propyl)isoindoline-1,3-dione as a light yellow oil. Yield (0.317 g, 82%): 1H NMR (400 MHz, DMSO-d6) δ 7.79-7.84 (m, 4H), 7.42 (d, J=17.2 Hz, 1H), 7.17-7.32 (m, 5H), 7.06-7.09 (m, 1H), 6.58 (d, J=8.4 Hz, 2H), 3.83 (s, 6H), 3.61 (t, J=7.2 Hz, 2H), 2.63 (t, J=8.0 Hz, 2H), 1.88-1.96 (m, 2H).
Reaction SMILES: C(N[C:8]1[N:9]=[C:10](NC(=O)C(C)(C)C)[C:11]2[C:16](CBr)=[C:15]([Br:19])[S:14][C:12]=2[N:13]=1)(=O)C(C)(C)C.C1(NC2C=CC=CC=2)C=CC=CC=1.[H-].[Na+].CO>C1COCC1>[Br:19][C:15]1[S:14][C:12]2[N:13]=[CH:8][N:9]=[CH:10][C:11]=2[CH:16]=1
Reactant: CC(C)(C)C(=O)Nc1nc(NC(=O)C(C)(C)C)c2c(CBr)c(Br)sc2n1
Agent: [H-]
Agent: [Na+]
Agent: c1ccc(Nc2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: Brc1cc2cncnc2s1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2,4-bis(pivaloylamino)-5-bromomethyl-6-bromothieno[2,3-d]pyrimidine prepared in Step 2 above (200 mg, 0.4 mmol), diphenylamine (1.3 g, 0.77 mmol) and NaH (50 mg, 2.1 mmol) in dry THF (10 mL) is stirred at room temperature for 2 days, the excess NaH is decomposed with MeOH (1 mL), the solvent is evaporated, and the residue is chromatographed on silica gel to obtain 2,4-bis(pivaloylamino)-5-N,N-diphenylaminomethyl)-6-bromothieno[2,3-d]pyrimidine.