Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@H:15]2[CH2:20][CH2:19][CH2:18][NH:17][C@H:16]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:29](OC=O)(=[O:31])C>O1CCCC1>[CH:29]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:15]([O:14][CH2:13][C:5]2[CH:4]=[C:3]([C:2]([F:27])([F:1])[F:28])[CH:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:6]=2)[C@@H:16]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:31]
Reactant: CC(=O)OC=O
Reactant: FC(F)(F)c1cc(CO[C@H]2CCCN[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=CN1CCC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1c1ccccc1

Procedure:
The title compound was prepared from (+)-cis-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenyl piperidine prepared from the hydrochloride salt, Example 5)(0.5 g) and formic-acetic anhydride (prepared from 90% formic acid (1.5 ml) and acetic anhydride (3 ml) at 60° C. for 30 minutes) in tetrahydrofuran for 48 h at 23° C. The solvent was evaporated in vacuo and the residue partitioned between diochloromethane and saturated aqueous sodium bicarbonate solution, dried (MgSO4), concentrated in vacuo and chromatographed on silica gel to give the title compound as an oil. Found: C, 57.79; H, 4.39; N, 3.13. Calcd for C21H19NO2F6.0.3(H2O), C, 57.75; H, 4.52; N, 3.21%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[N:6]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:5]2=[O:19].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[CH3:12][O:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[NH:1][S:21]([CH3:20])(=[O:23])=[O:22])[C:5](=[O:19])[N:6]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:7]2=[O:13]
Reactant: COC(=O)CN1C(=O)c2cc(N)c(OC)cc2C1=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)CN1C(=O)c2cc(NS(C)(=O)=O)c(OC)cc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
A solution of methyl 2-(5-amino-6-methoxy-1,3-dioxoisoindolin-2-yl)acetate (0.202 g, 0.764 mmol) in pyridine (10 ml) was cooled to 0° C., and methanesulfonyl chloride (0.071 ml, 0.917 mmol) was added. The mixture was warmed to room temperature and stirred for 1 hour. Additional methanesulfonyl chloride (0.090 ml, 1.146 mmol) was added over 30 hour, cooling to 0° C. and stirring at room temperature. The solvent was removed under vacuum, and the crude was partitioned between ethyl acetate and 1N HCl. The organic phase was washed with brine and dried over sodium sulfate. The solvent was removed and the crude was purified by chromatography on silica gel cartridge (petroleum ether:ethyl acetate from 6:4 to 100% ethyl acetate) affording methyl 2-(5-methoxy-6-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (0.200 g, 0.584 mmol, 76% yield). MS/ESI+ 342.9 [MH]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH:25]3[CH2:28][CH2:27][CH2:26]3)[N:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[C:19]=23)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>Cl.O1CCOCC1>[NH2:24][C:20]1[C:19]2[N:18]([C:17]([CH:25]3[CH2:28][CH2:27][CH2:26]3)=[N:16][C:15]=2[C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=2)[CH:23]=[CH:22][N:21]=1
Reactant: Nc1nccn2c(C3CCC3)nc(-c3cccc(OCc4ccccc4)c3)c12
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nccn2c(C3CCC3)nc(-c3cccc(O)c3)c12
Temperature: 25 °C

Procedure:
A solution of 1-(3-Benzyloxy-phenyl)-3-cyclobutyl-imidazo[1,5-a]pyrazin-8-ylamine (1.82 g, 4.92 mmol) in 4M HCl in dioxane (20 mL) was heated to 75° C. in a sealed tube for 1.5 h. The reaction was allowed to cool to rt, the dioxane was decanted off and the brown gum residue was cooled to 0° C. in an ice-bath and charged with 7N NH3 in MeOH until basic. The reaction mixture was concentrated in vacuo, triturated with EtOAc and CHCl3, and the NH4Cl salts filtered off. The filtrate was concentrated in vacuo and purified by flash silica chromatography (8% MeOH in CHCl3) resulting in an off-white solid; 1H NMR (DMSO-d6, 400 MHz) δ 1.84-1.99 (m, 1H), 2.00-2.16 (m, 1H), 2.34-2.48 (m, 4H), 3.86-4.00 (m, 1H), 6.08 (brs, 2H), 6.81 (dd, 1H, J=8.4 Hz, 8.0 Hz), 6.95-7.06 (m, 3H), 7.30 (t, 1H, J=8.4 Hz); 7.41 (d, 1H, J=5.2 Hz), 9.63 (brs, 1H); MS (ES+): m/z 281.39 [MH+].
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[C:7]([O:18][CH3:19])=[CH:8][C:9]([CH3:17])=[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:11]=1)([CH3:5])[CH3:4].[Cl:20][CH2:21][CH2:22][CH2:23]I.C(OCC)(=O)C>CN(C)C=O>[Cl:20][CH2:21][CH2:22][CH2:23][CH:12]([C:10]1[CH:11]=[C:6]([CH:3]([CH3:5])[CH3:4])[C:7]([O:18][CH3:19])=[CH:8][C:9]=1[CH3:17])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)Cc1cc(C(C)C)c(OC)cc1C
Reactant: ClCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(CCCCl)c1cc(C(C)C)c(OC)cc1C
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
60% sodium hydride (928 mg) was suspended in anhydrous N,N-dimethylformamide (50 mL). A solution of methyl (5-isopropyl-4-methoxy-2-methylphenyl)acetate (5 g) in anhydrous N,N-dimethylformamide (30 mL) was added in a nitrogen atmosphere, so that the internal temperature was maintained at 4 to 6° C. After stirring at the same temperature for five minutes, 1-chloro-3-iodopropane (4.5 mL) was added so that the internal temperature was maintained at 4 to 6° C. After addition of the reagent, the mixture was brought back to room temperature and stirred for four hours. Ethyl acetate was added to the reaction solution, followed by washing with water. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (7.7 g). The property values of the compound are as follows.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[C:10]([NH:18][C:19]1([CH2:23][C:24](OCC)=O)[CH2:22][CH2:21][CH2:20]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[OH:30].[NH4+].[Cl-]>C1COCC1>[C:10]([NH:18][C:19]1([C:23](=[O:30])[CH3:24])[CH2:22][CH2:21][CH2:20]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CO
Reactant: CCOC(=O)CC1(NC(=O)c2ccccc2)CCC1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)C1(NC(=O)c2ccccc2)CCC1
Temperature: -78 °C
Reaction time: 6 h
Yield: 32 %

Procedure:
DIBAL (40.0 mL, 1M solution in toluene) was added dropwise at −78° C. to a stirred solution of ethyl [1-(benzoylamino)cyclobutyl]acetate (6.86 g, 26.3 mmol) in THF (130 mL) over the course of 30 minutes. After stirring at −78° C. for 6 hours, MeOH (10 mL) was added dropwise to the mixture at −78° C. over the course of 30 minutes. Saturated aqueous NH4Cl (20 mL) was then added to the mixture, and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with Et2O, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (hexane:AcOEt=2:1) of the residue gave the title compound as a colorless solid (1.82 g, 32%). 1H-NMR (400 MHz, CDCl3) δ 1.87-2.07 (2H, m), 2.25-2.34 (2H, m), 2.36-2.45 (2H, m), 3.28 (2H, s), 6.57 (1H, brs), 7.39-7.45 (2H, m), 7.46-7.53 (1H, m), 7.70-7.76 (2H, m), 9.79 (1H, s).
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([O:10][C:11](=[O:24])[C:12](=[O:23])[CH2:13][C:14]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[CH3:9].[NH4+].[Cl-]>C1COCC1>[CH2:8]([O:10][C:11](=[O:24])[C:12]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([OH:23])[CH2:13][C:14]([CH3:15])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:22])[CH3:9]
Reactant: CCOC(=O)C(=O)CC(C)(C)c1ccccc1
Reactant: Cl[Mg]C1CCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(CC(C)(C)c1ccccc1)C1CCCC1
Reaction time: 3 h

Procedure:
2.13 ml of a 2 M ethereal cyclopentyl magnesium chloride solution is added in drops at −70° C. to a solution of 1.0 g of 4-methyl-4-phenyl-2-oxopentanoic acid-ethyl ester in 20 ml of THF. After 3 hours at −70° C., the batch is poured into cold, saturated NH4Cl solution and extracted with ethyl acetate. The extracts are dried (Na2SO4) and concentrated by evaporation. Column chromatography on silica gel with ethyl acetate-cyclohexane yields 320 mg of the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:13][CH2:14][N:15]([CH2:18][C:19]([NH2:21])=[O:20])[CH2:16][CH:17]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.[Cl-].[NH4+].C(O)C.O>[Fe]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]([NH2:21])=[O:20])[CH2:14][CH:13]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C2=CCN(CC(N)=O)CC2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(C2=CCN(CC(N)=O)CC2)ccc1N
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 2-[4-(3-Methoxy-4-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-acetamide (240 mg, 0.82 mmol), iron (138 mg, 2.47 mmol), ammonium chloride (22.0 mg, 0.412 mmol) in ethanol (7 mL, 100 mmol) and water (3 mL, 200 mmol) was heated at 80° C. After 3 h, MS showed product with no SM. The mixture was cooled, solvent was evaporated and was diluted with aq. Na2CO3 solution and EtOAc. The mixture was filtered through a pad of celite, extracted from EtOAc, combined organic was washed with brine. After drying, the solvent was evaporated to give the product, 2-[4-(4-Amino-3-methoxy-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-acetamide, as a foam (195 mg, 91%). The product was taken to the next step without further purification. MS: 262 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([N:11]=[C:12]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:5]=[C:6]([C:8]([OH:10])=O)[N:7]=1.[CH:19]([N:22](C(C)C)[CH2:23][CH3:24])(C)[CH3:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NCC)C>CN(C=O)C>[CH2:19]([N:22]([CH2:23][CH3:24])[C:8]([C:6]1[N:7]=[C:2]([NH2:1])[C:3]2[N:4]([N:11]=[C:12]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:5]=1)=[O:10])[CH3:20]
Reactant: Nc1nc(C(=O)O)cn2nc(-c3ccco3)nc12
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cn2nc(-c3ccco3)nc2c(N)n1

Procedure:
A solution of 8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxylic acid (20 mg, 0.082 mmol; see Example 8 above), diisopropylethylamine (14 μL, 0.082 mmol), HATU (47 mg, 0.123 mmol), and diethylamine (0.163 mmol) in DMF (300 μL) was stirred at room temperature for 1 hour. The solvent was removed in vacuo. The residue was purified by HPLC (C18, H2O:MeCN gradient). 1H NMR (300 MHz, DMSO-d6) δ 1.17 (t, J=6.9 Hz, 6H), 3.41 (m, 4H), 6:76 (dd, J3.4, 1.7 Hz, 1H), 7.18 (dd, J=3.4, 0.7 Hz, 1H), 7.69 (br. s, 2H), 7.96 (dd, J=1.7, 0.7 Hz), 8.34 (s, 1H). MS: m/z 301 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:14]COC)[CH2:13][CH2:12][CH2:11][CH2:10]1.[Li]CCCC.[B:23](OC(C)C)(OC(C)C)[O:24]C(C)C>C1COCC1>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]2[C:9]3([CH2:13][CH2:12][CH2:11][CH2:10]3)[O:14][B:23]([OH:24])[C:2]=2[CH:7]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCOC1(c2ccc(C)cc2Br)CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)B(O)OC21CCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
To a solution of 2-bromo-1-(1-(methoxymethoxy)cyclopentyl)-4-methylbenzene (2.2 g, 714 mmol) in THF (40 mL) at −78° C. was added n-BuLi (7.5 mL, 18.5 mmol) dropwise. The mixture was stirred at −78° C. for additional 1 h and then triisopropyl borate (2.8 g, 14.8 mmol) in 10 mL of THF was added below −70° C. The resulting mixture was kept stirring at −78° C. for 30 min and allowed to warm to rt and stirred overnight. Then it was quenched with aqueous NH4Cl and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified on column chromatography to provide the product (1.2 g, yield 81%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C:18]1=[O:26]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:17][C:18]1=[O:26])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: O=C1Cc2ccccc2N1
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3ccccc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was then condensed with 2-oxindole to give 0.25 g of 3-(3,5-Diisopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[N:16]([CH2:17][CH2:18][OH:19])[N:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]([NH:11][C:12]1[N:16]([CH2:17][CH2:18][OH:19])[N:15]=[CH:14][CH:13]=1)=[O:3]
Reactant: Nc1ccnn1CCO
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Solvent: O
Product: O=CNc1ccnn1CCO
Temperature: 25 °C

Procedure:
A mixture of acetic anhydride (44.5 ml) and formic acid (22.3 ml) was stirred at room temperature for an hour. To this mixture was added 5-amino-1-(2-hydroxyethyl)pyrazole (30 g) at 0°-10° C., and the mixture was stirred under ice-cooling for 30 minutes. The mixture was poured into ice-cooled water, adjusted to pH 10.5 with 40% potassium carbonate solution, and stirred under ice-cooling for 30 minutes. The mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate 6 times. The organic layer was dried over magnesium sulfate, and evaporated in vacuo to give 5-formamido-1-(2-hydroxyethyl)pyrazole (30.8 g).
Reaction SMILES: CON(C)[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH3:26])=[CH:16][C:15]=3[CH:27]=2)[CH:6]=1.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[Li]>>[CH3:26][C@@H:22]1[CH2:23][CH2:24][CH2:25][N:21]1[CH2:20][CH2:19][C:17]1[O:18][C:14]2[CH:13]=[CH:12][C:11]([C:7]3[CH:6]=[C:5]([C:4]([C:31]4[S:30][CH:34]=[CH:33][CH:32]=4)=[O:28])[CH:10]=[CH:9][CH:8]=3)=[CH:27][C:15]=2[CH:16]=1
Reactant: [Li]c1cccs1
Reactant: CON(C)C(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3cccc(C(=O)c4cccs4)c3)ccc2o1
Yield: 53 %

Procedure:
The product from Example 145 and 2-thienyllithium were processed as described in Example 146 to provide the title compound (53% yield). MS (ESI APCI) m/z 416 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 1.18 (d, 3H), 1.38-1.53 (m, 1H), 1.73-1.86 (m, 2H), 1.95-2.08 (m, 1H), 2.24-2.36 (m, 1H), 2.42-2.61 (m, 2H), 2.95-3.15 (m, 2H), 3.19-3.34 (m, 2H), 6.63 (d, 1H), 7.27 (d, 1H), 7.48-7.57 (m, 2H), 7.63 (dd, 1H), 7.76-7.84 (m, 3H), 7.90-7.98 (m, 2H), 8.07 (dd, 1H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH2:11])=[S:10].Br[C:13]1([C:17](OCC)=[O:18])[CH2:16][CH2:15][CH2:14]1>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][C:13]2([C:17](=[O:18])[N:11]=1)[CH2:16][CH2:15][CH2:14]2
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: NC(=S)NC1CC2CCC1C2
Product: O=C1N=C(NC2CC3CCC2C3)SC12CCC2

Procedure:
Synthesis was performed from N-bicyclo[2.2.1]hept-2-ylthiourea and ethyl 1-bromocyclobutanecarboxylate according to Method D.
Reaction SMILES: [F-].[K+].[O:3]=[CH:4][C:5]1[CH:13]=[CH:12][C:9]([O:10][CH3:11])=[C:7]([OH:8])[CH:6]=1.F[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26].O>CS(C)=O>[N+:25]([C:16]1[CH:17]=[C:18]([C:21]([F:22])([F:23])[F:24])[CH:19]=[CH:20][C:15]=1[O:8][C:7]1[CH:6]=[C:5]([CH:13]=[CH:12][C:9]=1[O:10][CH3:11])[CH:4]=[O:3])([O-:27])=[O:26]
Reactant: COc1ccc(C=O)cc1O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C=O)cc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 140 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
To a stirred suspension of potassium fluoride (457 mg, 7.8 mmol) in dry DMSO (20 ml) was added a solution of isovanillin (1.0 gm, 6.57 mmol) in dry DMSO (20 ml). The reaction contents were heated at 140° C. for 10 min. A solution of 4-fluoro-3-nitrobenzotrifluoride (1.37 gm, 6.57 mmol) in dry DMSO (10 ml) was added to the above suspension and the reaction mixture was stirred at 140° C. for 4.0 h. The reaction mixture was cooled to room temperature and the contents were poured into water (200 ml) and extracted with ethyl acetate (100 ml×3). The organic extracts were combined and washed with 1N sodium hydroxide (50 ml×2), water and brine and dried over anhydrous sodium sulfate. The organic layer was concentrated in vacuo to obtain 3-(2-nitro-4-trifluoromethyl phenoxy)-4-methoxy benzaldehyde as a pale yellow solid (2.0 gm).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:30]([OH:32])=O)=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[C:24](=[O:29])[CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][C:39]=1[N:40]1[CH2:45][C@H:44]([CH3:46])[CH2:43][C@H:42]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:50]([O:49][C:48]([NH:47][C@H:42]1[CH2:43][C@@H:44]([CH3:46])[CH2:45][N:40]([C:39]2[CH:38]=[CH:37][N:36]=[CH:35][C:34]=2[NH:33][C:30]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[C:24](=[O:29])[CH2:23]4)=[CH:18][CH:19]=3)[N:14]=2)=[O:32])[CH2:41]1)=[O:54])([CH3:51])([CH3:52])[CH3:53]
Reactant: CN1CCN(c2ccc3cc(NC(=O)OCc4ccccc4)c(C(=O)O)nc3c2)CC1=O
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)C(=O)C4)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.7 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-(4-methyl-3-oxopiperazin-1-yl)quinoline-2-carboxylic acid (0.012 g, 0.028 mmol), tert-butyl [(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (0.013 g, 0.043 mmol) and HATU (0.034 g, 0.089 mmol) in DMF (0.30 mL), DIPEA (0.019 mL, 0.11 mmol) was added. The resulting mixture was stirred at room temperature for 2 h, then quenched with 5 mL of EtOAc and 3 mL of 1 M NaOH. The resulting layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure, then purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 60 mL/min.) to afford the sub-title compound as a yellow solid (0.005 g, 20%). LCMS calc. for C39H46N8O6 [M+H]+: m/z=723.4. found: 723.4.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[C:13]([N+:20]([O-])=O)=[CH:12][C:11]=2[C:23]([F:26])([F:25])[F:24])[CH:9]=1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[C:13]([NH2:20])=[CH:12][C:11]=2[C:23]([F:25])([F:26])[F:24])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cn(-c2cc(C(=O)OC)c([N+](=O)[O-])cc2C(F)(F)F)cn1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cn(-c2cc(C(=O)OC)c(N)cc2C(F)(F)F)cn1
Yield: 92 %

Procedure:
A solution of 1.1 g (2.95 mmoles) of 1-(5-methoxycarbonyl-4-nitro-2-trifluoromethyl-phenyl)-1H-imidazole-4-carboxylic acid methyl ester in 400 ml methanol is treated with 163 mg of 10% palladium on charcoal and hydrogenated at room temperature under a pressure of 5 bar for 18 hours. After filtration of the catalyst and evaporation of the solvent the residue is chromatographed on silica gel using dichlormethane and rising quantities of up to 15% of methanol. Recrystallization of the residue from dichloromethane and hexane gives 932 mg (2.715 mmol, 92%) of 1-(4-amino-5-methoxycarbonyl-2-trifluoromethyl-phenyl)-1H-imidazole-4-carboxylic acid methyl ester, m.p. 206 -208° C., ES-MS: m/z 344 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[N:8]([CH3:13])[C:9]2=[O:12])=[CH:4][CH:3]=1.[N:21]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[NH:24][CH2:23][CH2:22]2.CC(C)([O-])C.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.O.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]>[N:21]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[N:24]([C:2]1[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=4)[N:8]([CH3:13])[C:9]3=[O:12])=[CH:4][CH:3]=1)[CH2:23][CH2:22]2
Reactant: Cn1c(-c2cccc(Cl)c2)cc2ccc(Br)cc2c1=O
Reactant: C1CN2CCC(CC2)N1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(-c2cccc(Cl)c2)cc2ccc(N3CCN4CCC3CC4)cc2c1=O
Temperature: 85 °C
Yield: 35 %

Procedure:
A mixture of 7-bromo-3-(3-chlorophenyl)-2-methylisoquinolin-1(2H)-one (Intermediate 24A) (50 mg, 0.143 mmol), 1,4-diazabicyclo[3.2.2]nonane (27.2 mg, 0.215 mmol), sodium t-butoxide (55.1 mg, 0.574 mmol), tris(dibenzylideneacetone)dipalladium(0) (13.13 mg, 0.014 mmol) and (+/−) BINAP (26.8 mg, 0.043 mmol) in degassed dioxane (1 mL) was heated to 85° C. under N2 in a sealed vessel overnight. Reaction mixture allowed to cool to room temperature, diluted with water and the product extracted into ethyl acetate. Organics washed several times with water, dried (MgSO4), filtered and then evaporated to dryness. The crude product was added to a silica gel column (25 g) and was eluted with 0-50% 2M ammonia in methanol in ethylacetate to afford 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-3-(3-chlorophenyl)-2-methylisoquinolin-1(2H)-one (19.4 mg, 0.05 mmol).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.Cl[CH2:11][CH:12]=O>>[Br:1][C:2]1[N:7]2[CH:11]=[CH:12][N:8]=[C:6]2[CH:5]=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(N)nc(Br)c1
Reactant: O=CCCl
Product: Cc1cc(Br)n2ccnc2c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
A mixture of 6-bromo-4-methyl-pyridin-2-ylamine (374 mg, 2.0 mmol) and chloroacetaldehyde (1 mL, 50 wt. % in water) in IMS (4 mL) was stirred at 100° C. in a sealed tube for 18 hours, then cooled to room temperature and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH then the product was eluted with 2 M NH3 in MeOH. After the solvents were removed, the residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 5:95) to give 5-Bromo-7-methyl-imidazo[1,2-a]pyridine as an orange solid (340 mg, 82%). 1H NMR (400 MHz, CHCl3-d): δ 7.72-7.70 (m, 1 H); 7.63-7.62 (m, 1 H); 7.38-7.37 (m, 1 H); 6.92-6.90 (m, 1 H); 2.40 (m, 3 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[N:5]=[C:4]([NH2:11])[CH:3]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)Cl>[Br:12][C:3]1[C:4]([NH2:11])=[N:5][C:6]([S:8][CH3:10])=[N:7][C:2]=1[Cl:1]
Reactant: CS(=O)c1nc(N)cc(Cl)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CSc1nc(N)c(Br)c(Cl)n1
Reaction time: 1 h

Procedure:
To a cold stirring solution of 10 g (52.2 mmol) 6-chloro-2-(methylsulfinyl)pyrimidine-4-amine in 450 ml of DCM, 10 g (56.2 mmol) of N-bromosuccinimide were added, and stirring was continued for 1 hour at room temperature to provide 5-bromo-6-chloro-2-(methylthio)pyrimidine-4-amine, which was used without further purification in the next step (see intermediate 3). The end of the reaction is followed by thin layer chromatography.
Reaction SMILES: [N:1]([CH2:4][C:5]1[O:9][C:8]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)=[N+]=[N-]>C(O)C.[Ni]>[NH2:1][CH2:4][C:5]1[O:9][C:8]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=NCc1ccc(CCC(=O)O)o1
Agent: [Ni]
Solvent: CCO
Product: NCc1ccc(CCC(=O)O)o1
Yield: 98.5 %

Procedure:
Treatment of a solution in ethanol (50 mL) at ambient temperature of 5-azidomethyl-2-carboxyethylfuran (585 mg, 3.00 mmol), prepared as in step 3, with Raney nickel 2800 and 4 atmospheres of H2 for 24 hours, followed by filtration of the reaction mixture and concentration in vacuo gave 5-aminomethyl-2-carboxyethylfuran (0.50 g) as a yellow oil.