Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:14][CH:15]1[CH2:17][O:16]1)[C:10]([O:12]C)=O.[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[NH:19][NH2:20]>CC(O)C.C(OC(=O)C)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:15]([OH:16])[CH2:17][N:20]([NH:19][C:18](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:10]1=[O:12]
Reactant: COC(=O)C(CC1CO1)c1ccc(F)cc1Cl
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NN1CC(O)CC(c2ccc(F)cc2Cl)C1=O

Procedure:
To a solution of methyl 2-(2-chloro-4-fluorophenyl)-3-(oxiran-2-yl)propanoate (4.56 g, 17.6 mmol) in 2-propanol (20 mL) was added tert-butyl carbazate (2.3 g, 17.6 mmol) and the reaction heated to reflux for 16 hours. The reaction was then concentrated to dryness, redissolved in toluene (20 mL) and 1,5,7-triazobicylo(4.4.0)dec-5-ene (0.6 g, 4.4 mmol) was added and the mixture heated to reflux for 3 hours. The reaction was then diluted with ethylacetate, washed with 1 N HCl, dried with sodium sulfate and the solvent was evaporated in vacuo. The residue was recystallised from hot ethyl acetate to afford the title compound was obtained as a colourless solid (1.7 g, 26%). The mother liquor contained the trans isomer.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].[B-].CCCC[N+](CCCC)(CCCC)CCCC.[Cl-].[NH4+]>C(Cl)Cl>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[C:3]([CH3:10])[CH:4]=1
Reactant: Cc1cc(C=O)ccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [B-]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(CO)ccc1O
Yield: 78.9 %

Procedure:
To a solution of 4-hydroxy-3-methylbenzaldehyde (10 g, 73.5 mmol) in dry CH2Cl2 (550 mL) under nitrogen at 5° C. was added tetra-N-butylammonium borohydride (20.58 g, 80 mmol) and the resultant mixture stirred for 1.25 h at 5° C. Saturated ammonium chloride solution (30 mL) was added to the reaction mixture and the resultant mixture stirred for 1 h at 5° C. Saturated ammonium chloride solution (60 mL) was added and the reaction mixture extracted with CH2Cl2, dried (Na2SO4) and the solvents removed in vacuo. Purification by flushing through silica (2×150 g) eluting with EtOAc afforded the title compound as an oily yellow solid (8.01 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:16]#[N:17])=[CH:13][NH:14][CH:15]=2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].I[CH3:21]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([C:16]#[N:17])=[CH:13][N:14]([CH3:21])[CH:15]=2)=[CH:9][CH:10]=1)=[O:4]
Reactant: CI
Reactant: COC(=O)c1ccc(-c2c[nH]cc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cn(C)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a stirred solution of 4-(4-methoxycarbonylphenyl)-1H-pyrrole-3-carbonitrile (3.00 g) in N,N-dimethylformamide (25 ml) was added sodium hydride (60% oil dispersion : 559 mg) at ambient temperature and the stirring was continued for half an hour at the same temperature. Iodomethane (1.99 g) was added to the mixture, and was stirred at ambient temperature for two hours. The reaction mixture was poured onto ice water and extracted with ethyl acetate and washed with 7% aqueous hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was recrystallized from ethanol to give 4-(4-methoxycarbonylphenyl)-1-methylpyrrole-3-carbonitrile (2.78 g) as pale yellow needles.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]2[C:9](=[O:10])[N:8]([CH:11]3[CH2:16][CH2:15][C:14](=[O:17])[NH:13][C:12]3=[O:18])[C:7](=[O:19])[C:6]=12.[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([NH:1][C:2]1[S:3][CH:4]=[C:5]2[C:9](=[O:10])[N:8]([CH:11]3[CH2:16][CH2:15][C:14](=[O:17])[NH:13][C:12]3=[O:18])[C:7](=[O:19])[C:6]=12)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1scc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Product: CC(=O)Nc1scc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O

Procedure:
0.084 g 1-amino-5-(2,6-dioxopiperidin-3-yl)-5H-thieno(3,4-c)pyrrole-4,6-dione was dissolved in 10 mL of acetic anhydride and refluxed for 6 h. The reaction mixture was cooled and evaporated to dryness. The remaining residue was purified on silica gel column chromatography to yield a solid (0.067 g). MS (m/z): 320 (M−1)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:12]=[CH:13][C:14]2[CH:18]=[C:17]([CH2:19]O)[S:16][C:15]=2[CH:21]=1.S(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:24][CH2:19][C:17]1[S:16][C:15]2[CH:21]=[C:11]([O:10][C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)[CH:12]=[CH:13][C:14]=2[CH:18]=1
Reactant: OCc1cc2ccc(Oc3nc4ccccc4s3)cc2s1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1cc2ccc(Oc3nc4ccccc4s3)cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a cooled (0° C.) solution [6-(benzothiazol-2-yloxy)-benzo[b]thiophen-2-yl]-methanol (256 mg, 0.8 mmol) in DCM (8 mL) was added thionyl chloride (60 μL, 98 mg, 0.8 mmol) and the reaction mixture was stirred (0° C., 2 h). The reaction mixture was partitioned between EtOAc (20 mL) and saturated NaHCO3 (10 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×20 mL). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using EtOAc:hexane (0-40%) to provide the title compound as yellow solid (0.17 g, 65%). MS (ESI): mass calcd. for C16H10ClNOS2, 331.0; m/z found, 332.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.84 (d, J=2.2, 1H), 7.78 (d, J=8.7, 1H), 7.74 (dd, J=8.1, 0.6, 1H), 7.68 (dd, J=8.0, 0.7, 1H), 7.43-7.26 (m, 4H), 4.86 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[C:12]([O:29][CH3:30])=[C:13]([CH:19]([CH2:25][N+:26]([O-])=O)[CH2:20][C:21]([O:23]C)=O)[C:14]([CH3:18])=[C:15]([Cl:17])[CH:16]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[Cl:17][C:15]1[C:14]([CH3:18])=[C:13]([CH:19]2[CH2:20][C:21](=[O:23])[NH:26][CH2:25]2)[C:12]([O:29][CH3:30])=[C:11]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH3:10])[CH:16]=1
Reactant: COC(=O)CC(C[N+](=O)[O-])c1c(C)c(Cl)cc(C(C)NC(=O)OC(C)(C)C)c1OC
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CNC(=O)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of methyl 3-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6-methylphenyl)-4-nitrobutanoate (0.92 g, 2.1 mmol) in methanol (15 mL) was treated with nickel chloride hexahydrate (0.99 g, 4.1 mmol) and stirred for 5 minutes. The reaction mixture was cooled to 0° C. and treated with sodium tetrahydroborate (0.84 g, 22 mmol) in four portions. The ice bath was removed and the reaction mixture was stirred for 30 min and heated at 60° C. for 4.5 hours. The reaction mixture was diluted with saturated sodium bicarbonate (20 mL) and EtOAc (50 mL) and filtered over Celite. The Celite was washed with EtOAc and the filtrate was concentrated to give the desired product as a mixture of diastereoisomers at the lactam carbon. The mixture of diastereoisomers was separated by chiral HPLC (ChiralPak AD-H column, 20×250 mm, 5 micron particle size, eluting with 60% ethanol in hexanes at 9 mL/min, column loading ˜3 mg/injection) to give peak 1 (0.39 g, 49%, retention time: 6.25 min) and peak 2 (0.32 g, 40%, retention time: 9.34 min) as white solids.
Reaction SMILES: [Na].[Cl-].[NH2:3][C:4]([NH2:6])=[NH2+:5].[C:7]([C:11]1[CH:19]=[C:18]2[C:14]([C:15](=[O:30])[N:16]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH:17]2[CH2:20][C:21](OCC)=[O:22])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]>C(O)C>[C:7]([C:11]1[CH:19]=[C:18]2[C:14]([C:15](=[O:30])[N:16]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH:17]2[CH2:20][C:21]([NH:5][C:4]([NH2:6])=[NH:3])=[O:22])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CCOC(=O)CC1c2cc(C(C)(C)C)ccc2C(=O)N1CC(C)C
Reactant: NC(N)=[NH2+]
Agent: [Cl-]
Agent: [Na]
Solvent: CCO
Product: CC(C)CN1C(=O)c2ccc(C(C)(C)C)cc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 16 h
Yield: 68.1 %

Procedure:
N-[(6-tert-Butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is prepared as described in Example 9, starting with 20 cm3 of absolute ethanol, 0.37 g of sodium, 1.56 g of guanidinium chloride and 3.53 g of ethyl (6-tert-butyl-2-isobutyl-3oxo-2,3-dihydro-1H-isoindol-1-yl)acetate in 10 cm3 of absolute ethanol. The reaction mixture is stirred at a temperature in the region of 20° C. for 16 hours and is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in a mixture of 15 cm3 of water and 45 cm3 of diethyl ether and then stirred at a temperature in the region of 0° C. for 2 hours. The precipitate obtained is filtered off, washed with twice 10 cm3 of ice-cold water and then dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 2.5 g of N-[(6-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine are thus obtained in the form of a brown powder melting at 214-215° C. Mass spectrum: DCI: m/e 345 (M+H)+.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[C:8]2[NH:17][C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:27])([CH3:25])[CH3:26])=[CH:20][CH:19]=2)[C:8]2[NH:17][C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(O)c1ccc(C(CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1
Temperature: 50 °C
Yield: 39.9 %

Procedure:
A mixture of 2-{4-[2-cyclopentyl-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-phenyl}-propan-2-ol (150 mg, 0.41 mmol) and 10% palladium on activated carbon (0.2 g) in methanol (50 mL) was heated at 50° C. under hydrogen (50 psi) for 5 h. After cooling to room temperature, the catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo. The residue was purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-{4-[2-cyclopentyl-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-phenyl}-propan-2-ol (60 mg, 40%) as a white solid: LC/MS m/e calcd for C23H27FN2O [M+H]+ 367.48, observed 367.3; 1H NMR (400 MHz, MeOD) 1H NMR (400 MHz, MeOD) δ ppm 7.96 (t, J=2.5 Hz, 1H), 7.61 (dd, J=9.2, 2.5 Hz, 1H), 7.43 (d, J=8.3 Hz, 2H), 7.28 (d, J=8.3 Hz, 2H), 6.31 (s, 1H), 4.14 (t, J=7.7 Hz, 1H), 2.05-2.25 (m, 2H), 1.57-1.89 (m, 5H), 1.51 (s, 6H), 1.43-1.50 (m, 2H), 1.21 (d, J=8.6 Hz, 2H).
Reaction SMILES: [C:1]([N:9]1[CH2:18][CH2:17][C@H:16]2[C@@H:11]([CH2:12][CH2:13][C:14](=[O:19])[CH2:15]2)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([Mg])=[CH:23][CH:22]=1.[Br-].[Cl-].[NH4+].[OH-].[Na+]>C1COCC1>[C:1]([N:9]1[CH2:18][CH2:17][C@H:16]2[C@@H:11]([CH2:12][CH2:13][C:14]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)([OH:19])[CH2:15]2)[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc([Mg])cc1
Reactant: O=C1CC[C@H]2CN(C(=O)c3ccccc3)CC[C@@H]2C1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)N1CC[C@@H]2CC(O)(c3ccc(F)cc3)CC[C@H]2C1
Temperature: 25 °C

Procedure:
A solution of trans-2-benzoyl-6-oxodecahydroisoquinoline (2.0 g, 7.8 mmol) in anhydrous THF was cooled to -78° C. with stirring under a nitrogen atmosphere. A solution of p-fluorophenylmagnesium, bromide in THF (1.0M, 7.8 mL, 7.8 mmol) was added dropwise. The reaction mixture was stirred at -78° C. for 3 h, then warmed to room temperature over 16 h. The reaction mixture was poured onto a saturated ammonium chloride solution, mixed, basified with 1N NaOH solution and extracted with ethyl acetate three times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Column chromatography (ethyl acetate) afforded: (1) the less polar hydroxyl epimer of the entitled product (Rf =0.52, 934 mg): mp 107°-108° C.; NMR (CDCl3, 300 MHz) 7.5-7.3(m, 7H), 7.05 (t,2H, J=7), 4.9-4.7 (m, 1H), 3.9-3.65 (m, 1H), 1.9-1.1 (m, 10H); CMR (CDCl3, 68 MHz): 170.2, 161.5 (d, J=245), 144.9, 136.1, 129.4, 128.3, 126.7, 126.1 (d, J=8), 114.7 (d, J=21), 72.9, 53.4, 48.4, 47.7, 45.0, 42.8, 41.9, 40.9, 38.0, 36.8, 32.9, 31.9, 25.3; HRMS:Calcd:353.1791, Found:353.1791; (2) a mixture of hydroxyl epimers of the entitled product (184 mg) and (3) the more polar hydroxyl epimer of the entitled product, an oil (Rf =0.41, 302 mg): NMR (CDCl3, 300 MHz): 7.55-7.3 (m, 7H), 7.05 (t, 2H, J=7), 4.9-4.6 (m, 1H), 3.9-3.6 (m, 1H), 3.1-1.0 (m, 13H); CMR (CDCl3, 68 MHz): 170.0, 166.8 (d, J=246), 135.8 (d, J=17), 129.4 (d, J=14), 128.3, 128.2, 128.1, 128.0, 126.7, 126.6, 115.0 (d, J=21), 72.4, 47.1, 44.8, 42.3, 41.6, 37.4; HRMS: Calcd 353.1791; Found:353.1791.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:21]1COCC1.[H-].[Na+].CI>O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:10][CH2:11][O:12][CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COCC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 28 %

Procedure:
To a solution of 174 (2.22 g, 6.93 mmol) and THF (30 mL).cooled to 0° C. and maintained under a N2 atmosphere was added NaH (0.333 g, 8.32 mmol, 60% in mineral oil). The ice bath was removed and the solution stirred for 30 min then MeI (0.519 mL, 8.32 mmol) was added and the yellow solution stirred overnight. The reaction was diluted with H2O and extracted with Et2O. The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography (SNAP 50) eluting with hexane/EtOAc (4:1) to afford 0.660 g (28%) of (R)-tert-butyl 1-(3,4-dichlorophenyl)-3-methoxypropylcarbamate (176) as a light yellow oil.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]([CH3:16])[CH2:12][C:13]([OH:15])=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][CH:18](O)[CH2:19][CH2:20][CH3:21]>OS(O)(=O)=O.C1(C)C=CC=CC=1>[CH3:17][CH:18]([O:14][C:13](=[O:15])[CH2:12][CH:11]([NH:10][S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8])[CH3:16])[CH2:19][CH2:20][CH3:21]
Reactant: CCCC(C)O
Reactant: CC(CC(=O)O)NS(=O)(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCC(C)OC(=O)CC(C)NS(=O)(=O)c1ccccc1
Yield: 77.6 %

Procedure:
The mixture of 2.0 gr DL-N benzensulfonyl-3 aminobutyric acid (I), 1.2 gr 2-Pentanol, 30 ml toluene and 0.04 gr H2SO4 (conc) was heated under reflux for ca 6 hr. The reaction was treated as in the previous example. 2.0 gr of the ester was obtained, confirmed by spectroscopy.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32](O)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[C:45]([O:44][C:43](=[O:49])[NH:42][C@H:39]1[CH2:38][CH2:37][C@@H:36]([NH:35][C:32]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:7]4[CH:8]=[C:9]([CH2:12][CH3:13])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:15]=3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[C:21]=2[CH3:31])=[O:33])[CH2:41][CH2:40]1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c14) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)C(=O)OC(C)(C)[O:13][C:12]2=O)=[CH:6][CH:5]=1.[O:30]1[C:35]2=[CH:36][CH:37]=[CH:38][C:34]2=[CH:33][CH:32]=[C:31]1[NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN1C(=O)CCC1.O>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([C:12](=[O:13])[N:39]([C:31]2[O:30][C:35]3=[CH:36][CH:37]=[CH:38][C:34]3=[CH:33][CH:32]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([Br:28])=[CH:26][CH:27]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CC2(Cc3ccc(Br)cc3)C(=O)OC(C)(C)OC2=O)cc1
Reactant: c1ccc(Nc2ccc3cccc-3o2)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(CC(Cc2ccc(Br)cc2)C(=O)N(c2ccccc2)c2ccc3cccc-3o2)cc1
Yield: 56.1 %

Procedure:
A solution of 4-[5-(4-Bromobenzyl)-2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl]-benzoic acid methyl ester (1.35 g, 2.93 mmol) and 4-benzofuran-2-ylphenylamine (736 mg, 3.52 mmol) in dry NMP (10 mL) was heated at 220° C. for 5 min in the microwave. The reaction mixture was diluted with water then extracted with EtOAc. After concentrating, the crude material was purified by flash chromatography on silica gel (ISCO cartridge, 40 g), eluting with a gradient of zero to 35% ethyl acetate in hexane over 30 minutes to afford 4-[2-(4-Benzofuran-2-ylphenylcarbamoyl)-3-(4-bromophenyl)-propyl]-benzoic acid methyl ester (935 mg, 56%). 1H NMR (300 MHz, DMSO-d6): δ 9.92 (s, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.80 (d, J=8.7 Hz, 2H), 7.64-7.17 (m, 13H), 3.81 (s, 3H), 3.10-2.93 (m, 3H), 2.85-2.71 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[C:11](Cl)[CH:12]=[CH:13][CH:14]=2)[C:9]([NH2:17])=[N:8]1)[CH3:2].[C:20]1(=O)N(C2C3C(=CC=CC=3)NN=2)C(=O)C2=CC=CC=C12.Br.BrCCCN1CCCCC1.C1(=O)N(C2C3C(=CC=CC=3Cl)NN=2)C(=O)C2=CC=CC=C12.Br.BrCCCN(CC)CC>>[N:3]1([CH2:4][CH2:5][CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([NH2:17])=[N:8]2)[CH2:18][CH2:19][CH2:20][CH2:2][CH2:1]1
Reactant: CCN(CC)CCCn1nc(N)c2c(Cl)cccc21
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2ccccc12
Agent: Br
Agent: BrCCCN1CCCCC1
Agent: CCN(CC)CCCBr
Product: Nc1nn(CCCN2CCCCC2)c2ccccc12

Procedure:
The same procedures for preparing 1-(3-diethylaminopropyl)-3-amino-4-chloroindazole as described in Example 89 were repeated except that 8 g of 3-phthalimidoindazole and 10 g of 3-bromopropylpiperidine hydrobromide were employed instead of the 3-phthalimido-4-chloroindazole and the 3-bromopropyldiethylamine hydrobromide, respectively. As a result, 12.3 g of 1-(3-piperidinopropyl)-3-aminoindazole was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([NH:21][CH2:22][CH2:23][OH:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:1]([N:8]1[CH2:9][C@@H:10]([OH:11])[C@H:12]([N:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22][CH2:23][OH:24])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCNCc1ccccc1
Reactant: c1ccc(CN2CC3OC3C2)cc1
Product: OCCN(Cc1ccccc1)[C@@H]1CN(Cc2ccccc2)C[C@H]1O

Procedure:
3-Benzyl-6-oxa-3-azabicyclo[3.1.0]hexane is reacted with 2-(benzylamino)-ethanol, analogously to Example D a), to give trans-1-benzyl-3-[N-benzyl-N-(2-hydroxyethyl)-amino]-4-hydroxypyrrolidine which is then reacted analogously to Example F a) to give 5,8-dibenzyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane which is purified by chromatography (silica gel, cyclohexane/tert.-butyl methyl ether/ethyl acetate 1:1:1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13]1[C:21]2[C:16](=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:19][CH:20]=2)[NH:15][N:14]=1.[CH2:26](Br)[CH:27]=[CH2:28]>CN(C=O)C>[CH2:28]([N:14]1[C:13]([C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][CH3:3])=[C:21]2[C:16]([C:17]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:19]=[CH:20]2)=[N:15]1)[CH:27]=[CH2:26]
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)c(OC)c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1nc2c(C(F)(F)F)cccc2c1-c1ccc(OC)cc1OC
Reaction time: 8 h
Yield: 34.9 %

Procedure:
Sodium hydride (60% in oil, 0.025 g, 1.04 mmol) was added in one portion to a solution of 3-(2,4-dimethoxyphenyl)-7-(trifluoromethyl)-1H-indazole (0.150 g, 0.49 mmol) in DMF. After the gas evolution ceased, allyl bromide (0.07 mL, 0.7 mmol) was added and the reaction mixture was stirred at ambient temperature to 50° C. overnight. The cool reaction mixture was partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried (Na2SO4). The resulting residue was purified by flash chromatography or by HPLC chromatography through silica gel columns, 150×12 mm (Biotage, Charlottesville, Va.), at 10 mL/min with methyl-t-butyl ether/hexane (gradient elution, 1:9 to 1:1) to give the title compound (0.062 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N:23]3[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:25][CH2:24]3)[CH:19]=2)[N:14]=[CH:13]1.[OH-].[Na+]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28]3)[CH:19]=2)[N:14]=[CH:13]1
Reactant: COCCN1CCN(c2ccc3ncn(-c4cc(C(=O)OC)ccc4C)c(=O)c3c2)CC1
Agent: [Na+]
Agent: [OH-]
Product: COCCN1CCN(c2ccc3ncn(-c4cc(C(=O)O)ccc4C)c(=O)c3c2)CC1

Procedure:
Using an analogous procedure to that described paragraph (C) in the portion of Example 1 which is concerned with the preparation of starting material methyl 4-methyl-3-[6-(4-(2-methoxyethyl)piperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoate was hydrolysed with 1N NaOH to give 4-methyl-3-[6-(4-(2-methoxyethyl)piperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoic acid; NMR Spectrum: (DMSOd6) 2.16 (s, 3H), 3.30 (m, 9H), 3.60 (m, 2H), 3.80 (m, 2H), 4.00 (m, 2H), 7.58 (m, 2H), 7.69 (m, 2H), 7.93 (s, 1H), 8.00 (d, 1H), 8.16 (s, 1H), 11.07 (s, 1H), 13.10 (s, 1H); Mass Spectrum: M+H+ 423.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:36])[NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]4[CH3:35])[C:16]4[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:17]=4[N:18]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:14]=[C:15]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]4[CH3:35])[C:16]4[CH2:21][NH:20][CH2:19][C:17]=4[N:18]=3)=[CH:11][CH:12]=2)=[O:36])[CH2:2][CH2:3]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CN(C(=O)OC(C)(C)C)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Temperature: 20 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
To a stirred solution of (S)-tert-butyl 2-(4-(3-cyclopropylureido)phenyl)-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (0.99 g, 1.99 mmol) in DCM (5 mL) was added TFA (2.5 mL) and stirred at room temperature (20° C.) overnight. The reaction mixture was diluted with methanol and adsorbed onto a mp-TsOH cartridge (2.5 g, 3 mmol/g). The cartridge was rinsed with MeOH (3 column volumes) and the product was eluted with 7M NH3 in MeOH. The basic fractions were concentrated in vacuo to leave a pale orange solid (0.46 g, 1.16 mmol, 58% yield).