Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[C:6]([CH2:10][C:11]([NH:13][CH3:14])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[BH4-].[Na+].C(O)(=O)C.Cl>O1CCOCC1>[O:1]1[C:5]2[C:6]([CH2:10][CH2:11][NH:13][CH3:14])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CNC(=O)Cc1cccc2ccoc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CNCCc1cccc2ccoc12
Temperature: 25 °C

Procedure:
8.70 g benzofuran-7-yl-N-methylacetamide and 5.21 g (0.138 mol) sodiumborohydride were dissolved in 100 ml dioxane. Acetic acid was added dropwise to the chilled solution. Then, the reaction mixture was warmed slowly and refluxed for 1 h. After cooling to room temperature, 25 ml 6N HCl was added and the mixture was warmed to reflux for 5 min. The mixture was cooled, pH adjusted to 10 and the mixture was extracted with dichloromethane. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The remaining oil was distilled (B.p. 111-114° C/l mm Hg). The compound was obtained as colourless oil, 3.7 g (46%).
Reaction SMILES: Cl.O1CCOCC1.Cl[C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([NH:20][CH3:21])=[O:19])[C:12]([Cl:26])=[CH:11][N:10]=1.[CH2:27]([N:29]1[CH:38]2[CH2:39][CH2:40][CH:30]1[C:31]1[CH:32]=[C:33]([NH2:41])[CH:34]=[CH:35][C:36]=1[CH2:37]2)[CH3:28].C(=O)([O-])[O-]>COCCO>[Cl:26][C:12]1[C:13]([NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([NH:20][CH3:21])=[O:19])=[N:14][C:9]([NH:41][C:33]2[CH:34]=[CH:35][C:36]3[CH2:37][CH:38]4[N:29]([CH2:27][CH3:28])[CH:30]([CH2:40][CH2:39]4)[C:31]=3[CH:32]=2)=[N:10][CH:11]=1
Reactant: CCN1C2CCC1c1cc(N)ccc1C2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: COCCO
Product: CCN1C2CCC1c1cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
2-methoxyethanol (8.6 mL), 4N HCl in p-dioxane (0.215 mL, 1.2 eq) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (129 mgs, 1 eq) and (+/−)-12-Ethyl-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine was heated to 120° C. for 2 h. The mixture cooled to room temp treated with 3 equivalents of MP-carbonate and stirred for 30 min. Filtration, followed by concentration and purification by ISCO chromatography (12 gram column, SiO2, gradient 20% EtOAc/hexane to 100% EtOAc) gave (+/−)-2-[5-Chloro-2-(12-ethyl-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (45 mg, 11%). MP: 218-221° C.; 1H-NMR (CDCl3) δ 11.10 (s, 1H), 8.65 (d, J=8.1 Hz, 1H), 8.1 (s, 1H), 7.51-7.47 (m, 2H), 7.28-7.26 (m, 1H), 7.12-7.10 (m, 1H), 7.00 (s, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.52-6.49 (m, 1H), 3.89-3.84 (m, 2H), 3.58-3.55 (m, 2H), 3.05-3.03 (m, 1H), 3.04 (d, J=5.1 Hz, 3H), 2.61-2.51 (m, 3H), 2.25-2.21 (m, 2H), 1.18-1.10 (m, 3H); LC/MS (ESI+): 463.34 (M+H).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]([F:43])([C:33]([F:42])([F:41])[C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[N:24][CH:25]=1.[CH2:44](O)[CH2:45]/[CH:46]=[CH:47]/[CH2:48][CH2:49][CH3:50].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:44]([O:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[N:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]([F:13])([F:43])[C:33]([F:41])([F:42])[C:34]([F:39])([F:40])[C:35]([F:36])([F:37])[F:38])=[CH:25][N:24]=2)=[CH:31][CH:30]=1)[CH2:45]/[CH:46]=[CH:47]/[CH2:48][CH2:49][CH3:50]
Reactant: Oc1ccc(-c2ncc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cn2)cc1
Reactant: CCC/C=C/CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC/C=C/CCOc1ccc(-c2ncc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of DEAD (0.261 g, 1.50 mol) in THF (20) was added dropwise to a stirred solution of 4-[5-(5,5,6,6,7,7,8,8,8-nonafluorooctyloxy)-pyrimidin-2-yl]-phenol (0.693 g, 1.50 mmol), trans-3-hepten-1-ol (0.171 g, 1.50 mmol) and triphenylphosphine (0.399 g, 1.50 mmol) in THF (30) and the reaction mixture stirred at room temperature for 16 h. The solvent was removed in vacuo and the residues purified by column chromatography [silica gel, eluted with hexane ethyl acetate (4:1)] to yield a colorless solid, which was recrystallized from ethanol.
Reaction SMILES: CO[C:3]([CH:5]1[C:10]2[S:11][CH:12]=[CH:13][C:9]=2[S:8](=[O:15])(=[O:14])[N:7]([CH3:16])[C:6]1=[O:17])=[O:4].[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>C1(C)C(C)=CC=CC=1>[CH3:16][N:7]1[C:6](=[O:17])[CH:5]([C:3](=[O:4])[NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[C:10]2[S:11][CH:12]=[CH:13][C:9]=2[S:8]1(=[O:14])=[O:15]
Reactant: COC(=O)C1C(=O)N(C)S(=O)(=O)c2ccsc21
Reactant: Nc1nccs1
Solvent: Cc1ccccc1C
Product: CN1C(=O)C(C(=O)Nc2nccs2)c2sccc2S1(=O)=O

Procedure:
0.15 G. of 3,4-dihydro-4-methoxycarbonyl-2-methyl-3-oxo-2H-thieno[2,3-e]1,2-thiazine 1,1-dioxide and 0.071 g. of 2-aminothiazole are dissolved in 30 ml. of absolute xylene and the solution is heated for half an hour under the reflux. After cooling, the crystals are removed by filtration, recrystallized from glacial acetic acid, and 3,4-dihydro-2-methyl-3-oxo-4-(2-thiazolyl-carbamoyl)-2H-thieno[2,3-e]1,2-thiazine 1,1-dioxide, melting point 236° C. to 238° C. (decomposition), is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7](/[CH:8]=[C:9](\[CH3:13])/[C:10]([OH:12])=[O:11])=[C:6]([O:14]C)[C:5]([O:16][CH3:17])=[C:4]([O:18][CH3:19])[C:3]=1[O:20]C>CCOCC>[CH3:19][O:18][C:4]1[C:3](=[O:20])[C:2]([CH3:1])=[C:7](/[CH:8]=[C:9](\[CH3:13])/[C:10]([OH:12])=[O:11])[C:6](=[O:14])[C:5]=1[O:16][CH3:17]
Reactant: COc1c(C)c(/C=C(\C)C(=O)O)c(OC)c(OC)c1OC
Solvent: CCOCC
Product: COC1=C(OC)C(=O)C(/C=C(\C)C(=O)O)=C(C)C1=O

Procedure:
Compound 10b was prepared from 9b (0.057 g, 0.19 mmol) as described above for 10a using Method B to give 0.016 g (0.060 mmol, 31%) of the product as a red solid following flash chromatography (1:1 Et2O:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:3]=1[C:4]([NH:6][CH:7]([CH3:9])[CH3:8])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.C(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:3]=1[CH2:4][NH:6][CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)NC(=O)c1cc(F)ccc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CC(C)NCc1cc(F)ccc1F
Yield: 64.8 %

Procedure:
2,5-Difluoro-N-isopropyl-benzamide (0.5 g, 0.0025 mol) was dissolved in THF (8 mL). Lithium aluminum hydride (8 mL of a 1M solution in THF) was added, and the reaction was heated at reflux. When complete by TLC (methanol/methylene chloride), the reaction was cooled, and quenched with water, aqueous NaOH (15%), water and Na2SO4. The white solid is filtered off, and the filtrate is concentrated in vacuo to give 0.3 g of the amine. The product was used in the next step without characterization.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8](Cl)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:11]([C:14]1[C:15]([NH2:23])=[N:16][N:17]2[CH:22]=[CH:21][CH:20]=[N:19][C:18]=12)([CH3:13])[CH3:12]>C(Cl)Cl.N1C=CC=CC=1>[CH:1]1([CH2:6][CH2:7][C:8]([NH:23][C:15]2[C:14]([CH:11]([CH3:13])[CH3:12])=[C:18]3[N:19]=[CH:20][CH:21]=[CH:22][N:17]3[N:16]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CC(C)c1c(N)nn2cccnc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1c(NC(=O)CCC2CCCC2)nn2cccnc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-cyclopentylpropionyl chloride (0.048 mL, 0.31 mmol) in CH2Cl2 (0.2 mL) was added to a stirring solution of the product from Example 112C (35 mg, 0.20 mmol) in pyridine (1.2 mL) in a 4 mL vial. The yellow solution was stirred at room temperature for 3 hours, and then concentrated under vacuum. The residue was dissolved in CH2Cl2 (3 mL) and concentrated under vacuum (repeated three times) to remove excess pyridine. The off-white solid residue was crystallized from 60% ethanol-water (8 mL) to provide the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 1.10-1.27 (m, 2H) 1.41 (d, J=7.1 Hz, 6H) 1.48-1.98 (m, 9H) 2.47 (t, J=7.6 Hz, 2H) 3.01-3.22 (m, 1H) 6.91 (dd, J=7.1, 4.1 Hz, 1H) 8.42 (dd, J=4.1, 2.0 Hz, 1H) 8.70 (dd, J=7.1, 1.7 Hz, 1H); MS (ESI) m/z 301 (M+H)+; Anal. Calculated for C17H24N4O: C, 67.97; H, 8.05; N, 18.65. Found: C, 68.03; H, 8.03; N, 18.60.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][N:23]=[C:22]2[O:29][CH3:30]>>[CH3:30][O:29][C:22]1[C:21]2[C:26](=[CH:27][CH:28]=[C:19]([N:7]3[C:8]4[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=4[C:5]4[CH2:15][N:14]5[CH2:13][CH2:12][CH:11]([C:6]3=4)[CH2:17][CH2:16]5)[CH:20]=2)[N:25]=[CH:24][N:23]=1
Reactant: COc1ncnc2ccc(Br)cc12
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Product: COc1ncnc2ccc(-n3c4c(c5cc(C)ccc53)CN3CCC4CC3)cc12

Procedure:
The reaction of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (136 mg, 0.6 mmol; Example 2B) and 6-bromo-4-methoxyquinazoline (215 mg, 0.9 mmol; ChemBridge) was performed as described in Example 68 to afford the title compound as the minor product: 1H NMR (300 MHz, methanol-d4) δ ppm 1.95-2.20 (m, 4H) 2.42 (s, 3H) 2.89-2.96 (m, 1H) 3.09-3.30 (m, 4H) 4.23 (s, 3H) 4.33 (s, 2H) 6.91-7.04 (m, 2H), 7.22 (s, 1H) 7.87 (dd, J=9, 2 Hz, 1H) 8.06-8.13 (m, 2H) 8.83 (s, 1H); MS (DCI/NH3) m/z 385 (M+H)+.
Reaction SMILES: C([N:3](CC)CC)C.[OH:8][CH:9]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)/[CH:10]=[CH:11]/[C@H:12]1[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[N:13]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26].ClC(OCC)=O.N>C(Cl)Cl.CCOC(C)=O>[OH:8][CH:9]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)/[CH:10]=[CH:11]/[C@H:12]1[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[N:13]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH2:3])=[O:26]
Reactant: O=C(O)CCCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)CCCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
Triethylamine (9 μL, 0.065 mmol) was added to a solution of 7-[(R)-2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acid (11.3 mg, 0.030 mmol) in CH2Cl2 (0.3 mL) at rt. After cooling to 0° C., ethyl chloroformate (3.2 μL, 0.033 mmol) was added. After 1 h at 0° C., a solution of ammonia (0.5 M in 1,4-dioxane, 0.3 mL, 0.15 mmol) was added and the reaction mixture was allowed to warm to rt. After 18 h at rt, the reaction mixture was diluted with EtOAc (10 mL) and washed with aqueous HCl (0.5 M, 3 mL), saturated aqueous NaHCO3 (5 mL) and brine (5 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 3.5 mg (31%) of the title compound.
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:14][CH:15]=[CH2:16])[C:5]1=[O:6])[CH:2]=[CH2:3].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH:22]=[CH:23][C:24](O)=O>>[CH2:14]([N:7]1[C:8](=[O:9])[C:10]2[NH:13][C:24](/[CH:23]=[CH:22]/[C:21]3[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:19]([O:18][CH3:17])[CH:20]=3)=[N:12][C:11]=2[N:4]([CH2:1][CH:2]=[CH2:3])[C:5]1=[O:6])[CH:15]=[CH2:16]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: C=CCn1c(N)c(N)c(=O)n(CC=C)c1=O
Product: C=CCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(OC)c3)nc2n(CC=C)c1=O

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 2.9 g (13.1 mmol) of 1,3-diallyl-5,6-diaminouracil and 2.99 g (14.4 mmol) of 3,4-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.80 g (yield of Compound 69 as pale yellow flocculent precipitates.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[N:14]([CH2:25][C:26]3[CH:30]=[C:29]([C:31]4[S:32][C:33]([Cl:36])=[CH:34][CH:35]=4)[O:28][N:27]=3)[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([N+:22]([O-])=O)=[CH:17][CH:16]=3)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].O.O.[Sn](Cl)(Cl)(Cl)[Cl:40].Cl.[OH-].[Na+]>C(O)C>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[N:14]([CH2:25][C:26]3[CH:30]=[C:29]([C:31]4[S:32][C:33]([Cl:36])=[CH:34][CH:35]=4)[O:28][N:27]=3)[C:15]3[C:20]([CH:21]=2)=[C:19]([Cl:40])[C:18]([NH2:22])=[CH:17][CH:16]=3)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: Cl[Sn](Cl)(Cl)Cl
Reactant: CC(C)N1CCC(NC(=O)c2cc3cc([N+](=O)[O-])ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)N1CCC(NC(=O)c2cc3c(Cl)c(N)ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
24.4 mg 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-nitro-1H-indole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide were added to a solution of 58.5 mg tin chloride dihydrate in 1 ml ethanol. 0.5 ml 12 N aqueous hydrochloric acid was added and the mixture was stirred at room temperature for 16 hours. After cooling of the reaction mixture it was basified to pH 12 with saturated aqueous solution of sodium hydroxide and the product isolated by filtration. The product was obtained as a white solid which was dried under reduced pressure.
Reaction SMILES: [C:1]([C:4]12[CH2:11][O:10][C:7]([CH3:12])([O:8][CH2:9]1)[O:6][CH2:5]2)([OH:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:28][C:29](O)([CH3:31])[CH3:30]>C(#N)C>[C:29]([O:2][C:1]([C:4]12[CH2:9][O:8][C:7]([CH3:12])([O:6][CH2:5]1)[O:10][CH2:11]2)=[O:3])([CH3:31])([CH3:30])[CH3:28]
Reactant: CC12OCC(C(=O)O)(CO1)CO2
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)C12COC(C)(OC1)OC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-carboxy-1-methyl-2,6,7-trioxabicyclo[2.2.2]octane (9.3 g, 0.053 mol) and 1,3-dicyclohexylcarbodiimide (10.9 g, 0,053 mol) in 100 mL of acetonitrile is stirred at 25° C. for 30 min. Then 2-methyl-2-propanol (3.9 g, 5.0 mL, 0.053 mol) is added and the resulting mixture is stirred for 15 hrs. The solids are filtered and the filtrate is evaporated under reduced pressure to yield 4-(t-butoxycarbonyl)-1-methyl-2,6,7-trioxabicyclo[2.2.2]octane as a crude oil. This material is dissolved in 100 mL of tetrahydrofuran and stirred with 50 mL of 10% hydrochloric acid for 1 hr. The pH of the solution is adjusted to 7 with solid sodium bicarbonate and the solvents are removed under reduced pressure. The solids are triturated with methanol and the combined methanol solutions are evaporated to give t-butyl-tris(hydroxymethyl)acetate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C@@H:15]2[C@:10]([CH3:23])([CH2:11][CH2:12][C:13]3[C:20]([Cl:21])=[C:19](Br)[CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[C:27](OCC)(=[O:29])C>CO.[Cu]Br>[CH2:1]([N:8]1[CH2:16][C@@H:15]2[C@:10]([CH3:23])([CH2:11][CH2:12][C:13]3[C:20]([Cl:21])=[C:19]([O:29][CH3:27])[CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: C[C@]12CCc3c(ccc(Br)c3Cl)[C@@H]1CN(Cc1ccccc1)C2
Agent: [Cu]Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1Cl)CC[C@]1(C)CN(Cc3ccccc3)C[C@@H]21
Temperature: 120 °C
Yield: 11 %

Procedure:
A mixture of trans-2-benzyl-7-bromo-6-chloro-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.704 mmol, 275 mg), sodium methoxide (8.75 mmol, 2 ml, 1890 mg), copper(I) bromide (0.352 mmol, 51.5 mg) and ethyl acetate (0.699 mmol, 69 μl, 62.2 mg) in MeOH (2 ml) was heated in a microwave reactor at 120° C. for 0.5 h. The reaction mixture was partitioned between DCM and water and the aqueous was further extracted with DCM. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo before being purified by silica column chromatography (eluting with neat DCM—5% MeOH in DCM) to afford the trans-2-benzyl-6-chloro-7-methoxy-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (26.4 mg), m/z=342.2, 344.2 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:6]1[CH:10]=[C:9]([NH:11][C:12]([CH:14]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[N:8]=[CH:7]1)C.[OH-:34].[K+].CO.O>C(OCC)(=O)C>[CH2:27]([CH:5]([N:6]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2([OH:34])[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[N:8]=[CH:7]1)[C:4]([OH:3])=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: [OH-]
Reactant: CCCCCCC(C(=O)OCC)n1cnc(NC(=O)C2c3ccccc3-c3ccccc32)c1
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCC(C(=O)O)n1cnc(NC(=O)C2(O)c3ccccc3-c3ccccc32)c1

Procedure:
When 2.1 g of α-hexyl-4-[(9H-fluoren-9-yl-carbonyl)amino]-1H-imidazole-1-acetic acid ethyl ester was heated with 3.0 g of potassium hydroxide, 30 ml of methanol, and 15 ml of water at reflux for one hour, upon adjustment of pH to 3.8, a thick oil formed. The oil was dissolved in ethyl acetate and separated from the aqueous layer. The organic layer was dried and concentrated in vacuo. The oil was taken up in ethanol and saturated with hydrogen chloride gas. The resulting product was purified by high pressure liquid chromatography to provide 0.3.70 g of the titled product, m.p. 128° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][N:12]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:7][CH:6]=1)=O.[BH4-].[Li+].Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[OH:2][CH2:3][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][N:12]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(C2CN(C(=O)OC(C)(C)C)CCN2C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(c2ccc(CO)cc2)C1
Temperature: 65 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
Di tert-butyl 2-(4-methoxycarbonylphenyl)piperazine-1,4-dicarboxylate (1.03 g, 2.449 mmol) was dissolved in tetrahydrofuran (10.30 mL) and lithium boranuide (106.7 mg, 4.898 mmol) was added portion wise. The reaction was heated at 65° C. over 18 hours. The reaction mixture was cooled to ambient temperature then poured onto crushed ice and whilst stirring 1 M hydrochloric acid was added drop wise until no effervescence was observed. The mixture was stirred for 1 hour then saturated aqueous sodium bicarbonate was added until the mixture was at pH 8. The aqueous layer was extracted with ethyl acetate (×3) and the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purified by column chromatography (ISCO Companion, 40 g column) loaded with dichloromethane and eluted with 10 to 100% ethyl acetate/petroleum ether. Product fractions were combined and concentrated in vacuo to give the sub-title product as a white solid. (754 mg, 78.4% yield). 1H NMR (400.0 MHz, CDCl3) δ 1.45-1.48 (m, 18H), 2.99 (br s, 2H), 3.33-3.37 (m, 1H), 3.95-3.98 (m, 2H), 4.45-4.48 (m, 1H), 4.70 (d, 2H), 5.30 (br s, 1H) and 7.33-7.35 (m, 4H) ppm; TLC (petroleum ether:ethyl acetate, 1:1 v/v) Rf=0.48
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([CH2:13]OS(C)(=O)=O)[O:10][N:9]=2)=[N:6][CH:7]=1.[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[Na+]>CN(C)C=O>[N:19]([CH2:13][CH:11]1[O:10][N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:12]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1CC(c2ccc(Br)cn2)=NO1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CC(c2ccc(Br)cn2)=NO1
Temperature: 75 °C
Yield: 58.6 %

Procedure:
Methanesulfonic acid 3-(5-bromo-pyridin-2-yl)-4,5-dihydro-isoxazol-5-ylmethyl ester (30.5 g, 90.77 mmol) was added to dimethyl formamide (50 ml) followed by addition of sodium azide (11.8 g, 181.5 mmol). The mixture was heated to 75° C. for five hours and then added to aqueous sodium chloride (100 ml) followed by extraction with ethyl acetate (3×200 ml). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to yield the desired product (15 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]2[O:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:6][CH:5]=1.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>>[CH:35]1([C:38]([O:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:12][CH:11]3[O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)=[CH:6][CH:5]=2)=[O:39])[CH2:37][CH2:36]1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCOC(=O)C3CC3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(k), by acylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethyl)-phenyl]-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate with cyclopropanecarbonyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-(2-cyclopropylcarbonyloxy-ethyl)-phenyl]-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate as a colourless oil; MS: 572 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]2[C:8]([NH2:13])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=1.[CH2:14]([O:21][C:22]1[CH:41]=[CH:40][C:25]([CH2:26][Sn](CCCC)(CCCC)CCCC)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN1CCCC1=O>[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][C:2]2[CH:3]=[N:4][N:5]([C:7]3[C:8]([NH2:13])=[N:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=2)=[CH:40][CH:41]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCCC[Sn](CCCC)(CCCC)Cc1ccc(OCc2ccccc2)cc1
Reactant: Nc1ncccc1-n1cc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN1CCCC1=O
Product: Nc1ncccc1-n1cc(Cc2ccc(OCc3ccccc3)cc2)cn1
Temperature: 120 °C
Reaction time: 5 h
Yield: 5.2 %

Procedure:
To a mixture of 3-(4-bromo-pyrazol-1-yl)-pyridin-2-ylamine (34 mg, 0.14 mmol) described in Manufacturing Example 39-1-4, (4-benzyloxy-benzyl)-tributyl-stannane (84 mg, 0.17 mmol) described in Manufacturing Example 39-2-1 and N-methylpyrrolidinone (1.5 mL) were added tri-o-tolylphosphine (17 mg, 0.057 mmol) and palladium (II) acetate (3.2 mg, 0.014 mmol) at room temperature, which was stirred for 5 hours at 120° C. The reaction mixture was cooled to room temperature, and filtered after addition of an aqueous potassium fluoride solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (2.6 mg, 4%) as a trifluoroacetic acid salt.