Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@H:7]2[N:12]3[CH:13]=[CH:14][C:15]4[CH:16]=[CH:17][CH:18]=[C:10]([C:11]=43)[O:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](Cl)(=[O:23])C([Cl:22])=O.C(N(CC)CC)C.[CH2:32]1[NH:37][CH2:36][CH2:35][N:34]2[CH2:38][CH2:39][CH2:40][CH2:41][C@@H:33]12>ClC(Cl)C(Cl)Cl>[ClH:22].[CH:1]1([C@H:7]2[N:12]3[CH:13]=[C:14]([C:19]([N:37]4[CH2:36][CH2:35][N:34]5[CH2:38][CH2:39][CH2:40][CH2:41][C@H:33]5[CH2:32]4)=[O:23])[C:15]4[CH:16]=[CH:17][CH:18]=[C:10]([C:11]=43)[O:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C1CCN2CCNC[C@@H]2C1
Reactant: c1cc2c3c(c1)ccn3[C@H](C1CCCCC1)CO2
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)C(Cl)Cl
Solvent: CCN(CC)CC
Product: Cl
Product: O=C(c1cn2c3c(cccc13)OC[C@H]2C1CCCCC1)N1CCN2CCCC[C@H]2C1
Temperature: 120 °C

Procedure:
To a solution of (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine (100 mg, 0.41 mmol) in 1,1,2,2-tetrachloroethane (2.0 ml), was added oxalyl chloride (58 mg, 0.46 mmol) with stirring under a stream of nitrogen. The mixture was heated at 120° C. for 1.5 h. The mixture was cooled to room temperature and triethylamine (46 mg, 0.46 mmol) and (S)-octahydro-2H-pyrido[1,2-a]pyrazine (70 mg, 0.50 mmol) were added. The mixture was stirred at room temperature for 19 h and then partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane, and the combined organic layers washed with brine, dried over Na2SO4 and concentrated. The resulting brown oil was purified by flash chromatography eluting with 50% (v/v) ethyl acetate in n-heptane, then 0-17% (v/v) methanol in ethyl acetate to afford the title compound as the free base. Hydrochloride salt formation was achieved by the addition of hydrogen chloride (2 M solution in diethyl ether, 1 ml) to a solution of the free base in diethyl ether (2 ml) and ethanol (2 ml). The solvent was removed in vacuo and the precipitate was dried to afford the title compound (1:1 hydrochloride salt) as a solid (78 mg, 0.18 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][NH:6][C:5]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:4]=2[O:3]1.[H-].[Na+].Cl[C:19]1[C:24]([C:25]([O:27]C)=O)=[N:23][CH:22]=[CH:21][N:20]=1.CN(C)[CH:31]=[O:32]>>[CH3:1][C:2]1([CH3:15])[CH2:7][N:6]([C:25]([C:24]2[C:19]([O:32][CH3:31])=[N:20][CH:21]=[CH:22][N:23]=2)=[O:27])[C:5]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:4]=2[O:3]1
Reactant: COC(=O)c1nccnc1Cl
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc2O1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1nccnc1C(=O)N1CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 40 ml of N,N-dimethylformamide was dissolved 3.33 g of 3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine followed by addition of 0.77 g of sodium hydride. The mixture was stirred at room temperature for 30 minutes and ice-cooled. Then, 6 ml of a solution of 2.76 g of methyl 2-chloropyrazine-3-carboxylate in N,N-dimethylformamide was added dropwise at a temperature not exceeding 5° C. The reaction mixture was then stirred at room temperature for 3.5 hours, at the end of which time it was poured in ice-water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography. The resulting crude crystals were recrystallized from ethanol to give 1.27 g of 3,4-dihydro-2,2-dimethyl-4-(2-methoxy-3-pyrazinyl)carbonyl-6-nitro-2H-1,4-benzoxazine. This compound was found to have the following physicochemical properties.
Reaction SMILES: [CH3:1][C:2]1[N:3]2[CH2:9][CH2:8][CH:7]([C:10]([O:12]CC)=[O:11])[C:4]2=[N:5][N:6]=1.[Li+].[OH-]>C1COCC1.O.CO>[CH3:1][C:2]1[N:3]2[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[C:4]2=[N:5][N:6]=1
Reactant: CCOC(=O)C1CCn2c(C)nnc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1nnc2n1CCC2C(=O)O
Temperature: 60 °C

Procedure:
To a solution of ethyl 3-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]-triazole-7-carboxylate (400 mg, 2.05 mmol) from step A in THF/water/MeOH was added LiOH (250 mg, 10.3 mmol) and the resulting solution was heated to 60° C. for 16 h. The solution was cooled to room temperature and concentrated to remove organic solvents. The aqueous layer was then acidified to pH of ˜5 using 2N HCl. The mixture was concentrated to dryness under vacuum, azeotroping with toluene (2×20 mL) to make sure all water was removed. The material was used without further purification with lithium chloride as a by-product. LC-MS: m/z (ES)=168 (MH)+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)[N:3]=1.[B-](F)(F)(F)[CH:23]=[CH2:24].[K+].C(O)(C)C.C(N(CC)CC)C>O1CCCC1>[CH3:21][C:17]1[N:16]=[C:15]([CH2:14][N:4]2[C:5]3[C:10](=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:6]=3)[C:2]([CH:23]=[CH2:24])=[N:3]2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)n1
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=Cc1nn(Cc2cccc(C)n2)c2cccc([N+](=O)[O-])c12
Temperature: 95 °C
Yield: 87.4 %

Procedure:
To a reaction vial was added 3-iodo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (216 mg, 0.548 mmol) and potassium trifluoro(vinyl)borate (156 mg, 1.64 mmol). Isopropanol (2 mL) and tetrahydrofuran (0.5 mL) were added. Argon was bubbled through the mixture for 20 minutes. Triethylamine (229 μL, 1.64 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (44.8 mg, 0.0548 mmol) were added. The vial was sealed and the mixture was heated at 90-100° C. for 3 hours. The mixture was allowed to cool and filtered through glass fiber filter paper, washing with ethyl acetate. The solution was concentrated under reduced pressure. The residue was dissolved in chloroform (30 mL) and washed with water (10 mL). The solution was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 1-((6-methylpyridin-2-yl)methyl)-4-nitro-3-vinyl-1H-indazole as an oil (141 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH3:16])=[N:12][C:11]=2[CH:17]([CH3:19])[CH3:18])[CH:5]=[C:6]([CH3:8])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:28])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:8][C:6]1[CH:5]=[C:4]([S:9]([C:10]2[N:14]([CH3:15])[C:13]([CH3:16])=[N:12][C:11]=2[CH:17]([CH3:19])[CH3:18])=[O:28])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2C)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C)cc(S(=O)c2c(C(C)C)nc(C)n2C)c1
Reaction time: 0.17 h
Yield: 62.6 %

Procedure:
In methylene chloride (10 ml) was dissolved 150 mg (0.55 mmol) of 5-(3,5-dimethylphenylthio)-4-isopropyl-1,2-dimethyl-1H-imidazole, followed by addition of 177 mg (0.82 mmol) of 80% metachloroperbenzoic acid under ice-cooling, and the mixture was stirred for 10 minutes. To the reaction mixture, an aqueous solution of sodium thiosulfate and then, an aqueous sodium hydrogen carbonate solution was added, and extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue purified by silica gel chromatography (ethyl acetate), and recrystallized from n-hexane to give 100 mg of Compound I-104 (yield 63%). mp 100-101° C.
Reaction SMILES: [F:1][CH:2]([F:39])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([C:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH:25]=3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1>CO.C1COCC1.[Pd]>[F:39][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(C2=CCN(C(=O)OC(C)(C)C)CC2)nc(N2CCOCC2)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(C2CCN(C(=O)OC(C)(C)C)CC2)nc(N2CCOCC2)n1

Procedure:
A solution of tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3,6-dihydro-1(2H)-pyridinecarboxylate (1.79 g, 3.29 mmol) in a mixture of MeOH (80 mL) and THF (80 mL) was hydrogenated over 10% Pd on carbon (100 mg). After removal of the hydrogen, the mixture was refluxed in air for additional 2 hrs. The catalyst Pd/C was removed by filtration through celite, and the solvents were removed under vacuum. Recrystallization of the residue from methanol gave tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperidine-carboxylate: mp (MeOH) 177-179° C.; 1H NMR (CDCl3) δ 8.01 (dd, J=8.4, 0.7 Hz, 1H), 7.58 (t, JHF=53.6 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 6.84 (d, J=7.8 Hz, 1H), 4.22 (m, 2H), 4.05 (s, 3H), 3.99 (m, 2H), 3.94 (m, 2H), 3.81 (m, 4H), 2.94-2.78 (m, 3H), 2.05 (dd, J=13.0, 1.9 Hz, 2H), 1.81 (qd, J=12.7, 4.4 Hz, 2H), 1.49 (s, 9H); Anal. Calcd. for C26H33F2N7O4: C, 57.2; H, 6.1; N, 18.0. Found: C, 57.4; H, 6.15; N, 18.1%.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[N:7][CH:8]=1.[C:13]1(N2CCOCC2)[CH2:17][CH2:16][CH2:15][CH:14]=1.Cl.C(=O)(O)[O-:26].[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[C:14]2[CH2:15][CH2:16][CH2:17][C:13]2=[O:26])=[N:7][CH:8]=1
Reactant: O=C([O-])O
Reactant: C1=C(N2CCOCC2)CCC1
Reactant: O=Cc1ccc(C(F)(F)F)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCCC1=Cc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 5-(trifluoromethyl)pyridine-2-carbaldehyde (3.32 g, 18.96 mmol) and 4-(cyclopent-1-en-1-yl)morpholine (CAS number 936-52-7; 2.97 ml, 18.58 mmol) in toluene (50 ml) was heated to 90° C. for 18 hours. The reaction was then cooled to room temperature and concentrated HCl (2 ml) and water (2 ml) was added drop wise. The reaction was stirred at room temperature for 20 minutes and then neutralised with a saturated solution of sodium bicarbonate and then basified with 2M NaOH (aq). The organics were extracted with ethyl acetate (2×40 ml) and the combined organics were washed with brine (10 ml), dried over magnesium sulfate, filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-20% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.O=P(Cl)(Cl)[Cl:20]>CN(C=O)C>[Cl:20][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc2c(O)cc(C(F)(F)F)nc12
Solvent: CN(C)C=O
Product: COc1cccc2c(Cl)cc(C(F)(F)F)nc12
Reaction time: 8 h

Procedure:
4-Hydroxy-8-methoxy-2-trifluoromethylquinoline (18.77 g) is dissolved in. 450 mL 8:1 C2Cl2:DMF. POCl3 (50 mL) is added dropwise and the reaction is allowed to stir overnight. The reaction is then poured into 500 mL ice/H2O and the aqueous is extracted 2× with CH2Cl2. The organic portions are combined, washed 1× with brine, dried over MgSO4, and evaporated. The resulting oil crystallizes upon standing. The solid is recrystallized from 95% EtOH. A second crop of crystals could be obtained by concentrating down the EtOH filtrate. The total yield of product is 15.36 g.
Reaction SMILES: [NH2:1][C:2]1[N:12]2[C:13]3[N:8]([C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)=[CH:10][CH2:11]2)[N:7]=[CH:6][C:5]=3[C:4](=[O:24])[N:3]=1.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>N1C=CC=CC=1>[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:1][C:2]2[N:12]3[C:13]4[N:8]([C:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=5)=[CH:10][CH2:11]3)[N:7]=[CH:6][C:5]=4[C:4](=[O:24])[N:3]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: Nc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2nc(=O)c3cnn4c3n2CC=C4c2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 200 mg amount of 5-amino-8-[3-(trifluoro-methyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one (prepared as described in Example 29) was suspended in 3 ml of pyridine, then 0.2 ml of p-methoxybenzoyl chloride was added in one portion and the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched in 100 ml of water and the solid which formed was collected by filtration and washed with ether to give 164 mg of the desired product as a white solid, m.p. 271°-273° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([NH:10][C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=2[N+:19]([O-])=O)[CH2:8][C@H:7]([CH2:22][O:23]C(=O)C)[C@@H:6]1[O:27]C(=O)C)(=O)C.[CH2:31](O)[CH2:32]C>[Ni]>[Cl:18][C:14]1[C:15]([Cl:17])=[CH:16][C:11]2[N:10]([C@H:9]3[C@@H:5]([OH:4])[C@@H:6]([OH:27])[C@@H:7]([CH2:22][OH:23])[CH2:8]3)[C:31]([CH3:32])=[N:19][C:12]=2[CH:13]=1
Reactant: CCCO
Reactant: CC(=O)OC[C@H]1C[C@@H](Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Ni]
Product: Cc1nc2cc(Cl)c(Cl)cc2n1[C@@H]1C[C@H](CO)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 26 %

Procedure:
(1R,2S,3R,5R)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyl diacetate (1.29 g, 2.78 mmol) in n-propanol (100 mL) was shaken with Raney nickel (Aldrich, slurry in water, 200 mg wet) under hydrogen (40 psi) on a Parr shaker for 4 hours. Catalyst was filtered off with Celite and the volatiles were evaporated in vacuo. The residual oil was refluxed in 96% formic acid (45 mL) for 5 hours. Concentrated hydrochloric acid (5 mL) was added and reflux continued for an additional 4 hours. Volatiles were evaporated in vacuo and the residue was dissolved in 1N sodium hydroxide (10 mL). The solution was stirred at ambient temperature for 18 hours, neutralized with acetic acid, and concentrated in vacuo. The residue was chromatographed on silica gel. Elution with 15% methanol-chloroform gave (1R,2S,3R,5R)-5-(5,6-dichloro-2-methyl-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol as white powder (236 mg, 26%), m.p. 198°-200° C.; 1H-NMR(DMSO-d6) δ: 8.30 and 7.72 (both s, 1 each, 2 aromatic CH), 5.0-4.8 (m, 3,2 OH and NCH), 4.56 (t, J=5.1 Hz, 1, CH2OH), 4.2-4.1 (m, 2,2 OCH), 3.8-3.5 (m, 2, CH2O), 2.58 (s, 3, CH3), 2.4-2.2 (m, 1, CH), 2.2-1.9 (m, 2, CH2); mass spectrum(CI): 331(M+1); [α]20589 -13.5°, [α]20578 -13.9°, [α]20546 -15.9°, [α]20436 -30.3° (c=0.251, methanol).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=1.[Br:13]Br>ClCCl>[Br:13][C:3]1[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:5][NH:6][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1cc(-c2ccccc2)n[nH]1
Solvent: ClCCl
Product: Cc1[nH]nc(-c2ccccc2)c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
To a solution of 5-methyl-3-phenyl-1H-pyrazole (8.0 g, 50.6 mmol) in dichloromethane (150 mL) was added bromine (8.08 g, 50.6 mmol) dropwise at 0° C. The reaction was stirred at 0° C. for 30 min and then at room temperature for 2 h before quenching with aqueous Na2SO3 (10% w/w, 10 mL). The organic solvent was removed and the aqueous phase was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a yellow oil (9.5 g). LCMS m/z=236.9 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 3H), 7.30-7.57 (m, 5H), 13.12 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:7][CH:6]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17]C)[C:10]=3[CH:9]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C@H:20]([OH:33])[CH2:21][O:22][C:23]1[C:28]2[CH:29]=[C:30]([CH3:32])[O:31][C:27]=2[CH:26]=[CH:25][CH:24]=1.C([S-])C.[Na+]>CN(C=O)C>[CH3:1][C:2]1([CH3:34])[CH2:7][CH:6]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:10]=3[CH:9]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C@H:20]([OH:33])[CH2:21][O:22][C:23]1[C:28]2[CH:29]=[C:30]([CH3:32])[O:31][C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc2sc(C3CCN(C[C@H](O)COc4cccc5oc(C)cc45)C(C)(C)C3)cc12
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(OC[C@@H](O)CN3CCC(c4cc5c(O)cccc5s4)CC3(C)C)cccc2o1
Yield: 47.3 %

Procedure:
A solution of (2S)-3-[2,2-dimethyl-4-(4-methoxybenzo[b]thiophen-2-yl)piperidin-1-yl]-1-(2-methylbenzofuran-4-yl)oxy-2-propanol (0.7661 g, 1.64 mmol) and sodium ethanethiolate (2.21 g, 26.3 mmol) in DMF (28 mL) was heated at 90° C. for 16 h and concentrated under reduced pressure. The residue was diluted with 50 mL of brine and extracted with CH2Cl2 (3×50 mL). The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography [0 to 6% (2.0 M NH3 in MeOH)/CH2Cl2]. The residual DMF was removed as an azeotrope with xylenes to give the title compound as an off-white foam (0.3609 g, 47%). IR (KBr) 1281, 1087 cm−1. Ion Spray MS 466.2 (M+H)+; 464.3 (M−H)−. [α]D=3.42 (c 0.584, MeOH). C27H31NO4S.0.1CH2Cl2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH2:37](O)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH3:37])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1C
Yield: 100.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-octadecanol (62 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (96 mg, yield 97%).
Reaction SMILES: F[C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)=[N:11][C:10]=2[C:25](OCC)=[O:26])=[O:7])=[CH:4][CH:3]=1.[NH2:32][CH2:33][CH2:34][OH:35]>CN1C(=O)CCC1.CCOC(C)=O>[OH:35][CH2:34][CH2:33][NH:32][C:25]([C:10]1[N:11]=[C:12]([NH:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[S:13][C:9]=1[NH:8][C:6](=[O:7])[C:5]1[CH:30]=[CH:31][C:2]([NH:11][CH2:10][CH2:25][OH:26])=[CH:3][CH:4]=1)=[O:26]
Reactant: NCCO
Reactant: CCOC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=C(Nc1sc(Nc2ccc3ccccc3c2)nc1C(=O)NCCO)c1ccc(NCCO)cc1
Yield: 47.5 %

Procedure:
A solution of Ethyl 5-(4-fluorobenzamido)-2-(naphthalen-2-ylamino)thiazole-4-carboxylate (25 mg, 0.06 mmol) and 2-aminoethanol (0.024 mL, 0.40 mmol) in NMP (0.5 mL) was treated using a microwave synthesizer for 70 min (Biotage, 150° C.). The reaction mixture was diluted with EtOAc. The organic layer was washed with H2O, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel chromatography eluted with 2.5% MeOH in DCM to give 7 mg (25% yield) of the titled compound.
Reaction SMILES: [O:1]1[C:6]2[C:7]3[CH2:13][CH2:12][CH2:11][C:8]=3[CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH:14]=O.[C:16]1([CH2:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H][H]>O(C(C)C)C(C)C.CN(C)C(=O)C.[Pd]>[C:16]1([CH2:22][NH:23][CH2:14][CH:2]2[CH2:3][CH2:4][C:5]3[CH:10]=[CH:9][C:8]4[CH2:11][CH2:12][CH2:13][C:7]=4[C:6]=3[O:1]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [H][H]
Reactant: O=CC1CCc2ccc3c(c2O1)CCC3
Reactant: NCc1ccccc1
Agent: [Pd]
Solvent: CC(C)OC(C)C
Solvent: CC(=O)N(C)C
Product: c1ccc(CNCC2CCc3ccc4c(c3O2)CCC4)cc1
Yield: 73.8 %

Procedure:
A mixture of intermediate (5-a) (0.03 mol) and benzenemethanamine (0.073 mol) in 2,2'-oxybispropane (250 ml) and N,N-dimethylacetamide (10 ml) was hydrogenated with palladium on activated carbon (10%) (1 g) as a catalyst. After uptake of hydrogen (1 eq.), the catalyst was filtered off. The filtrate was evaporated. The residue was stirred in a mixture of water and 1,1'-oxybisethane. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated, yielding 6.5 g of (±)-2,3,4,7,8,9-hexahydro-N-(phenylmethyl)cyclopenta[h]-1-benzopyran-2-methanamine (interm. 14-a).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@H:10]([O:25]C(=O)C2C=CC([N+]([O-])=O)=CC=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:10]([OH:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](O)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (±)-cis-4-benzyloxycarbonylamino-3-(4-nitro-benzoyloxy)-piperidine-1-carboxylic acid tert-butyl ester (0.63 mmol, 0.315 g) in THF (5 mL) at 0° C. was added LiOH (0.16 g) dissolved in water (1.5 mL) and continued stirring at 0° C. for 30 min followed by 2 h at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (10 mL) and extracted with ethyl acetate. The combined organic layers were dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to provide (±)-cis-4-benzyloxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.