Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][NH:17][C:16](=[O:20])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1C=CC(S(O[CH2:33][C:34]2[S:35][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:38]=2)(=O)=O)=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][N:17]([CH2:33][C:34]4[S:35][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:38]=4)[C:16](=[O:20])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=c1nc(N2CCC(O)(c3ccc(F)cc3)CC2)nc[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCc2ccc(C(F)(F)F)s2)cc1
Product: O=c1nc(N2CCC(O)(c3ccc(F)cc3)CC2)ncn1Cc1ccc(C(F)(F)F)s1
Yield: 12.9 %

Procedure:
4-[4-(4-Fluorophenyl)-4-hydroxypiperidin-1-yl]-1,3,5-triazin-2(1H)-one (100 mg, 0.34 mmol) synthesized in Reference Synthesis Example 14 and [5-(trifluoromethyl)thiophen-2-yl]methyl 4-methylbenzenesulfonate (558 mg, 0.67 mmol) synthesized in Reference Synthesis Example 51 were used to obtain the title compound (20 mg, yield 13%) by synthesis in a similar manner to Reference Synthesis Example 8.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:18]2[C:17]([O:19][CH3:20])=[N:16][C:15]([NH:21][CH:22]=[O:23])=[N:14][C:13]=2[N:12]([C@@H:24]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[C@@H:26]([O:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:25]2)[CH:11]=1>C(Cl)Cl>[CH3:30][CH:29]([CH3:31])[C:28]([O:27][C@@H:26]1[C@@H:33]([CH2:35][O:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[O:34][C@@H:24]([N:12]2[C:13]3[N:14]=[C:15]([NH:21][CH:22]=[O:23])[N:16]=[C:17]([O:19][CH3:20])[C:18]=3[C:10]([Cl:9])=[C:11]2[Cl:1])[CH2:25]1)=[O:32]
Reactant: COc1nc(NC=O)nc2c1c(Cl)cn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: COc1nc(NC=O)nc2c1c(Cl)c(Cl)n2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
N-Chlorosuccinimide (117 mg, 0.9 mmol) is added to a solution of compound (45) (200 mg, 0.4 mmol in 5 ml of DMF). After it had been stirred (at room temperature for 16 h), the solution is added to a mixture of CH2Cl2/5% aq. NaHCO3 (50 ml, 9:1). The organic phase is separated off, washed with water, dried over Na2SO4, filtered and evaporated. The evaporated residue is dissolved in CH2Cl2 and this solution is chromatographed on silica gel (column: 5×20 cm, CH2Cl2/acetone, 95:5). The main zone is separated off. Colorless crystals (149 mg, 72%) are obtained after evaporating off the solvent and crystallizing from cyclohexane. Melting point: 127-128° C. 1H-NMR ([D6] DMSO): δ=1.01 (dd, CH3), 1.14 (d, J=7.0, CH3), 2.44, 2.47, 2.60, 3.53 (4 m, CH and Hαβ-C(2′)), 4.05 (s, OCH3), 4.17 (m, H—C(5′)), 4.30 (m, H—C(4′)), 5.56 (m, H—C(3′)), 6.41 (m, H—C(1′)), 9.44 (d, J=9.1, NH), 10.94 (d, J=9.8, HCO). Anal. calculated for C21H26Cl2N4O7 (517.4): C 48.75, H 5.07, N 10.83; found: C 49.04, H 5.09, N 10.66.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:24])[C:12]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:24])[C:12]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:21])=[CH:17][N:16]=1
Reactant: NN1CCOCC1
Reactant: Cn1nnc(-c2ccccc2F)c1COc1ccc(C(=O)O)cn1
Product: Cn1nnc(-c2ccccc2F)c1COc1ccc(C(=O)NN2CCOCC2)cn1
Yield: 72 %

Procedure:
As described for example 19b, 6-((4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methoxy)nicotinic acid (98 mg, 0.3 mmol) was converted, using 4-aminomorpholine instead of 4-aminotetrahydropyran, to the title compound (89 mg, 72%) which was obtained as a white foam. MS: m/e=413.4 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([NH:15]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[C:9]([OH:13])=[C:8]([Br:14])[CH:7]=1.[CH3:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([CH3:33])[CH:32]=1)[CH2:28]Br>>[NH2:15][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]([Br:14])[C:9]([O:13][CH2:24][C:25]2[CH:26]=[C:27]([CH3:28])[CH:30]=[C:31]([CH3:33])[CH:32]=2)=[C:10]([Br:12])[CH:11]=1)[C:3]([OH:2])=[O:23]
Reactant: COC(=O)C(Cc1cc(Br)c(O)c(Br)c1)NC(=O)OC(C)(C)C
Reactant: Cc1cc(C)cc(CBr)c1
Product: Cc1cc(C)cc(COc2c(Br)cc(CC(N)C(=O)O)cc2Br)c1
Yield: 34.8 %

Procedure:
Methyl-2-tert-butoxycarbonylamino-3-(3,5-dibromo-4-hydroxyphenyl)-propionate (0.20 g, 0.44 mmol) was coupled with 3,5-dimethyl benzylbromide (0.22 g, 1.1 mmol), using the method described in Example 2. After deprotection and final purification on HPLC, using the same conditions as described in Example 1(b), 70 mg (35%) of 2-amino-3-[3,5-dibromo-4-(3,5-dimethylbenzyloxy)phenyl]propionic acid was obtained. LC-MS (electrospray): m/z 458 (M+1).
Reaction SMILES: Cl.[C:2]([NH:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8])(=[O:4])[CH3:3].[CH3:18]O>>[C:2]([NH:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[C:7]([O:9][CH3:18])=[O:8])(=[O:4])[CH3:3]
Reactant: CC(=O)NC(Cc1ccc(Br)cc1)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)C(Cc1ccc(Br)cc1)NC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (5 mL, 20 mmol) was added to an ambient temperature solution of 2-(acetylamino)-3-(4-bromophenyl)propanoic acid (10 g, 34.9 mmol) in methanol (50 mL). After stirring at ambient temperature overnight, the reaction mixture was concentrated in vacuo to afford methyl 2-(acetylamino)-3-(4-bromophenyl)propanoate which was used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]([Cl:46])([Cl:45])[C:3]([O:6][C:7]([N:9]1[C@H:14]2[C:15]([C:37]([O:39]CC)=[O:38])=[C:16]([C:18]3[CH:19]=[N:20][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]4[C:33]([Cl:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=4[Cl:36])=[CH:22][CH:23]=3)[CH2:17][C@@H:10]1[CH2:11][N:12]([C:42](=[O:44])[CH3:43])[CH2:13]2)=[O:8])([CH3:5])[CH3:4].[OH-].[Na+]>CCO>[Cl:46][C:2]([Cl:1])([Cl:45])[C:3]([O:6][C:7]([N:9]1[C@H:14]2[C:15]([C:37]([OH:39])=[O:38])=[C:16]([C:18]3[CH:19]=[N:20][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]4[C:29]([Cl:36])=[CH:30][C:31]([CH3:35])=[CH:32][C:33]=4[Cl:34])=[CH:22][CH:23]=3)[CH2:17][C@@H:10]1[CH2:11][N:12]([C:42](=[O:44])[CH3:43])[CH2:13]2)=[O:8])([CH3:5])[CH3:4]
Reactant: CCOC(=O)C1=C(c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)nc2)C[C@@H]2CN(C(C)=O)C[C@H]1N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N1C[C@H]2CC(c3ccc(OCCOc4c(Cl)cc(C)cc4Cl)nc3)=C(C(=O)O)[C@@H](C1)N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
To a sol. of compound C9 (3.03 g, 3.81 mmol) in EtOH (30 mL) was added aq. 1M NaOH (15 mL). This mixture was heated to 80° C., and stirred at this temperature for 2.5 h. The mixture was partially concentrated under reduced pressure. The residue was acidified with aq. 2M HCl, and the mixture was extracted with EtOAc. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the crude title compound mixed with (rac.)-(1R*,5S*)-3-acetyl-7-{6-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-pyridin-3-yl}-3,9-diaza-bicyclo[3.3.1]non-7-ene-6,9-dicarboxylic acid 9-(2,2,2-trichloro-1,1-dimethyl-ethyl) ester (2.70 g, quantitative yield) that was used further without purification. LC-MS: tR=1.08 min; ES+: 710.09.
Reaction SMILES: C([Li])CCC.[O:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11]#N.Cl.[O:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>CCCCCC.O>[O:14]1[CH2:18][CH2:17][CH2:16][C@@H:15]1[C:10](=[O:6])[CH2:9][CH2:8][CH2:7][CH3:11]
Reactant: N#C[C@H]1CCCO1
Reactant: C1CCOC1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: CCCCC(=O)[C@H]1CCCO1
Reaction time: 1 h

Procedure:
A 1 L reactor at a temperature of 0° C. was added with 0.4 L of 1.6 M n-butyllithium in n-hexane, to which 13.5 g of (R)-2-tetrahydrofuran nitrile as previously obtained, in 0.07 L of tetrahydrofuran was slowly added dropwise. As such, the reaction was carried out for 1 hour with stirring, while the temperature within the reactor was controlled below 15° C. Next, the resulting solution was added dropwise to 65 g of concentrated hydrochloric acid in 0.4 L of water, while the temperature of the reaction was controlled below 25° C. Thereafter, the extraction was conducted by use of ethylacetate, followed by removing the solvent therein under reduced pressure, and the remainder was vacuum distilled off to produce 19.6 g of (R)-1-(2-tetrahydrofuranyl)-1-pentanone having an optical purity of 98.5% ee.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.CCN(C(C)C)C(C)C.[Br:18][C:19]1[C:20](Cl)=[C:21]([C:27](=[O:34])[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[C:22]([CH3:26])=[N:23][C:24]=1[CH3:25]>CC#N>[Br:18][C:19]1[C:20]([N:4]2[CH2:5][CH:6]([CH3:8])[CH2:7][CH:2]([CH3:1])[CH2:3]2)=[C:21]([C:27](=[O:34])[C:28]([O:30][CH:31]([CH3:32])[CH3:33])=[O:29])[C:22]([CH3:26])=[N:23][C:24]=1[CH3:25]
Reactant: CC1CNCC(C)C1
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(Cl)c1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CC(C)CC(C)C2)c1Br
Temperature: 80 °C
Reaction time: 24 h
Yield: 20.7 %

Procedure:
To a solution of 3,5-dimethylpiperidine (1.1 g, 9.86 mmol) and DIEA (3.1 mL, 18 mmol) in anhydrous CH3CN (40 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (3.0 g, 8.87 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 24 h; cooled, concentrated, and charged (DCM) to a 120 g ISCO silica gel cartridge and gradient eluted (5-15% EtOAc/hexanes) using an Isolera chromatography station to give isopropyl 2-(5-bromo-4-(3,5-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate 756 mg (20%) as a mixture of diastereomers. A sample of the product subjected to prep HPLC on Waters-Atlantis column (30×100 mm S5) running 15 min gradient from 10-100% B (MeOH/water/TFA), yielding two bands. The major isomer. 1H NMR (500 MHz, CDCl3) δ 5.21-5.14 (m, 1H), 2.87 (br. s, 4H), 2.70 (s, 3H), 2.41 (s, 3H), 1.77-1.71 (m, 3H), 1.29 (d, J=6.2 Hz, 6H), 0.85 (d, J=6.6 Hz, 6H), 0.68 (q, J=11.9 Hz, 1H). UPLC (M+H)=413.15.
Reaction SMILES: [C:1]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:23][C:24]1[S:28][C:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:26][N:25]=1.Cl>N1C=CC=CC=1>[C:1]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:23][C:24]2[S:28][C:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:26][N:25]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)Cc1nnc(N)s1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(CC(=O)OCC)s2)cc1
Yield: 63 %

Procedure:
To a solution of the 4-decanamidobenzenesulfonyl chloride (608 mg, 1.76 mmol) in pyridine (8 mL) was added ethyl 2-(5-amino-1,3,4-thiadiazol-2-yl)acetate (300 mg, 1.60 mmol). The reaction mixture was stirred at room temperature for 4.5 h, than 2 M HCl was added to quench the reaction. The mixture was extracted with ethyl acetate (3×40 mL). The organic extracts were washed with water (30 mL), brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography over silica gel (70-230 mesh) eluted with CH2Cl2:methanol 19:1 to give the product as a solid, mp 89-90° C., in 63% yield (500 mg, 1.01 mmol); 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3H, J=6.9 Hz), 1.25-1.34 (m, 15H), 1.65-1.76 (m, 2H), 2.39 (t, 2H, J=7.5 Hz), 3.87 (s, 2H), 4.24 (q, 2H, J=7.2 Hz), 7.58 (d, 2H, J=9.0 Hz), 7.74 (d, 2H, J=8.7 Hz); 13C NMR (75 MHz, DMSO-d6) δ 14.0, 14.0, 22.0, 25.5, 29.0, 29.0, 29.2, 31.3, 36.4, 37.9, 60.1, 118.9, 127.0, 139.4, 142.3, 154.0, 168.9, 169.9, 172.3; MS (LCQ, ESI+) Calcd for C22H33N4O5S2 497.2. found 497.1 (M+H)+; HRMS (ESI+, m/z) Calcd for C22H33N4O5S2 497.1875. found 497.1873 (M+H)+.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:12])[C:6]=2[O:5][CH:4]=[CH:3][CH2:2]1.[Cl:13][C:14]([Cl:22])([Cl:21])[S:15][N:16]([CH3:20])[C:17](Cl)=[O:18]>C1C=CC=CC=1>[O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][C:17](=[O:18])[N:16]([S:15][C:14]([Cl:22])([Cl:21])[Cl:13])[CH3:20])[C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1cccc2c1OC=CCO2
Reactant: CN(SC(Cl)(Cl)Cl)C(=O)Cl
Solvent: c1ccccc1
Product: CN(SC(Cl)(Cl)Cl)C(=O)Oc1cccc2c1OCCCO2

Procedure:
1.3 G. of sodium hydride (50% dispersion in oil) are washed twice with petroleum ether (40°-45° C.) and then suspended in 30 ml. of absolute benzene in a flask. 4.15 G. 1,5-benzodioxepin-6-ol (0.025 mol) are added stepwise with stirring and under a nitrogen atmosphere. This mixture is stirred for 30 minutes at room temperature and then a solution of 6.7 g. of N-trichloromethylthio-N-methyl carbamyl chloride (freshly prepared) in 30 ml. of absolute benzene is added over a 30 minute period. The resulting mixture is stirred at room temperature for four hours, then poured into 50 ml. of ice water and extracted three times with 30 ml. of benzene. The benzene extracts are washed with water, dried over sodium sulfate and evaporated. The crude product is chromatographed on silica gel and eluted with dichloromethylene. On evaporation, 3,4-dihydro-2H-1,5-benzodioxepin-6-yl-[(trichloromethyl)thio]-methylcarbamate is obtained as a yellow oil; MD24 :1.5658.
Reaction SMILES: O([C:8]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][N+:10]([O-:12])=[O:11])C1C=CC=CC=1.[NH2:20][CH2:21][CH2:22][S:23][CH2:24][C:25]1[N:26]=[C:27]([CH2:30][N:31]([CH3:33])[CH3:32])[S:28][CH:29]=1.C(O)(C)C>C(Cl)Cl>[CH3:33][N:31]([CH2:30][C:27]1[S:28][CH:29]=[C:25]([CH2:24][S:23][CH2:22][CH2:21][NH:20][C:8]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:9][N+:10]([O-:12])=[O:11])[N:26]=1)[CH3:32]
Reactant: O=[N+]([O-])C=C(Oc1ccccc1)Oc1ccccc1
Reactant: CN(C)Cc1nc(CSCCN)cs1
Solvent: CC(C)O
Solvent: ClCCl
Product: CN(C)Cc1nc(CSCCNC(=C[N+](=O)[O-])Oc2ccccc2)cs1

Procedure:
A solution of 0.4 g (1.32 mmol) of 85% pure 1,1-diphenoxy-2-nitroethene, 0.35 g (1.52 mmol) of 4-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl-2-thiazolemethanamine, 5 ml of isopropyl alcohol and 5 ml of methylene chloride ws stirred at room temperature for about two hours to provide N-[2-[[[2-[(dimethylamino)methyl]-4-thiazolyl]methyl]thio]ethyl]-2-nitro-1-phenoxy-1-etheneamine in situ. The product was not isolated but used directly in the reaction described in part B.
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48]>CN(C)C=O.O>[C:47]([O:49][CH2:50][CH2:51][O:38][C:35]1[CH:36]=[CH:37][C:32]([CH:2]([OH:1])[CH:3]([NH:18][C:19]([C:21]2[C:26]3[CH:27]=[CH:28][CH2:29][CH2:30][CH2:31][C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:20])[CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:6]=2)=[CH:33][CH:34]=1)(=[O:48])[CH3:46]
Reactant: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1)c1cccc2c1C=CCCC2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCOc1ccc(C(O)C(Cc2cccc(OC(F)(F)C(F)F)c2)NC(=O)c2cccc3c2C=CCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide (600 mg, 1.13 mmol) in N,N-dimethylformamide (20 ml) were added potassium carbonate (470 mg, 3.40 mmol) and ethyl bromoacetate (570 mg, 3.40 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from ethyl acetate-hexane gave the objective substance (167 mg, 24%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:35])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[N:36]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(Cl)Cl>[N:36]1([CH:42]2[CH2:47][CH2:46][N:45]([C:13](=[O:14])[CH:12]([NH:16][C:17]([N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[NH:27][C:26]4=[O:35])[CH2:21][CH2:20]3)=[O:18])[CH2:11][C:4]3[CH:5]=[C:6]4[C:10](=[C:2]([CH3:1])[CH:3]=3)[NH:9][N:8]=[CH:7]4)[CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc2cn[nH]c12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A stirred solution of (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid (65.7 mg, 0.138 mmol) in 2:1 dimethylformamide/methylene chloride (1.5 mL) at 0° C. was treated with 4-(1-piperidyl)-piperidine (46.5 mg, 2 equiv), diisopropylethylamine (0.048 mL, 2 equiv) and PyBOP® (75.5 mg, 1.05 equiv). The ice bath was allowed to melt and the mixture was stirred at room temperature overnight. The solvents were removed under high vacuum and the residue was purified by flash chromatography on silica gel, eluting with 18:1 methylene chloride/methanol containing 1% triethylamine, to give the product as a pale-yellow solid (80.4 mg, 93%). 1H-NMR (CD3OD, 500 MHz) δ −0.28 (1H, m), 0.75 (1H, m), 1.2-2.0 (12H, m), 2.08 (2H, m), 2.4-2.5 (3H, m), 2.59 (3H, s), 2.68 (2H, m), 2.90 (4H, m), 3.08 (4H, m), 3.9-5.1 (4H, several m), 6.81 (1H, d), 6.96 (1H, t), 7.16 (3H, m), 7.49 (1H, s), 8.03 (1H, s). Mass spec.: 627.29 (MH)+.
Reaction SMILES: C[O-].[Na+].CO.[N+](C1C=CC=CC=1S([NH:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)=O)([O-])=O.O.Cl>O1CCCC1.CCOCC>[CH:19]([NH2:18])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
A 28% sodium methoxide/methanol solution (0.42 ml; 1.49 molar equivalents) was added to a solution of N-(2-nitrobenzenesulfonyl)benzhydrylamine (503.3 mg) in dry tetrahydrofuran (5 ml) at room temperature in an argon atmosphere, followed by stirring for 2 hours at room temperature. When water (8.5 ml), 3 N hydrochloric acid (1.5 ml) and ether (5 ml) were added to the concentrate obtained by removing the reaction solvents by evaporation under reduced pressure, an insoluble solid was observed. Accordingly, 2 N sulfuric acid (1.5 ml) and ether (10 ml) were further added. The insoluble solid remained, so that it was separated by filtration. Solution separation was conducted for the filtrate, and the organic layer was extracted again with a mixed solution of 2 N sulfuric acid (1 ml)/water (9 ml). Five normal sodium hydroxide (4 ml) was added to the resulting aqueous layer, which was combined with the solid previously separated by filtration, and extraction was conducted four times with ether (10 ml), followed by drying over sodium sulfate, filtration and concentration. Hexane (15 ml) was added to the concentrate containing the solid, and insoluble matter was filtered and washed with hexane (10 ml). The resulting filtrate was concentrated and dried under vacuum to obtain benzhydrylamine (164.3 mg; yield: 65.6%). Furthermore, the ether layer remained in the preceding extraction with water was dried over sodium sulfate and filtered, and combined with the filtered solid obtained after above-described washing with hexane, followed by concentration. Hexane (15 ml) was added to the concentrate containing the solid, and the solid was filtered and washed with hexane (10 ml), followed by drying under vacuum to recover unreacted materials (162.3 mg; yield: 32.2%).
Reaction SMILES: NN.[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:22][O:23][N:24]3C(=O)C4C(=CC=CC=4)C3=O)[N:16]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1>C(O)C>[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:22][O:23][NH2:24])[N:16]([CH2:17][C:18]([CH3:20])([OH:21])[CH3:19])[C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: CC(C)(O)Cn1c(CON2C(=O)c3ccccc3C2=O)nc2c(N)nc3ccccc3c21
Agent: NN
Solvent: CCO
Product: CC(C)(O)Cn1c(CON)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.3 %

Procedure:
Hydrazine (20 mL) was added to a stirred suspension of 2-{[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}-1H-isoindole-1,3(2H)-dione (14.0 g, 32.4 mmol) in ethanol (100 mL). The mixture was stirred at room temperature and after 5 minutes a solution formed. After 1 hour, a solid began to form and additional ethanol (100 mL) was added. After 4.5 hours, the solid was isolated by filtration, washed with dichloromethane, and dried to yield 9.30 g of 1-{4-amino-2-[(aminooxy)methyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol as a yellow solid, some of which was used without further purification in the next step. Two batches of the product (6.63 g and 1.00 g) were purified by chromatography using a HORIZON HPFC system (silica gel, gradient elution with 5-15% of 2 M NH3 in methanol/chloroform) to provide 4.45 g and 650 mg of 1-{4-amino-2-[(aminooxy)methyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol as a yellow solid, respectively. Some of the chromatographed product (650 mg) was crystallized from acetonitrile to yield 377 mg of 1-{4-amino-2-[(aminooxy)methyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol as pale yellow crystals, mp 178.0-179.0° C.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:15]([O:17][CH3:18])=[O:16])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH2:25]([O:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:15]([O:17][CH3:18])=[O:16])[O:9]2)=[CH:4][CH:3]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCCc1c(O)ccc2c1OC(C(=O)OC)CC2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCc2ccccc2)ccc2c1OC(C(=O)OC)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.7 %

Procedure:
A 250 ml single neck round bottom flask was charged with 5.25 g (21 mmole) of methyl 7-hydroxy-8-n-propylchroman-2-carboxylate, 150 ml of dimethylformamide, 3.59 g (26 mmole) of anhydrous potassium carbonate, and 4.30 g (25 mmole) of benzyl bromide. The flask was stoppered and stirred (magnetic stirrer) at room temperature for 4 hours. The insoluble solids were separated by filtration and the dimethylformamide removed by rotary evaporation. The residue was dissolved in 200 ml ethyl acetate, clarified by filtration, and concentrated to an oily residue by rotary evaporation. The resultant crude material was purified by high pressure liquid chromatography (5% ethyl acetate-hexane), to obtain 5.48 g (77%) of the title compound as a clear oil. Calc: C, 74.09; H, 7.11; Found; C, 74.11; H, 7.06.