Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([C:18](=[O:35])[C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])=[CH:21][C:20]=3[Cl:34])[CH:12]=2)[N:8]=[N:7]1)C.[Li+].[OH-].O.Cl>CO.CCOC(C)=O>[Cl:34][C:20]1[CH:21]=[C:22]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])[CH:23]=[CH:24][C:19]=1[C:18]([C:13]1[CH:12]=[C:11]([C:9]2[N:8]=[N:7][N:6]([CH2:5][C:4]([OH:36])=[O:3])[CH:10]=2)[CH:16]=[CH:15][C:14]=1[CH3:17])=[O:35]
Reactant: CCOC(=O)Cn1cc(-c2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(-c2cn(CC(=O)O)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reaction time: 2 h

Procedure:
A solution of compound 110 (236 mg, 0.46 mmol) in MeOH (3.0 mL) was added LiOH (55 mg, 2.31 mmol) and water (0.3 mL). The reaction mixture was stirred for 2 h under reflux. The reaction mixture was poured into a mixture of EtOAc/saturated NaCl. Aq. HCl (1 N, 0.5 mL) was added. The aqueous phase was washed with more EtOAc. The collected organic phases were washed with water, brine and then dried (MgSO4), filtered and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography using a mixture of MeOH/DCM/acetic acid 400:2:1 as the eluent to afford the title compound as yellow foam. 13C NMR (DMSO-d6) δ 194.9, 168.4, 158.7 (dd), 155.7 (dd), 149.3, 145.3, 139.8, 136.0, 133.7, 133.7, 131.7, 128.1, 127.1, 126.5, 126.4 (dd), 125.0, 124.2 (dd), 122.8, 114.8, 112.0 (dd), 111.8, 105.0 (dd), 50.9, 19.4
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:20]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:19]([CH3:28])[C:18]([CH:29]2[O:34][CH2:33][CH2:32][NH:31][CH2:30]2)=[N:17]1.[C:35]1(=O)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]2[N:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[Cl:9])[N:17]=[C:18]([CH:29]3[O:34][CH2:33][CH2:32][N:31]([CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)[CH2:30]3)[C:19]=2[CH3:28])=[CH:26][CH:25]=1
Reactant: Cc1c(C2CNCCO2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1c(C2CN(C3CCCCC3)CCO2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Triethyl amine (37 μl, 0.27 mmol) was added into the solution of 2-[1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazol-3-yl]-morpholine hydrochloride 5A-2 (75 mg, 0.18 mmol) and cyclohexanone (18 μl, 0.18 mmol) in 0.5 ml 1,2-dichloroethane. The reaction mixture was then treated with sodium triacetoxyborohydride (52 mg, 0.25 mmol) followed by acetic acid at room temperature. Upon the completion of the reaction, the reaction mixture was partitioned with ethyl acetate and saturated NaHCO3. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography (silica, 60% ethyl acetate/hexanes) to give the title compound 5A-3 as a white solid (40 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=3)[CH2:18][CH:19]([CH3:21])[CH3:20])=[C:14]([CH3:40])[C:13]=2[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=3)[CH2:18][CH:19]([CH3:21])[CH3:20])=[C:14]([CH3:40])[C:13]=2[CH:41]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2oc3ccc(OCc4ccccc4)cc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(CC(C)C)Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)oc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 3-[{[4-({1-[5-(benzyloxy)-3-methyl-1-benzofuran-2-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (0.46 g) synthesized in the above-mentioned (4) was dissolved in ethanol (5 mL), 1N aqueous sodium hydroxide solution (1.5 mL) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, 1N hydrochloric acid (1.5 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title object compound (0.45 g, quantitative) as a colorless solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Si:13]([O:20][CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([Cl:30])[N:23]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[Cl-].[NH4+].[O:33]1CCC[CH2:34]1>O.CN(C)C=O>[Si:13]([O:20][CH2:21][C:22]1[N:23]=[C:24]([Cl:30])[C:25]([CH:34]=[O:33])=[C:26]([O:28][CH3:29])[CH:27]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: COc1cc(Cl)nc(CO[Si](C)(C)C(C)(C)C)c1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CO[Si](C)(C)C(C)(C)C)nc(Cl)c1C=O
Reaction time: 0.08 h

Procedure:
To a solution of 6-chloro-2-hydroxymethyl-4-methoxypyridine (1.85 g), which was prepared by a method mentioned in Tokkaihei 10-59942 (JP1998-59942A), and imidazole (0.87 g) in N,N-dimethylformamide (30 mL) was added tert-butyldimethylchlorosilane (1.77 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water twice, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=85/15) to give 2-(tert-butyldimethylsilyloxy)methyl-6-chloro-4-methoxypyridine (2.83 g). To a solution of N,N-diisopropylamine (0.54 mL) in tetrahydrofuran (20 mL) was added n-butyllithium (2.77 mol/L n-hexane solution, 1.25 mL) at −78° C., and the mixture was stirred at the same temperature for 5 minutes. To the reaction mixture was added a solution of 2-(tert-butyldimethylsilyloxy)methyl-6-chloro-4-methoxypyridine (1 g) in tetrahydrofuran (5 mL), and the mixture was stirred at the same temperature for 20 minutes. To the reaction mixture was added N,N-dimethylformamide (0.32 mL), and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was stirred at room temperature for 5 minutes. The mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=3/1) to give 6-(tert-butyldimethylsilyloxy)methyl-2-chloro-4-methoxy-3-formylpyridine (0.28 g). The title compound was prepared in a similar manner to that described in Reference Example 15 using 6-(tert-butyldimethylsilyloxy)methyl-2-chloro-4-methoxy-3-formylpyridine instead of 2,6-dibromo-3-formylpyridine.
Reaction SMILES: [CH2:1]([Li])CCC.[Br-].C1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)=O>O1CCCC1>[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)=[CH2:1]
Reactant: O=C(CCCCCCCBr)c1ccc(F)cc1
Reactant: [Li]CCCC
Agent: [Br-]
Agent: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C=C(CCCCCCCBr)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of butyl lithium (2.5M. 3.2 ml) in anhydrous tetrahydrofuran (75 ml) was added triphenylmethylphosphonium bromide (2.86 g) in portions over 10 min. The mixture was stirred at 25° C. for 3 h and a solution of 8-bromo-1-(4-fluorophenyl)octan-1-one (1.20 g) in dry tetrahydrofuran (15 ml) added dropwise over 5 min. After stirring at 25° C. for 1 h, the mixture was heated at reflux for 24 h. The mixture was evaporated under reduced pressure and partitioned between diethyl ether (70 ml) and water (4×30 ml). The organic layer was washed with brine and dried over magnesium sulfate. Removal of the solvent under reduced pressure gave an oil that was chromatographed on silica gel using 5% diethyl ether in hexane. This gave 9-bromo-2-(4-fluorophenyl)-1-nonene (0.75 g). 1H-NMR (CDCl3) δ 1.2-1.55 (8H, m), 1.80 (2H, m), 2.46 (2H, t), 3.39 (2H, t), 5.03 (1H, bs), 5.20 (1H, bs), 7.03 (2H, m) and 7.3-7.45 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C@:11]12[CH2:19][O:18][C@H:17]([CH3:20])[C@H:16]1[C:15](=[O:21])[N:14]([CH3:22])[C:13]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:12]2.[H][H]>C(O)C.[Pd]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@:11]23[CH2:19][O:18][C@H:17]([CH3:20])[C@H:16]2[C:15](=[O:21])[N:14]([CH3:22])[C:13]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[N:12]3)[CH:4]=1
Reactant: C[C@H]1OC[C@]2(c3cc([N+](=O)[O-])ccc3F)N=C(NC(=O)OC(C)(C)C)N(C)C(=O)[C@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1OC[C@]2(c3cc(N)ccc3F)N=C(NC(=O)OC(C)(C)C)N(C)C(=O)[C@H]12
Yield: 100 %

Procedure:
A solution of tert-butyl ((4aS,5R,7aS)-7a-(2-fluoro-5-nitrophenyl)-3,5-dimethyl-4-oxo-3,4,4a,5,7,7a-hexahydrofuro[3,4-d]pyrimidin-2-yl)carbamate (1.6 g, 3.77 mmol) in ethanol (30 ml) was hydrogenated over 10% Pd/C (200 mg) at RT under a balloon of hydrogen for 4 h. The catalyst was removed by filtration through Celite-washing with ethanol. The filtrate was evaporated to give the title compound (1.48 g, colourless foam). 1H NMR (400 MHz, CDCl3) δ ppm 1.50 (d, J=6.06 Hz, 3H) 1.54 (s, 9H) 3.29 (s, 3H) 3.35 (dd, J=9.22, 1.89 Hz, 1H) 3.63 (s, 2H) 4.25-4.30 (m, 1H) 4.33-4.42 (m, 2H) 6.44 (dd, J=6.32, 2.78 Hz, 1H) 6.56-6.63 (m, 1H) 6.91 (dd, J=10.99, 8.72 Hz, 1H) 10.47 (br. s., 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][C:16](C)(C)C)=[O:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH3:24]O>>[NH2:1][C@H:2]([C:3]([O:5][CH3:24])=[O:4])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=1
Reactant: CO
Reactant: CC(C)(C)OC(=O)c1ccc(C[C@H](N)C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C[C@H](N)C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of (S)-2-amino-3-(4-(tert-butoxycarbonyl)phenyl)propanoic acid (500.0 mg, 1.88 mmol) in MeOH (20 mL) at 0° C. was slowly added thionyl chloride (447.64 mg, 3.77 mmol). The reaction was stirred for 1 h at 0° C. then warmed to RT and stirred for 1 h. The solvent was removed under reduced pressure. The reaction mixture was washed with saturated aqueous NaHCO3 (20 ml) and extracted with DCM (3×10 ml). The organic layer was dried over MgSO4 and concentrated. The crude product was purified by chromatography (EA/hexanes) to afford 425 mg (95%) of (S)-methyl 4-(2-amino-3-methoxy-3-oxopropyl)benzoate as the HCl salt. LCMS-ESI (m/z) calculated for C12H15NO4: 237.1. found 238.0 [M+H]+, tR=1.01 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 3H), 7.94 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.3 Hz, 2H), 4.37 (t, J=6.8 Hz, 1H), 3.86 (s, 3H), 3.68 (s, 3H), 3.20 (dd, J=11.8, 6.8 Hz, 2H).
Reaction SMILES: C(OC([N:8]1[C@H:13]([C:14](=[O:22])[NH:15][CH2:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=O)(C)(C)C.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>C(Cl)Cl>[F:26][C:25]([F:28])([F:27])[C:23]([OH:29])=[O:24].[CH3:19][C:18]([CH3:21])([CH3:20])[CH2:17][CH2:16][NH:15][C:14]([C@@H:13]1[CH2:12][C@@H:11]2[C@@H:9]([CH2:10]2)[NH:8]1)=[O:22]
Reactant: CC(C)(C)CCNC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CCNC(=O)[C@@H]1C[C@H]2C[C@H]2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1R,3S,5R)-3-(3,3-dimethyl-butylcarbamoyl)-2-aza-bicyclo[3.1.0]hexane 2-carboxylic acid tert-butyl ester (310 mg, 1 mmol) in CH2Cl2 (8 mL) was added TFA (0.769 mL, 10 mmol) and the solution was stirred at RT for 2 h. The crude reaction mixture was concentrated under vacuum and was used without further purification in the next step. UPLC/MS: 211.3 [M+H]+; tR (HPLC conditions b): 1.07 min.
Reaction SMILES: [CH2:1]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][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][CH3:54])[CH:31]=1)[CH2:27]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O[C:56]1[CH:63]=[C:62]([O:64][CH3:65])[CH:61]=[CH:60][C:57]=1[CH:58]=[O:59].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][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][CH3:54])[CH:31]=1)[CH2:27][C:56]1[CH:63]=[C:62]([O:64][CH3:65])[CH:61]=[CH:60][C:57]=1[CH:58]=[O:59])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCCCCCCCCCCCCCCC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCCCCCOc1cc(Cc2cc(OC)ccc2C=O)cc(OCCCCCCCCCCCCCCCCCCCCCC)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 96.6 %

Procedure:
3,5-Di(docosyloxy)benzylchloride (450 mg, 0.58 mmol), 2-hydroxy-4-methoxybenzaldehyde (185 mg, 1.22 mmol) and potassium carbonate (200 mg, 1.45 mmol) were suspended in DMF (4.5 ml), and the mixture was stirred at 80° C. for 6 hr. The reaction mixture was extracted with chloroform (20 ml), and washed 3 times with 1N hydrochloric acid (7 ml). The solvent was evaporated and the obtained residue was precipitated with methanol (5 ml) to give 2-[3′,5′-di(docosyloxy)benzyl]-4-methoxybenzaldehyde (502 g, 0.56 mmol, 97%).
Reaction SMILES: CN(C)CCO[C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[O:27])[C:11]3[C:16]([N:17]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.[Cl:29]C1C=CC2C(=O)C3C(NC=2C=1)=CC=CC=3.C(Br)C1C=CC=CC=1.[H-].[Na+]>CN(C)C=O>[Cl:29][C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[O:27])[C:11]3[C:16]([N:17]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: O=c1c2ccccc2[nH]c2cc(Cl)ccc12
Reactant: CN(C)CCOc1ccc2c(=O)c3ccccc3n(Cc3ccccc3)c2c1
Agent: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2ccccc2n(Cc2ccccc2)c2cc(Cl)ccc12

Procedure:
3-(2-dimethylaminoethoxy)-10-benzyl-9(10H)-acridinone [IV; R' is C6H5CH2, R" is H, --O--Y--N=Z is 3--O--CH2CH2N(CH3)2 ], m.p. 134°-136° C. (light yellow powder). The intermediate 3-chloro-10-benzyl-9(10H)-acridinone, m.p. 186°-190° C. (yellow crystals) was prepared from 3-chloro-9(10H)-acridinone and benzyl bromide with sodium hydride in dimethylformamide.
Reaction SMILES: [C@H:1]1([OH:8])[CH2:6][CH2:5][CH2:4][C@@H:3]([OH:7])[CH2:2]1.CC(C)([O-])C.[K+].Br[CH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:18]=1[C:19]([O:21][CH3:22])=[O:20].BrCC1C=CC=C(C)C=1C(Br)=O.CC1C=CC=C(C)C=1C(OC)=O>CN1C(=O)CCC1.O>[OH:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][C@H:1]([O:8][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:18]=2[C:19]([O:21][CH3:22])=[O:20])[CH2:2]1
Reactant: O[C@@H]1CCC[C@H](O)C1
Reactant: COC(=O)c1c(C)cccc1CBr
Agent: CC(C)(C)[O-]
Agent: COC(=O)c1c(C)cccc1C
Agent: Cc1cccc(CBr)c1C(=O)Br
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1c(C)cccc1CO[C@H]1CCC[C@@H](O)C1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
500 g (4.3 mol) of cis-1,3-cyclohexanediol were dissolved in 5 l of NMP and admixed with 336 g (3.0 mol) of potassium tert-butoxide (KOtBu). The internal temperature rose to 28° C. The mixture was stirred for 30 min, then cooled to −5° C. and admixed dropwise with 370 g (approx. 94%, approx. 1.4 mol) of methyl 2-bromomethyl-6-methylbenzoate which may be prepared, for example, by methanolyzing 2-bromomethyl-6-methylbenzoyl bromide or by brominating methyl 2,6-dimethylbenzoate. The mixture was stirred for 30 min and then diluted with 5 l of water. After washing three times with 3 l of n-heptane each time and discarding the n-heptane solutions, the remaining aqueous phase was extracted four times with 2.5 l of MTBE each time. The combined MTBE phases were washed once with 5 l of water, dried over Na2SO4 and subsequently concentrated by evaporation under reduced pressure. 234 g of the desired compound were obtained as a yellowish oil and were used in the next reaction (for example an optical resolution) without further purification; 1H NMR (CDCl3), δ =1.27 (m, 1H), 1.45 (m, 1H), 1.55 (m, 1H), 1.74 (m, 1H), 1.83 (m, 1H), 2.05 (m, 1H), 2.34 (s, 3H), 3.47 (m, 1H), 3.72 (m, 1H), 3.91 (s, 3H), 4.58 (dd, 2H), 7.15 (d, 1H), 7.20 (d, 2H), 7.27 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Br[CH2:19][CH2:20][OH:21].CCN(C(C)C)C(C)C.CN(C=O)C>O>[OH:21][CH2:20][CH2:19][N:13]1[CH2:14][CH2:15][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][C:2]([F:1])([F:16])[F:17])[CH2:11][CH2:12]1
Reactant: OCCBr
Reactant: FC(F)(F)Oc1ccccc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: OCCN1CCN(c2ccccc2OC(F)(F)F)CC1
Temperature: 65 °C
Yield: 63 %

Procedure:
A stirred mixture of 1.23 g of 1-(2-trifluoromethoxyphenyl)piperazine, 0.73 mL of 97% 2-bromoethanol, 1.25 mL of DIPEA and 4 mL of DMF was heated at 65° C. for 6 h. After cooling to r.t., the mixture was diluted with H2O (50 mL) and extracted with CH2Cl2 (3×30 mL). The organic layer was dried (anhydrous Na2SO4) and evaporated to dryness in vacuo. The residue was purified by flash chromatography (CH2Cl2-MeOH 100:1.5) affording 0.911 g (63%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][C@H:8]([NH:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Br:31])[N:26]=1)[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([O:15][CH2:16][CH3:17])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:43](OC1C=CC([N+]([O-])=O)=CC=1)=[O:44].O1CCOCC1>ClCCl.CCOC(C)=O>[C:1]([O:5][C:6](=[O:32])[CH2:7][C@H:8]([N:18]1[CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Br:31])[N:26]=2)[C:43]1=[O:44])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([O:15][CH2:16][CH3:17])[CH:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cncc([C@H](CC(=O)OC(C)(C)C)NCCNCCCc2cccc(Br)n2)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOc1cncc([C@H](CC(=O)OC(C)(C)C)N2CCN(CCCc3cccc(Br)n3)C2=O)c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 20-10 (0.80 g, 1.57 mmol) and diisopropylethylamine (0.823 mL, 4.72 mmol) in dichloromethane (10 mL) at 0° C. was added p-nitrophenyl chloroformate (0.333 g, 1.65 mmol). The solution stirred for 30 minutes and dioxane (10 mL) was added, then refluxed for 4 hours. EtOAc (100 mL) was added and the organics were washed with 10% K2CO3, dried, and concentrated in vacuo. The residue was chromatographed (silica gel, [70:20:10 CHCl3 /EtOAc/MeOH]) to give 20-11.
Reaction SMILES: [CH:1]([CH:3]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH:4]1[OH:20])=[CH2:2].N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C=O)C.CCOCC.C(=O)(O)[O-].[Na+]>[CH:1]([CH:3]1[C:7]2([CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)[CH2:6][CH2:5][CH:4]1[O:20][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH2:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CC1C(O)CCC12CCN(C(=O)OC(C)(C)C)CC2
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CC1C(O[Si](C)(C)C(C)(C)C)CCC12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.2 %

Procedure:
To a solution of tert-butyl 1-vinyl-2-hydroxy-8-azaspiro[4.5]decane-8-carboxylate (0.462 g, 1.64 mmoL) from Step A in DMF (8 mL) was added imidazole (0.335 mg, 4.92 mmol) and then tert-butyldimethylsilyl chloride (0.370 g, 2.4 mmol). The reaction was stirred at room temperature for 20 h and then diluted with ether and sodium bicarbonate solution. The mixture was extracted twice with ether. The combined ether layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography eluting with 5% ethyl acetate in hexanes to afford the title compound (0.56 g) as a mixture of isomers.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH:4]([CH2:13][C:14](=[O:36])[NH:15][O:16][C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[OH-].[Na+]>CO.O>[C:9]([O:8][C:6](=[O:7])[CH2:5][CH:4]([CH2:13][C:14](=[O:36])[NH:15][O:16][C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]([OH:37])=[O:2])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)C(CC(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CC(CC(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of the diester of example 62 (10.5 g, 20.8 mmol) in methanol (100 mL) was cooled in an ice bath and was treated drop wise with a solution of sodium hydroxide (1N, 42 mL). Stirring was continued for 30 minutes and then for an additional 48 hours at room temperature. The methanol was evaporated in a rotary evaporator and the alkaline reaction mixture was diluted with water followed by extracting with ether. The pH was adjusted to 4 by the addition of HCl (2N) and the acidic solution was extracted several times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the desired product (10.2, 100%) as a white foam: 1H NMR (CDCl3, 400 MHz) 7.70 (d, 1H), 7.26–7.46 (m, 16H), 2.72–2.99 (m, 1H), 1.99–2.42 (m, 4H), 1.42 (s, 9H).
Reaction SMILES: [N:1]([C@H:4]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([Cl:20])=[C:14]([Cl:19])[CH:15]=3)[C:10]2=[O:21])[CH2:5]1)=[N+]=[N-].C(O)C>ClCCl>[NH2:1][C@H:4]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([Cl:20])=[C:14]([Cl:19])[CH:15]=3)[C:10]2=[O:21])[CH2:5]1
Reactant: [N-]=[N+]=N[C@H]1CC[C@H](N2C(=O)c3cc(Cl)c(Cl)cc3C2=O)C1
Solvent: ClCCl
Solvent: CCO
Product: N[C@H]1CC[C@H](N2C(=O)c3cc(Cl)c(Cl)cc3C2=O)C1

Procedure:
Trans 2-(3-azido-cyclopentyl)-5,6-dichloro-isoindole-1,3-dione (0.727 g, 2.24 mmol) and lindlar catalyt (0.36 g) was added to a mixture of ethanol and dichloromethane and placed under a hydrogen balloon overnight. The mixture was filtered and the solid rinsed with dichloromethane. The organic layers were concentrated in vacuo, dissolved in methanol and diluted with acetonitrile. The solid was removed by filtration and the filtrate purified by preparative TLC (dichloromethane/methanol/triethylamine). The solid and material from TLC was recrystallized from MeCN/MeOH to give trans 2-(3-amino-cyclopentyl)-5,6-dichloro-isoindole-1,3-dione as an off white solid (0.145 g, contains also trans 2-(3-amino-cyclopentyl)-5-chloro-isoindole-1,3-dione)