Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C@@H:21]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=1)[C:22]([N:24]([CH2:36][CH:37]([O:41][CH2:42][CH3:43])[O:38][CH2:39][CH3:40])[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1)=[O:23]>>[CH2:1]([NH:8][C:9]([NH:11][N:12]([C:14]([CH3:19])([CH3:18])[C:15]([NH:20][C@@H:21]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:54])([CH3:53])[CH3:55])=[CH:47][CH:46]=1)[C:22]([N:24]([CH2:36][CH:37]([O:41][CH2:42][CH3:43])[O:38][CH2:39][CH3:40])[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:17])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(NC(=O)NCc1ccccc1)C(C)(C)C(=O)O
Reactant: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Product: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)C(C)(C)N(C)NC(=O)NCc1ccccc1)OCC
Yield: 58 %

Procedure:
According to the procedure described in the synthesis method of Compound II-1, 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)-2-methylpropanoic acid (Compound VI-5) (441 mg, 1.67 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N-(2,2-diethoxyethyl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) (544.6 mg, 1.11 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol=98:2) to obtain the title compound (476 mg, 58%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[O:15])([CH3:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([NH:13][C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=2)([CH3:12])[CH3:11])=[O:15])=[CH:18][CH:19]=1
Reactant: CC(=O)c1cccc(C(C)(C)NC(=O)Nc2ccc(Cl)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)c1cccc(C(C)(C)NC(=O)Nc2ccc(Cl)cc2)c1
Reaction time: 1 h
Yield: 81.6 %

Procedure:
A solution of 1-(2-(3-acetylphenyl)propan-2-yl)-3-(4-chlorophenyl)urea (25 mg, 0.07 mmol) in THF was cooled in an ice bath to 0° C. Lithium aluminum hydride solution (2 M in THF, 0.8 equiv) was added drop wise over 5 min and then the reaction was continued for approximately 1 h at 0° C. until starting material disappeared. The reaction was carefully quenched with a solution of sodium sulfate. The reaction mixture was filtered through a sintered funnel and the supernatant washed with dichloromethane. Combined organic fractions were concentrated under reduced pressure. The residue was purified by column chromatography using chloroform-methanol as a eluent to give 10 (19 mg, 74%). 1H NMR (DMSO-d6, 400 MHz) δ 1.25 (d, J=6 Hz, 3H), 1.54 (s, 6H), 4.64 (pent, J=4.4 Hz, 1H), 5.09 (d, J=4 Hz, 1H), 6.56 (s, 1H), 7.11-7.19 (m, 5H), 7.28 (s, 1H), 7.31 (d, J=9.2 Hz, 1H), 8.51 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 26.78, 30.33, 30.44, 55.06, 68.94, 119.47, 122.42, 123.70, 124.88, 128.28, 129.10, 140.18, 147.68, 148.65, 154.48; ESI-HRMS for C18H22N2O2Cl (M+H)+ calcd. 333.1370. found 333.1378.
Reaction SMILES: C[O:2][C:3]([C:5]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][C:18]2[N:22]=[C:21]([C:23]3[O:31][C:30]4[CH:29]=[CH:28][N:27]=[CH:26][C:25]=4[CH:24]=3)[O:20][N:19]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:7])[CH3:6])=[O:4].O[Li].O>C1COCC1.O>[C:3]([C:5]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][C:18]2[N:22]=[C:21]([C:23]3[O:31][C:30]4[CH:29]=[CH:28][N:27]=[CH:26][C:25]=4[CH:24]=3)[O:20][N:19]=2)[CH2:15][CH2:16]1)=[O:10])([CH3:6])[CH3:7])([OH:4])=[O:2]
Reactant: COC(=O)C(C)(C)OC(=O)N1CCC(Cc2noc(-c3cc4cnccc4o3)n2)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(OC(=O)N1CCC(Cc2noc(-c3cc4cnccc4o3)n2)CC1)C(=O)O
Reaction time: 16 h

Procedure:
A stirred solution of 4-(5-furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidine-1-carboxylic acid 1-methoxycarbonyl-1-methylethyl ester (Example 72, 43 mg, 100 μmol) in THF-H2O (3:1, 2 mL) was treated with LiOH.H2O (9 mg, 220 μmol). After 16 h, the THF was evaporated in vacuo, then the remainder was diluted with H2O (2 mL), before being washed with EtOAc (2×5 mL). The aqueous phase was neutralised with 1 M HCl, then the mixture was extracted with EtOAc (3×10 mL). The combined EtOAc extracts were dried (MgSO4), filtered, and concentrated to furnish the title compound: RT=2.74 min; m/z (ES+)=415.1 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=1I.C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:21]2[CH:22]=[C:23]([S:26]([CH3:29])(=[O:27])=[O:28])[CH:24]=[CH:25][C:20]=2[F:19])[CH:11]=1
Reactant: CS(=O)(=O)c1ccc(F)c(I)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(F)c(C#Cc2cc(Cl)ccc2OCC(=O)O)c1
Temperature: 60 °C
Reaction time: 60 h

Procedure:
A mixture of (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3, 164 mg; 0.61 mmol), 1-fluoro-2-iodo-4-(methylsulfonyl)benzene (Intermediate 58, 184 mg; 0.61 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(ii) (27 mg; 0.04 mmol) and cuprous iodide (7 mg; 0.04 mmol) was degassed during two minutes under nitrogen then anhydrous THF (3 mL) and triethylamine (170 μL; 1.23 mmol) were added and reaction mixture was stirred at 60° C. for 60 hours. The solvent was evaporated and the residue was treated with an HCl solution (4 N in dioxane, 3.7 mL). After stirring for 16 hours, the solvents were removed under vacuum and the crude product purified by preparative HPLC. The title compound was obtained as a brown solid.
Reaction SMILES: N[C:2](N)=[O:3].[NH2:5][C:6]([CH3:13])([CH3:12])[CH2:7][NH:8][CH2:9][CH2:10][OH:11].N>>[OH:11][CH2:10][CH2:9][N:8]1[CH2:7][C:6]([CH3:13])([CH3:12])[NH:5][C:2]1=[O:3]
Reactant: NC(N)=O
Reactant: CC(C)(N)CNCCO
Agent: N
Product: CC1(C)CN(CCO)C(=O)N1
Yield: 41.7 %

Procedure:
A mixture of urea (5.4 g, 91 mmol) and 2-((2-amino-2-methylpropyl)amino)ethanol (12 g, 91 mmol) was heated in a 200° C. sand bath for approximately 45 min until ammonia evolution had ceased. The crude mixture was purified by column chromatography, eluting from silica gel with a gradient of 0-10% methanol in dichloromethane to give 6.0 g of a white solid. 1H NMR (CDCl3, 400 MHz) δ 1.33 (s, 6H), 3.21 (s, 2H), 3.27-3.30 (t, J=5.2, 2H), 3.69-3.71 (q, J=5.2 Hz, 2H), 4.01-4.04 (t, J=5.4, 1H), 5.31 (br s, 1H); LRMS (ESI/APCI) m/z 159 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C@H:9]3[C@@H:11]([O:21][CH2:22][O:23][CH3:24])[C@H:12]([O:17][CH2:18][O:19][CH3:20])[C@@H:13]([CH2:15][OH:16])[O:14][C@H:8]3[N:7]([CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[C:6]=2[CH:32]=1.O1CCC[CH2:34]1.CN(C)C=O.[H-].[Na+].C1(C)C=CC(S(OC)(=O)=O)=CC=1>O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C@H:9]3[C@@H:11]([O:21][CH2:22][O:23][CH3:24])[C@H:12]([O:17][CH2:18][O:19][CH3:20])[C@@H:13]([CH2:15][O:16][CH3:34])[O:14][C@H:8]3[N:7]([CH2:25][CH2:26][N:27]([CH2:28][CH3:29])[CH2:30][CH3:31])[C:6]=2[CH:32]=1
Reactant: C1CCOC1
Reactant: CCN(CC)CCN1c2cc(Cl)ccc2S[C@H]2[C@@H](OCOC)[C@H](OCOC)[C@@H](CO)O[C@H]21
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CCN(CC)CCN1c2cc(Cl)ccc2S[C@H]2[C@@H](OCOC)[C@H](OCOC)[C@@H](COC)O[C@H]21
Reaction time: 5 h

Procedure:
To the solution of 92 mg of the compound (25) obtained in Example 24 in 4.5 ml of a mixed solution of tetrahydrofuran-dimethylformamide (2:1), 30 mg of sodium hydride and 80 μl of methyl p-toluenesulfonate were added, and the mixture was stirred for five hours. After methanol was added to the solution, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, and saturated aqueous sodium chloride successively and was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography, and the title compound was obtained from the fraction of chloroformmethanol (19:1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH:3]=1.[CH3:16]CCCCCC.C(OCC)(=O)C>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH3:16])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH:3]=1
Reactant: Cc1ccccc1-c1cc(Cl)nnc1N
Reactant: CCCCCCC
Solvent: CCOC(C)=O
Product: CNc1nnc(Cl)cc1-c1ccccc1C
Yield: 17 %

Procedure:
The title compound was prepared in analogy to example 1, intermediate a, from 6-chloro-4-o-tolyl-pyridazin-3-ylamine and using a gradient of n-heptane:ethyl acetate (100:0 to 0:70) eluant for the chromatographic purification. A second purification step on a 20 g column using an MPLC (Flashmaster) system (gradient of n-heptane:ethyl acetate (100:0 to 40:60)) furnished the title compound as a colorless solid (17%). MS (ESI+): m/z=234.080 ([M+H]+).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[C:14]3[C:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[C:20]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:7]=1.[OH-].[Na+]>C1COCC1>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]2[C:14]3[C:13]([NH:12][C:8]4[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=4)[O:5][CH2:4][C:3]([OH:35])=[O:2])=[N:18][CH:17]=[N:16][C:15]=3[O:19][C:20]=2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)COc1cccc(Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(F)cc4)c23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1cccc(Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(F)cc4)c23)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Dissolve 21.1 mg (0.045 mmol) of 3-{[5-(4-fluorophenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenoxyacetic acid methyl ester in 1 ml of THF, add 0.135 ml of 1N sodium hydroxide solution at RT and stir at 50° C. for 1 h. Cool to RT and remove the THF under reduced pressure. Add water to the residue, and then, with ice cooling, 1N hydrochloric acid. Filter off the precipitated solid, wash repeatedly with water and dry at 40° C. under reduced pressure. 11.5 mg (56.2% of theory) of the target compound are obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[C:10]([C:21]([OH:23])=[O:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CO.[H][H]>COC(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C@H:10]([C:21]([OH:23])=[O:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1C1=C(C(=O)O)CN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Solvent: COC(C)(C)C
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1ccccc1[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O
Temperature: 25 °C

Procedure:
In a glove box an autoclave was charged with 4-o-tolyl-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester (2.5 g), [Ru(OAc)2 ((R)-(2-furyl)-MeOBIPHEP)] (24 mg), triethylamine (1.1 mL) and methanol (25 mL). The asymmetric hydrogenation was run for 60 h at 80° C. under 40 bar of hydrogen. After cooling to room temperature the pressure was released from the autoclave, the methanol solution was diluted with tert-butyl methyl ether (320 mL) and extracted with 1 M aqueous sodium hydroxide solution (2×, 320 mL). The aqueous layer was poured on ice, acidified with ice-cold 2 M aqueous hydrochloric acid solution to pH 1 and extracted with ethyl acetate (3×). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo and triturated from n-heptane to give (3S,4S)-4-o-tolyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester as a white solid, MS: 318.2.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][CH2:15][C:16](Cl)=[O:17].CCN(C(C)C)C(C)C>>[Cl:14][CH2:15][C:16]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Yield: 81.1 %

Procedure:
The above-prepared tert-butyl piperazine-1-carboxylate (500 mg, 2.68 mmol) was treated with chloroacetyl chloride (360 mg, 2.95 mmol) in the presence of DIEA (1.04 g, 8.05 mmol) to give tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate (571 mg, 81% yield) after purification by flash chromatography on a silica gel column (hexane/EtOAc=1:2). C11H19ClN2O3; white solid; mp 68-70° C.; 1H NMR (400 MHz, CDCl3) δ 4.06 (2H, s), 3.58 (2H, m), 3.49 (4H, s), 3.44 (2H, m) 1.47 (9H, s); 13C NMR (100 MHz, CDCl3) δ 164.5, 153.7, 80.2, 46.2, 43.3 (2×), 42.1, 40.9, 28.5; ESI-HRMS calcd for C11H20ClN2O3: 285.0982. found: m/z 285.0985 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[O:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)CC1CCCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC1CCCCO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a solution of (tetrahydro-pyran-2-yl)-acetic acid ethyl ester (77.1 g, 0.45 mol) in tetrahydrofuran (1.5 L) at 0° C. was added lithium aluminium hydride (22.1 g, 0.58 mol) in several portions. The mixture was stirred at 0° C. for 2 h and quenched with 1 N sodium hydroxide solution. The mixture was filtered and the filter cake was washed with dichloromethane (4×300 mL). The combined organic layers were concentrated in vacuo. The crude product was purified by distillation under reduced pressure to afford 2-(tetrahydro-pyran-2-yl)-ethanol (53.5 g, 92% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:16][C:17](=[O:36])[CH:18]=[CH:19][CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28]C(OCC)=O)=[C:24]([O:34][CH3:35])[CH:23]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6]/[CH:7]=[C:8](/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])\[CH3:9])\[CH3:4].[OH-].[Na+].Cl>CO>[CH2:1]([NH:16][C:17](=[O:36])[CH:18]=[CH:19][CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([O:34][CH3:35])[CH:23]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6]/[CH:7]=[C:8](/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])\[CH3:9])\[CH3:4]
Reactant: CCOC(=O)Oc1ccc(C=CC=CC(=O)NC/C=C(\C)CC/C=C(\C)CCC=C(C)C)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C=CC=CC(=O)NC/C=C(\C)CC/C=C(\C)CCC=C(C)C)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of 2.06 g of 5-(4'-ethoxycarbonyloxy-3'-methoxyphenyl)pentadienoic acid (E,E)-farnesylamide in 40 ml of methanol is added 20 ml of 2N aqueous solution of sodium hydroxide. The mixture is stirred at room temperature for one hour. The reaction mixture, after acidified with 1N hydrochloric acid, is extracted with chloroform. The organic layer is washed with water and dried over sodium sulfate. The solvent is distilled off under reduced pressure, and the residue is subjected to column chromatography on silica gel. From the fraction eluted with chloroform is obtained 1.67 g of 5-(4'-hydroxy3'-methoxyphenyl)pentadienoic acid (E,E)-farnesylamide (13). Spectroscopic data of the product support the structure of the formula (13) below.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[C:11]([Cl:24])[CH:10]=2)=[C:4]([CH2:25][O:26][CH2:27][CH2:28]O)[CH:3]=1.[C:30]1([NH:37][C:35](=[O:36])[NH:34][C:32]1=[O:33])=[O:31]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[C:11]([Cl:24])[CH:10]=2)=[C:4]([CH:3]=1)[CH2:25][O:26][CH2:27][CH2:28][N:34]1[C:32](=[O:33])[C:30](=[O:31])[NH:37][C:35]1=[O:36]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2COCCO)cc1Cl
Reactant: O=C1NC(=O)C(=O)N1
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2COCCN2C(=O)NC(=O)C2=O)cc1Cl

Procedure:
Compound 158 (47 mg, 0.1 mmol) and parabanic acid (16 mg, 0.14 mmol) were treated as described in the preparation of compound 219. Purification was done by flash chromatography (CH2Cl2/ethyl acetate 4:1) to provide the title compound, which was impure. The product was further purified by preparative TLC (CH2Cl2/ethyl acetate 20:1) to furnish the title compound as yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:16]([OH:18])[CH3:17])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cs].Br[CH2:21][C:22]1([CH3:26])[CH2:25][O:24][CH2:23]1>CN(C)C=O>[CH3:21][C:22]1([CH2:26][O:14][C:13](=[O:15])[CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH:16]([OH:18])[CH3:17])[CH2:25][O:24][CH2:23]1
Reactant: CC1(CBr)COC1
Reactant: CC(O)C(NC(=O)OCc1ccccc1)C(=O)O
Agent: [Cs]
Solvent: CN(C)C=O
Product: CC(O)C(NC(=O)OCc1ccccc1)C(=O)OCC1(C)COC1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
To a N,N-dimethylformamide (750 ml) solution 2-benzyloxycarbonylamino-3-hydroxy-butyric acid, cesium salt (123.9 g, 0.322 mol) at about 23° C. was added 3-bromomethyl-3-methyl-oxetane (60 ml, 0.420 mol). The reaction was stirred at about 23° C. for about 18 hours and was then concentrated in vacuo. The residue was diluted with ethyl acetate and extracted with saturated sodium bicarbonate, washed with saturated ammonium chloride and saturated sodium chloride, dried with sodium sulfate and concentrated to give 100 g of the title compound.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC([NH:14][C@:15]([C:24]1[O:28][C:27]([C:29]2[CH:30]=[C:31]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])[CH:32]=[C:33]([CH2:35]Br)[CH:34]=2)=[N:26][N:25]=1)([CH3:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O)(C)(C)C>>[NH2:14][C@:15]([C:24]1[O:28][C:27]([C:29]2[CH:30]=[C:31]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])[CH:32]=[C:33]([CH2:35][O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:34]=2)=[N:26][N:25]=1)([CH3:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(c1cc(CBr)cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c1)S(C)(=O)=O
Reactant: OC1CCCC1
Product: CN(c1cc(COC2CCCC2)cc(-c2nnc([C@](C)(N)Cc3ccccc3)o2)c1)S(C)(=O)=O

Procedure:
Prepared from cyclopentanol and 3-(5-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(bromomethyl)-N-methyl-N-(methylsulfonyl)benzenamine using a similar procedure as described for the preparation of Example 40. 1H NMR (CD3OD) δ 7.93 (m, 2H), 7.68 (s, 1H), 7.32 (m, 3H), 7.09 (m, 2H), 4.59 (s, 2H), 4.10 (m, 1H), 3.45 (s, 2H), 3.38 (s, 3H), 2.96 (s, 3H), 1.88 (s, 3H), 1.78 (m, 6H), 1.60 (m, 2H).
Reaction SMILES: Cl.[Cl:2]/[C:3](/[C:13]([F:16])([F:15])[F:14])=[CH:4]\[C@@H:5]1[C@H:7]([C:8]([OH:10])=[O:9])[C:6]1([CH3:12])[CH3:11].Cl/C(/C(F)(F)F)=C\[C@H]1[C@H](C(O)=O)C1(C)C>C(Cl)Cl>[Cl:2][C:3]([C:13]([F:14])([F:15])[F:16])=[CH:4][CH:5]1[CH:7]([C:8]([OH:10])=[O:9])[C:6]1([CH3:12])[CH3:11]
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)O
Agent: CC1(C)[C@@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)O
Agent: Cl
Solvent: ClCCl
Product: CC1(C)C(C=C(Cl)C(F)(F)F)C1C(=O)O

Procedure:
The aqueous alkali phase was acidified with hydrochloric acid, and the precipitated product was isolated by extraction with methylene chloride, giving 341 g of a crystalline mass comprising 92 g of cis-3-(Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropanecarboxylic acid and 206 g of trans-3-(Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropanecarboxylic acid.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:18]([C:20]([CH2:22][CH2:23][C@@:9]34[OH:24])=[O:21])[O:19][C:4]([C:5]=25)=[C:3]([OH:25])[CH:2]=1.Cl.N1C=CN=C1.[C:32]([Si:36]([CH3:39])([CH3:38])Cl)([CH3:35])([CH3:34])[CH3:33].O>C(OCC)C>[Si:36]([O:25][C:3]1[CH:2]=[CH:1][C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C:5]=2[C:4]=1[O:19][C@H:18]4[C:20](=[O:21])[CH2:22][CH2:23][C@@:9]35[OH:24])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:39])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 76 %

Procedure:
3.49 g of naltrexone hydrochloride was suspended in 10.5 ml of N,N-dimethylfonnamde. After adding 3.46 g of imidazole, 3.48 g of tert-butyldimethylchlorosilane was added followed by stirring for 35 minutes at room temperature. 30 ml of water and 50 ml of diethyl ether were added to the reaction system followed by separation. The aqueous layer was extracted twice with 30 ml of diethyl ether. The combined extracts were dried over anhydrous sodium sulfate and concentrated. The resulting residue was recrystallized from ethanol to obtain 3.2 g of the target compound (yield: 76%).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:13])[C:5]1=O.O.[NH2:16][CH2:17][CH:18]([OH:20])[CH3:19]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:13][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][C:4]1[CH:3]=[CH:2][N:16]([CH2:17][CH:18]([OH:20])[CH3:19])[C:5]=12
Reactant: CC(O)CN
Reactant: O=CCC1Cc2c(Cl)cccc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(O)Cn1ccc2c1-c1cccc(Cl)c1C2
Reaction time: 0.75 h
Yield: 59.5 %

Procedure:
A solution of 2.08 g of (RS)-2-(2-oxoethyl)-4-chloro-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/hexane 1:2). 1.47 g (59%) of (RS)-1-(5-chloro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.