Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[C:8]([C:15]1[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][N:16]=1)=[C:9](Cl)[CH2:10]2)=[O:5])[CH3:2].C(N(CC)CC)C.C(O)=O>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[C:8]([C:15]1[CH:19]=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:17][N:16]=1)=[CH:9][CH2:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C2CCC1C(c1cc(-c3ccccc3)on1)=C(Cl)C2
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: CCO
Product: CCOC(=O)N1C2CC=C(c3cc(-c4ccccc4)on3)C1CC2

Procedure:
1.3 g (3.6 mmol) 8-ethoxycarbonyl-3-chloro-2-(5-phenyl-3-isoxazolyl)-8-azabicyclo[3.2.1]oct-2-ene was dissolved in 30 ml ethanol. 300 mg Pd/C 5%, triethylamine (7 ml) and formic acid (3 ml) was added and the reaction mixture heated at reflux for 4 h. The mixture was concentrated in vacuo, water (50 ml) was added and the solution extracted with ethylether 3×20 ml. The organic phase was dried over magnesiumsulphate and concentrated in vacuo. The crude product was purified by column chromatography with methylenchloride/ethylacetate (9:1) as eluent. Yield 600 mg oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:36])=[C:4]([C:12]2(O)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13]2=[O:34])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.BrC1C=CC(C2(O)C3C(=CC=CC=3)N(CC3OC(C(F)(F)F)=CC=3)C2=O)=C(O)C=1>>[Cl:1][C:2]1[C:3]([OH:36])=[C:4]([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13]2=[O:34])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1c(O)c(Cl)cc2c1OCCO2
Agent: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C1(O)c1ccc(Br)cc1O
Product: O=C1C(c2c(O)c(Cl)cc3c2OCCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations using 3-(7-chloro-6-hydroxy-2,3-dihydro-1,4-benzodioxin-5-yl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one to replace 3-(4-bromo-2-hydroxyphenyl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one, 3-(7-chloro-6-hydroxy-2,3-dihydro-1,4-benzodioxin-5-yl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one was obtained (74%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.44-7.27 (m, 10H), 7.08-6.78 (m, 4H), 6.49-6.42 (m, 1H), 5.76 (s, 0.5H), 5.30 (s, 0.5H), 5.27 (s, 0.5H), 5.03 (s, 0.5H), 4.39-4.25 (m, 2H), 4.06-3.90 (m, 1H), 3.75-3.50 (m, 1H); MS (ES+) m/z 484.3 (M+1), 486.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:17](=[O:27])[CH2:18][NH:19][C:20](OC(C)(C)C)=[O:21])[CH:7]2[CH2:13]C(O)=O.BrC1C(F)=CC=C2C=1CCN(C(=O)CNC(OC(C)(C)C)=O)C2CC(OC)=O.[OH-].[Na+]>CCO>[Br:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:17](=[O:27])[CH2:18][NH:19][C:20](=[O:21])[CH:13]=[C:7]12
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCc2c(ccc(F)c2Br)C1CC(=O)O
Agent: COC(=O)CC1c2ccc(F)c(Br)c2CCN1C(=O)CNC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C=C2c3ccc(F)c(Br)c3CCN2C(=O)CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(5-bromo-2-(2-((tert-butoxycarbonyl)amino)acetyl)-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid. To a stirred solution of methyl 2-(5-bromo-2-(2-((tert-butoxycarbonyl)amino)acetyl)-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (62.6 g, 136 mmol) in EtOH (500 mL), 4N aqueous NaOH (39.5 mL, 158 mmol) was added and the solution was stirred at RT for 2 h. The white precipitate was filtered off and the white solid was washed with a small amount of EtOH (1×) and diethyl ether (2×). The sodium salt was partitioned between 0.5N aqueous HCl and DCM, the organic layer was separated and washed with 0.5N aqueous HCl (1×) and brine (1×). The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was dried under high vacuo overnight to yield the title compound as white foam (58.45 g). UPLC-MS: MS 445.2/447.2 (M+H+); UPLC rt 0.99 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([O:28][CH3:29])=[C:26]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[N:39][CH:40]=[CH:41][CH:42]=4)[N:37]=3)[CH2:32][CH2:31]2)[N:25]=[C:24]([O:46][CH3:47])[N:23]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pt]=O>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([O:28][CH3:29])=[C:26]([N:30]2[CH2:31][CH2:32][CH:33]([C:36]3[CH:45]=[CH:44][C:43]4[CH2:42][CH2:41][CH2:40][NH:39][C:38]=4[N:37]=3)[CH2:34][CH2:35]2)[N:25]=[C:24]([O:46][CH3:47])[N:23]=1)[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1nc(NCC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)c(OC)c(N2CCC(c3ccc4cccnc4n3)CC2)n1
Agent: O=[Pt]
Solvent: CCO
Product: COc1nc(NCC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)c(OC)c(N2CCC(c3ccc4c(n3)NCCC4)CC2)n1
Reaction time: 2 h
Yield: 35.1 %

Procedure:
A mixture of 85 mg (1.32 mmoles) of tert-butyl 2-benzyloxycarbonylamino-3-[2,5-dimethoxy-6-(4-[1,8]naphthyridin-2-yl-piperidin-1-yl)-pyrimidin-4-ylamino]-propionate and 30 mg of platinum oxide in 50 ml of ethanol is stirred for 2 hours under hydrogen at atmospheric pressure. The reaction mixture is filtered on Clarcel then evaporated to dryness under reduced pressure (2 kPa). The residue is chromatographed on silica with a gradient of heptane-ethyl acetate-methanol of 100-0-0 to 0-100-0 then 0-95-5. 300 mg of expected product is obtained in the form of a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH:19]([NH:28]C(=O)OC(C)(C)C)[NH:20]C(=O)OC(C)(C)C)=[CH:12][CH:11]=2)[N:9]=1)(=[O:3])[CH3:2].[ClH:36]>O1CCOCC1>[ClH:36].[NH2:28][C:19]([NH:18][CH2:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][CH:7]=2)=[CH:15][CH:14]=1)=[NH:20]
Reactant: CC(=O)Nc1nc(-c2ccc(CCNC(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)cs1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(-c2ccc(CCNC(=N)N)cc2)cs1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.6 %

Procedure:
Di-tert-butyl {[(2-{4-[2-(acetylamino)-1,3-thiazol-4-yl]phenyl}ethyl)amino]methylidene}biscarbamate (268 mg, 79.2%) (170 mg) was dissolved in 4 N hydrogen chloride in 1,4-dioxane (5 mL). The mixture was stirred at room temperature for 2 days, and then evaporated in vacuo. The residue was washed with ethyl ether, dried in vacuo to give N-{4-[4-(2-{[amino(imino)methyl]amino}ethyl)phenyl]-1,3-thiazol-2-yl}acetamide hydrochloride (50 mg, 43.6%).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH:13]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([OH:25])=O)=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:26]([OH:28])=[O:27].OC1C2N=NNC=2C=CC=1.[CH2:39]([NH:41][CH2:42][CH3:43])[CH3:40]>CN(C)C=O>[CH2:39]([N:41]([CH2:42][CH3:43])[C:23]([C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[CH:13]=[C:14]([C:26]([OH:28])=[O:27])[CH:15]=[CH:16]2)=[O:25])[CH3:40]
Reactant: CCNCC
Reactant: O=C(O)c1ccc2cc(C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc2cc(C(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (22.2 g, 115 mmol) was added to a solution of 2,6-naphthalenedicarboxylic acid (25 g, 115 mmol) and hydroxybenzotriazole (15.6 g, 115 mmol) in dimethylformamide (1800 ml) and the mixture was stirred at room temperature for 2 hours. Diethyl amine (34.3 ml, 345 mmol) was added and the solution was stirred overnight at room temperature. The solvent was then evaporated under reduced pressure and the crude was treated with 1N HCl (500 ml) and ethyl acetate (500 ml), insoluble compounds were filtered off and the phases were separated. The organic phase was extracted with 5% sodium carbonate (3×200 ml) and the combined aqueous solutions were acidified with concentrated HCl and extracted with ethyl acetate (3×200 ml). The organic solution was then washed with 1N HCl (6×100 ml), dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure yielding 18.5 g (Yield 60%) of pure 6-(diethylaminocarbonyl)-2-naphthalenecarboxylic acid; m.p.=122-124° C.
Reaction SMILES: C[O:2][C:3]([N:5]([C:16]1[CH:21]=[CH:20][C:19]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:18][CH:17]=1)[CH2:6][C:7]([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:8])=O.Cl>[OH-].[K+]>[S:22]([C:19]1[CH:20]=[CH:21][C:16]([N:5]2[CH2:6][C:7](=[O:8])[N:9]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:3]2=[O:2])=[CH:17][CH:18]=1)(=[O:25])(=[O:24])[NH2:23]
Reactant: COC(=O)N(CC(=O)NC1CCCCC1)c1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: NS(=O)(=O)c1ccc(N2CC(=O)N(C3CCCCC3)C2=O)cc1
Yield: 74 %

Procedure:
2-(N-Methoxycarbonyl-4-sulphamoylphenylamino)-N-cyclohexylacetamide (3.7 g) was dissolved in hot conc. KOH (15.0 ml). The solution was cooled and acidified with conc. HCl. The mixture was heated for 30 min. on a water bath and then filtered to yield 2.5 g product, m.p. 237° - 238°C (ethanol/water
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7][CH2:8][CH2:9][CH2:10][O:11]C1CCCCO1>C(O)(=O)C.C1COCC1.O>[OH:11][CH2:10][CH2:9][CH2:8][S:7][C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1
Reactant: Cn1ccnc1SCCCOC1CCCCO1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccnc1SCCCO
Yield: 96.8 %

Procedure:
A solution of 1-methyl-2-(3-(2-tetrahydropyranyloxy)propylthio)imidazole (2.0 g, 7.8mmol) in acetic acid (8 ml), THF (4 ml) and water (2 ml) was heated at 50° C. for 4 hours. The volatiles were removed by evaporation and the residue azeotroped with toluene to give 2-(3-hydroxypropylthio)-1-methylimidazole (1.3 g, 100%) as an off-white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O)=[CH:12][CH:11]=[CH:10][C:9]=2[C:29]1[CH:34]=[CH:33][C:32]([C:35]([O:37]C)=[O:36])=[CH:31][C:30]=1[CH3:39])=[O:5])C.[Cl:40][C:41]1[CH:46]=[C:45]([Cl:47])[C:44]([Cl:48])=[CH:43][C:42]=1[OH:49].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:8]=2[NH:7][C:6]([C:4]([OH:5])=[O:3])=[C:14]3[CH2:15][CH2:16][CH2:17][O:49][C:42]2[CH:43]=[C:44]([Cl:48])[C:45]([Cl:47])=[CH:46][C:41]=2[Cl:40])=[C:30]([CH3:39])[CH:31]=1)([OH:37])=[O:36]
Reactant: CCOC(=O)c1[nH]c2c(-c3ccc(C(=O)OC)cc3C)cccc2c1CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)O)ccc1-c1cccc2c(CCCOc3cc(Cl)c(Cl)cc3Cl)c(C(=O)O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of EXAMPLE 127C (60 mg) in DMF (1 mL) was added 2,4,5-trichlorophenol (43 mg) and Cs2CO3 (500 mg). The mixture was stirred at room temperature overnight, diluted with ethyl acetate (150 mL), and washed with water and brine. After drying over Na2SO4, the combined organic layers were concentrated, and the concentrate was saponified with LiOH as described in EXAMPLE 65B. 1H NMR (300 MHz, DMSO-d6) δ 12.92 (m, 1H), 10.88 (s, 1H), 7.89 (s, 1H), 7.82 (m, 2H), 7.38 (s, 1H), 7.32 (d, 1H), 7.10 (m, 2H), 4.13 (t, 2H), 3.25 (t, 2H), 2.13 (m, 2H), 2.10 (s, 3H).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][C@H:18]2[NH:28][C:29](=[O:37])[O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:13]1=[O:38])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([CH3:26])([CH3:27])[CH3:25])[CH2:19][C@H:18]2[NH:28][C:29](=[O:37])[O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:36])[CH3:35])[C:13]1=[O:38]
Reactant: [H][H]
Reactant: CC(C)(C)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](NC(=O)OCC[Si](C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)N[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](NC(=O)OCC[Si](C)(C)C)C1
Reaction time: 1 h
Yield: 99 %

Procedure:
A sample of 2-(trimethylsilyl)ethyl (1R,2S,5R)-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexylcarbamate and its 5S diastereomer (68 mg, 0.141 mmol; see Example 11, Step 4) was dissolved in MeOH (3 mL) prior to the addition of 10% Pd/C (100 mg, 0.940 mmol) and a hydrogen balloon. After 1 h, the solution was filtered and concentrated in vacuo. The reaction was then set-up again with fresh reagents. After 1 h, the solution was filtered and concentrated to give 2-(trimethylsilyl)ethyl (1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexylcarbamate as a mixture with its 5S diastereomer (139.4 mg, 0.338 mmol, 99% yield): LC/MS found [M+H]+=413.4.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]=[CH:31][C:32]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:33])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[O:16])[CH2:11][CH2:10]1)=[O:8].[H][H]>C1COCC1.CO.[Pd]>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([N:9]1[CH2:10][CH2:11][N:12]([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([N:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)=[O:33])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[O:16])[CH2:13][CH2:14]1)=[O:8]
Reactant: [H][H]
Reactant: Cn1cccc1C(=O)N1CCN(C(=O)NC2CCN(c3ccc(C=CC(=O)N4CCOCC4)cc3)CC2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cccc1C(=O)N1CCN(C(=O)NC2CCN(c3ccc(CCC(=O)N4CCOCC4)cc3)CC2)CC1

Procedure:
The 4-((1-methylpyrrol-2-yl)-carbonyl)-N-(1-(4-(3-morpholino-3-oxopropen-1-yl)-phenyl)-piperidin-4-yl)-1-piperazinecarboxamide (100 mg, 0.19 mmol) obtained in Example 11 was dissolved in THF (20 ml) and methanol (5 ml), and 10% Pd—C (39 mg) was added thereto, followed by stirring in a hydrogen atmosphere for 12 hours. After the insoluble material was filtered with Celite, the filtrate was evaporated under reduced pressure, thereby obtaining 4-((1-methylpyrrol-2-yl)-carbonyl)-N-(1-(4-(3-morpholino-3-oxopropyl)-phenyl)-piperidin-4-yl)-1-piperazinecarboxamide (84 mg, 84%) as a white solid.
Reaction SMILES: C([C:5]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:6]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][C@H:25]([OH:32])[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:16][CH:15]=1)(C)(C)C.[ClH:40]>O1CCOCC1>[ClH:40].[ClH:40].[OH:32][C@H:25]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[CH2:24][NH:23][CH2:22][CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][CH:5]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N(CCCc1ccc(-c2ccc(C(=O)O)cc2C(C)(C)C)cc1)C[C@H](O)c1cccnc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2ccc(CCCNC[C@H](O)c3cccnc3)cc2)cc1

Procedure:
A solution of tert-butyl 4′-[3-[(tert-butoxycarbonyl)-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]propyl]-1,1′-biphenyl-4-carboxylic acid (90 mg) and 4N hydrochloride in dioxane (5.0 ml) was stirred at room temperature for 24 hours. The resultant solid was collected by filtration and dried to give 4′-[3-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]-amino]propyl]-1,1′-biphenyl-4-carboxylic acid dihydrochloride (80 mg) as a white solid.
Reaction SMILES: [CH2:1]([OH:19])[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][CH3:18].[C:20]([C:24]1[CH:25]=[C:26]([CH:33]=[C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:35]=1[OH:36])[CH2:27][CH2:28][C:29](OC)=[O:30])([CH3:23])([CH3:22])[CH3:21]>>[C:37]([C:34]1[CH:33]=[C:26]([CH:25]=[C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:35]=1[OH:36])[CH2:27][CH2:28][C:29]([O:19][CH2:1][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][CH3:18])=[O:30])([CH3:39])([CH3:40])[CH3:38]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 2.5 h

Procedure:
The general procedure of Example 1 is repeated, but using 382.9 g (1.416 mole) of octadecyl alcohol and 471.3 g (1.612 mole) of methyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate and employing 2 ounces (30.1 g) of PROPAK® and 2.5 ounces (69.4 g) of TiS catalyst. The system is brought to reflux at a pressure of 6-8 mm Hg and a temperature of between 190 and 202° C. After 2.5 hours, analysis of the contents of the reaction flask using Gas Chromatography shows a mixture of 51.7 wt % of the title compound, 26.2 wt % of methyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate and 20.8 wt % octadecyl alcohol.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8]C(OCC1C=CC=CC=1)=O)(=[O:3])[CH3:2].[ClH:19]>C(O)(C)C.[C].[Pd]>[ClH:19].[C:1]([O:4][CH2:5][CH2:6][CH2:7][NH2:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCNC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: CC(=O)OCCCN

Procedure:
In 200 ml of isopropanol was dissolved 28 g of the 1-acetoxy-3-(benzyloxycarbonylamino)propane, and 2.5 g of 5% palladium-carbon and 10 ml of conc. hydrochloric acid were added thereto, after which the resulting mixture was subjected to catalytic reduction at room temperature. Subsequently, the palladium-carbon was removed by filtration and the solvent was removed by distillation under reduced pressure to obtain 12 g of oily 1-acetoxy-3-aminopropane hydrochloride.
Reaction SMILES: [CH3:1][CH:2]([OH:6])[CH:3]([OH:5])[CH3:4].CCN(CC)CC.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:14][S:15]([O:5][CH:3]([CH:2]([O:6][S:15]([CH3:14])(=[O:17])=[O:16])[CH3:1])[CH3:4])(=[O:17])=[O:16]
Reactant: CC(O)C(C)O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)C(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
To a solution of butane 2,3-diol (15 g, 0.166 mol) and Et3N (57.7 mL, 0.415 mol) in CH2Cl2 (150 mL) at 0° C. was slowly added a solution of CH3SO2Cl (32.1 mL, 0.415 mol) in CH2Cl2 (75 mL). The mixture was stirred at 0° C. for 2 h and diluted with CH2Cl2. The mixture was washed with water, 1N HCl, 5% aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford butane-2,3-diol dimethanesulfonate (40 g, 98%) as a light yellow oil. 1HNMR (CDCl3): δ 4.9 (m, 2H, CH), 3.05 (s, 6H, CH3), 1.4 (m, 6H, CH3).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1([C:16]2[NH:20][C:19](=[O:21])[O:18][N:17]=2)[CH2:11][CH:10]1[CH2:12][CH:13]([CH3:15])[CH3:14])(C)(C)C.[ClH:23]>O1CCOCC1.CCOCC>[ClH:23].[NH2:7][CH2:8][C:9]1([C:16]2[NH:20][C:19](=[O:21])[O:18][N:17]=2)[CH2:11][CH:10]1[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CC1CC1(CNC(=O)OC(C)(C)C)c1noc(=O)[nH]1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)CC1CC1(CN)c1noc(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of {2-isobutyl-1-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-cyclopropylmethyl}-carbamic acid tert-butyl ester (4.2 g, 13.5 mmol) in dry 1,4-dioxane (20 ml) was added 4N HCl (40 mL, in 1,4-dioxane). The reaction mixture was stirred at room temperature overnight and diluted with ether (100 mL). The precipitate was collected and washed with ether and dried to give 2.6 g (79%) of 3-(1-aminomethyl-2-isobutyl-cyclopropyl)-4H-[1,2,4]oxadiazol-5-one hydrochloride as a white solid: mp: 181-182° C.; 1H NMR (300 MHz, D2O) δ 0.94-0.98 (m, 6H), 1.21 (m, 1H), 1.35 (m, 1H), 1.58 (m, 3H), 1.73 (m, 1H), 3.24 (d, J=14.2 Hz, 1H), 3.71 (d, J=14.3 Hz, 1H); 13C NMR (75 MHz, D2O) δ 19.3, 19.6, 21.8, 22.1, 26.6, 28.2, 36.7, 39.5, 162.2, 162.6; MS (APCI) m/z 212 [M+H]+. Anal. Calc'd For C10H17N3O2—HCl: C, 48.49; H, 7.32; N, 16.96; Cl, 14.31. Found: C, 48.49; H, 7.17; N, 16.84; Cl, 13.94.
Reaction SMILES: F[C:2]1[C:16]([CH:17]=[O:18])=[CH:15][C:5]2[C:6]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])=[N:7][O:8][C:4]=2[C:3]=1[F:19].[CH3:20][C@H:21]1[O:26][C@H:25]([CH3:27])[CH2:24][NH:23][CH2:22]1>>[CH3:27][C@@H:25]1[CH2:24][N:23]([C:2]2[C:16]([CH:17]=[O:18])=[CH:15][C:5]3[C:6]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])=[N:7][O:8][C:4]=3[C:3]=2[F:19])[CH2:22][C@@H:21]([CH3:20])[O:26]1
Reactant: C[C@@H]1CNC[C@@H](C)O1
Reactant: CC(C)NC(=O)c1noc2c(F)c(F)c(C=O)cc12
Product: CC(C)NC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@H](C)C3)c(C=O)cc12

Procedure:
The title compound was prepared from 6,7-difluoro-5-formyl-N-isopropylbenzo[d]isoxazole-3-carboxamide (Intermediate 242) and (2R,6R)-2,6-dimethylmorpholine.
Reaction SMILES: [CH3:1][C:2]1([OH:39])[CH:25]=[C:24]2[C@:19]([CH3:37])([CH2:20][CH2:21][C@H:22]([O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH2:23]2)[C@@H:18]2[C@@H:3]1[C@H:4]1[C@:15]([CH3:38])([CH2:16][CH2:17]2)[C@@H:7]([C@H:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:6][CH2:5]1.[CH3:40][Si](C=[N+]=[N-])(C)C.N#N>C1(C)C=CC=CC=1.CO>[OH:39][C:2]1([CH3:1])[CH:25]=[C:24]2[C@:19]([CH3:37])([CH2:20][CH2:21][C@H:22]([O:26][Si:27]([CH:28]([CH3:30])[CH3:29])([CH:31]([CH3:32])[CH3:33])[CH:34]([CH3:36])[CH3:35])[CH2:23]2)[C@@H:18]2[C@@H:3]1[C@H:4]1[C@:15]([CH3:38])([CH2:16][CH2:17]2)[C@@H:7]([C@H:8]([CH3:14])[CH2:9][CH2:10][C:11]([O:13][CH3:40])=[O:12])[CH2:6][CH2:5]1
Reactant: CC(C)[Si](O[C@H]1CC[C@@]2(C)C(=CC(C)(O)[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)O)[C@@]4(C)CC[C@@H]32)C1)(C(C)C)C(C)C
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@@]1(C)CC[C@H](O[Si](C(C)C)(C(C)C)C(C)C)CC1=CC3(C)O

Procedure:
To a solution of 7-hydroxy-7-methyl-3β-triisopropylsilyl-oxychol-5-en-24-oic acid (5) (5.38 g, 9.68 mmoles) in toluene (70 ml) and methanol (20 ml) was added dropwise at room temperature trimethylsilyldiazomethane (2.0N in hexane, ~5 ml). After 30 minutes N2 evolution ceased, and the reaction mixture was a pale yellow. The solvent was removed in vacuo to give 4.67 g of crude 6 as a brown syrup. NMR (CDCl3) indicated a mixture of 7-isomers: δ0.69 (two peaks, 18-Me); 3.63 (s, CO2Me); 5.12 & 5.18 (6-H). The mixture was used directly in the next reaction (Example 6).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:12][C:11]3([CH2:21][C:20](=[O:22])[C:19]4[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:27][O:28]C5CCCCO5)=[O:26])[CH:18]=4)[O:13]3)[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(Cl)Cl.O1CCOCC1>[C:1]1([CH2:7][CH2:8][N:9]2[CH2:12][C:11]3([CH2:21][C:20](=[O:22])[C:19]4[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:27][OH:28])=[O:26])[CH:18]=4)[O:13]3)[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(CCc3ccccc3)C1)O2)NOC1CCCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(CCc3ccccc3)C1)O2)NO
Yield: 88.8 %

Procedure:
(E)-3-[1′-(2-Phenyl-ethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (180 mg, 0.39 mmol) in DCM (7 ml) was treated with 4 M HCl in dioxane (1 ml) as described in Example 30, Step C, giving (E)-3-[1′-(2-phenyl-ethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hydroxy-acrylamide (131 mg, hydrochloride salt) as a white solid.