Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10].[O:13]=[S:14]1(=[O:31])[CH2:19][CH2:18][N:17]2[CH:20]=[CH:21][CH:22]=[C:23]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C:16]2=[N:15]1.O>CS(C)=O>[CH3:10][C:9]([CH3:12])([CH3:11])[CH2:8][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]2[C:16]3=[N:15][S:14](=[O:31])(=[O:13])[CH2:19][CH2:18][N:17]3[CH:20]=[CH:21][CH:22]=2)=[CH:29][CH:28]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)COc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 150 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
A mixture of potassium carbonate (300 mg), 1-iodo-2,2-dimethylpropane (430 mg) and 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (200 mg) in DMSO (5 mL) was stirred at 150° C. for 1 hr. Water was added to give a precipitate. The precipitate was collected by filtration and washed with Et2O-water. The precipitate was crystallized from CH3CN-IPE to give the title compound (182 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.[C:11]([O:15][C:16](=[O:34])[N:17]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:11]([O:15][C:16](=[O:34])[N:17]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:2]2[CH:7]=[N:6][C:5]([C:8](=[O:9])[NH2:10])=[CH:4][N:3]=2)=[CH:29][CH:28]=1)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N(CCc1ccccc1)Cc1ccc(O)cc1
Reactant: NC(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCc1ccccc1)Cc1ccc(Oc2cnc(C(N)=O)cn2)cc1
Temperature: 140 °C
Yield: 12.7 %

Procedure:
Take up 5-chloropyrazine-2-carboxamide (0.0527 g, 0.334 mmol), (4-hydroxybenzyl)phenethylcarbamic acid tert-butyl ester (Example 380, Part B) (0.110 g, 0.334 mmol) and K2CO3 (0.116 g, 0.836 mmol) in DMF (0.80 mL). Heat at 140° C. for 21.5 hours. Concentrate the reaction mixture then purify by flash chromatography, eluting with 50% ethyl acetate in hexanes to give the title compound (0.019 g, 12.7%):
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:45]2([CH3:46])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:44]2[CH2:43][CH2:42][C@@:41]2([CH3:47])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24]/[CH:25]=[CH:26]/[CH2:27][C:28]([CH2:39][CH3:40])([O:31][Si](CC)(CC)CC)[CH2:29][CH3:30])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:48][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH2:29]([C:28]([OH:31])([CH2:39][CH3:40])[CH2:27]/[CH:26]=[CH:25]/[O:24][C:21]([CH3:23])([C:20]1[C@:41]2([CH3:47])[C@H:17]([C:16]3[C@H:44]([CH2:43][CH2:42]2)[C@:45]2([CH3:46])[C:13]([CH2:12][C@@H:11]([OH:48])[CH2:10][C@@H:9]2[OH:8])=[CH:14][CH:15]=3)[CH2:18][CH:19]=1)[CH3:22])[CH3:30]
Reactant: CCC(CC)(C/C=C/OC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)O[Si](CC)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(O)(CC)C/C=C/OC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 98.8 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20-{4-ethyl-4-triethylsilyloxy-(2E)-hexenyloxy}-20-methylpregna-5,7,16-triene (350 mg, 0.430 mmol) and a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (15 ml) were subjected to reaction using a procedure similar to that of Example 5(2) (3 hours), worked up and purified by column chromatography (ethyl acetate) to give the titled compound (200 mg, 100%) as a yellow foam.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([N+:22]([O-])=O)[CH:15]=2)=[CH2:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(OCC)(=O)C.C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([NH2:22])[CH:15]=2)=[CH2:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: C=C(c1ccc(OC)c(OCC)c1)c1ccc(OC)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: C=C(c1ccc(OC)c(N)c1)c1ccc(OC)c(OCC)c1
Temperature: 70 °C
Yield: 47.7 %

Procedure:
To a stirred solution of 1-(3-ethoxy-4-methoxy-phenyl)-1-(3-nitro-4-methoxy-phenyl)-ethene (0.9 g, 2.8 mmol) in ethyl acetate (10 mL) and ethanol (20 mL) was added tin (II) chloride dihydrate (3.5 g, 15.4 mmol). The mixture was heated at 70° C. for 1 hr. The mixture was poured into ice water (100 mL) and basified with 10 N sodium hydroxide to pH=10. The mixture was extracted with ethyl acetate (5×35 mL). The combined organic layers were washed water (60 mL), brine (60 mL) and dried (MgSO4). Removal of solvent and chromatography (silica gel) gave 5-[1-(3-ethoxy-4-methoxy-phenyl) -vinyl]-2-methoxy-phenylamine as a solid (0.4 g, 48% yield): mp 91-93° C.; 1H NMR (CDCl3) δ 1.43 (t, J=7.1 Hz, 3H, CH3), 3.75 (b, 2H, NH2), 3.86 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 4.06 (q, J=7.1 Hz, 2H, OCH2), 5.28 (d, J=6.5 Hz, 2H, CH2), 6.91-6.72 (m, 6H, CH); 13C NMR (CDCl3) δ 14.76, 55.50, 55.94, 64.26, 109.85, 110.91, 111.53, 113.12, 115.03, 118.67, 120.92, 134.59, 134.73, 135.58, 147.14, 147.69, 148.97, 149.59; Anal. Calcd for C18H21NO3: C, 72.22; H, 7.07; N, 4.68. Found: C, 72.16; H, 7.10; N, 4.74.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20](S(C)(=O)=O)[N:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:20]3[N:21]=[C:22]([O:24][CH3:25])[CH:23]=[C:18]([O:17][CH3:16])[N:19]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: NC1CCCc2c1[nH]c1ccc(Cl)cc21
Product: COc1cc(OC)nc(NC2CCCc3c2[nH]c2ccc(Cl)cc32)n1

Procedure:
6-Chloro-N-(4,6-dimethoxypyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 4,6-dimethoxy-2-methylsulfonylpyrimidine in a similar manner as described above to give 8 mg (10% yield) of a pale yellow solid. 1H-NMR (CDCl3): δ 8.79 (s, 1H), 7.45 (s, 1H), 7.18 (dd, 1H), 7.08 (dd, 1H), 5.50 (s, 1H), 5.24 (m, 1H), 5.18 (m, 1H), 3.88 (2 s, 6H), 2.70 (m, 2H), 2.28 (m, 1H), 2.04-1.83 (m, 3H); MS m/z 359 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:30])[CH:9]([CH2:15][C:16]2[CH:29]=[CH:28][C:19]3[O:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[O:23][C:18]=3[CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:30])[CH:9]([CH2:15][C:16]2[CH:29]=[CH:28][C:19]3[O:20][C:21]([F:26])([F:27])[C:22]([F:25])([F:24])[O:23][C:18]=3[CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc2c(c1)OC(F)(F)C(F)(F)O2)C(O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1ccc2c(c1)OC(F)(F)C(F)(F)O2)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]propanoate (4.20 g, 9.71 mmol) in methanol (20 ml) was added 2N aqueous sodium hydroxide solution (9.7 ml, 19.4 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated, acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the objective substance (3.50 g, 89%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1.[O-]S(C(F)(F)[F:20])(=O)=O.ClC1C=CC=C(Cl)[N+]=1F.C(=O)([O-])O.[Na+]>O1CCCC1>[F:20][C:9]1[C:10]([CH:13]=[O:14])=[CH:11][NH:12][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1
Agent: F[n+]1c(Cl)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1c[nH]c(-c2ccccc2F)c1F
Reaction time: 2 h
Yield: 12.7 %

Procedure:
To a solution (60 mL) of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (3.1 g) in tetrahydrofuran was added 2,6-dichloro-N-fluoropyridinium triflate (5.6 g) at 0° C., and the mixture was stirred at the same temperature for 2 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give the title compound as white crystals (yield 0.43 g, 13%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:19]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[Cl:27])[CH:18]=[N:17][N:16]=4)[S:8][C:7]=3[C:6]=2[CH:28]=1.[CH2:29]([N:33]1C=CN=C1)CCC>[Cu]I.C1(C)C=CC=CC=1>[Cl:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:19]1[CH:18]=[N:17][N:16]=[C:15]1[C:9]1[S:8][C:7]2[C:6]3[CH:28]=[C:2]([C:29]#[N:33])[CH:3]=[CH:4][C:5]=3[O:14][CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: CCCCn1ccnc1
Reactant: Fc1ccc(-n2cnnc2-c2cc3c(s2)-c2cc(Br)ccc2OCC3)c(Cl)c1
Agent: [Cu]I
Solvent: Cc1ccccc1
Product: N#Cc1ccc2c(c1)-c1sc(-c3nncn3-c3ccc(F)cc3Cl)cc1CCO2
Temperature: 160 °C
Yield: 30.3 %

Procedure:
A microwave tube was charged with 3-(9-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-4-(2-chloro-4-fluoro-phenyl)-4H-[1,2,4]triazole (0.57 g; 1.2 mmol), K4-[Fe(CN)6] (101 mg; 0.24 mmol), CuI (23 mg; 0.12 mmol), 1-butylimidazole (0.32 ml; 2.4 mmol) and toluene (5 ml). The mixture was flushed with argon and heated in a microwave at 160° C. for 4 h. LCMS shows approx. 40% conversion so the same amount of K4[Fe(CN)6], CuI and 1-butylimidazole was added again and reaction mixture heated in a microwave at 170° C. for a further 4 h. The reaction mixture was partitioned between CH2Cl2 and water, the organic layer was dried (Na2SO4) and purified by ISCO then prep. LCMS to give 355 as a white solid (154 mg; 30%). δH (400 MHz, CDCl3) 3.19 (t, J=5.2, 2H), 4.36 (t, J=5.2, 2H), 7.08-7.11 (m, 2H), 7.23-7.32 (m, 1H), 7.43-7.52 (m, 3H), 7.81 (d, J=2.0, 1H), 8.23 (s, 1H). [M+H]+: 423
Reaction SMILES: O[NH:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[H][H]>[Ni].COCCO>[NH2:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)c2c(NO)cccc21
Reactant: [H][H]
Agent: [Ni]
Solvent: COCCO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 80 °C

Procedure:
To 100 parts of ethyleneglycol monomethyl ether (so called methyl-Cellosolve) there were added 5.0 parts of 1-hydroxylaminoanthraquinone and 0.25 part of Raney nickel. The reaction mixture was heated to 80°C over 30 minutes and maintained at 80°C for 4 hours, with stirring, while introducing thereinto 0.04 parts/hour of gaseous hydrogen. The reaction mixture was then purged of gaseous hydrogen with gaseous nitrogen, heated to 100°C and filtered while hot to separate the catalyst as residue. The filtrate was, while maintained at 80°C, added with 100 parts of water, with stirring, to precipitate crystals. The slurry thus formed was then cooled to room temperature and filtered. The residue was washed with 5 parts of methanol and dried to obtain 4.2 parts of 1-aminoanthraquinone of a purity of 97 %. In the filtrate there remained 0.1 part of 1-aminoanthraquinone dissolved.
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].Cl[CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:20]1([CH2:19][CH:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(Cc1cccc2ccccc12)C(=O)OC(C)(C)C
Temperature: 30 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
A suspension of 5.96 g (0.124 mol) of NaH.oil (50%) was washed with THF to remove the oil, then suspended in 450 mL THF. Di-t-butyl malonate (25.4 mL, 0.113 mol) was then added causing a mild exotherm. The solution was heated to reflux for 45 minutes, then cooled to 30° C. A solution of 20.0 g (0.113 mol) of 1-chloromethylnaphthalene in 50 mL THF was then added and the solution heated at reflux for 3 hours, then left stirring overnight. The mixture was filtered and the filtrate removed under reduced pressure. The residue was taken up in EtOAc and washed with 1N citric acid, saturated NaCl, saturated NaHCO3, then saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure left 39.65 g (98.4% yield) of the product as an oil.
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:9][C:8](=O)[CH:7]1[CH2:6][CH:5]=[CH:4]2.[OH2:11].[O:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:3]12[CH2:9][C:8](=[CH:14][C:13]([O:12][CH2:16][CH3:15])=[O:11])[CH:7]1[CH2:6][CH:5]=[CH:4]2
Reactant: O=C1CC2C=CCC12
Reactant: O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C=C1CC2C=CCC12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of triethylphosphonoacetate (10.7 g; 48 mmol) in tetrahydrofuran (5 ml) was added to a suspension of 60% sodium hydride dispersion (1.91 g; 48 mmol) in tetrahydrofuran (30 ml) maintaining the temperature between 5–15° C. A solution of bicyclo[3.2.0]hept-2-en-6-one (5 g; 46 mmol) in tetrahydrofuran (5 ml) was added maintaining the temperature between 5–15° C. The reaction mixture was stirred at ambient temperature for 30 minutes then demineralised water (30 ml) added. The phases are separated and toluene (20 ml) was added to the organic layer which was washed with demineralised water (2×20 ml). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield the title compound as a oil (7.74 g).
Reaction SMILES: [CH2:1]([C@H:8]([NH:31][C:32](=[O:38])[O:33][C:34](C)([CH3:36])[CH3:35])[C@@H:9]([OH:30])[CH:10]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39](O)(=[O:41])C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([C@H:8]([NH:31][C:32](=[O:38])[O:33][C@H:34]1[CH2:36][CH2:39][O:41][CH2:35]1)[C@@H:9]([OH:30])[CH:10]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)NC(OC2CCCCC2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Reactant: CC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)NC(OC2CCCCC2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CCOC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
tert-butyl N-((1S,2R)-1-benzyl-3-(cyclohexyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate (0.09 mmol, 50 mg) was dissolved in a 1:1 solution of CH2Cl2/TFA (1 mL) and allowed to stir at room temperature for 1 hour. The solution was then extracted into ethyl acetate, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated to a clear oil. The resulting oil was then dissolved in THF (1 mL) and combined with 2,5-dioxo-1-pyrrolidinyl [(3S)tetrahydro-3-furanyl]carbonate (0.05 mmol, 13 mg) DIEA (0.08 mmol, 14 gL) and allowed to stir for 15 hours. The reaction was neutralized by the addition of acetic acid and partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, and dried over magnesium sulfate. The crude product was concentrated to a white solid and purified by silica gel chromatography (1:1 hexanes/ethyl acetate), providing 19 mg (37%) of a white solid. H1-NMR (CDCl3): δ7.70 (2H,d), 7.29-7.17 (6H,m), 6.97 (2H,d), 5.1 (1H,s), 4.76 (1H,d), 4.17 (1H,m), 3.86 (3H,s), 3.87-3.70 (6H,m), 3.68-3.60 (1H,m), 3.06 (1H,bs), 2.89 (2H,m), 2.02 (3H,m), 1.89 (1H,m), 1.71 (2H,m),1.28-1.08 (6H,m); MS (ESI): M+Na=585.
Reaction SMILES: [OH:1][C@H:2]([C@@H:20]([NH:28][C:29](=[O:48])[C@H:30]([CH2:44][C:45](=[O:47])[NH2:46])[NH:31][C:32]([C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]=1)=[O:33])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][N:4]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[NH:5]C(OC(C)(C)C)=O>C(O)=O>[OH:1][C@H:2]([C@@H:20]([NH:28][C:29](=[O:48])[C@H:30]([CH2:44][C:45](=[O:47])[NH2:46])[NH:31][C:32]([C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]=1)=[O:33])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][N:4]([CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[NH2:5]
Reactant: CC(C)(C)OC(=O)NN(CC1CCCCC1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1
Solvent: O=CO
Product: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)CC1CCCCC1

Procedure:
Analogously to Example 98 (see below), 921 mg (1.39 mmol) of 1-[2(S)-hydroxy-3(S)-(N-(quinoline-2-carbonyl)-(L)-asparagyl) amino-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-[tert-butoxy-carbonyl]-hydrazine (Example 100 A), see below) in 37 ml of formic acid are reacted to form the title compound and used directly in the next step.
Reaction SMILES: [BH3-][C:2]#N.[Na+].[NH2:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.O=[C:14]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:15]([OH:17])=O>CO.O=C(CCC(O)=O)C(O)=O>[OH:12][C:8]1[CH:7]=[C:6]([N:5]2[C:15](=[O:17])[CH2:14][CH2:18][CH:19]2[C:20]([O:22][CH3:2])=[O:21])[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)CCC(=O)C(=O)O
Reactant: Nc1cccc(O)c1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCC(=O)N1c1cccc(O)c1
Reaction time: 17 h
Yield: 88.6 %

Procedure:
NaBH3CN (11.55 g, 0.18 mol) was added to a stirred solution of 3-aminophenol (10.00 g, 0.09 mol) and 2-ketoglutaric acid (17.41 g, 0.12 mol) in MeOH (350 mL). After about 17 hours, 2-ketoglutaric acid (1.00 g, 7 mmol) was added and the mixture stirred for about 1 hour. cH2SO4 was added until pH=1 and the mixture heated to reflux. cH2SO4 (3 mL) was added after about 3 hours and then again about 1 hour later. The mixture was heated at reflux overnight, the solvent evaporated and the residue diluted with water and 10% Na2CO3 solution. The mixture was extracted with CH2Cl2, the extracts dried over Na2SO4 and concentrated to leave an oil that crystallized. This was dissolved in CH2Cl 2 containing a small amount of MeOH and diluted with hexanes to give methyl 1-(3-hydroxyphenyl)-5-oxo-2-pyrrolidinecarboxylate (18.75 g, 87%). An analytical sample was prepared by recrystallizing a 1 g sample from a mixture of CH2Cl2 and hexanes to give 0.98 g of pure material, mp 125-127° C. IR (KBr) 3200 (OH), 1730 (CO2Me), 1660 (CONH) cm-1. 1H NMR (CDCl3) δ2.16 (1H, m, CH.CH2CO), 2.40-2.70 (2H, m, CH2CO), 2.80 (1H, m, CH.CH2CO), 3.72 (3H, s, CO2CH3), 4.75 (1H, dd, J=6 Hz, J'=3 Hz, CHCO2CH3), 6.54 (1H, dd, J=8 Hz, J'=2 Hz, aromatic H), 6.68 (1H, dd, J=8 Hz, J'=2 Hz, aromatic H), 7.15 (1H, t, J=8 Hz, aromatic H meta to OH), 7.73 (1H, t, J=2 Hz, aromatic H ortho to N and OH), 8.35 (1H, bs, OH); 13C NMR (CDCl3) δ22.97, 31.11, 52.73, 61.83, 109.21, 110.78, 113.20, 129.70, 138.58, 157.38, 172.04, 175.47; MS m/z 236 (MH+).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].[H-].[Na+].Cl[CH:22]([CH3:27])[CH2:23][CH2:24][C:25]#[N:26]>CN(C)C=O>[CH2:1]([O:8][N:9]([CH2:27][CH2:22][CH2:23][CH2:24][C:25]#[N:26])[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Cl)CCC#N
Reactant: CC(C)(C)OC(=O)NOCc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCCCC#N)OCc1ccccc1
Temperature: 85 °C
Reaction time: 3.5 h

Procedure:
To a solution of tert-butyl benzyloxycarbamate in anhydrous dimethylformamide were added 5 mol % of sodium iodide and portionwise 1.36 eq. of sodium hydride (60% dispersion in mineral oil). The mixture was stirred at room temperature for 15 min. before 1.05 eq. of 4-chlorovaleronitrile were added. The mixture was heated to 85° C. and stirred for 3.5 h. After cooling to room temperature the mixture was quenched with water and extracted with diethyl ether. The combined organic phases were concentrated and washed with half saturated aq. sodium thiosulfate, water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The oily residue was washed with petroleum ether and dried under high vacuum to yield Tert-butyl benzyloxy(4-cyanobutyl)carbamate as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([N:17]3[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18]3)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[OH:25][C:26]1([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)=[CH:35][N:34]=2)[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClCCl>[N:40]1[CH:41]=[CH:42][CH:43]=[N:44][C:39]=1[C:36]1[CH:37]=[CH:38][C:33]([C:26]2([OH:25])[CH2:31][CH2:30][CH:29]([NH:22][C@H:19]3[CH2:20][CH2:21][N:17]([C:15]([CH:12]4[CH2:11][CH2:10][N:9]([C:7]5[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:23])[F:24])[N:8]=5)[CH2:14][CH2:13]4)=[O:16])[CH2:18]3)[CH2:28][CH2:27]2)=[N:34][CH:35]=1
Reactant: O=C1CCC(O)(c2ccc(-c3ncccn3)cn2)CC1
Reactant: N[C@H]1CCN(C(=O)C2CCN(c3cccc(C(F)(F)F)n3)CC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCN(c2cccc(C(F)(F)F)n2)CC1)N1CC[C@H](NC2CCC(O)(c3ccc(-c4ncccn4)cn3)CC2)C1

Procedure:
A solution of (3S)-1-({1-[6-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}carbonyl)pyrrolidin-3-amine (40 mg, 0.1 mmol), 4-hydroxy-4-(5-pyrimidin-2-ylpyridin-2-yl)cyclohexanone (47 mg, 0.18 mmol), sodium triacetoxyborohydride (50 mg, 0.23 mmol), and triethylamine (35 mg, 0.35 mmol) in dichloromethane (10 mL) was stirred at room temperature overnight. The reaction mixture was passed through a silica gel pad. The filtrate was concentrated and purified by HPLC to give the cis- and trans-isomers. MS (M+H) 596.2 for both isomers.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[CH2:12][NH:11][CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.[CH3:25][N:26]([CH3:33])[C:27]1([C:30](O)=[O:31])[CH2:29][CH2:28]1>>[CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=4)[CH2:12][N:11]([C:30]([C:27]4([N:26]([CH3:33])[CH3:25])[CH2:29][CH2:28]4)=[O:31])[CH2:10]3)[O:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CN(C)C1(C(=O)O)CC1
Reactant: FC(F)(F)c1ccc(C2CNCC(c3nc(C4CC4)no3)C2)cc1
Product: CN(C)C1(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(C4CC4)no3)C2)CC1

Procedure:
100 mg (0.30 mmol) of the compound from Example 183A and 42 mg (0.33 mmol) of 1-(dimethylamino)cyclopropanecarboxylic acid were reacted according to the General Method 7. Yield: 120 mg (90% of theory)