Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]([CH3:41])[CH3:40])[C:34]=1[N:42]=[C:43]=[O:44])([CH3:32])[CH3:31]>>[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]([CH3:40])[CH3:41])[C:34]=1[NH:42][C:43](=[O:44])[N:15]([C:12]1[CH:13]=[CH:14][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=1)[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:21][CH:22]=1)([CH3:31])[CH3:32]
Reactant: CCCCCCCCc1ccc(NCc2ccc(Oc3ccccc3)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CCCCCCCCc1ccc(N(Cc2ccc(Oc3ccccc3)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 23.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (4-octylphenyl)[(4-phenoxyphenyl)methyl]amine (1.53 g) and 2,6-diisopropylphenyl isocyanate (0.88 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-(4-octylphenyl)-N-[(4-phenoxyphenyl)methyl]urea (0.55 g) was obtained.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:20])[C@H:7]([CH2:16][CH2:17][CH2:18][CH3:19])[NH:8]C(OC(C)(C)C)=O)[CH2:2][CH2:3][CH3:4].C([Cl:24])(=O)C>CO>[ClH:24].[CH2:1]([NH:5][C:6](=[O:20])[C@H:7]([CH2:16][CH2:17][CH2:18][CH3:19])[NH2:8])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)Cl
Reactant: CCCCNC(=O)[C@H](CCCC)NC(=O)OC(C)(C)C
Solvent: CO
Product: CCCCNC(=O)[C@@H](N)CCCC
Product: Cl
Reaction time: 0.75 h

Procedure:
The N-Boc-L-norleucine butylamide in methanol is treated with acetyl chloride. After 45 minutes, all volatiles are removed under reduced pressure to yield L-norleucine butylamide hydrochloride.
Reaction SMILES: C[Si](Cl)(C)C.Br[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH3:15][C:16]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:21]=[C:20]([B:31]2[O:35]C(C)(C)[C:33](C)(C)[O:32]2)[C:17]=1C=O>C1COCC1.[Zn]>[OH:35][B:31]1[C:20]2[CH:21]=[C:22]([O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[CH:23]=[C:16]([CH3:15])[C:17]=2[CH:33]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[O:32]1
Reactant: Cc1cc(OC2CCCCO2)cc(B2OC(C)(C)C(C)(C)O2)c1C=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Cc1cc(OC2CCCCO2)cc2c1C(CC(=O)OC(C)(C)C)OB2O
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 70.1 %

Procedure:
To a suspension of zinc powder (2.81 g, 43.35 mmol) in dry THF was added TMSCl (0.94 g, 8.67 mmol) at 40° C. The mixture was stirred at 55° C. for 15 min. The mixture was allowed to cooled to 30° C. and tert-butyl 2-bromoacetate (6.76 g, 34.68 mmol) was added slowly to the reaction mixture between 37-40° C. After completion of addition, the resulting mixture was stirred at room temperature for an additional 30 min. To a solution of 2-methyl-4-(tetrahydro-2H-pyran-2-yloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (3 g, 8.67 mmol) in 20 mL dry THF at −78° C. was added dropwise the above prepared reaction mixture. The reaction mixture was stirred at room temperature for 1 h and quenched by ice-water at 0° C. The mixture was extracted with EtOAc (3×15 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column (EA:PE=1:10) to give 2.2 g of desired product as a light yellow oil.
Reaction SMILES: [Mg].[F:2][C:3](S(C1C=CC=CC=1)(=O)=O)(S(C1C=CC=CC=1)(=O)=O)[CH:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1)[CH2:5][OH:6].O>C(Br)Br.C[Si](Cl)(C)C.CO>[F:2][CH2:3][CH:4]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:11][CH:12]=1)[CH2:5][OH:6]
Reactant: CC(C)Cc1ccc(C(CO)C(F)(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: [Mg]
Solvent: CO
Solvent: BrCBr
Solvent: O
Product: CC(C)Cc1ccc(C(CO)CF)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
One drop of CH2Br2 and then 1 drop of TMSCl were charged into a 5 mL solution of magnesium ribbon (707 mg, 29.1 mmol, 45.0 eq) in MeOH. The solution was cooled to 0° C., and then a 5 mL solution of 3-fluoro-2-(4-isobutylphenyl)-3,3-bis(phenylsulfonyl)propan-1-ol (317 mg, 0.646 mmol, 1.0 eq) in MeOH was added dropwise thereto. The solution was stirred for 2 hours at 0° C., and then water was charged thereto to stop the reaction. The aqueous solution was acidified using 1 M HCR. The aqueous layer was extracted with methylene chloride and then the extract was dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure by distillation, and then the resultant product was purified by column chromatography (hexane:ethyl acetate=7:3) to obtain 3-fluoro-2-(4-isobutylphenyl)propan-1-ol (119 mg, 87%).
Reaction SMILES: Br.Br[CH2:3][CH2:4][C:5]1[C:10](=[O:11])[N:9]2[C:12]([CH3:15])=[CH:13][S:14][C:8]2=[N:7][C:6]=1[CH3:16].[F:17][C:18]1[CH:32]=[CH:31][C:21]2[C:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:23][O:24][C:20]=2[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[F:17][C:18]1[CH:32]=[CH:31][C:21]2[C:22]([CH:25]3[CH2:26][CH2:27][N:28]([CH2:3][CH2:4][C:5]4[C:10](=[O:11])[N:9]5[C:12]([CH3:15])=[CH:13][S:14][C:8]5=[N:7][C:6]=4[CH3:16])[CH2:29][CH2:30]3)=[N:23][O:24][C:20]=2[CH:19]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1nc2scc(C)n2c(=O)c1CCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2scc(C)n2c(=O)c1CCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 8 h
Yield: 62 %

Procedure:
A mixture of 7.4 parts of 6-(2-bromoethyl)-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one monohydrobromide, 4.4 parts of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole, 10 parts of sodium carbonate and 90 parts of N,N-dimethylformamide was stirred overnight at 80°-85° C. After cooling, the reaction mixture was poured into water. The product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. 2-Propanol was added to the residue. The product was filtered off and dried, yielding 5.3 parts (62%) of 6-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one; mp. 231.0° C. (compound 13).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[C:5]([NH:10][CH3:11])=[N:6][C:7]=1[O:8][CH3:9].[H][H].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[N:25]=[C:26]=[S:27]>C1COCC1.[Ni]>[Br:1][C:2]1[CH:3]=[C:4]([NH:12][C:26]([NH:25][C:19]2[C:20]([Cl:24])=[CH:21][CH:22]=[CH:23][C:18]=2[Cl:17])=[S:27])[C:5]([NH:10][CH3:11])=[N:6][C:7]=1[O:8][CH3:9]
Reactant: [H][H]
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: CNc1nc(OC)c(Br)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: CNc1nc(OC)c(Br)cc1NC(=S)Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Bromo-6-methoxy-N-methyl-3-nitropyridin-2-amine (0.5 g, 1.9 mmol) in THF was combined with Raney nickel (70 mg) and hydrogenated in a Parr apparatus at ambient temperature for 10 h at 3.5 bar hydrogen pressure. Then the mixture was directly filtered into a mixture of 1,3-dichloro-2-isothiocyanatobenzene (0.39 g, 1.9 mmol) in THF and stirred overnight at ambient temperature. The solvent was removed i. vac. and the residue was purified by HPLC (C18 Symmetry, 8 μm, eluent: H2O+0.15% HCOOH+15-100% acetonitrile).
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[OH:25][C@@H:26]([C@H:28]1[C:48](=[O:49])[N:30]2[CH:31]([C:35]([O:37]CC3C=CC([N+]([O-])=O)=CC=3)=[O:36])[C:32](=O)[CH2:33][C@H:29]12)[CH3:27].[CH3:50][N+:51]1([CH3:57])[CH2:55][CH2:54][C@H:53]([SH:56])[CH2:52]1.C(NC(C)C)(C)C>C(#N)C>[CH3:50][N+:51]1([CH3:57])[CH2:55][CH2:54][C@H:53]([S:56][C:32]2[CH2:33][C@@H:29]3[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:48](=[O:49])[N:30]3[C:31]=2[C:35]([O-:37])=[O:36])[CH2:52]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: C[N+]1(C)CC[C@H](S)C1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)NC(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@H]3CC[N+](C)(C)C3)C[C@H]12
Reaction time: 1 h
Yield: 18.4 %

Procedure:
183 μl of diisopropylethylamine and 218 μl of diphenylphosphoryl chloride were simultaneously added, whilst ice-cooling, to a solution of 348 mg of 4-nitrobenzyl (5R, 6S)-6-[(1R)-1-hydroxyethyl]-2oxo-1-carbapenam-3-carboxylate dissolved in 4 ml of dry acetonitrile, and the mixture was stirred at the same temperature for 1 hour. At the end of this time a solution of 338 mg of the crude (3S)-1,1-dimethyl-3-mercaptopyrrolidinium salt prepared as described in Example 5-(1) in 4 ml of dry acetonitrile and 201 μl of diisopropylamine were added to the mixture, whilst ice-cooling. The mixture was then allowed to stand at the same temperature for 1 hour and then for two days in a refrigerator. At the end of this time, the reaction mixture was washed by decantation with diethyl ether. The resulting product was dissolved in a mixture of 30 ml of tetrahydrofuran and 30 ml of a 0.1M phosphate buffer (pH 7.0) and hydrogenated at room temperature for 2.5 hours in the presence of 400 mg of 10% w/w palladium-on-charcoal. At the end of this time, an insoluble material was removed by filtration and the filtrate was washed with diethyl ether. The aqueous layer was concentrated by evaporation under reduced pressure and then subjected to column chromatography through Diaion HP-20AG (Mitsubishi Chemicals Industries Inc.). The title compound was prepared as a crude product from the fractions eluted with water. The crude compound was then further purified by chromatography through a Lobar column (Merck, LiChroprep RP-8, size B) and the fractions eluted with 5% by volume aqueous methanol were collected, concentrated by evaporation under reduced pressure and lyophilized to afford 60 mg of the title compound.
Reaction SMILES: F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[F:25][C:26]1[CH:27]=[C:28]([CH2:33][C@@H:34]([CH2:38][NH:39][C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])[C:35]([OH:37])=O)[CH:29]=[CH:30][C:31]=1[F:32].NCC(CC1C=CC=CC=1)C([NH:55][C:56]1[S:57][C:58]([Cl:68])=[C:59]([C:61]2[N:65]([CH3:66])[N:64]=[CH:63][C:62]=2[Cl:67])[CH:60]=1)=O.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:68][C:58]1[S:57][C:56]([NH:55][C:35](=[O:37])[C@@H:34]([CH2:33][C:28]2[CH:29]=[CH:30][C:31]([F:32])=[C:26]([F:25])[CH:27]=2)[CH2:38][NH:39][C:40](=[O:41])[O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:60][C:59]=1[C:61]1[N:65]([CH3:66])[N:64]=[CH:63][C:62]=1[Cl:67]
Reactant: O=C(NC[C@H](Cc1ccc(F)c(F)c1)C(=O)O)OCc1ccccc1
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)C(CN)Cc2ccccc2)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)[C@H](CNC(=O)OCc2ccccc2)Cc2ccc(F)c(F)c2)sc1Cl
Reaction time: 12 h
Yield: 20.1 %

Procedure:
Bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (401 mg, 0.859 mmol) was added in one portion to a solution of (2S)-3-(3,4-difluorophenyl)-2-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]propanoic acid (200 mg, 0.573 mmol)[prepared in Preparation 4] and [5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]amine-HCl (163 mg, 0.573 mmol)[prepared in Example 3] in N,N-diisopropylethylamine (0.500 ml, 2.86 mmol) and dichloromethane (7.174 ml). After 12 h, the solution was dry loaded onto silica and purified by chromatography (0-50% EtOAc in hexanes) affording phenylmethyl {(2S)-3-{[5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]amino}-2-[(3,4-difluorophenyl)methyl]-3-oxopropyl}carbamate (70 mg, 0.115 mmol, 20.05% yield) as an orange solid: LCMS (ES) m/e 579, 581 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) d ppm 11.61 (s, 1 H) 7.67 (s, 1 H) 7.53 (br. s., 1 H) 7.32 (s, 7 H) 7.03 (br. s., 1 H) 6.55 (s, 1 H) 5.01 (s, 2 H) 3.68 (s, 3 H) 3.19-3.28 (m, 2 H) 2.76-3.00 (m, 3 H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[I:15]I>O>[I:15][C:6]1[C:5]([OH:8])=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1ccc(O)cn1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(O)c(I)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
To a mixture of 6-methylpyridin-3-ol (235 g, 2.75 mol) and water (5.28 L) at 0° C. was added Na2CO3 (440 g, 5.5 mol) and the mixture was stirred at room temperature for 30 minutes. A solution of I2 (760 g, 3.85 mol) and KI (760 g, 5.83 mol) in water (5.28 L) was added dropwise to the reaction over a period of 1 hour. The mixture was stirred at room temperature for 3 hours and the resulting precipitate was collected by filtration to afford 2-iodo-6-methylpyridin-3-ol (390 g, 77.0%) as a yellow solid which was used without further purification.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.Br[CH2:15][CH2:16][O:17][CH3:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][C:7]=1[O:8][CH2:15][CH2:16][O:17][CH3:18])[C:1]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(C(=O)OC)cc1OC
Yield: 99.8 %

Procedure:
A mixture of methyl vanillate (6.376 g, 35 mmol), 1-bromo-2-methoxyethane (5.56 g, 40 mmol), and K2CO3 (5.528 g, 40 mmol) in DMF (40 mL) were reacted according to the procedure described in Example 6A Step 1, to afford methyl 3-methoxy-4-(2-methoxyethoxyl)benzoate as a solid (8.394 g, 99.8%). 1H NMR (300 MHz, CDCl3) δ 7.65 (dd, 1H), 7.54 (d, 1H), 6.92 (d, 1H), 4.23 (q, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.81 (t, 2H), 3.45 (s, 3H); LC-MS (ESI) m/z 241 (M+H)+.
Reaction SMILES: [Br:1]Br.[CH:3]([O:6][C:7]([N:9]1[CH2:15][CH2:14][CH2:13][CH:12]([N:16]([C:32](=[O:34])[CH3:33])[CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=2)[C:11]2[CH:35]=[CH:36][C:37]([CH3:39])=[CH:38][C:10]1=2)=[O:8])([CH3:5])[CH3:4]>C(O)(=O)C.C(OCC)(=O)C>[CH:3]([O:6][C:7]([N:9]1[CH2:15][CH2:14][CH2:13][CH:12]([N:16]([C:32](=[O:34])[CH3:33])[CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[C:20]([C:28]([F:29])([F:30])[F:31])[CH:19]=2)[C:11]2[CH:35]=[C:36]([Br:1])[C:37]([CH3:39])=[CH:38][C:10]1=2)=[O:8])([CH3:4])[CH3:5]
Reactant: BrBr
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(C)ccc21
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(C)c(Br)cc21
Temperature: 50 °C
Yield: 100.3 %

Procedure:
Add bromine (0.016 mL, 0.303 mmol) dropwise to a solution of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-methyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.153 g, 0.288 mmol) in glacial acetic acid (2.8 mL) and heat at 50° C. under nitrogen for 18 h. Cool the mixture to room temperature, dilute with ethyl acetate (50 mL) and wash with saturated sodium bicarbonate (2×50 mL) and 10% aqueous sodium thiosulfate (50 mL), then dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure to provide the title compound as a white solid (0.176 g, >99%): ESI MS 609 (M+H).
Reaction SMILES: [N:1](=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12]([CH2:13][C@@H:14]([OH:22])[CH2:15][CH2:16]1)=[CH:11][CH2:10]3)[OH:2].C1(N=C=NC2CCCCC2)CCCCC1.[N+:38]([C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][CH:42]=1)([O-:40])=[O:39]>ClCCl>[N+:38]([C:41]1[CH:42]=[CH:43][C:44]([C:45]([O:22][C@H:14]2[CH2:15][CH2:16][C@@:17]3([CH3:18])[C:12](=[CH:11][CH2:10][C@@H:9]4[C@@H:19]3[CH2:20][CH2:21][C@@:4]3([CH3:5])[C@H:6]4[CH2:7][CH2:8][C:3]3=[N:1][OH:2])[CH2:13]2)=[O:46])=[CH:48][CH:49]=1)([O-:40])=[O:39]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NO)CC[C@@H]12
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@]12CC[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NO)CC[C@@H]12
Temperature: 25 °C
Reaction time: 48 h
Yield: 47 %

Procedure:
To the stirred solution of 17-oximino-5-androsten-3β-ol (9) (0.5 g, 1.6 mmol) and dicyclohexylcarbodiimide (DCC) (0.34 g, 1.6 mmol) in anhydrous dichloromethane (30.0 ml), p-nitrobenzoic acid (0.27 g, 1.6 mmol) was added. The reaction mixture was stirred for 48 hr at room temperature (20-25°) and completion of the reaction was monitored by TLC. The precipitated dicyclohexylurea (DCU) was filtered and the solvent removed under vacuum. The resulting residue was crystallized from ethyl acetate:petroleum ether (60:80) to give 17-oximino-5-androsten-3β-yl 4-nitrobenzoate (11) (0.34 g, 68.0%) mp 185-188° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[OH:33][CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]1>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:37]3[CH2:38][CH2:39][CH2:40][CH:35]([CH2:34][OH:33])[CH2:36]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Reactant: OCC1CCCNC1
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCCC(CO)C3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with 3-hydroxymethyl piperidine. A yellow solid 115 was obtained (0.0279 g, 60%). 1H-NMR (CDCl3, 400 MHz) δ 1.32–1.42 (m, 1H), 1.63–1.74 (m, 1H), 1.86–1.95 (m, 2H), 2.04–2.14 (m, 1H), 3.18–3.25 (m, 1H), 3.33–3.39 (m, 1H), 3.47–3.52 (m, 1H), 3.71 (dd, J=4.0 Hz, 11.0 Hz, 1H), 3.83 (s, 3H), 4.02–4.07 (m, 1H), 4.48–4.53 (m, 1H), 6.93 (d, J=6.6 Hz, 1H), 7.00–7.08 (m, 4H), 7.45–7.52 (m, 3H), 7.84 (s, 1H), 8.35 (d, J=6.5 Hz, 1H); MS (APCI) m/z 475 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.O>CN1C(=O)CCC1>[N+:15]([C:5]1[CH:4]=[CH:3][C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:17])=[O:16]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1ccc(Br)cc1Nc1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(N2CCNCC2)cc1Nc1ccccc1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
A solution of N-(5-bromo-2-nitrophenyl)benzenamine (250 mg, 0.85 mmol) and piperazine (366 mg, 4.26 mmol) in NMP (1 mL) was heated to 110° C. for 16 h. The solution whole cooled to room temperature to which was slowly added H2O (5 mL). The resulting yellow precipitate was filtered, washed with 10 mL of water, dried (high vacuum, 14 h) to furnish 2-nitro-N-phenyl-5-(piperazin-1-yl)aniline (165 mg, 0.55 mmol), 65% yield. 1H NMR (500 MHz, CDCl3) d (ppm) 9.89 (s, 1H), 8.15 (d, J=9.0 Hz, 1H), 7.45 (m, 2H), 7.34 (d, J=7.0 Hz, 2H), 7.25 (t, J=7.0 Hz, 1H), 6.43 (d, J=2.5 Hz, 1H), 6.35 (dd, 2.5 Hz, 9.75 Hz, 1H), 3.29 (m, 4H), 2.92 (m, 4H).+ESI HRMS (calcd for C16H19N4O2, M+1) 299.1508, found 391.150
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11]C(C=O)=[CH:7][CH:6]=1.[CH3:13][O:14][C:15]([O:18][CH3:19])([CH3:17])C>CO.C(Cl)Cl>[CH3:19][O:18][CH:15]([O:14][CH3:13])[C:17]1[CH:11]=[CH:12][C:5]([O:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=1
Reactant: COC(C)(C)OC
Reactant: O=Cc1ccc(OCCO)cc1
Solvent: CO
Solvent: ClCCl
Product: COC(OC)c1ccc(OCCO)cc1
Reaction time: 5 h
Yield: 69.9 %

Procedure:
To a solution of 4-hydroxyethoxybenzaldehyde (Bernstein et aL, J. Am. Chem. Soc., 73: 906-912 (1951); 8.5 g, 51.2 mmol), 2,2-dimethoxypropane (30 mL, 244 mmol) in a mixture of methanol (40 mL) and CH2Cl2 (100 mL) was added anhydrous Amberlyst 15 (Aldrich) (1.0 g). The mixture was stirred for 5 hrs, the catalyst was removed by filtration and the filtrate was concentrated to give the crude product contaminated with the starting aldehyde. This material was chromatographed on silica eluting with 1:1 ethyl acetate-hexane. The pure product fractions were pooled and concentrated. Drying under vacuum afforded 7.6 g (70%) of the title compound as a pale yellow, viscous liquid. 1H NMR: d 7.28 (d, J=9 Hz, 2 H), 6.92 (d, J=9 Hz, 2H), 5.31 (s, 1H), 4.86 (t, J=5.5 Hz, 1H), 3.98 (t, J=5 Hz, 2H), 3.71 (q, J=5 Hz, 2H), 3.20 (s, 3H). 13C NMR: d 158.60, 130.19, 127.74, 113.90, 102.46, 69.43, 59.52, 52.27.
Reaction SMILES: [BrH:1].[N:2]([CH2:5][C@H:6]1[O:15][CH:10](OC(=O)C)[C@H:9]([O:16][C:17](=[O:19])[CH3:18])[C@@H:8]([O:20][C:21](=[O:23])[CH3:22])[C@H:7]1[O:24][C:25](=[O:27])[CH3:26])=[N+:3]=[N-:4].C(OCC)(=O)C>C(O)(=O)C.C(Cl)Cl>[C:17]([O:16][C@@H:9]1[C@@H:8]([O:20][C:21](=[O:23])[CH3:22])[C@@H:7]([O:24][C:25](=[O:27])[CH3:26])[C@@H:6]([CH2:5][N:2]=[N+:3]=[N-:4])[O:15][C@@H:10]1[Br:1])(=[O:19])[CH3:18]
Reactant: Br
Reactant: CC(=O)OC1O[C@H](CN=[N+]=[N-])[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)O[C@H](CN=[N+]=[N-])[C@@H]1OC(C)=O
Temperature: 0 °C

Procedure:
Hydrogen bromide (2 mL of a 30% solution in acetic acid) was added to a solution of 6-azido-6-deoxy-1,2,3,4-tetra-O-acetyl-galactopyranose 36 (α:β, 0.8:1) (320 mg, 0.86 mmol) in anhydrous DCM (10 mL). The mixture was stirred under argon at 0° C. After 1¾h, t.1.c. (petrol:ethyl acetate, 2:1) indicated the formation of two products (Rf 0.5, 0.2) with some remaining starting material (Rf 0.3). The reaction mixture was quenched with ice/water (30 mL), diluted with DCM (40 mL), neutralized with sodium bicarbonate (2×40 mL), washed with brine (40 mL), dried (MgSO4), filtered and concentrated in vacuo to yield 350 mg of crude product, which was used without further purification, but a small portion was retained and purified by flash column chromatography (DCM:ether, 60:1) to afford 2,3,4-tri-O-acetyl-6-azido-6-deoxy-α-D-galactopyranosylbromide 37 as a white solid Rf 0.5 (60:1, DCM:ether); m.p. 81.5-82.2C (ether/petrol) [Lit. 82-83° C. (ether/petrol) Jezo, I. and Zemek, J., Chemicke Zvesti, 33, 533-541 (1979)]; [α]D25+70.8 (c, 1.7 in CHCl3) [Lit. [α]D22 +133.8 (c, 1 in CHCl3)], νmax (thin film) 2107 (sh, N3), 1750 (st, C═O)cm−1; δH (400 MHz, CDCl3) 2.03, 2.12, 2,18 (9H, 3 x s, 3 x CH3), 3.30-3.40 (2H, m, H-6, H-6′), 4.47 (1H, t, H-5), 5.04 (1H, dd, J1,2 4.0, J2,3 10.7, H-2), 5.43 (1H, dd, J3,4 3.2, H-3), 5.69 (1H, m, H-4), 6.69 (1H, d, H-1).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].COC1C=CC(C[N:31]2[N:35]=[N:34][C:33]([C:36](Cl)=[O:37])=[N:32]2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][C@H:3]([NH:2][C:36]([C:33]1[N:32]=[N:31][NH:35][N:34]=1)=[O:37])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:13][CH:12]=1)[CH3:9]
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: COc1ccc(Cn2nnc(C(=O)Cl)n2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1nn[nH]n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of intermediate 8-1 in DCM (8 ml) at room temperature is added 2-(4-methoxy-benzyl)-2H-tetrazole-5-carbonyl chloride and followed by TEA (Intermediate 22: 0.293 ml, 2.100 mmol). The reaction is stirred at room temperature for 5 min. The reaction is quenched by brine and is extracted with DCM. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography (15% to 40% EtOAc/Heptane). The obtained residue in TFA (5 ml, 64.9 mmol) is heated at 80° C. for 0.5 hours. The reaction is concentrated under reduced pressure to give (R)-4-(3′-chloro-biphenyl-4-yl)-3-[(2H-tetrazole-5-carbonyl)-amino]-butyric acid ethyl ester.