Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:23])[C:9]([CH2:21]Cl)=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:24]([CH3:26])[CH3:25].Cl.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:23])[C:9]([CH2:21][N:24]([CH3:26])[CH3:25])=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(C)c(CCl)c(C)c(NC(=O)C(C)(C)C)c21
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCc2c(C)c(CN(C)C)c(C)c(NC(=O)C(C)(C)C)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.1 %

Procedure:
N-(1-Acetyl-5-chloromethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (2.0 g) was dissolved in CHCl3 (40 ml) and (CH3)2NH.HCl (3.5 g) and K2CO3 (11.8 g) were added, which was followed by stirring at room temperature for 4 hr. CHCl3 (300 ml) was added, and the mixture was washed successively with 2N-hydrochloric acid, 2N aqueous NaOH and saturated brine, and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3 /MeOH=10/1-1/1) to give 700 mg of N-(1-acetyl-5-dimethylaminomethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1(O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](Oc2ccccc2)CN1C(=O)OC(C)(C)C
Yield: 86.5 %

Procedure:
To a stirred mixture of methyl (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarboxylate (4.69 g, 19.1 mmol), phenol (1.98 g, 21.0 mmol) and PPh3 (5.51 g, 21.0 mmol) in THF (80 ml) was added DIAD (4.13 ml, 21.0 mmol) at room temperature under an atmosphere of nitrogen. The mixture was stirred over night. After removal of the solvent, the resulting residue was chromatographed on silica gel [700 g, CHCl3/EtOAc (10/1)], to give methyl (2S,4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidinylcarboxylate (5.31 g, 86%) as a colorless oil. 1H-NMR (CDCl3) δ1.43 (br, 9H, one of isomers), 1.48 (br, 9H, one of isomers), 2.48 (m, 1H), 3.75 (br, 3H), 4.42-4.96 (m, 2H), 6.88-7.35 (m, 5H).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@@H:10]([C:22]([N:24]1[CH2:43][CH2:42][CH2:41][C@H:25]1[C:26]([NH:28][C@H:29]([C:34]([NH:36][CH2:37][C:38]([NH2:40])=[O:39])=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:27])=[O:23])[NH:11]C(OCC1C=CC=CC=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.C(Cl)(Cl)(Cl)Cl.CO>[Pd].C(N(CC)CC)C>[CH2:1]([S:8][CH2:9][C@@H:10]([C:22]([N:24]1[CH2:43][CH2:42][CH2:41][C@H:25]1[C:26]([NH:28][C@H:29]([C:34]([NH:36][CH2:37][C:38]([NH2:40])=[O:39])=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:27])=[O:23])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CSCc1ccccc1)NC(=O)OCc1ccccc1)C(=O)NCC(N)=O
Agent: [Pd]
Agent: N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CSCc1ccccc1)C(=O)NCC(N)=O
Reaction time: 0.17 h

Procedure:
S-Benzyl-N-benzyloxycarbonyl-L-cysteinyl-L-prolyl-L-leucyl-glycinamide (300 mg.) was dissolved in 35 ml. of anhydrous liquid ammonia and hydrogenated in the presence of freshly prepared palladium black (ca 0.1g.) and triethylamine (0.28 ml.) at the boiling point of the solvent. The reaction was followed by thin layer chromatography (solvent system CCl4 /CH3OH/CH3COOH8:1:1) which showed incomplete reaction (50-60%) after 6 hours. Evaporation of ammonia under nitrogen was followed by addition of methanol (10 ml.) and stirring for 10 min. The catalyst was then removed by filtration and washed with methanol (10 ml.). The combined filtrate and washings were passed through a column (1.2 × 10 cm) of Dowex 50 × 8 (H+ form) which was washed with methanol. The desired material was then eluted with 2N ammonium hydroxide-methanol (1:1) and the eluate evaporated in vacuo. Crystallization from water gave 95.2 mg. (42.3%); m.p. 130°-134°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]([NH:7][C:8]1[CH:9]=[C:10]([O:30][CH3:31])[C:11]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[C:13]2[CH3:18])[CH3:6].[CH3:32][C:33]([CH3:35])=O.[C:36]([OH:43])(=[O:42])[CH2:37][CH2:38][C:39]([OH:41])=[O:40]>CCO.[Pt]=O>[C:36]([OH:43])(=[O:42])[CH2:37][CH2:38][C:39]([OH:41])=[O:40].[CH:33]([NH:1][CH2:2][CH2:3][CH2:4][CH:5]([NH:7][C:8]1[CH:9]=[C:10]([O:30][CH3:31])[C:11]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=2)=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[C:13]2[CH3:18])[CH3:6])([CH3:35])[CH3:32]
Reactant: COc1cc(NC(C)CCCN)c2nccc(C)c2c1Oc1cccc(C(F)(F)F)c1
Reactant: CC(C)=O
Agent: O=[Pt]
Agent: O=C(O)CCC(=O)O
Solvent: CCO
Product: COc1cc(NC(C)CCCNC(C)C)c2nccc(C)c2c1Oc1cccc(C(F)(F)F)c1
Reaction time: 5 h

Procedure:
A solution of 8-(4-amino-1-methylbutylamino)-6-methoxy-4-methyl-5-(3-trifluoromethylphenoxy)quinoline as the free base (4.7 g, 10.8 mmol) prepared as in Example 1 in EtOH (60 mL) containing acetone (1.8 mL), prereduced platinum oxide (0.6 g) and molecular sieves (3A) was reduced on a Parr apparatus at 45 psig for 5 hours. An additional quantity of acetone (0.9 mL) was added and the reduction was continued an additional 18 hours. The catalyst and molecular sieves were filtered (celite) and the solvent was removed in vacuo. The residue was dissolved in acetonitrile (50 mL) and succinic acid (1.35 g, 1 mol equivalent) was added with stirring. The solid was filtered after cooling in the refrigerator overnight to yield the title compound 5, 5.8 g (91%), mp 143°-146°. Recrystallization from acetonitrile (75 mL) yielded pure title compound, 5.2 g, (81%), mp 145°-147.5°.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH2:10])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:12][CH2:13][CH2:14][CH3:15]>>[C:1]([C:5]1[O:9][N:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:7](=[NH:10])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: CCCCBr
Product: CCCCn1oc(C(C)(C)C)cc1=N
Temperature: 85 °C
Reaction time: 70 h
Yield: 100 %

Procedure:
A mixture of 5-tert-butylisoxazol-3-amine (3.0 g, 21 mmol) and 1-bromobutane (3.5 mL, 32 mmol) was warmed to 85° C. and was allowed to stir for 70 h. The mixture was cooled to ambient temperature and was purified by column chromatography (silica gel, 60% hexanes/EtOAc) to give the title compound (4.2 g, 21 mmol, 99% yield). MS (DCI/NH3) m/z 197 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:19]([CH:20]=[O:21])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:22])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.C(Cl)Cl.C(N(CC)CC)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>O>[C:33]([O:1][C:2]1[C:19]([CH:20]=[O:21])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:22])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1)(=[O:35])[CH3:34]
Reactant: C[C@]12CC[C@@H]3c4cc(C=O)c(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc2c(cc1C=O)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of 3-hydroxyestra-1,3,5(10)-trien-17-one-2-carboxaldehyde (60, 1.92 g, 6.43 mmol) of CH2Cl2 (30 mL) was added triethylamine (2.3 mL, 16 mmol) and acetic anhydride (0.94 mL, 9.6 mmol) at room temperature. The reaction mixture was stirred for 16 h, H2O was added, and the mixture was extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and then dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:EtOAc (2:1→3:2, v/v) to afford 2.08 g of 61 (95% yield) mp: 179-181° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Br:49][C:50]1[CH:61]=[CH:60][C:53]2[NH:54][C:55]([CH:57]([NH2:59])[CH3:58])=[N:56][C:52]=2[CH:51]=1.BrBr>O1CCCC1.C(Cl)Cl.C(O)C>[Br:49][C:50]1[CH:61]=[CH:60][C:53]2[NH:54][C:55]([CH:57]([NH:59][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH3:58])=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: CC(N)c1nc2cc(Br)ccc2[nH]1
Agent: BrBr
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC(C)c2nc3cc(Br)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 49 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and 1-(5-bromo-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 49%; Rf value: 0.52 (silica gel; methylene chloride/ethanol=9:1); C22H23BrN4O2 (455.35); mass spectrum: (M+H)+=455/457 (bromine isotope).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][NH2:9])=[CH:4][CH:3]=1.C1([O:18][C:19](=O)[NH:20][C:21]2[C:30]3[CH2:29][CH:28]([OH:31])[CH2:27][CH2:26][C:25]=3[CH:24]=[CH:23][CH:22]=2)C=CC=CC=1.O>CS(C)=O>[F:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][NH:9][C:19]([NH:20][C:21]2[C:30]3[CH2:29][CH:28]([OH:31])[CH2:27][CH2:26][C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:4][CH:3]=1
Reactant: NCCOc1ccc(F)cc1
Reactant: O=C(Nc1cccc2c1CC(O)CC2)Oc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: O=C(NCCOc1ccc(F)cc1)Nc1cccc2c1CC(O)CC2
Reaction time: 0.67 h
Yield: 89.2 %

Procedure:
To 2-(4-Fluorophenoxy)ethylamine (27.4 mg, 0.18 mmol) was added a solution of (7-Hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-carbamic acid phenyl ester (50.0 mg, 0.18 mmol) in 1.5 mL dimethylsulfoxide. The mixture was stirred for 40 minutes, and then poured into water. The resulting solid was filtered and dried under reduced pressure (54.2 mg, 89.2% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[OH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][C:32]2[N:37]=[C:36]3[CH2:38][O:39][C:40](=O)[C:35]3=[CH:34][CH:33]=2)[CH2:25][CH2:24]1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:40]1[C:35]2[C:36](=[N:37][C:32]([CH2:31][CH2:30][CH2:29][N:26]3[CH2:27][CH2:28][CH:23]([OH:22])[CH2:24][CH2:25]3)=[CH:33][CH:34]=2)[CH2:38][O:39]1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: O=C1OCc2nc(CCCN3CCC(O)CC3)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2nc(CCCN3CCC(O)CC3)ccc21
Reaction time: 0.33 h
Yield: 3.4 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (163 mg, 1.09 mmol.) in THF (2 mL) is placed under an argon atmosphere cooled in an ice bath. A solution of lithium bis(trimethylsilyl)amide (3.6 mL of a 1M in THF, 3.6 mmol, 5 eq.) is added slowly at 0° C. and the resulting solution is stirred for 20 min. The ice-bath is then removed and a solution of 2-[3-(4-Hydroxy-piperidin-1-yl)-propyl]-7H-furo[3,4-b]pyridin-5-one (200 mg, 0.72 mmol) in THF (1 mL) is added dropwise to the reaction mixture. The lactone does not dissolve well, so rest of the lactone is added as a solid. The resulting solution is stirred for 3 h and then poured into 10% aqueous HCl solution (50 mL) and stirred for 48 h at room temperature. Extraction with EtOAc followed by chromatography (silica gel, MeOH/Chloroform) provides the title compound (10 mg) as a solid.
Reaction SMILES: [CH3:1][CH:2]([NH:28][CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[CH:3]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)[CH2:4][C:5]1[O:6][C:7]([C:10](=[O:18])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=1.C([O:43][CH:44]([C:60]([O-])=[O:61])[CH:45]([C:54]([O:56][CH:57]([CH3:59])[CH3:58])=[O:55])[CH2:46][CH2:47][C:48]([O:50][CH:51]([CH3:53])[CH3:52])=[O:49])(=O)C.CC(C)[O-].[Na+].O>C(O)(C)C>[OH:43][CH:44]([C:60](=[O:61])[N:28]([CH:2]([CH3:1])[CH:3]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)[CH2:4][C:5]1[O:6][C:7]([C:10](=[O:18])[NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[CH:45]([C:54]([O:56][CH:57]([CH3:59])[CH3:58])=[O:55])[CH2:46][CH2:47][C:48]([O:50][CH:51]([CH3:53])[CH3:52])=[O:49]
Reactant: CC(=O)OC(C(=O)[O-])C(CCC(=O)OC(C)C)C(=O)OC(C)C
Reactant: CC(NCc1ccc2ccccc2c1)C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)OC(=O)CCC(C(=O)OC(C)C)C(O)C(=O)N(Cc1ccc2ccccc2c1)C(C)C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
99 mg of isopropyl 5-acetoxy-4-isopropoxycarbonyl-5-[N-[(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl]-N-(2-naphthylmethyl)carbamoyl]pentanoate obtained by subjecting N-{(1RS,2RS)-1-methyl-2-(4-nitrophenyl)3-{5-(phenylcarbamoyl)-2-furyl}propyl]-2-naphthylmethylamine obtained in Example 23(1) and 2,4-diisopropyl 1-acetoxy-1,2,4-butanetricarboxylate obtained in Reference Example 5 to a condensation reaction in accordance with the method of Example 24(1), was dissolved in 3 ml of isopropanol, and 9.8 mg of sodium isopropoxide was added thereto, followed by stirring at room temperature for one hour. The reaction solution was poured into water and extracted with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 43 mg (yield: 45%) of the above-identified compound.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:16]([OH:26])[C@@H:15]([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][C@H:10]1[S:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.[Br:45][CH2:46][C:47](Br)=[O:48]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:17]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C@@:16]([C:47](=[O:48])[CH2:46][Br:45])([OH:26])[C@@H:15]([CH2:27][O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:14][C@H:10]1[S:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCS[C@@H]1O[C@H](COCc2ccccc2)[C@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=C(Br)CBr
Agent: CN(C)c1ccncc1
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CCS[C@@H]1O[C@H](COCc2ccccc2)[C@@](O)(C(=O)CBr)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Yield: 305.9 %

Procedure:
A mixture of ethyl 2,3,6-tri-O-benzyl-1-thio-β-D-galactopyranoside (4.14 g, 8.38 mmol), sym. collidine (3.65 g, 30.16 mmol), and 4-dimethylaminopyridine in dry CH2Cl2 (60 ml) was stirred at 0° C. and bromoacetyl bromide (2.53, 2.57 mmol) in CH2Cl2 added dropwise in 15 minutes. The reaction mixture was diluted with CH2Cl2 (100 ml) and washed with 5% HCl solution (3×30 ml) and saturated NaHCO3 solution (30 ml). The solution was dried over MgSO4 and evaporated. The residue was purified by chromatography using hexane/EtOAc 2:1 as the mobile phase to give ethyl 2,3,6-tri-O-benzyl-4-bromoacetyl-1-thio-β-D-galacto-pyranoside (4.84 g, 94%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH2:24]([O:23][C:21](=[O:22])[C:20]1[CH:26]=[CH:27][C:17]([O:15][CH2:14][CH:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]2)=[CH:18][CH:19]=1)[CH3:25]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)c1ccc(OCC2CCCN(C(=O)OC(C)(C)C)C2)cc1

Procedure:
N-t-Butyloxycarbonyl-3-piperidinylmethanol was etherified with ethyl 4-hydroxybenzoate using the DEAD/triphenylphosphine procedure given in Step 1 of Example 25. The crude product was purified by pressurized silica gel column chromatography using a gradient elution of 10-25% EtOAc-hexanes. 4-(N-t-Butyloxycarbonyl-3-piperidinylmethoxy)benzoic acid ethyl ester was obtained as an oil (58% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2[CH:21]=1.[CH3:22][O:23][CH2:24][CH2:25][NH:26][CH2:27][CH3:28]>>[CH2:27]([N:26]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2[CH:21]=1)[CH2:25][CH2:24][O:23][CH3:22])[CH3:28]
Reactant: CCNCCOC
Reactant: Fc1ccc(-c2csc3cc(OCCCBr)ccc23)cc1
Product: CCN(CCCOc1ccc2c(-c3ccc(F)cc3)csc2c1)CCOC

Procedure:
In analogy to example 3.1, 6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and N-(2-methoxyethyl)ethylamine were converted to yield Ethyl-{3-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-(2-methoxy-ethyl)-amine as colorless oil, MS: 388 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[O:11][CH2:12][CH:13]([OH:18])[CH2:14][N:15]=[N+]=[N-].O>O1CCCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[O:11][CH2:12][CH:13]([OH:18])[CH2:14][NH2:15]
Reactant: [N-]=[N+]=NCC(O)COc1cccc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCC(O)COc1cccc(Cl)c1
Reaction time: 1.5 h
Yield: 43.4 %

Procedure:
0.19 g of lithium aluminum hydride was gradually added, whilst ice-cooling and under a stream of nitrogen gas, to a solution of 0.39 g of 3-(3-chlorophenoxy)-2-hydroxypropylazide (prepared as described in Preparation 12) in 5 ml of anhydrous tetrahydrofuran. The mixture was then stirred for a further 1.5 hours under the same conditions, after which excess lithium aluminum hydride was decomposed by adding water. Insolubles were then removed by filtration from the reaction mixture, using a Celite (trade name) filter aid, and the filtrate was dried over anhydrous sodium sulfate. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, to give 0.15 g of the title compound as white crystals, melting at 55° C. to 58° C.
Reaction SMILES: [CH3:1][C@@:2]12[C@@:10]([OH:15])([C:11]([CH2:13][OH:14])=[O:12])[C@H:9]([OH:16])[CH2:8][C@H:7]1[C@@H:6]1[CH2:17][CH2:18][C:19]3[C@@:25]([CH3:26])([C@@:5]1([F:27])[C@@H:4]([OH:28])[CH2:3]2)[CH:24]=[CH:23][C:21](=[O:22])[CH:20]=3>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH3:26][C@@:25]12[C@@:5]3([F:27])[C@@H:4]([OH:28])[CH2:3][C@:2]4([CH3:1])[C@@:10]([OH:15])([C:11]([CH2:13][OH:14])=[O:12])[C@H:9]([OH:16])[CH2:8][C@H:7]4[C@@H:6]3[CH2:17][CH2:18][C:19]1=[CH:20][C:21](=[O:22])[CH2:23][CH2:24]2
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](O)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](O)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Reaction time: 0.75 h

Procedure:
A suspension of 3.0 g of tris(triphenylphosphine)rhodium chloride in 1000 ml of degassed toluene was hydrogenated for 45 min at room temperature and atmospheric pressure. A solution of 5.0 g of triamcinolone in 500 ml of absolute ethanol was added and the hydrogenation was continued for 48 h. The reaction mixture was evaporated to dryness and suspended in 50 ml of methylene chloride. After filtration the solid phase was repeatedly washed with small portions of methylene chloride and yielded after drying 4.4 g of 9α-fluoro-11β,16α,17α,21-tetrahydroxypregn-4-ene-3,20-dione. Molecular weight 396 (calc. 396.5).
Reaction SMILES: [OH-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][CH:7]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20])[C:8]([O:10]C)=[O:9].CO>O1CCCC1>[Cl:3][CH2:4][CH2:5][CH2:6][CH:7]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[C:19]([F:22])([F:20])[F:21])[C:8]([OH:10])=[O:9]
Reactant: COC(=O)C(CCCCl)c1ccc(Cl)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(CCCCl)c1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
A 5 N sodium hydroxide aqueous solution (13 mL) was added to a mixed solution of methyl 5-chloro-2-(4-chloro-2-trifluoromethylphenyl)pentanoate (5.3 g) in tetrahydrofuran (15 mL)-methanol (15 mL), and the mixture was stirred at room temperature for two hours and 10 minutes. After adding ice water to the reaction solution, the organic solvent was evaporated from the reaction solution under reduced pressure. The resulting aqueous layer was washed with heptane. The aqueous layer was made acidic with 5 N hydrochloric acid under ice-cooling, followed by extraction with ethyl acetate twice. The combined ethyl acetate layers were washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 4.75 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH2:13][CH2:14][NH2:15].[OH-].[Na+]>S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[CH3:1][C:2]1[N:6]([CH2:13][CH2:14][NH2:15])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: NCCCl
Reactant: Cc1nc2ccccc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CC#N
Product: Cc1nc2ccccc2n1CCN
Temperature: 25 °C
Yield: 54.5 %

Procedure:
A mixture of 2-methylbenzimidazole (4.93 g, 37.3 mmol), 2-chloroethylamine hydrochloride (4.67 g, 40.3 mmol), tetrabutylammonium sulfate (0.51 g, 1.5 mmol), sodium hydroxide (5.37 g, 134.2 mmol) and acetonitrile (80 mL) are stirred at reflux for 48 hrs. The resulting mixture is cooled to room temperature, filtered and concentrated in vacuo. The residue is purified by flash column chromatography (silica gel) using 1-3% MeOH—CH2Cl2 saturated with ammonium hydroxide as eluent to afford the title compound (3.56 g, MH+=176).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[CH2:17]([N:1]([C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[O:9])[CH2:4][CH2:3]1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(OCc1ccccc1)[C@H]1CC[C@@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 102.8 %

Procedure:
cis-4-Aminocyclohexanecarboxylic acid (10.0 g, 67.48 mmol) was dissolved in 140 mL of dry acetonitrile. Solid potassium carbonate (28.0 g, 202.6 mmol) was added. The suspension was heated to about 80° C. To this solution, was added benzyl bromide (28.09 mL, 236.2 mmol) in 70 mL of acetonitrile, dropwise via addition funnel. The reaction mixture was stirred at about 80° C. under nitrogen for about 2 hours then about 40° C. overnight. The reaction was cooled to room temperature and the suspension was filtered. The filtrate was concentrated under reduced pressure. The compound was purified using column chromatography on silica gel (100% hexanes to remove excess benzyl bromide, then 10% ethyl acetate in hexanes). The product was isolated as a white solid (14.35 g, 51% yield): ES-MS (m/z) 414.