Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:13])=[C:8]([C:10]([OH:12])=O)[CH:9]=1)=[O:4].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH3:47][O:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][C:58]([NH2:61])=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:47][O:48][C:49]1[CH:50]=[CH:51][C:52]([C:55]2[CH:60]=[CH:59][C:58]([NH:61][C:10]([C:8]3[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[O:6][C:7]=3[CH3:13])=[O:12])=[CH:57][CH:56]=2)=[CH:53][CH:54]=1
Reactant: COC(=O)c1cc(C(=O)O)c(C)o1
Reactant: COc1ccc(-c2ccc(N)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(NC(=O)c3cc(C(=O)O)oc3C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
To a solution of 5-methyl-furan-2,4-dicarboxylic acid-2-methyl ester (23) (100 mg) in N,N-dimethylformamide (3.0 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (228 mg), diisopropylethylamine (0.56 mL) and 4′-methoxy-biphenyl-4-ylamine (120 mg). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and washed successively with water (2×20 mL), 0.1 M hydrochloric acid (20 mL), water (20 mL), saturated sodium hydrogen carbonate (10 mL) and brine (10 mL). This solution was dried and concentrated in vacuo. The residue (170 mg) was dissolved in dichloromethane (5 mL), treated with triethylamine (0.3 mL) 0.0 and a scavenger resin PS-TsCl (0.6 g) and the mixture shaken for 3 hours at room temperature. The reaction mixture was filtered and concentrated in-vacuo. The residue was dissolved in methanol/tetrahydrofuran (1:3 by volume) (20 mL), treated with 1.0 M aqueous lithium hydroxide solution (2.0 mL) and allowed to stir at room temperature for 4 hours. The pH of the reaction mixture was adjusted to between pH 4 and pH 5 by careful addition of 1.0 M hydrochloric acid (1.0 mL) and partly concentrated in vacuo. The residue was then partitioned between ethyl acetate (2×25 mL) and water (25 mL) and the combined organic extracts were washed with brine (35 mL), dried (Na2SO4), and concentrated in vacuo afforded compound 24 as beige solid (58 mg). LC/MS System D: Rt=7.23 mins, m/z (ES+)=351 (MH+ for C20H17NO5).
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[C@@H:3]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:18]([O-:20])=[O:19])[C:9]1=[O:21])[C:4]([O:6]C)=[O:5].[OH-].[Li+].C(O)(C)(C)C.O.Cl>>[CH3:1][CH:2]([CH3:22])[C@@H:3]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:18]([O-:20])=[O:19])[C:9]1=[O:21])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)[C@@H](C(C)C)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)[C@H](C(=O)O)n1ccc2c([N+](=O)[O-])cccc2c1=O

Procedure:
(R)-Methyl 3-methyl-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)butanoate (0.6 g, 0.002 mol) was stirred with lithium hydroxide (0.09 g, 0.004 mol) in tert-butyl alcohol (4 mL, 0.04 mol) and water (2 mL, 0.1 mol) at 0° C. for 3 hours. 1 N HCl was added until pH<7 and then reaction mixture was extracted with CH2Cl2 (40 mL×3). The organic layers were dried over MgSO4, filtered, purified via flash chromatography (12 g of silica gel, 0-50% EtOAc/Hexane) and the product was recovered as a yellow oil. MS m/z 291.0 (M+H)+.
Reaction SMILES: COC1C=CC(C[NH:10][C:11]2[N:16]=[C:15]([C:17]3[N:22]=[CH:21][C:20]4[CH:23]=[N:24][N:25]([C:26]5[N:31]=[C:30]([N:32]6[CH2:38][CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]6)[CH:29]=[CH:28][CH:27]=5)[C:19]=4[CH:18]=3)[CH:14]=[N:13][CH:12]=2)=CC=1.Cl.OS(C(F)(F)F)(=O)=O>ClCCl.O1CCOCC1>[N:32]1([C:30]2[N:31]=[C:26]([N:25]3[C:19]4[CH:18]=[C:17]([C:15]5[N:16]=[C:11]([NH2:10])[CH:12]=[N:13][CH:14]=5)[N:22]=[CH:21][C:20]=4[CH:23]=[N:24]3)[CH:27]=[CH:28][CH:29]=2)[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1
Reactant: COc1ccc(CNc2cncc(-c3cc4c(cn3)cnn4-c3cccc(N4CCCN(C(=O)OC(C)(C)C)CC4)n3)n2)cc1
Agent: Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCNCC3)n2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.1 %

Procedure:
To a mixture of tert-butyl 4-[6-[6-[6-[(4-methoxyphenyl)methylamino]pyrazin-2-yl]pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-1,4-diazepane-1-carboxylate (0.4789 mmol; 291 mg) in Dichloromethane (5 mL) was added Hydrogen Chloride, 4.0 M in 1,4-Dioxane (5 mL), and TRIFLIC ACID (4.789 mmol; 733.3 mg; 0.4293 mL). The reaction mixture was stirred at room temperature for 3 days. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 247 as an off-white solid (50.3 mg, 27%). 1H NMR (400 MHz, DMSO) δ 9.45-9.41 (s, 1H), 9.26-9.22 (s, 1H), 8.76-8.73 (s, 1H), 8.64-8.58 (s, 1H), 7.99-7.96 (s, 1H), 7.73-7.67 (t, J=8.1 Hz, 1H), 7.16-7.12 (d, J=7.7 Hz, 1H), 6.63-6.58 (d, J=8.5 Hz, 1H), 6.33-6.25 (s, 2H), 3.89-3.82 (dd, J=11.0, 5.2 Hz, 4H), 3.03-2.98 (m, 2H), 2.73-2.66 (m, 2H), 1.91-1.84 (dd, J=11.5, 5.8 Hz, 2H); MS (ESI) m/z: 388.2 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](CC(C2C=CC=CC=2)=O)=[CH:4][CH:3]=1.[BH4-].[Na+].C([O:21][CH2:22][CH3:23])C>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:22]([OH:21])[CH3:23])=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: O=C(Cc1ccc(F)cc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
1-(4-Fluorophenyl)ethanol was prepared by mixing 10 g (72 mmol) of 4-fluorophenylacetophenone and 2.74 g (72 mmol) of sodium borohydride in 100 mL of ethanol. After one hour the solvent was removied under vacuum and the residue was taken up in diethyl ether. The ether solution was dried over anhydrous magnesium sulfate and evaporated to yield the crude product which was used without further purification.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[OH:27][C:28]1[C:29]([CH:38]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]([CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[C:39]2=[O:53])=[CH:30][C:31]2[CH2:32][CH2:33][CH2:34][CH2:35][C:36]=2[CH:37]=1>>[OH:16][CH2:5][C:38]1([C:29]2[C:28]([OH:27])=[CH:37][C:36]3[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=3[CH:30]=2)[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]([CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[C:39]1=[O:53]
Reactant: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)CCCC3)c2ccccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)CCCC3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with ethyl [3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained: MS (ES+) m/z 378 (M−17), 418 (M+23).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([OH:19])=O)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[N:22][CH:21]=1.CC#N>O=S(Cl)Cl.CN1C(=O)CCC1>[N:20]1[CH:25]=[CH:24][C:23]([NH:26][C:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)=[O:19])=[N:22][CH:21]=1
Reactant: O=C(O)c1cn(Cc2ccccc2)c2ccccc12
Reactant: Nc1ccncn1
Solvent: O=S(Cl)Cl
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: O=C(Nc1ccncn1)c1cn(Cc2ccccc2)c2ccccc12
Reaction time: 0.5 h

Procedure:
1-Benzylindole-3-carboxylic acid (25.9 mg, 96 mmol) was dissolved in SOCl2 (1 mL) and the mixture was stirred for 30 min before the volatiles were removed in vacuo. The residue was dissolved in MeCN (200 μL) and added to a solution of pyrimidin-4-yl-amine (10 mg, 105 mmol) in NMP (200 μL). The reaction mixture was stirred 16 hours at room temperature before the MeCN was removed in vacuo. The residue was purified using HPLC method D to give title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].CCN(C(C)C)C(C)C.[Cl:29][C:30]1[CH:31]=[C:32]([C@@H:36]([C@@H:45]2[CH2:50][CH2:49][CH2:48][NH:47][CH2:46]2)[O:37][CH2:38][CH2:39][NH:40][C:41](=[O:44])[O:42][CH3:43])[CH:33]=[CH:34][CH:35]=1.N1([C:56](N2C=CN=C2)=[S:57])C=CN=C1>C(OCC)(=O)C>[Cl:29][C:30]1[CH:31]=[C:32]([C@@H:36]([C@@H:45]2[CH2:50][CH2:49][CH2:48][N:47]([C:56](=[S:57])[NH:1][C@H:2]([CH2:3][N:4]([CH3:12])[C:5]([O:6][C:7]([CH3:9])([CH3:10])[CH3:8])=[O:11])[CH2:13][CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[CH2:46]2)[O:37][CH2:38][CH2:39][NH:40][C:41](=[O:44])[O:42][CH3:43])[CH:33]=[CH:34][CH:35]=1
Reactant: CN(C[C@@H](N)CC1CCCCC1)C(=O)OC(C)(C)C
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCNC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=S)N[C@@H](CC2CCCCC2)CN(C)C(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
To a solution of (S)-tert-butyl 2-amino-3-cyclohexylpropyl(methyl)carbamate (326 mg, 1 mmol), DIEA (258 mg, 2 mmol) and methyl 2-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)ethylcarbamate (270 mg, 1 mmol) in ethyl acetate (6 mL) was added dropwise a solution of di-imidazol-1-yl-methanethione (194 mg, 1 mmol) in ethyl acetate (4 mL) at 0-5° C. After addition, the mixture was allowed to warm to room temperature for 3-4 h, the mixture was washed with water (20 mL) and brine (20 ml), the organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the residue, which was purified by preparative TLC to afford methyl 2-((R)-(3-chlorophenyl)((R)-1-((S)-1-cyclohexyl-3-(N-methyl-N-(tert-butoxycarbonyl)amino)propan-2-ylcarbamothioyl)piperidin-3-yl)methoxy)ethylcarbamate. MS ESI +ve m/z 638 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1.[Li]CCCC.[F:15][C:16]([F:23])([CH3:22])[C:17](OCC)=[O:18]>CCOCC>[Cl:9][C:4]1[CH:3]=[C:2]([C:17](=[O:18])[C:16]([F:23])([F:15])[CH3:22])[CH:7]=[CH:6][C:5]=1[Cl:8]
Reactant: CCOC(=O)C(C)(F)F
Reactant: Clc1ccc(Br)cc1Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(F)(F)C(=O)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a magnetically stirred solution of 4-bromo-1,2-dichlorobenzene (5.64 g, 24.98 mmol) in dry Et2O (109 mL) was added n-BuLi (10.86 mL, 24.98 mmol) via an addition funnel under a nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 30 min, A solution of ethyl 2,2-difluoropropanoate (3.0 g, 21.7 mmol) in Et2O (10 mL) was added dropwise over 15 min and allowed to stir for 1 h. The reaction was then carefully quenched with 1 N HCl (4 mL) and allowed to warm to 23° C. The solution was dilute with Et2O and washed with water. The combined organic layers were dried over Na2SO4, concentrated under reduced pressure and the resulting material was purified via flash column chromatography using 100% hexanes to 5% acetone/95% hexanes as eluent. The relevant fractions were concentrated under reduced pressure to afford the title compound as a colorless oil (3.89 g, 71%): 1H NMR (400 MHz, CDCl3) δ 8.21-8.18 (m, 1H), 7.99-7.93 (m, 1H), 7.59 (dd, J=8.4, 4.2 Hz, 1H), 1.89 (t, J=19.6 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −92.08-−93.21 (m); EISMS m/z 240 ([M−H]+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]([C:12]2[C:17]([F:18])=[CH:16][C:15]([N:19]3[CH2:23][C@H:22]([CH2:24][N:25]([C:33]4[CH:37]=[CH:36][O:35][N:34]=4)C(OC(C)(C)C)=O)[O:21][C:20]3=[O:38])=[CH:14][C:13]=2[F:39])=[CH:8][CH2:7]1)=[O:5].FC(F)(F)C(O)=O>ClCCl.O>[OH:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]([C:12]2[C:13]([F:39])=[CH:14][C:15]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:33]4[CH:37]=[CH:36][O:35][N:34]=4)[O:21][C:20]3=[O:38])=[CH:16][C:17]=2[F:18])=[CH:8][CH2:7]1)=[O:5]
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CN(c2cc(F)c(C3=CCN(C(=O)CCO)CC3)c(F)c2)C(=O)O1)c1ccon1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(CCO)N1CC=C(c2c(F)cc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)CC1
Reaction time: 0.17 h
Yield: 70.9 %

Procedure:
3-(4-(1-(3-Hydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-5(R)-(N-(t-butoxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one (176 mg, 0.32 mM), was dissolved in dichloromethane (1 ml) and treated with trifluoroacetic acid (1 ml) at ambient temperature. After stirring for 10 minutes, the mixture was diluted with water (15 ml) and dichloromethane (15 ml), the organic layer separated, washed with water (2×15 ml), and dried (magnesium sulfate). Solvent was removed, and the residue triturated with diethyl ether to give the desired product (102 mg). NMR (DMSO-d6) δ: 2.20 (m, 1H); 2.28 (m, 1H); 2.48 (m overlapped by DMSO, 2H); 3.42 (br m overlapped by H2O, ˜4H); 3.55 (br m, ˜3H); 3.83 (t, 1H); 4.01 (m, 1H); 4.06 (m, 2H); 4.81 (m, 1H); 5.78 (s, 1H); 5.92 (s, 1H); 6.47 (br s, 1H); 7.26 (d, 2H); 8.31 (s, 1H). MS (ESP): 449 (MH+) for C21H22F2N4O5
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:7][C:6]=1[CH3:18])=O.[NH2:19][C:20]([NH2:22])=[S:21]>CCO>[CH3:17][O:16][CH2:15][CH2:14][CH2:13][O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]2[N:19]=[C:20]([NH2:22])[S:21][CH:2]=2)=[C:6]([CH3:18])[CH:7]=1
Reactant: COCCCOc1cc(C)c(C(=O)CBr)c(C)c1
Reactant: NC(N)=S
Solvent: CCO
Product: COCCCOc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 68.8 %

Procedure:
A reaction mixture containing 2-bromo-1-(4-(3-methoxypropoxy)-2,6-dimethylphenyl)ethanone (500.0 mg, 1.6 mmol, 1.0 equiv) and thiourea (126.8 mg, 1.6 mmol, 1.0 equiv) in EtOH (10.0 mL) was heated at reflux for 16 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30% EtOAc in hexanes as eluant) to provide 4-(4-(3-methoxypropoxy)-2,6-dimethylphenyl)thiazol-2-amine (328.9 mg, 1.1 mmol) as yellow solids in 71% yield: 1H NMR (CDCl3, 500 MHz) δ 9.35 (brs, 1H), 9.00 (brs, 1H), 6.64 (s, 2H), 6.22 (s, 1H), 4.04-4.05 (m, 2H), 3.54-3.56 (m, 2H), 3.37 (s, 3H), 2.19 (s, 6H), 2.03-2.06 (m, 2H); ESI-MS m/z 293.8 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:17])[CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH2:13][NH:12][C:11]1=[S:16])[CH3:4].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][C:28]([CH:30]=O)=[C:27]([C:32](OCC)=[O:33])[CH:26]=2)=[CH:21][CH:20]=1.C(OCC)(=O)C>C1COCC1.CCCCCC>[CH2:3]([O:5][C:6](=[O:17])[CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]2[N:12]([C:32](=[O:33])[C:27]3[CH:26]=[C:25]([C:22]4[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=4)[O:29][C:28]=3[CH:30]=2)[C:11]1=[S:16])[CH3:4]
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)oc1C=O
Reactant: CCOC(=O)CCCN1C(=O)CNC1=S
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CCCN1C(=O)c2cc3oc(-c4ccc(Cl)cc4)cc3c(=O)n2C1=S
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
As further depicted in Scheme 40 below, NaH (88 mg of 60% oil dispersion, 53 mg, 2.2 mmol) is added in four portions over 10 minutes under a nitrogen atmosphere to a solution of 4-(5-oxo-2-thioxo-imidazolidin-1-yl)-butyric acid ethyl ester (230 mg, 1 mmol) and ethyl 5-(4-chlorophenyl)-2-formyl-3-furoate (293 mg, 1.05 mmol obtained from Maybridge Ltd.; Cat. No. SP 00067) in anhydrous THF (20 ml). After the ensuing mildly exothermic reaction is completed, the reaction mixture is refluxed for 8-10 hours while monitoring the reaction progress by TLC analysis using an ethyl acetate:hexane mixture as eluent. Thereafter the solvent is removed under reduced pressure, and 6 M HCl (50 ml) is added to the residue while cooling the reaction vessel. Ether (50 ml) is added and the resulting heterogeneous mixture is stirred vigorously at 0° C. for 20 minutes, filtered, washed with ether and water and the solvents are removed under heat at 50° C. overnight to give Compound 48.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:12][C:8]=1[C:9]([OH:11])=O)[CH:2]=[C:3]([CH3:5])[CH3:4].[NH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:29][CH3:30]>>[CH2:29]([N:25]1[CH2:26][CH2:27][CH2:28][CH:24]1[CH2:23][NH:22][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][C:7]=1[O:6][CH2:1][CH:2]=[C:3]([CH3:4])[CH3:5])[CH3:30]
Reactant: CCN1CCCC1CN
Reactant: CC(C)=CCOc1ccc(OCC=C(C)C)c(C(=O)O)c1
Product: CCN1CCCC1CNC(=O)c1cc(OCC=C(C)C)ccc1OCC=C(C)C
Yield: 70 %

Procedure:
In a manner identical to Example 15, 2,5-diprenyloxybenzoic acid(1.45 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.40 g(70%) of the aimed compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=O.Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][CH:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=[N:13][OH:14]
Reactant: NO
Reactant: CC(C)=CCCC(C)CC=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)=CCCC(C)CC=NO

Procedure:
3,7-Dimethyloct-6-enal (15.4 g) in 50 ml ethyl alchohol was added to a solution of hydroxylamine hydrochloride (7 g) and sodium carbonate (5 g) in 25 ml of water. The mixture was heated on the steambath for 15 minutes and then allowed to cool. Addition of an excess of water yielded 3,7-dimethyloct-6-enal oxime as an oil. The oil was extracted with ether and the organic layer dried and evaporated. The residue was added dropwise to a solution of lithium aluminum hydride (3.8 g) in 380 ml anhydrous ethyl ether. After refluxing overnight an additional quantity of lithium aluminum hydride (0.78 g) was added to complete the reduction. Decomposition of the reaction mixture with excess aqueous sodium hydroxide (200 ml of 10% solution), separation of the ether layer, and distillation yielded 3,7-dimethyloct-6-enyl amine (10 g) bp 60°/0.5 mm). To an ice cold solution of this amine (1.5 g) and triethylamine (1.1 g) in ether (25 ml) was added dropwise a solution of ethyl chloroformate (1.1 g) in ether (10 ml). The reaction mixture was allowed to stand overnight at room temperature. The triethylamine hydrochloride was filtered off and the ether solution washed with water, dilute hydrochloric acid, and again with water. The ether solution was dried and evaporated and the residue distilled to yield 2 g carbamic acid (3,7-dimethyl-6-octenyl)-, ethyl ester (Compound 7), bp 102°-103°/0.1 mm. The ester was epoxidized as described in the previous examples to yield VII. The crude reaction product can be readily purified by chromatography using neutral activated alumina.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[F:19])=[O:11].ClC1C=CC(C(C2C=CC(F)=CC=2)O)=CC=1F>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)([OH:11])[CH3:9])=[C:13]([F:19])[CH:14]=1
Reactant: CC(=O)c1ccc(Cl)cc1F
Reactant: Fc1ccc(Br)cc1
Agent: OC(c1ccc(F)cc1)c1ccc(Cl)c(F)c1
Product: CC(O)(c1ccc(F)cc1)c1ccc(Cl)cc1F

Procedure:
The title compound was prepared starting from 4.22 g (24.14 mmol) of 4-bromofluorobenzene and 5.00 g (28.97 mmol) of 4-chloro-2-fluoroacetophenone in analogy to the synthesis of the compound from Example 176A. A difference was that the crude product was purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 9/1). 5.23 g (73% of theory) of the title compound were obtained.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:39])[C@H:16]2[CH2:20][C@H:19](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:18][N:17]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:40]([NH:48][C:49]1[CH:54]=[CH:53][NH:52][C:51](=[O:55])[N:50]=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.ClCCl>[C:8]1([CH:7]([O:14][C:15](=[O:39])[C@H:16]2[CH2:20][C@@H:19]([N:52]3[CH:53]=[CH:54][C:49]([NH:48][C:40](=[O:47])[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[N:50][C:51]3=[O:55])[CH2:18][N:17]2[C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2C[C@H](C(=O)OC(c3ccccc3)c3ccccc3)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: O=C(Nc1cc[nH]c(=O)n1)c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](n2ccc(NC(=O)c3ccccc3)nc2=O)C[C@@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A reaction mixture containing the trans-D tosylate (7) (1.10 g, 2.00 mmol), N4-benzoylcytosine (0.475 g, 2.20 mmol), anhydrous K2CO3 (0.300 g, 2.20mmol) and 18-crown-6 (200 mg) in DMF (10 ml) was stirred at 70-80° C. under argon overnight. The white suspension was diluted with dichloromethane (75 ml), filtered through celite and the organic phase washed with water. Evaporation gave the crude product as an oil which was purified by column chromatography (SiO2, ethyl acetate). The more polar fractions (Rf 0.33) were combined and evaporated to give the N1-isomer (0.299 g, 25%) as a white foam. Recrystallisation from ethanol-water gave white crystals of N-tert-butoxycarbonyl-cis-4-(N4-benzoylcytosin-1-yl)-D-proline diphenylmethyl ester (11), m.p. 133-135° C., (Found C, 65.8; H, 6.5; N, 8.8%; C34H34N4O6.C2H5OH.H2O requires C, 65.6; H, 6.4; N, 8.5%), δH (200 MHz; CDCl3) 1.30 and 1.49 (9H, 2×s, Boc rotamers), 2.20 and 2.90 [2H, br m, CH2(3′)], 3.50-3.80 and 3.95-4.15 [2H, 2×br m, CH2(5′)], 4.45-4.70 [1H, br m, CH(2′)], 5.28 [1H, br m, CH(4′)], 6.87 (1H, s, CHPh2), 7.15-7.40 (10H, m, phenyl CH), 7.40-7.75 [5H, m, CH(5), CH(6) and benzoyl m- and p-CH], 7.89 (2H, d, J=7.4 Hz, benzoyl o-CH), 8.83 (1H, br s, NH); δC (50.28 MHz; CDCl3) 27.7 and 28.0 (Boc CH3 rotamers), 34.4 and 36.0 [CH2(3′) rotamers], 49.6 and 50.5 [CH2(5′) rotamers], 54.3 and 54.9 [CH(4′) rotamers], 57.6 [CH(2′)], 78.0 and 78.3 (CHPh2 rotamers), 81.3 (Boc C), 96.8 [CH(5)], 127.0-129.2 (aromatic CH), 133.4 (benzoyl C), 139.5 (aromatic C), 145.2 and 145.7 [CH(6) rotamers], 153.8 (Boc CO rotamers), 155.6 [C(2)], 162.0 [C(4)], 166.8 (benzoyl CO), 171.3 (ester CO); m/z (ES MS) 595 (M+H+, 100%); νmax (KBr)/cm−1 1743 (C═O), 1704s (C═O); λmax (CHCl3)/nm 266 (ε/dm3.mol−1.cm−1 8.9×104), 312 (3.4×104); [α]D23−13.6 (c=0.50, CHCl3).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13]([OH:25])(=[O:24])[CH2:14][C:15]([CH2:20][C:21]([OH:23])=[O:22])([C:17]([OH:19])=[O:18])[OH:16]>O>[C:13]([O-:25])(=[O:24])[CH2:14][C:15]([CH2:20][C:21]([O-:23])=[O:22])([C:17]([OH:19])=[O:18])[OH:16].[OH:1][NH+:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[OH:1][NH+:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Product: CC1(C)CC(O)CC(C)(C)[NH+]1O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)O
Reaction time: 0.5 h

Procedure:
To a glass 0.5 L reaction bottle are added 20.0 g (116 mmol) of 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine, 11.12 g (58 mmol) citric acid, 200 mg 5% Pt on C and 100 mL water. Catalytic hydrogenation is carried out at 50 psi for 30 minutes at room temperature. Catalyst is removed by filtration through a pad of Celite. The aqueous salt solution has a pH of 4.39. Removal of water yields the product as a hygroscopic glassy solid.