Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:5][C:4]=1[N+:23]([O-])=O.[BH4-].[Na+]>CO.[O-]S([O-])(=O)=O.[Cu+2]>[NH2:23][C:4]1[CH:5]=[C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:16])[CH2:13][CH2:14]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1[N+](=O)[O-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CO
Product: COc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1N
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To a stirred solution of (4-(4-methoxy-3-nitrophenyl)piperazin-1-yl) (phenyl)methanone (3.41 g, 10 mmol) and 2M CuSO4 (0.160 g, 1 mmol) in methanol (50 mL), NaBH4 (1.89 g, 50 mmol) was added in portions at room temperature. After stirring it for 30 min, it was filtered through celite, filtrate was evaporated under vacuum. Flash column chromatography afforded (4-(3-amino-4-methoxyphenyl)piperazin-1-yl) (phenyl)methanone (2.7 g,) 87% yield. 1H NMR (500 MHz, CDCl3): δ 3.0 (bs, 2H), 3.15 (bs, 2H), 3.59 (bs, 2H), 3.84 (s, 5H), 3.98 (bs, 2H), 6.34 (dd, J=2.8 Hz, 1H), 6.43 (d, J=2.7 Hz, 1H), 6.75 (d, J=8.6 Hz, 1H), 7.45 (m, 5H). 13C NMR (500 MHz, CDCl3): δ 42.4, 48.0, 56.3, 51.2, 51.5, 56.1, 105.9, 107.1, 111.3, 127.3, 128.7, 129.9, 135.9, 136.9, 142.6, 146.0, 170.5.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]([C:13]#[N:14])[CH:6]2[CH2:15][CH:16]([CH3:18])[CH3:17]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:1]
Reactant: CC(C)CC1C(C#N)=CNc2ccc(CO)cc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(C)Cc1c(C#N)cnc2ccc(C=O)cc12
Yield: 55.6 %

Procedure:
To the solution of 6-hydroxymethyl-4-isobutyl-1,4-dihydro-quinoline-3-carbonitrile (200 mg, 0.83 mmol) in chloroform (6 mL) was added manganese dioxide (300 mg). The mixture was stirred at reflux for 10 h. After removal of the solid by filtration, the filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0%-30% ethyl acetate in hexanes in 30 min) afforded 6-formyl-4-isobutyl-quinoline-3-carbonitrile (110 mg, 56%) as a white solid. LC-MS m/e 239 (MH+).
Reaction SMILES: ClC1C=C([C@@H](N2CC[C@H](OCOC)C2)CO)C=CC=1.[Cl:20][C:21]1[CH:22]=[C:23]([C@H:27](O)[CH2:28][N:29]2[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][O:36][CH3:37])[CH2:30]2)[CH:24]=[CH:25][CH:26]=1.[CH3:39][NH:40][C:41]1[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([C@H:27]([N:40]([C:41]2[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=2)[CH3:39])[CH2:28][N:29]2[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][O:36][CH3:37])[CH2:30]2)[CH:24]=[CH:25][CH:26]=1
Reactant: COCO[C@H]1CCN(C[C@@H](O)c2cccc(Cl)c2)C1
Reactant: CNc1ccc(C(=O)OC)cc1
Agent: COCO[C@H]1CCN([C@@H](CO)c2cccc(Cl)c2)C1
Product: COCO[C@H]1CCN(C[C@H](c2cccc(Cl)c2)N(C)c2ccc(C(=O)OC)cc2)C1
Yield: 66 %

Procedure:
This was prepared from the mixture of 2-(R)-(3-chlorophenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol and 1-(S)-(3-chlorophenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol and methyl 4-methylaminobenzoate in 66% yield according to a procedure similar to that described in Example 1 (i).
Reaction SMILES: F[B-](F)(F)F.[F:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Si:37]([O:44][CH2:45][C:46](=O)[CH2:47][NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]>C1COCC1>[Si:37]([O:44][CH2:45][C:46](=[CH:7][F:6])[CH2:47][NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)NCC(=O)CO[Si](C)(C)C(C)(C)C
Reactant: FC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=CF)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a vigorously stirring suspension of fluoromethyl(triphenyl)-phosphonium tetrafluoroborate (18.9 g, 49.4 mmol) in dry THF (190 mL) at −20° C. under N2 was added sodium bis(trimethylsilyl)amide (1.0 M in THF; 49.4 mL, 49.4 mmol) slowly over 10 min. The resulting deep orange solution was left to stir at this temperature for 15 min. A solution of tert-butyl 3-(tert-butyldimethylsilyloxy)-2-oxopropylcarbamate (10.0 g, 33.0 mmol) in THF (10 mL) was then added slowly over 10 min. After complete addition, stirring was continued for a further 1 h during which time the reaction was allowed to warm slowly to room temperature. The reaction was quenched by addition of water (5 mL) and the reaction mixture was concentrated in vacuo. The residue was partitioned between water (100 mL) and diethyl ether (100 mL) and the aqueous layer was extracted with further diethyl ether (2×100 ml). The combined organics were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified over silica gel eluting with n-hexane followed by 6% ethylacetate in n-hexane to give tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-3-fluoroallylcarbamate as a mixture of E/Z double-bond isomers (E/Z=1:1; 9.9 g; 94%). The isomers were not separated at this stage.
Reaction SMILES: C(O[C:6]([NH:8][NH:9][CH2:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1[OH:18])=O)(C)(C)C.CCO.[CH2:22]([O:24][C:25](=[O:35])[CH2:26][C:27](=CN(C)C)[C:28](=O)[CH3:29])[CH3:23]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:22]([O:24][C:25](=[O:35])[CH2:26][C:27]1[CH:6]=[N:8][N:9]([CH2:10][C:11]2[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=2[OH:18])[C:28]=1[CH3:29])[CH3:23]
Reactant: CCOC(=O)CC(=CN(C)C)C(C)=O
Reactant: CC(C)(C)OC(=O)NNCc1cc(Br)ccc1O
Solvent: CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1cnn(Cc2cc(Br)ccc2O)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
A suspension of N′-(5-bromo-2-hydroxy-benzyl)-hydrazinecarboxylic acid tert-butyl ester 1 1 g (3.1 mmol) in a mixture of CH2Cl2 (8 mL) and TFA (8 mL) was stirred at RT for 2 hours. The volatiles were removed in vacuo. The residue was dissolved in abs. EtOH (7 mL) and added to 3-[1-dimethylamino-methylidene]-4-oxo-pentanoic acid ethyl ester (4.8 mmol) at RT. The resulting mixture was stirred at RT for 1 hour, refluxed for 2 h, let cool down and stirred at RT for 16 h. The oily residue obtained after removing the volatiles in vacuo was purified by MPLC (10 g SiO2 cartridge, eluent 90% iso-hexane-10% EtOAc) to give 0.18 g of [1-(5-Bromo-2-hydroxy-benzyl)-5-methyl-1H-pyrazol-4-yl]-acetic acid ethyl ester, 2.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[SH:41][C@@H:42]1[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]2[CH2:54][CH2:53][C@@H:52]([CH2:55][NH:56][C:57]([O:59][CH2:60][C:61]3[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=3)=[O:58])[CH2:51]2)=[O:49])[CH2:43]1.C(OCC)(=O)C>C(#N)C.C(N(CC)C(C)C)(C)C>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8]([S:41][C@@H:42]3[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]4[CH2:54][CH2:53][C@@H:52]([CH2:55][NH:56][C:57]([O:59][CH2:60][C:61]5[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=5)=[O:58])[CH2:51]4)=[O:49])[CH2:43]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)N1CC[C@@H](CNC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@@H](CNC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C)C3)[C@H](C)[C@H]12
Yield: 78.4 %

Procedure:
To a solution of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (0.73 g) in anhydrous acetonitrile (7 ml), N,N-diisopropylethylamine (0.22 ml) and a solution of (2S,4S)-4-mercapto-1-methyl-2-[(3S)-3-(4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidine (0.57 g) in anhydrous acetonitrile (10 ml) were added while stirring in an ice bath. The resulting mixture was stirred overnight at 0° C. To the reaction mixture, ethyl acetate was added. The resulting mixture was washed with water and saturated saline solution, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate/methanol=7/3), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-1-methyl-2-[(3S)-3-(4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (0.78 g) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][NH:9][C:10](=[O:18])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1)([O-])=O>[C].[Pd].C(O)C>[NH2:1][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][NH:9][C:10](=[O:18])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCC(=O)NCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC(=O)NCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 40.3 %

Procedure:
A mixture of ethyl 4-[(4-nitrobenzyl)amino]-4-oxobutanoate (10 g), 10% palladium carbon (1 g) and ethanol (300 ml) was stirred under a hydrogen atmosphere at room temperature for 14 hrs. Palladium carbon was removed from the reaction mixture by filtration, and the filtrate was concentrated. Recrystallization of the residue from ethyl acetate-hexane gave ethyl 4-[(4-aminobenzyl)amino]-4-oxobutanoate (3.6 g, 40%) as colorless prism crystals. melting point: 62-64° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:13])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2.Cl[C:15]1[N:20]=[CH:19][N:18]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[NH:31][C:32]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][N:35]2[CH2:40][CH:41]([CH3:43])[CH3:42])=[O:33])[CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C([O-])(O)=O.[Na+]>[NH2:1][C:2]1[C:3](=[O:13])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:15]1[N:20]=[CH:19][N:18]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:22]=3[NH:31][C:32]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][N:35]3[CH2:40][CH:41]([CH3:43])[CH3:42])=[O:33])[CH:16]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: CC(C)CN1CCCCC1C(=O)Nc1cc(C(F)(F)F)ccc1-c1cc(Cl)ncn1
Reactant: Nc1nc2c(O)cccc2[nH]c1=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CN1CCCCC1C(=O)Nc1cc(C(F)(F)F)ccc1-c1cc(Oc2cccc3[nH]c(=O)c(N)nc23)ncn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 3-amino-5-hydroxyquinoxalin-2(1H)-one (0.067 g, 0.38 mmol, prepared as described in WO04014871), N-(2-(6-chloropyrimidin-4-yl)-5-(trifluoromethyl)-phenyl)-1-isobutylpiperidine-2-carboxamide, Example 39(e), (0.14 g, 0.32 mmol) and Cs2CO3 (0.12 g, 0.38 mmol, Strem) in DMF (2.5 mL) was stirred for 3 d at 25° C. The mixture was diluted with aqueous solution of NaHCO3 (100 mL) and extracted with 1:1 mixture of EtOAc/hexane (2×75 mL). The combined extracts were washed with H2O (2×75 mL) and brine (75 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. Purification of the residue by silica gel column chromatography (gradient: 25-60% EtOAc/hexane) afforded the title compound as a white solid. MS (ESI, pos. ion.) m/z: 582 (M+1). Mp: >250° C.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[C:14]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:15][C:16]3[C:21]([N:22]=1)=[CH:20][C:19]([C:23]([O:25]C)=[O:24])=[CH:18][CH:17]=3)[CH2:8][CH2:7][CH2:6]2.[OH-].[Na+].CC(O)=O>CO.O>[CH3:1][N:2]([CH3:34])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[C:14]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)=[N:15][C:16]3[C:21]([N:22]=1)=[CH:20][C:19]([C:23]([OH:25])=[O:24])=[CH:18][CH:17]=3)[CH2:8][CH2:7][CH2:6]2
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(N(C)C)ccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CN(C)c1ccc2c(c1)CCCN2c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.7 %

Procedure:
To a solution of methyl 3-[6-(dimethylamino)-1,2,3,4-tetrahydroquinolin-1-yl]-2-(4-fluorophenyl)quinoxaline-6-carboxylate (30 mg, 0.07 mmol) in methanol (20 ml) and water (2 ml) was added sodium hydroxide (10 mg, 0.25 mmol) and the reaction was stirred overnight at room temperature. The resulting solution was diluted with water (100 ml), adjusted pH to 5 with AcOH, extracted with ethyl acetate (3×20 ml), dried over anhydrous magnesium sulfate and concentrated in vacuo to give 3-[6-(dimethylamino)-1,2,3,4-tetrahydroquinolin-1-yl]-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a red solid (3 mg, 10%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[C:11]([O:20][CH3:21])[CH:10]=1)=[O:7].[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl>CO.C(OCC)(=O)C.[Pd].N1C=CC=CC=1>[CH3:28][S:29]([NH:25][C:24]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[C:11]([O:20][CH3:21])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[O:2][CH3:1])(=[O:31])=[O:30]
Reactant: COc1cc(NC(=O)c2ccc([N+](=O)[O-])c(OC)c2)ccc1NS(C)(=O)=O
Reactant: CS(=O)(=O)Cl
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CO
Product: COc1cc(NC(=O)c2ccc(NS(C)(=O)=O)c(OC)c2)ccc1NS(C)(=O)=O
Reaction time: 2 h
Yield: 100 %

Procedure:
A suspension of 3-methoxy-4-nitro-N-(4-methanesulfonylamino-3-methoxyphenyl)benzamide (2.03 g) in methanol (50 ml) and ethyl acetate (50 ml) was stirred under hydrogen with palladium on carbon (10%, 50 mg) for 18 hours. The solvents were removed in vacuo to give a brown gum. The residue was dissolved in pyridine (5 ml) and cooled to 0° C. when methanesulfonyl chloride (1 ml) was added, the mixture was kept at 0° C. for a further 2 hours then brought to R.T. for 1 h. The mixture was poured onto ice (50 g) and hydrochloric acid (3M, 50 g), the resultant brown solid filtered and washed with water to give 4-methanesulfonylamino-3-methoxy-N-(4-methanesulfonylamino-3-methoxyphenyl)benzamide (2.1 g, 100%) as a pale brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=2[CH3:21])=[O:10])[CH:5]=[CH:6][CH:7]=1.[H][H]>CN(C)C=O.[Pd]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[O:10])=[C:13]([CH3:21])[CH:14]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1NC(=O)Nc1cccc(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cc1cc(N)ccc1NC(=O)Nc1cccc(F)c1

Procedure:
A solution of EXAMPLE 100A (1.28 g, 4.43 mmol) in 12 mL of N,N-dimethylformamide was degassed and hydrogenated under an atmosphere of hydrogen (balloon) in the presence of catalytic amount of 10% Pd on carbon for 24 hours. The mixture was filtered and the filtrate was extracted with ethyl acetate. The organic extract was washed with brine, dried with MgSO4 and concentrated to provide EXAMPLE 100B. MS (ESI(+)) m/e 260 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][C:16]([CH3:23])=[CH:17][C:18]([O:20]CC)=[O:19].[OH-].[K+]>C(O)C>[F:1][C:2]([F:31])([F:32])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:26]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[C:16](/[CH3:23])=[CH:17]/[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)C=C(C)C=CCCCCCCOCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(/C=C/CCCCCCOCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C\C(=O)O

Procedure:
The above ester (10.2 mmol) was hydrolysed by potassium hydroxide (41.2 mmol) in aqueous ethanol at room temperature over 24 hours. After standard work-up, the residue was triturated with hexane to give (2E,4E) 11-(3',5'-bistrifluoromethylbenzyloxy)-3-methylundeca-2, 4-dienoic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([OH:13])=[CH:7][CH:8]=2)[O:3]1.[OH-].[Na+].C1C=CC=CC=1.[Cl-].C([NH+](CCCC)CCCC)CCC.[Br:37][CH2:38][CH2:39]Br>C(Cl)Cl>[CH3:1][C:2]1([CH3:14])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([O:13][CH2:39][CH2:38][Br:37])=[CH:7][CH:8]=2)[O:3]1
Reactant: BrCCBr
Reactant: CC1=CC(C)(C)Oc2cc(O)ccc21
Agent: CCCC[NH+](CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClCCl
Product: CC1=CC(C)(C)Oc2cc(OCCBr)ccc21
Yield: 65 %

Procedure:
To a 8% aqueous solution of 0.1 mole (19.02 g.) 2,2,4-trimethyl-7-hydroxy-(2H)-chromene and 0.2 mole (8 g.) sodium hydroxide 4 g. of benzene-tributyl-ammonium-chloride as phase transfer catalyst and a solution of 0.2 mole 1,2-dibromo-ethane in 200 ml. methylene-chloride are added under stirring and the solution is heated for 12 hours. After cooling the organic layer is separated and dried above sodium sulphate and evaporated. The residue is dissolved in 50 ml. diethyl-ether and the substance is precipitated by adding 300 ml. of n-hexane. The solvent is decanted from the precipitated substance. Thus 19.38 g. (0.065 mole) product are obtained in the form of a white waxy oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.[CH2:33]([O:35][C:36](=[O:44])[CH2:37][CH2:38][CH2:39][CH2:40][C:41](O)=[O:42])[CH3:34].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[C:36]([O:35][CH2:33][CH3:34])(=[O:44])[CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)=[O:42]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Reactant: CCOC(=O)CCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 0.25 g, 0.57 mmol), adipic acid monoethyl ester (0.25 g, 1.44 mmol), 4-dimethylaminopyridine (0.02 g, 0.16 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride were combined in DMF (4 ml). The suspension was allowed to stir for one hour at room temperature resulting in a clear solution. The mixture was then diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The residue obtained upon filtration and evaporation was purified by chromatography (silica gel, 0.5 to 10% methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with diethyl ether yielded the title compound as a white powder (0.275 g), melting point: 88° C.
Reaction SMILES: C(ONC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[S:16][C:17]([CH3:26])=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[CH3:26][C:17]1[S:16][C:15]([N:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)=[N:19][C:18]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1sc(N2CCN(C(=O)NOC(C)(C)C)CC2)nc1-c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1sc(N2CCNCC2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
To a solution of N-(tert-butoxy)-4-(5-methyl-4-phenyl-1,3-thiazol-2-yl)piperazine-1-carboxamide (2.45 g, 6.82 mmol) in ethyl acetate (200 ml) was added a 4N hydrogen chloride solution in ethyl acetate (40 ml), and the mixture was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in water. The solution was neutralized with 1N sodium hydroxide, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 1.51 g (85.6%) of the desired product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:16]=[C:17]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:18]([NH2:21])=[CH:19][CH:20]=3)=[N:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.[N:31]#[C:32]Br.C(=O)([O-])O.[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]4[N:21]=[C:32]([NH2:31])[N:22]([C:23]5[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=5)[C:17]=4[CH:16]=3)=[N:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Nc2cc(-c3nnc(CCc4cccc(F)c4)o3)ccc2N)cc1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-n2c(N)nc3ccc(-c4nnc(CCc5cccc(F)c5)o4)cc32)cc1
Yield: 61.8 %

Procedure:
A solution of 4-[5-[2-(3-fluorophenyl)ethyl]-1,3,4-oxadiazol-2-yl]-N2-(4-methoxyphenyl)benzene-1,2-diamine (0.20 g, 0.49 mmol) and cyanogen bromide (0.11 g, 1.03 mmol) in ethanol (5 mL) was stirred at 60° C. for 4 hr. After cooling, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=1/2-1/3) to give the title compound (0.13 g, yield 62%) as colorless crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][OH:8].C[Si](Cl)(C)C.[C:14]1([C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:21]Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1.C(Cl)Cl>[OH:1][CH2:2][CH2:3][N:4]([S:21][C:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:5][CH2:6][CH2:7][OH:8]
Reactant: ClSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCCNCCO
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: OCCCN(CCO)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2-hydroxyethyl)-3-amino-1-propanol (5.0 g, 41.9 mmol) is coevaporated several times with pyridine (20 mL) and then dissolved in pyridine (100 mL). The reaction flask is flushed with Argon and trimethylsilylchloride (2.47 g, 209.5 mmol) is added dropwise. The reaction mixture is stirred for 1 hour. Triphenyl methanesulfenyl chloride (14.32 g, 46.09 mmol) is dissolved in CH2Cl2 and added via dropping funnel to the cooled reaction mixture. The reaction mixture is warmed to room temperature and stirred for 18 hours. The reaction mixture is concentrated in vacuo and the resultant residue is partitioned between H2O and EtOAc (100 ml, 1:1). The H2O layer is separated and extracted with EtOAc (3×50 ml). The EtOAc extracts are pooled, dried (MgSO4) and filtered. The filtrate is concentrated in vacuo and the residue is purified by silica gel flash column chromatography with EtOAc/hexanes as the eluent. The appropriate fractions are pooled and concentrated in vacuo to give the title compound.