Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Li+].C(OP([CH:11]([CH:17]([CH3:19])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.[CH2:42]([O:49][C:50]([N:52]1[C@@H:56]([CH2:57][CH:58]([CH3:60])[CH3:59])[C@H:55]([CH:61]=O)[O:54][C:53]1([CH3:64])[CH3:63])=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O1CCCC1>[CH2:42]([O:49][C:50]([N:52]1[C@@H:56]([CH2:57][CH:58]([CH3:59])[CH3:60])[C@H:55]([CH:61]=[C:11]([CH:17]([CH3:18])[CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:54][C:53]1([CH3:63])[CH3:64])=[O:51])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC(C)C[C@H]1[C@H](C=O)OC(C)(C)N1C(=O)OCc1ccccc1
Reactant: CCOC(=O)C(C(C)C)P(=O)(OCC)OCC
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)C(C)C

Procedure:
123 mg of lithium chloride was suspended in 10 ml of dry tetrahydrofuran under an argon atmosphere, and 0.69 ml of ethyl 2-diethylphosphono-3-methylbutanoate was added thereto under stirring. Then, 2.7 ml of a 20% dry tetrahydrofuran solution of diazabicycloundecene was added thereto and stirred for 10 minutes at room temperature. A solution prepared by dissolving 773 mg of (4S,5R)-3-benzyloxycarbonyl-2,2-dimethyl-5-formyl-4-isobutyloxazolidine in dry tetrahydrofuran was gradually dropwise added thereto, and the mixture was stirred overnight at room temperature. The inorganic salt precipitated was filtered off and the solvent was distilled off under reduced pressure. The residue was dissolved in 300 ml of benzene, washed with water and dried oer anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (32 g of Kiesel gel 60) by using a mixture of n-hexane/ethyl acetate (10/1) to obtain 623 mg of ethyl 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5-yl]-2-isopropyl-2-propenoate as a colorless oily substance.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH:12]2[O:13][CH2:14][C:15](=O)[CH:11]2[O:10][CH2:9]1.[NH3:17].[BH4-].[Na+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH:12]2[O:13][CH2:14][CH:15]([NH2:17])[CH:11]2[O:10][CH2:9]1
Reactant: O=C1COC2C(OC3CCCCO3)COC12
Reactant: N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Product: NC1COC2C(OC3CCCCO3)COC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-((tetrahydro-2H-pyran-2-yl)oxy)tetrahydrofuro[3,2-b]furan-3(2H)-one (3.5 g, 15.3 mmol) in a solution of NH3 in MeOH (30 mL, 7 M) was added titanium isopropoxide (10.9 g, 38.3 mmol) at rt, and then the mixture was stirred at rt overnight. To the reaction mixture was added NaBH4 (1.16 g, 30.6 mmol) slowly at rt, and the mixture was stirred at rt for another 10 h and then quenched with H2O (50 mL). The resulting mixture was filtered and washed with EtOAc (50 mL). The filtrate was extracted with EtOAc (80 mL×3), and then the combined organic phases were washed with brine (200 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo to give product as crude oil (3.6 g, crude product).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:16]=[CH:17][N:18]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:7]=1.Cl.Cl.[NH2:21][CH2:22][CH2:23][NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[Cl:15][C:9]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([NH:21][CH2:22][CH2:23][NH:24][C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=2)[C:3]2[N:4]([CH:16]=[CH:17][N:18]=2)[CH:5]=1
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: Clc1ccc(-c2cn3ccnc3c(Cl)n2)c(Cl)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cn3ccnc23)nc1
Temperature: 120 °C

Procedure:
108 mg (0.3625 mmol) of the 8-chloro-6-(2,4-dichlorophenyl)imidazo[1,2-a]pyrazine (Example 5A) were initially charged in 3 ml of DMSO, and 150 mg (0.543 mmol) of 6-[(2-aminoethyl)amino]nicotinonitrile (Example 2A) and 0.63 ml (3.62 mmol) of N,N-diisopropylethylamine were added. The mixture was heated at 120° C. for 12 h. Purification by chromatography on silica gel 60 (mobile phase: dichloromethane/methanol 100:1) gave 12 mg (7% of theory) of the product.
Reaction SMILES: C([O-])(=O)/C=C\C([O-])=O.C[O:10][C:11](=[O:35])[C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17](=[O:34])[C@H:18]([CH3:33])[NH:19][C@H:20]([C:28]([O:30]CC)=[O:29])[CH2:21][S:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.[OH-].[Na+].Cl>C(O)C>[C:28]([C@@H:20]([NH:19][C@H:18]([C:17]([N:13]1[CH2:14][CH2:15][CH2:16][C@H:12]1[C:11]([OH:35])=[O:10])=[O:34])[CH3:33])[CH2:21][S:22][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27]1)([OH:30])=[O:29]
Reactant: CCOC(=O)[C@H](CSC1CCCC1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC
Agent: Cl
Agent: O=C([O-])/C=C\C(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](N[C@@H](CSC1CCCC1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
A 300 mg portion of maleate of β-isomer of N-[(R)-1-ethoxycarbonyl-2-cyclopentylthioethyl]-alanyl-(S)-proline methyl ester prepared in Example 57 was dissolved in 2 ml of ethanol. To the solution was added dropwise 2.9 ml of 1N-NaOH at room temperature. The mixture was stirred overnight and neutralized with 2N-HCl with ice cooling. The solvent was completely removed by distillation. The residue was dissolved in methanol and the solution was subjected to high performance liquid chromatography (column=Chemcosorb 7-ODS-H, eluent=a 50:50:0.4 mixture of methanol, water and acetic acid) for separation. The solvent was distilled off. After addition of 4 ml of ether, the precipitated crystals were collected by filtration, giving the title compound as white crystals. Yield 160 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:25]([CH:26]=[CH2:27])=[N:24][N:23]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[C:18]=3[N:19]=[C:20]([Cl:22])[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:35]1[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=1)[CH2:38][N:39]([CH3:41])[CH3:40].C(=O)([O-])O.[Na+].CN(C)C=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:25](/[CH:26]=[CH:27]/[C:35]4[CH:44]=[CH:43][CH:42]=[C:37]([CH2:38][N:39]([CH3:41])[CH3:40])[CH:36]=4)=[N:24][N:23]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[C:18]=3[N:19]=[C:20]([Cl:22])[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1nn(C2CCCCO2)c2nc(Cl)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c12
Reactant: CN(C)Cc1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CN(C)Cc1cccc(/C=C/c2nn(C3CCCCO3)c3nc(Cl)cc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)c23)c1
Temperature: 100 °C
Yield: 28.7 %

Procedure:
In a 250 ml round bottom flask were charged 4-[6-chloro-1-(tetrahydro-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (1.2 g, 2.52 mmol), (3-iodo-benzyl)-dimethyl-amine (1.64 g, 6.3 mmol), tetrabutylammonium bromide (0.32 g, 1 mmol), sodium hydrogen carbonate (0.53 g, 6.3 mmol) and anhydrous dimethylformamide (42 ml). The mixture was degassed during 10 minutes using argon, palladium acetate (0.05 g, 0.25 mmol) was then added. The resulting solution was heated at 100° C. under argon overnight. Dimethylformamide was eliminated under vacuum, dichloromethane and water were added to the residue, after extraction the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. Further purification on a silica gel column chromatography using a gradient of methanol (0-5%) in dichloromethane afforded the title compound as brown solid (0.44 g, 29%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:34]([O:36][C:37](=[O:52])[CH2:38][CH2:39][N:40]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C@H:41]([CH3:44])[CH2:42]O)[CH3:35].[N-:53]=[N+:54]=[N-:55]>O1CCCC1>[CH2:34]([O:36][C:37](=[O:52])[CH2:38][CH2:39][N:40]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C@H:41]([CH3:44])[CH2:42][N:53]=[N+:54]=[N-:55])[CH3:35]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CCN(C(=O)OC(C)(C)C)[C@H](C)CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCN(C(=O)OC(C)(C)C)[C@H](C)CN=[N+]=[N-]

Procedure:
Triphenylphosphine (12.0 g, 45.9 mmol) and diisopropyl azodicarboxylate (9.88 g, 45.9 mmol) were added at room temperature to a solution of 3-[tert-butoxycarbonyl-((R)-2-hydroxy-1-methyl-ethyl)-amino]-propionic acid ethyl ester in tetrahydrofuran (600 ml), then after 2 min diphenylphorphoryl azide (12.6 g, 45.9 mmol) was added. After 16 h the reaction mixture was concentrated and the residue purified by chromatography (SiO2; heptane-ethyl acetate gradient) to afford slightly impure 3-[tert-butoxycarbonyl-((R)-2-azido-1-methyl-ethyl)-amino]-propionic acid ethyl ester (8.82 g). This was dissolved in methanol (880 ml), then after addition of palladium (10% on activated charcoal, 1.6 g) and potassium carbonate (42.6 g, 308 mmol) the reaction mixture was hydrogenated at room temperature and atmospheric pressure for 16 h. Insoluble material was removed by filtration and the filtrate concentrated. Chromatography (SiO2; heptane/ethyl acetate 1:1, then dichloromethane/methanol/25% aq. ammonia solution 97.5:2.5:0.25) produced the title compound (2.20 g, 21%). White solid, MS (ISP)=229.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH2:27].C(Cl)CCl.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:18][C:19]([F:28])([F:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH:27][C:15]([C@@H:12]1[CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:14][CH2:13]1)=[O:17]
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)NCc2ccccc2C(F)(F)F)CC1
Reaction time: 8 h

Procedure:
To a solution of cis-4-({[(1,1-dimethylethyl) oxy]carbonyl}amino)cyclohexanecarboxylic acid (3.0 g, 12 mmol, 1.0 equiv) and 1-[2-(trifluoromethyl)phenyl]methanamine (1.9 mL, 14 mmol, 1.0 equiv) in CH2Cl2 (82 mL) at room temperature, DMAP (301 mg, 2.47 mmol, 0.2 equiv) was added. EDC (2.95 g, 15.4 mmol, 1.25 equiv), and diisopropylethylamine (DIEA, 2.7 ml, 15 mmol, 1.25 equiv) were added. Stirring was continued overnight at room temperature. The solution was diluted with CH2Cl2 (100 ml), washed with saturated sodium bicarbonate (200 mL), water (200 mL), and brine (200 mL). The CH2Cl2 extracts were dried with MgSO4, filtered, and concentrated under reduced pressure to yield the title compound. MS (ES+): m/e 400.8 [M+Na]+.
Reaction SMILES: O1CCCC1.[Br-].[CH2:7]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C([Li])CCC.[CH:43]([C:45]1[CH:46]=[C:47]([C:50]([O:52][CH3:53])=[O:51])[NH:48][CH:49]=1)=O>CCCCCC.O.C(O)C>[CH:43](/[C:45]1[CH:46]=[C:47]([C:50]([O:52][CH3:53])=[O:51])[NH:48][CH:49]=1)=[CH:18]\[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: COC(=O)c1cc(C=O)c[nH]1
Reactant: CCCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCCC/C=C/c1c[nH]c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.6 %

Procedure:
To a tetrahydrofuran suspension (200 ml) of 32 g (62.7 mmol) of dodecyltriphenylphosphonium bromide was added dropwise 40 ml of a ca. 15% solution of n-butyllithium in hexane under ice-cooling. After stirring the reaction mixture for 30 minutes, the temperature was dropped to -78° C. A tetrahydrofuran solution (100 ml) of 4.8 g (31.4 mmol) of methyl 4-formylpyrrole-2-carboxylate was then added dropwise. After stirring for 1 hour, 190 ml of ethanol was further added thereto dropwise. The reaction mixture was stirred for 1.5 hour at -78° C., and for another 12 hours while the temperature was gradually raised to room temperature. The resulting mixture was diluted with water, extracted with ethyl acetate, washed with aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removing he solvent under reduced pressure, the residue was purified by subjecting it to column chromatography (eluent: ethyl acetate/hexane=1/10) and by recrystallizing twice from hexane to obtain 1.30 g (14% yield) of methyl 4-(1-trans-tridecenyl)pyrrole-2-carboxylate, m.p. 65°-67° C.
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[C:17]([C:19]4[C:20]5[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:21]=5[N:22]=[CH:23][N:24]=4)[CH:16]=[CH:15]3)[CH2:11]2)[CH2:6][CH2:5]1.[F:39][C:40]1[C:48]([C:49]([F:52])([F:51])[F:50])=[N:47][CH:46]=[CH:45][C:41]=1[C:42](O)=[O:43].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[F:39][C:40]1[C:48]([C:49]([F:52])([F:50])[F:51])=[N:47][CH:46]=[CH:45][C:41]=1[C:42]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:11][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[C:17]([C:19]4[C:20]5[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[C:21]=5[N:22]=[CH:23][N:24]=4)[CH:16]=[CH:15]3)[CH2:13]2)[CH2:6][CH2:5]1)=[O:43]
Reactant: O=C(O)c1ccnc(C(F)(F)F)c1F
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3ccn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3ccn(C4(CC#N)CN(C5CCN(C(=O)c6ccnc(C(F)(F)F)c6F)CC5)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride (1.22 g, 2.03 mmol), 3-fluoro-2-(trifluoromethyl)isonicotinic acid (460 mg, 2.2 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.07 g, 2.42 mmol) and triethylamine (2.0 mL, 14 mmol) in DMF (20.0 mL) was stirred at room temperature overnight. LS-MS showed the reaction was complete. EtOAc (60 mL) and saturated NaHCO3 aqueous solution (60 mL) were added to the reaction mixture. After stirring at room temperature for 10 minutes, the organic phase was separated and the aqueous layer was extracted with EtOAc three times. The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. Purification by flash chromatography provided {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile as a white powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](C#N)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.N1C2C(=CC=CC=2)C=C1C#N>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: N#Cc1cc2ccccc2[nH]1
Product: c1ccc2[nH]ccc2c1

Procedure:
The A ring indole of compounds 31 and 32 was synthesized using the same approach as 8f described in Scheme 3 above from 1H-indole-5-carbonitrile or 1H-indole-2-carbonitrile as starting material. Crude product was purified by column chromatography. Description of synthesis of compounds 31 and 32 is provided below in Example 11.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[NH2:23][CH2:24][CH:25]1[C:29](=[N:30][O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][NH:27][CH2:26]1>>[NH2:23][CH2:24][CH:25]1[C:29](=[N:30][O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][N:27]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:16])[CH2:26]1
Reactant: CC(C)(C)ON=C1CNCC1CN
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Product: CC(C)(C)ON=C1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1CN
Temperature: 25 °C
Yield: 67.3 %

Procedure:
141 mg (0.5 mmole) of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 143 mg (0.55 mmole) of 3-aminomethyl-4-t-butyloxyiminopyrrolidine dihydrochloride were refluxed for 2.5 hours under heating according to the same manner as Example 89 and cooled down to room temperature. Then, the resulting product was then separated and purified with preparative HPLC to obtain 151 mg (Yield: 67%) of the title compound.
Reaction SMILES: [Li]N([Si](C)(C)C)[Si](C)(C)C.CC1C=CC(S([CH2:21][N+:22]#[C-:23])(=O)=O)=CC=1.[C:24]([O:35][CH3:36])(=[O:34])/[CH:25]=[CH:26]/[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]>C1COCC1>[CH3:36][O:35][C:24](=[O:34])[CH2:25][CH2:26][CH2:27][C:28]1[C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:21][NH:22][CH:23]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)/C=C/CCCC(=O)OC
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: COC(=O)CCCc1c[nH]cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.6 %

Procedure:
To a 1 M solution of LiN(TMS)2 in THF (5.9 mL, 5.9 mmol) cooled ate −78° C. under argon was added a solution of TOSMIC (1.15 g, 5.9 mmol) in THF (15 mL) dropwise. After 40 min at −78° C. a solution of dimethyl (2E)-hept-2-enedioate (1.1 g, 5.9 mmol) in THF (15 mL) at −78° C. was added slowly. The solution was stirred for 10 min, then the cold bath was removed and the reaction was allowed to warm at room temperature. THF was evaporated and the residue partioned between H2O (200 mL) and DCM (200 mL) Acqueous layer was extracted with DCM and the combined organic layers anidrified on Na2SO4, filtered and concentred to give a residue which was chromatographed on silica gel (eluant: AcOEt/hexane 3/7) to afford 633 mg (yield: 40%) of the title compound as white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].O[C:16]1[CH:25]=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:16]1[CH:25]=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: Oc1cnc2ccccc2n1
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1COc1cnc2ccccc2n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 39.8 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (100 mg, 0.53 mmol) in THF (6 mL) was added 2-hydroxyquinoxaline (77 mg, 0.53 mmol) and tributyl phosphine (206 μL, 0.79 mmol) at ambient temperature under an argon atmosphere. After cooling to 0° C., N,N,N′,N′-tetramethylazodicarboxamide (137 mg, 0.79 mmol) was added. The resulting orange solution was stirred for 16 h at ambient temperature followed by 2.5 h at 50° C. Then triphenylphosphine (208 mg, 0.79 mmol), 2-hydroxyquinoxaline (77 mg, 0.53 mmol) and diethyl azodicarboxylate (127 μL, 0.79 mmol) were added and the reaction mixture was stirred for 4 h at 50° C. The reaction mixture was then evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 0:100) afforded the title compound (67 mg, 40%) as a white solid. MS: m/e=318.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)=O.[Cl-].[OH:18][NH3+:19].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)=[N:19][OH:18]
Reactant: [NH3+]O
Reactant: COc1ccc(C(=O)C(F)(F)F)cc1OC
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=NO)C(F)(F)F)cc1OC
Temperature: 0 °C
Yield: 95.2 %

Procedure:
2.9 g (9.7 mmol) of 2,2,2-trifluoro-1-(3,4-dimethoxyphenyl)-ethanone are dissolved in 12 ml of ethanol at 80° C. To the solution are added dropwise 0.83 g (12.0 mmol) of hydroxylammonium chloride and 1.2 g (15.0 mmol) of sodium acetate dissolved in 6 ml of water. The reaction mixture is refluxed for 7.5 hours, poured into ice water, and extracted with ether. The organic phase is washed with water and brine, dried over MgSO4, and concentrated, yielding 2.3 g of 2,2,2-trifluoro-1-(3,4-dimethoxyphenyl)-ethanone oxime. The crude product is used in the next reaction step without further purification.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C@@H:16]([C:34]([OH:36])=[O:35])[CH2:17][C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([O:25]CC4C=CC=CC=4)=[C:20]([CH3:33])[CH:19]=3)=[O:14])[CH2:9][CH2:8]2)[N:5]=[C:4]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[NH:3]1.[H][H].C1COCC1>C(Cl)Cl.[Pd]>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C@@H:16]([C:34]([OH:36])=[O:35])[CH2:17][C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([OH:25])=[C:20]([CH3:33])[CH:19]=3)=[O:14])[CH2:9][CH2:8]2)[N:5]=[C:4]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(n3nc(-c4ccccc4)[nH]c3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(n3nc(-c4ccccc4)[nH]c3=O)CC2)C(=O)O)cc(C)c1O
Reaction time: 12 h

Procedure:
A solution of 2.50 g (4.38 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate in 50 mL DCM was combined with 250 mg 10% Pd/C and hydrogenated at RT and 3 bar hydrogen pressure for 4.5 h. To complete the reaction a further 250 mg of catalyst were added, the mixture was hydrogenated for 12 h at 40° C., combined with 25 mL THF and 250 mg catalyst and hydrogenated for a further 12 h at 40° C. The catalyst was removed by suction filtering and the filtrate was concentrated by evaporation i. vac. The residue was stirred with DIPE, suction filtered and dried.
Reaction SMILES: [CH2:1]([O:17][CH2:18][C@H:19]([OH:22])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25].CCN(CC)CC.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:27]([O:21][CH2:20][C@@H:19]([OH:22])[CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: CCCCCCCCCCCCCCCCOC[C@H](O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCOC[C@H](O)CO[Si](C)(C)C(C)(C)C

Procedure:
A solution of (R)-3-(hexadecyloxy)propane-1,2-diol (1 eq), TBDMSCl (1.4 eq), NEt3 (1.4 eq) and DMAP (0.05 eq) in DCM (0.5 M) was stirred at 25° C. over night. The reaction was diluted with DCM and was with H2O twice, and the aqueous phase was back extracted with DCM. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-20% EtOAc/Hex to give (S)-1-(tert-butyldimethylsilyloxy)-3-(hexadecyloxy)propan-2-ol as a colorless oil.