Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[Li+].[OH-]>O.CO>[CH3:1][O:2][C:3]1([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: COC(=O)CCSC(c1ccccc1)C1(OC)CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC1(C(SCCC(=O)O)c2ccccc2)CCOCC1
Yield: 103.6 %

Procedure:
A solution of methyl 3-[[(4-methoxy)tetrahydropyran-4-yl]phenyl-methyl-thio]propionate (Step 1) (0.91 g, 2.8 mmol) and LiOH (0.29 g, 7.01 mmol) in 10% water and methanol (10 mL) was stirred for 18 h at room temperature. The solvents were removed at reduced pressure, and the concentrated residue was partitioned between ethyl acetate (200 mL) and 1 N HCl (100 mL). The organic layer was separated and washed with saturated brine (1×100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was vacuum dried to give 0.9 g of 3-[[(4-methoxy)tetrahydropyran-4-yl]phenylmethyl-thio]propionic acid as a clear, colorless oil: HRMS calcd for C16H22O4S 310.1239, found 310.1241.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:15]=[O:16])[CH:12]=[N:13][CH:14]=2)[O:3]1.CNC>>[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:17])[O:3][B:4]([C:9]2[CH:10]=[C:11]([CH2:15][OH:16])[CH:12]=[N:13][CH:14]=2)[O:5]1
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Agent: CNC
Product: CC1(C)OB(c2cncc(CO)c2)OC1(C)C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
10% Pd/c (100 mg) was flushed with argon in a flask, and ethanol was carefully added. 5(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-3-carbaldehyde (100 mg, 0.429 mmol) and dimethylamine (429 μL, 0.858 mmol) were added and the mixture stirred for 3 hrs under hydrogen. The reaction mixture was filtered through celite and the filterate was concentrated to afford an orang solid (81 mg, 80%). 1H NMR (300 MHz, CDCl3): δ 8.85 (d, 1H), 8.63 (d, 1H), 8.10 (d, 1M), 2.25 (s, 2H), 1.36 (s, 12H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH2:24]([O:26][CH2:27][CH2:28][NH:29][C:30]1[CH2:34][S:33][C:32](=[O:35])[N:31]=1)[CH3:25].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:34]2/[C:30]([NH:29][CH2:28][CH2:27][O:26][CH2:24][CH3:25])=[N:31][C:32](=[O:35])[S:33]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CCOCCNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CCOCCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (2 g) in 2-propanol (20 mL) were added 4-[(2-ethoxyethyl)amino]-1,3-thiazol-2(5H)-one (1.67 g) and piperidinium acetate (0.856 g). The reaction mixture was stirred at 80° C. for 2 hr, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.1 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19](=[O:27])[NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:3]=1.Br[CH2:29][CH:30]1[CH2:32][CH2:31]1>>[CH:30]1([CH2:29][N:24]2[CH2:25][CH2:26][CH:21]([NH:20][C:19](=[O:27])[CH2:18][O:17][C:4]3[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=3)[CH2:22][CH2:23]2)[CH2:32][CH2:31]1
Reactant: Cc1nc(OCC(=O)NC2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Reactant: BrCC1CC1
Product: Cc1nc(OCC(=O)NC2CCN(CC3CC3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 57 and bromomethyl cyclopropane in the same manner as in Example 32.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[C:13]1[CH:21]=[C:17]([C:18]([OH:20])=[O:19])[C:16]([OH:22])=[C:15]([I:23])[CH:14]=1.[CH2:24](O)[CH3:25]>>[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[C:13]1[CH:21]=[C:17]([C:18]([O:20][CH2:24][CH3:25])=[O:19])[C:16]([OH:22])=[C:15]([I:23])[CH:14]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)cc(I)c1O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(-c2ccc(F)cc2F)cc(I)c1O
Reaction time: 0.25 h

Procedure:
11.5 ml of ethyl alcohol and 2.9 ml of thionyl chloride (SOCl2) were placed in a flask under an inert atmosphere. It was stirred for 15 min and 1.67 g (4.56 mmol) of 5-(2,4-difluorophenyl)-3-iodo-salicylic acid was added. It was stirred continuously at room temperature until no evolution was observed by HPLC. The solvent was evaporated at low pressure and extracted with ethyl acetate. A crude of 97% purity was obtained and then purified by chromatography on silica gel.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][NH2:30])[CH:25]=[CH:26][CH:27]=1.CCN(C(C)C)C(C)C>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][NH:30][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: COc1cccc(CCN)c1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CCNC2=NC(=O)/C(=C/c3ccc4ncccc4c3)S2)c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-(3-Methoxy-phenyl)-ethyl amine and DIEA to give 2-[2-(3-methoxy-phenyl)-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 390 (MH+).
Reaction SMILES: COC1C=CC(C[O:8][C:9](=[O:37])[C@@H:10]2[CH2:14][C@@H:13]([O:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][N:11]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[O:25])=CC=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[N+:34]([C:31]1[CH:32]=[CH:33][C:28]([CH2:27][O:26][C:24]([N:11]2[CH2:12][C@H:13]([O:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][C@H:10]2[C:9]([OH:37])=[O:8])=[O:25])=[CH:29][CH:30]=1)([O-:36])=[O:35]
Reactant: COc1ccc(COC(=O)[C@@H]2C[C@@H](OC(=O)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1

Procedure:
Trans-1-(p-Nitrobenzyloxycarbonyl)-4-benzoyloxy-L-proline p-methoxybenzyl ester (61.3 g) and anisole (12.8 ml) were stirred together with 70 ml of trifluoroacetic acid at room temperature for 30 minutes. The reaction mixture was distilled to remove tri-fluoroacetic acid, and the residue was diluted with ethyl acetate and a saturated sodium bicarbonate solution. The precipitated crystals were separated by filtration and dissolved in methanol. The solution was acidified with 6N hydrochloric acid to pH 1.0, diluted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation to give trans-1-(p-nitrobenzyloxycarbonyl)-4-benzoyloxy-L-proline.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12.Cl.C(=O)([O-])[O-].[Na+].[Na+].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([NH:26][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cc(Cl)c2[nH]ncc2n1
Reactant: NCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(NCc2ccccc2)c2[nH]ncc2n1

Procedure:
7-Chloro-5-methyl-1H-pyrazolo[4,3-b]pyridine (1 g) and benzylamine (30 ml) were heated under reflux for 6 h. The benzylamine was removed in vacuo to yield an oily solid which was digested with 20% hydrochloric acid. The digest was basified with 10% sodium carbonate solution to yield two phases. The solid in the aqueous phase was filtered off to yield the product (0.71 g). The remaining oily phase was extracted with boiling chloroform (3×20 ml) and the extract dried (MgSO4) and evaporated to yield a second crop of product (0.54 g). The combined solids (1.25 g, 91%) were recrystallised from ethanol/petroleum ether to yield the 7-benzylamino-compound as white crystals m.p. 205°-206°.
Reaction SMILES: Cl.[O:2]=[C:3]1[N:9]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C@H:19]([CH2:41][C:42]3[CH:47]=[C:46]([Br:48])[CH:45]=[C:44]([Br:49])[CH:43]=3)[C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH:28]4[CH2:33][CH2:32][N:31](OC(C)(C)C)[C:30](=C=O)[CH2:29]4)[CH2:24][CH2:23]3)=[O:21])=[O:17])[CH2:12][CH2:11]2)[CH2:8][CH2:7][C:6]2[CH:50]=[CH:51][CH:52]=[CH:53][C:5]=2[NH:4]1.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>O>[O:2]=[C:3]1[N:9]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C@H:19]([CH2:41][C:42]3[CH:47]=[C:46]([Br:48])[CH:45]=[C:44]([Br:49])[CH:43]=3)[C:20](=[O:21])[N:22]3[CH2:27][CH2:26][N:25]([CH:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)[CH2:24][CH2:23]3)=[O:17])[CH2:12][CH2:11]2)[CH2:8][CH2:7][C:6]2[CH:50]=[CH:51][CH:52]=[CH:53][C:5]=2[NH:4]1
Reactant: CC(C)(C)ON1CCC(N2CCN(C(=O)[C@@H](Cc3cc(Br)cc(Br)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O[C@H](Cc1cc(Br)cc(Br)c1)C(=O)N1CCN(C2CCNCC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.8 mL HCl (3.2 M) were added to a solution of 180 mg (0.21 mmol) of (R)-1-(3,5-dibromo-benzyl)-2-[4-(1-tert-butoxy-carbonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 64) in 2 mL water and the reaction mixture was stirred for 3 h at RT. The mixture was combined with 25 mL EtOAc and 20 mL 17% Na2CO3 solution, the organic phase was separated off, the aqueous phase was extracted again with 25 mL EtOAc, the combined organic phases were washed with 10 mL saturated NaCl solution and dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was suspended in diethyl ether, the organic phase was decanted off and the residue was dried.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.ClCCl.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>CN(C1C=CN=CC=1)C.O>[CH2:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]
Reactant: COC(=O)c1ccc2c(c1)CCNC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CCN(C(=O)OCc1ccccc1)C2
Temperature: 0 °C

Procedure:
A mixture of 10 g methyl 1,2,3,4-tetrahydroisoquinoline-6-carboxylate hydrochloride, 10 ml triethylamine, and 15 ml dichloromethane with 525 mg DMAP is stirred at 0° C. and 9.3 ml of benzyl chloroformate are added dropwise. After stirring overnight at ambient temperature, the reaction mixture is added to cold water. The organic phase is washed, dried, and evaporated. The crude product is purified by a silica gel chromatography.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[CH3:9][N:10]([CH3:19])[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>C(O)C>[CH3:9][N:10]([CH3:19])[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[N:8][CH2:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: NCCc1cccs1
Reactant: CN(C)c1ccc(C=O)cc1
Solvent: CCO
Product: CN(C)c1ccc(C=NCCc2cccs2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 67 %

Procedure:
2-(2-Thienyl)-ethylamine (5 g, 39.4 mmol), 4-dimethylaminobenzaldehyde (5.9 g, 94 mmol) triethylamine (6 ml) and ethanol (150 ml) were mixed at room temperature. The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated to 75 ml by evaporation in vacuo and the solid formed was filtered and dried to afford 6.82 g (67%) dimethyl-{4-[(2-thiophen-2-yl-ethylimino)-methyl]-phenyl}-amine.
Reaction SMILES: [S-2:1].[Na+:2].[Na+].Cl[C:5]1[N:10]=[C:9]2[CH2:11][CH2:12][CH2:13][C:8]2=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]=1[C:20]#[N:21]>CN(C=O)C>[C:20]([C:6]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:13][CH2:12][CH2:11][C:9]2=[N:10][C:5]=1[S-:1])#[N:21].[Na+:2]
Reactant: [S-2]
Reactant: N#Cc1c(Cl)nc2c(c1-c1ccccc1)CCC2
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c([S-])nc2c(c1-c1ccccc1)CCC2
Temperature: 30 °C
Reaction time: 5 h

Procedure:
147 mg (1.89 mmol) of sodium sulfide are added to a solution of 400 mg (1.57 mmol) of the compound from Example 17A in 4.8 ml DMF, and the mixture was stirred at 30° C. for 5 h. Without further work-up, the reaction mixture was directly reacted further.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.C(OP([CH2:46][C:47]#[N:48])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:46]/[C:47]#[N:48])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C#N)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.8 %

Procedure:
To a mixture of 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-4-carbaldehyde (580 mg), diethylphosphonoacetonitrile (230 mg) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 56.0 mg) at 0° C., and the mixture was stirred at room temperature for 5 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give (E)-3-(3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazol-4-yl)-2-propenonitrile (460 mg, yield 76%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:2, v/v). The crystals were recrystallized from acetone-hexane. melting point: 184-185° C.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([N+:18]([O-])=O)[CH:11]=2)[CH2:6][CH2:5]1)[CH3:3]>C(O)C.[Pd]>[CH3:3][CH:2]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH:11]=2)[NH2:18])[CH2:8][CH2:9]1)[CH3:1]
Reactant: COc1ccc(N2CCN(C(C)C)CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N2CCN(C(C)C)CC2)cc1N
Yield: 78.3 %

Procedure:
A solution of 1-(1-methylethyl)-4-[4-(methyloxy)-3-nitrophenyl]piperazine (0.6 g, 2.15 mmol) in absolute ethanol (100 mL) was hydrogenated with 10% Pd/C (Lancaster) at 50 psi overnight. The catalyst was removed by vacuum filtration through a celite pad, rinsed with methanol, the filtrate was concentrated under reduced pressure, and the crude aniline was purified by chromatography on SiO2 (dichloromethane to 10% methanol/dichloromethane with 0.1% NH4OH) to provide 5-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)aniline as a white solid (0.42 g, 80%). ESIMS (M+H)+=250.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:17][C@H:18]3[C:23]([O:25]C(C)(C)C)=[O:24])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:38]CCl.Cl>C(OCC)C>[ClH:38].[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:17][C@H:18]3[C:23]([OH:25])=[O:24])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CCOCC
Product: O=C(O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 25; 20 mg, 0.04 mmol), dichloromethane (1 ml) and 1M HCl in diethyl ether (0.5 ml) was kept at room temperature for 2 weeks. The white solid was filtered off, washed with a 1:1 mixture dichloromethane:diethyl ether to give the title compound (11 mg).
Reaction SMILES: C(C(C(OCC)=O)=NC=C(N1CCOCC1)C1C=CC=CC=1)#N.[C:24]([C:26]([C:43]([O:45][CH3:46])=[O:44])=[N:27][C:28]([CH3:42])=[C:29]([N:36]1CCOCC1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)#[N:25]>>[C:24]([C:26]([C:43]([O:45][CH3:46])=[O:44])=[N:27][C:28]([CH3:42])=[C:29]([NH2:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)#[N:25]
Reactant: COC(=O)C(C#N)=NC(C)=C(c1ccccc1)N1CCOCC1
Agent: CCOC(=O)C(C#N)=NC=C(c1ccccc1)N1CCOCC1
Product: COC(=O)C(C#N)=NC(C)=C(N)c1ccccc1

Procedure:
One operates as in Example 12, but the 1-cyano-1-ethoxycarbonyl-4-morpholino-4-phenyl-2-aza-1,3-butadiene is replaced by 1-cyano-1-methoxycarbonyl-3-methyl-4-morpholino-4-phenyl-2-aza-1,3-butadiene and the reaction is effected at -30°C. 4.1 parts of 1-cyano-1-methoxycarbonyl-3-methyl-4-amino--4-phenyl-2-aza-1,3-butadiene are obtained after a reaction time of 3 days. After recrystallisation from methanol the product melts at 145°C.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.C(B(CC)CC)C.[CH2:19](Br)[CH:20]=[CH2:21].OO.[OH-].[Na+]>C1COCC1>[CH2:21]([CH:8]1[CH2:9][CH:4]2[O:11][CH2:1][CH2:2][O:3][CH:5]2[CH2:6][C:7]1=[O:10])[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CCB(CC)CC
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC1CC2OCCOC2CC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
A solution of 1,4-cyclohexanedione monoethylene ketal (9.37 g, 60 mmol) in THF (50 mL) was added to a suspension of KH (2.57 g, 63 mmol) in THF (200 mL) at rt under argon. After being stirred at rt (25° C.) for 30 min, the mixture was cooled to 0° C., and triethylborane (75 mL of 1M solution in THF) was added. The mixture was stirred for 30 min prior to the introduction of allyl bromide (7.8 mL, 90 mmol). After 1 h, H2O2 (30%, 50 mL) and NaOH (3M, 50 mL) were added at 0° C., and stirring was continued for 30 min at rt prior to removal of THF by rotary evaporation. The aqueous residue was extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated. Flash chromatography (30% ethyl acetate in hexanes) gave 10.1 g (86%) of 2 as an oil: IR (neat) 2957, 2887, 1714, 1438, 1140, 1049 cm-1 ; 1H NMR δ5.72 (m, 1H), 5.02 (m, 2H), 4.01 (m, 4H), 2.65 (m, 3H), 2.46 (m, 1H), 2.05 (m, 4H); 13C NMR δ210.6, 135.7, 116.6, 107.3, 64.6, 64.4, 45.7, 39.8, 38.0, 34.4, 33.1; MS m/z 196 (M30 ), 168, 155, 99.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].[CH:10](=O)/[CH:11]=[CH:12]/[CH3:13].C(OCC)(=O)C>Cl>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:4]=1[N:5]=[C:12]([CH3:13])[CH:11]=[CH:10]2)[CH3:2]
Reactant: C/C=C/C=O
Reactant: CCc1ccccc1N
Agent: Cl
Solvent: CCOC(C)=O
Product: CCc1cccc2ccc(C)nc12
Temperature: 25 °C
Yield: 59.1 %

Procedure:
A solution of 2-ethylaniline (4.00 g, 33.0 mmol) in 6 N HCl (40 mL) was added (E)-but-2-enal (6.20 ml, 75.9 mmol) dropwise at reflux. The reaction was heated at reflux for 3 hours. After cooling to ambient temperature, ethyl acetate (40 mL) was added. The aqueous layer was separated, basified with ammonium hydroxide to about pH 9, and extracted with DCM (2×50 mL). The combined organic layer was dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3:1 hexane/DCM) to give 8-ethyl-2-methylquinoline (3.34 g, 59.1%) as a solid.
Reaction SMILES: [C:1]1(/[C:7](=[N:22]\[O:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])/[CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+:33]>CO>[C:1]1(/[C:7](=[N:22]\[O:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O-:30])=[O:29])/[CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:33]
Reactant: O=C(O)CCCCO/N=C(\c1ccccc1)C(Cc1ccc(F)cc1)n1ccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C([O-])CCCCO/N=C(\c1ccccc1)C(Cc1ccc(F)cc1)n1ccnc1
Yield: 449.7 %

Procedure:
To a stirred solution of 1 g (0.0005 moles) of (±) (E)-5-[1-phenyl-2-(imidazol-1-yl)-2-(4-fluorobenzyl)ethylidene] aminoxypentanoic acid in 10 ml of methanol, 820 mg (0.015 moles) of a sodium methoxide solution in methanol are added. The reaction mixture is evaporated and the precipitate product is filtered off and dried yielding 970 mg (60%) of sodium (±)(E)-5-[1-phenyl-2-(imidazol-1-yl)-2-(4-fluorobenzyl)ethylidene]aminoxypentanoate.
Reaction SMILES: CO[C:3]1[CH:31]=CC(CS[C@@H]2CN(C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H](C(O)=O)C2)=C[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.FC(F)(F)C(O)=O.[N+](C1C=CC(COC(N=C(NC(OCC2C=CC([N+]([O-])=O)=CC=2)=O)N[CH2:65][C:66]([NH:68][CH:69]2[CH2:72]N[CH2:70]2)=O)=O)=CC=1)([O-])=O>C(#N)C>[CH:3]([N:68]([CH2:66][CH3:65])[CH:69]([CH3:70])[CH3:72])([CH3:31])[CH3:4]
Reactant: O=C(CNC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC1CNC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (1.43 g) in anhydrous acetonitrile (22 ml), N,N-carbonyldiimidazole (545 mg) was added. The resulting mixture was stirred at room temperature for 30 minutes. To the reaction mixture, N,N-diisopropylethylamine (581 μl) and a solution of the compound (2.78 g), which had been obtained in (2), in anhydrous acetonitrile (23 ml) were added and the mixture was stirred overnight at room temperature. To the reaction mixture, dichloromethane was added. The resulting mixture was washed with water and saturated saline, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure, whereby 2.57 g of the title compound were obtained as a colorless amorphous substance.