Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]3[NH:27][CH:28]=[CH:29][C:22]=23)[CH2:17][CH2:16]1)(C)(C)C>ClCCl>[NH:27]1[C:23]2=[N:24][CH:25]=[CH:26][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([NH2:14])[CH2:16][CH2:17]3)=[C:22]2[CH:29]=[CH:28]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccnc3[nH]ccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(c2ccnc3[nH]ccc23)CC1
Reaction time: 2.5 h
Yield: 96.7 %

Procedure:
Trifluoroacetic acid (1 ml) was added dropwise to a solution of [1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (19 mg, 0.06 mmol) in dichloromethane (1 ml), with stirring and cooling on ice. After 2.5 hours, the solvents were concentrated in vacuo and the crude product was purified on a basic resin NH2 cartridge (2 g, 15 ml) eluting with methanol to afford the required compound (12.5 mg, 0.058 mmol, 96%). LC-MS (LCT) Rt 0.95 [M+H]+217
Reaction SMILES: [CH:1]1([CH:6]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:25])=[CH:20][CH:19]=2)[C:7]2[S:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:6]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:25])=[CH:20][CH:19]=2)[C:7]2[S:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2sc3ccccc3c2C)C2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCC2)sc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclopentyl(3-methyl-1-benzothiophen-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (228 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (198 mg, 92%) as a white solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19].O>O1CCCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:18](=[O:19])[O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc2[nH]cnc2c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1ccc2[nH]cnc2c1)OCC(Cl)(Cl)Cl

Procedure:
To a solution of 1H-benzimidazol-5-amine (1.00 g, 7.51 mmol) and pyridine (0.73 ml, 9.01 mmol) in tetrahydrofuran (25 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.25 ml, 9.01 mmol), and the mixture was stirred at room temperature for 1.5 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 1.49 g (64.4%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:13][NH:14][C:15]([NH2:17])=[S:16])[C:9](=NO)[CH3:10])=[CH:4][CH:3]=1.[C:18](=O)([O-])[O-].[K+].[K+].C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[N:14][C:15]([S:16][CH3:18])=[N:17][C:9]=2[CH3:10])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=NO)C(=NNC(N)=S)c1ccc(Cl)cc1
Agent: [K+]
Solvent: O
Product: CSc1nnc(-c2ccc(Cl)cc2)c(C)n1
Reaction time: 0.25 h
Yield: 58 %

Procedure:
A mixture of 4'-chloro-2-hydroxyiminopropiophenone thiosemicarbazone (113.21 g), potassium carbonate (128.71 g) and water (990 ml) was refluxed for 25 hours with stirring, and the reaction mixture was treated with activated charcoal and filtered by suction. To the filtrate was added dropwise methyl iodide (76 g) with stirring, and the stirring was continued for 15 minutes at room temperature. The resulting solid was collected by filtration, washed with water and dissolved in chloroform. The solution was treated with silica gel and filtered, and the filtrate was evaporated under reduced pressure. The residue was washed with diisopropyl ether and dried to give a solid of 6-(4-chlorophenyl)-5-methyl-3-methylthio-1,2,4-triazine (61.1 g).
Reaction SMILES: [CH:1]1([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][C:11]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[CH:12][CH:13]=3)[C:8]2=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]([O:36][C:37](N=[N+]=[N-])=[O:38])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:23]([O:36][C:37]([N:19]1[CH2:18][CH2:17][N:16]([C:11]2[CH:10]=[C:9]3[C:14]([CH2:15][N:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[C:8]3=[O:22])=[CH:13][CH:12]=2)[CH2:21][CH2:20]1)=[O:38])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: [N-]=[N+]=NC(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=C1c2cc(N3CCNCC3)ccc2CN1C1CCCCC1
Product: O=C(OC(c1ccccc1)c1ccccc1)N1CCN(c2ccc3c(c2)C(=O)N(C2CCCCC2)C3)CC1

Procedure:
In the same manner as in Example 28, the title compound was prepared from the compound obtained in step (e) of Example 1 and benzhydryloxycarbonyl azide.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11]CC(C)=C)=[CH:9][C:8]([CH3:16])=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[CH:17]=[O:18].[CH3:19][C:20]1[CH:28]=C(CC(C)=C)C(C)=C2[C:21]=1C=CN2C=O>CN(C)C1C=CC=CC=1.CCCCCC>[OH:11][C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[C:8]([CH3:16])[C:9]=1[CH2:21][C:20]([CH3:28])=[CH2:19])[N:6]([CH:17]=[O:18])[CH2:5][CH2:4]2
Reactant: C=C(C)Cc1cc(C)c2ccn(C=O)c2c1C
Reactant: C=C(C)COc1cc(C)c2c(c1C)CCN2C=O
Solvent: CCCCCC
Solvent: CN(C)c1ccccc1
Product: C=C(C)Cc1c(C)c2c(c(C)c1O)CCN2C=O
Temperature: 220 °C
Reaction time: 7 h
Yield: 91 %

Procedure:
2,3-Dihydro-5-hydroxy group-4,7-dimethyl-6-(2-methyl-2-propenyl)-1H-indole-1-carbaldehyde 2,3-Dihydro-4,7-dimethyl-5-[(2-methyl-2-propenyl)oxy]-1H-indole-1-carbaldehyde (6.00 g, 24.4 mmol) was suspended in N,N-dimethylaniline (25 ml) and stirred under argon atmosphere at 220° C. for 7 hours. The reaction mixture was cooled and diluted with hexane (50 ml) and stirred for 30 minutes. The precipitated crystals were filtered and washed with hexane to obtain 5.45 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:33]=[CH:32][C:20]([O:21][C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25](OC)=[O:26])=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:34]([F:37])([F:36])[F:35])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[CH2:1]([N:8]1[C:16]([C:17]2[CH:33]=[CH:32][C:20]([O:21][C:22]3[CH:23]=[C:24]([CH2:25][OH:26])[CH:29]=[CH:30][CH:31]=3)=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:34]([F:36])([F:37])[F:35])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(Oc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1cccc(Oc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound was prepared from methyl 3-{4-[2-benzyl-7-(trifluoromethyl)-2H-indazol-3-yl]phenoxy}benzoate (Example 912; 30 mg, 0.060 mmol), which was dissolved in 1.5 ml diethylether and treated with LiAlH4. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and stirred for 15 minutes. The slurry was filtered and the product extracted with Et2O/NH4Cl (aq, sat). After evaporation of the solvents, the crude material was purified by HPLC using a gradient with an acidic mobile phase on an ACE-C8 column to afford 19.6 mg of analytically pure product.
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].[C:24]([O:31][CH:32](Cl)[CH3:33])(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C1(C)C=CC=CC=1.CCCCCC.[K+].[Br-]>>[C:24]([O:31][CH:32]([O:14][C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16])[CH3:33])(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Reactant: CCCCCC(=O)OC(C)Cl
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCCC(=O)OC(C)OC1=C(C(=O)Nc2ccccn2)N(C)S(=O)(=O)c2ccccc21

Procedure:
By the procedure of Example 11, piroxicam (2.00 g, 6.0 mmol) and alpha-chloroethyl hexanoate (3.51 g, 19.6 mmol) were converted to chromatographed title product as yellow oil which was crystallized from toluene/hexane (1.21 g, 2.5 mmol, 42.1%): mp 62°-65° C.; IR (KBr) 1755, 1676 cm-1 ; 1H NMR (CDCl3) delta 0.81 (t, J=7 Hz, 3H), 1.00-1.30 (m 4H), 1.35-1.53 (m, 2H), 1.73 (d, J=6 Hz, 3H), 2.08-2.32 (m, 2H), 3.12 (s, 3H), 6.39 (q, J=6 Hz, 1H), 7.05-7.32 (m, 1H), 7.57-7.95 (m, 5H), 8.30-8.43 (m, 2H), 9.58 (br s, 1H): precise mass calcd for C23H28N3O6S m/e (P+ +H) 474.1703, found 474.1645.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[CH2:18][CH:17]([NH2:24])[CH2:16][CH2:15]2.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.O>CC#N.CCOCC.C(Cl)(Cl)Cl>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:24][CH:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][C:21]([O:22][CH3:23])=[C:12]([O:11][CH3:10])[CH:13]=2)[CH2:18]1)=[O:9]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: COc1cc2c(cc1OC)CC(N)CC2
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: O
Product: COc1cc2c(cc1OC)CC(NC(=O)[C@@H]1CCC(=O)N1)CC2
Yield: 81.6 %

Procedure:
To L-pyroglutamic acid (1 g, 7.7 mmoles) in CH3CN (80 mL), 1,2,3,4-tetrahydro-6,7-dimethoxy-2-naphtylamine (1.59 g, 7.7 mmoles) and EEDQ (2.85 g, 11 mmoles) were added under stirring. To the resulting mixture water was added till complete solubilization and the solution was kept at room temperature under stirring for 20 hours. The solvent was evapored and the residue taken up with CHCl3. Et2O was added under stirring. The solid which formed was filtered off giving 2 g of the title compound. Yield 81%.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:28](=[O:29])[C:27]3[CH:26]=[C:25]([C:30]4[C:31]([O:38][CH3:39])=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=4)[N:24]([CH:40]([CH3:42])[CH3:41])[C:23]=3[CH:22]2[C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[Cl:49][C:46]1[CH:47]=[CH:48][C:43]([CH:22]2[C:23]3[N:24]([CH:40]([CH3:42])[CH3:41])[C:25]([C:30]4[C:31]([O:38][CH3:39])=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=4)=[CH:26][C:27]=3[C:28](=[O:29])[N:21]2[CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[CH:44][CH:45]=1
Reactant: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(Cl)cc2)N(C2CCN(C(=O)OC(C)(C)C)CC2)C3=O)c(OC)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(Cl)cc2)N(C2CCNCC2)C3=O)c(OC)n1
Reaction time: 1 h

Procedure:
TFA (32.4 mmol) was added to a solution of 4-[6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-5-yl]-piperidine-1-carboxylic acid tert-butyl ester (Step I06.1) (0.755 mmol) in CH2Cl2 (4 mL) at 0° C. After 1 h, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3 and diluted with EtOAc, THF and NaCl. The separated aqueous phase was extracted with EtOAc/THF (2×). The combined organic phases were dried (MgSO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a white solid (TFA-salt). tR: 4.34 min (HPLC 4); ESI-MS: tR=0.82 min, [M+H]+ 496/498(LC-MS 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:45])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:31]([O:33]CC)=[O:32])([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH2:14][C:13](=[O:36])[NH:12][CH:11]3[C:37]3[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=3[CH3:44])[C:5]2=[CH:4][CH:3]=1.O[Li].O.O>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:45])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:31]([OH:33])=[O:32])([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH2:14][C:13](=[O:36])[NH:12][CH:11]3[C:37]3[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=3[CH3:44])[C:5]2=[CH:4][CH:3]=1
Reactant: CCCC(CCC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)OCC
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CCCC(CCC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-propyl-butoxy)-phenyl]-2′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (280 mg, 0.41 mmol), LiOH.H2O (1 g, 24.6 mmol), H2O (12 mL) and methanol (38 mL) was refluxed for 2 h. After cooled to room temperature, the solution was concentrated and then the mixture was acidified to “pH” 1-2 by addition of concentrated HCl solution and then extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated to give the title compound as a light yellow solid (220 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[N:15]3[C:11]([O:12][CH:13]=[CH:14]3)=[N:10][C:9]=2[C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=2[F:24])=[CH:4][CH:3]=1.C(O)CCC.O.[NH2:31][NH2:32]>O.CCOC(C)=O>[NH:31]([C:2]1[N:7]=[N:6][C:5]([C:8]2[N:15]3[C:11]([O:12][CH:13]=[CH:14]3)=[N:10][C:9]=2[C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=2[F:24])=[CH:4][CH:3]=1)[NH2:32]
Reactant: Fc1cc(F)c(-c2nc3occn3c2-c2ccc(Cl)nn2)cc1F
Reactant: NN
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: O
Product: NNc1ccc(-c2c(-c3cc(F)c(F)cc3F)nc3occn23)nn1
Temperature: 100 °C
Yield: 77.3 %

Procedure:
A flask was charged with 5-(6-chloropyridazin-3-yl)-6-(2,4,5-trifluorophenyl)imidazo[2,1-b]oxazole (0.25 g, 0.71 mmol; prepared using General Procedure H from 3,6-dichloropyridazine followed by General Procedure I from 5-iodo-6-(2,4,5-trifluorophenyl)imidazo[2,1-b]oxazole [Example #7, step C]) and n-butanol (2.0 mL) to give a tan suspension. Water (1.0 mL) was added, followed by hydrazine hydrate (0.42 mL, 8.6 mmol). The resulting mixture was heated at about 100° C. for about 20 h. To the cooled reaction mixture were added EtOAc and water and the layers were separated. The aqueous solution was extracted with EtOAc (2×50 mL) and the combined organic extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound (0.19 g, 77%): LC/MS (Table 1, Method b) Rt=1.58 min; MS m/z 347.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:18]3=4)[CH2:10][CH:9]2[CH3:33])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>CN(C)C=O>[CH3:42][O:41][C:39](=[O:40])[CH2:38][O:32][C:30]1[CH:29]=[CH:28][C:19]2[O:20][CH2:21][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:17](=[CH:16][CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([OH:34])[CH:9]([CH3:33])[CH2:10]3)[C:18]=2[CH:31]=1
Reactant: CC1CN(CCC=C2c3cc(O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)C1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.5 %

Procedure:
A solution of 5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3-methyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-ol (0.14 g, 0.28 mmol) in dimethylformamide (3 mL) was treated with sodium hydride (60% in mineral oil, 0.016 g, 0.4 mmol) and methyl bromoacetate (0.038 mL, 0.4 mmol). The mixture was allowed to stir at rt for 2 hr, then quenched with aqueous brine, and extracted with ethyl acetate (3×10 mL). The combined organics were washed several time with water, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate→87:10:3 ethyl acetate/methanol/triethylamine) to yield 0.07 g (50%) of the title compound, ESI-MS m/z: 549 [M+1].
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[N+:24]([C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)([O-:26])=[O:25].N1C=CC=CC=1>ClCCl>[F:23][C:2]([F:22])([F:1])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([S:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([N+:24]([O-:26])=[O:25])[CH:28]=3)(=[O:34])=[O:35])[CH2:20][CH2:21]2)=[CH:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(S(=O)(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
1,1,1,3,3,3-Hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)propan-2-ol (2.366 mmol, 810 mg), 3-nitrobenzene-1-sulfonyl chloride (2.366 mmol, 524 mg) and pyridine (4.73 mmol, 0.383 mL, 374 mg) were combined in dichloromethane (20 mL) and stirred at room temperature for 1 hour. The reaction mixture was washed with water, and the organic layer was separated, dried and concentrated under vacuum. The residue was purified by SCX chromatography to afford the title compound (875.3 mg). MS (ESI) m/z 528.0 [M+H]+
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(NS(CCOC)(=O)=O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[C:33]12([CH2:43][O:44][C:45]3[C:60]([Cl:61])=[CH:59][C:48]([C:49]([NH:51][S:52]([CH2:55][CH2:56][O:57]C)(=[O:54])=[O:53])=[O:50])=[C:47]([F:62])[CH:46]=3)[CH2:42][CH:37]3[CH2:38][CH:39]([CH2:41][CH:35]([CH2:36]3)[CH2:34]1)[CH2:40]2>>[C:33]12([CH2:43][O:44][C:45]3[C:60]([Cl:61])=[CH:59][C:48]([C:49]([NH:51][S:52]([CH2:55][CH2:56][OH:57])(=[O:54])=[O:53])=[O:50])=[C:47]([F:62])[CH:46]=3)[CH2:34][CH:35]3[CH2:41][CH:39]([CH2:38][CH:37]([CH2:36]3)[CH2:42]1)[CH2:40]2
Reactant: COCCS(=O)(=O)NC(=O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: COCCS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: O=C(NS(=O)(=O)CCO)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 121 and making variation as required to replace 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-((2-methoxyethyl)sulfonyl)benzamide with 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluoro-N-((2-methoxyethyl)sulfonyl)benzamide, the title compound was obtained as a colorless solid (0.04 g, 15%): 1H NMR (300 MHz, CDCl3) δ 8.74-8.61 (m, 1H), 8.11-8.03 (m, 1H), 6.75-6.64 (m, 1H), 4.23-4.08 (m, 2H), 3.86-3.76 (m, 2H), 3.59 (s, 2H), 2.50-2.40 (m, 1H), 2.12-1.96 (m, 3H), 1.86-1.62 (m, 12H); MS (ES−) m/z 444.3 (M−1), 446.3 (M−1);
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14]C(=O)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:20]([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])C.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C(O)C>[CH2:25]([O:24][C:20]1([O:21][CH2:22][CH3:23])[CH2:12][CH2:11][CH:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:15][CH2:14]1)[CH3:26]
Reactant: O=C1CCC(COCc2ccccc2)CC1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC1(OCC)CCC(COCc2ccccc2)CC1

Procedure:
4-Benzyloxymethylcyclohexanone (168 g, 0.77 mol) is dissolved in ethanol (2000 mL), and then triethylorthoformate (350 mL) and p-toluenesulfonic acid (13.3 g) are added. The resulting mixture is stirred and refluxed for 6 hours. After addition of triethylamine (10.5 mL) at room temperature, the mixture is concentrated (500 mL). After addition of sat. NaHCO3 aq., the resulting mixture is extracted with EtOAc. The water layer is extracted with EtOAc and the combined organic layer is washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude mixture is purified by short pad silica gel column chromatography to afford (4,4-diethoxycyclohexylmethoxymethyl)benzene.
Reaction SMILES: [O:1]=[CH:2]/[C:3](/[CH3:10])=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6]>CO>[O:1]=[CH:2][CH:3]([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)/C=C(\C)C=O
Solvent: CO
Product: CCOC(=O)CC(C)C=O

Procedure:
In another example, an all-trans-13,14-dihydroretinol can be synthesized as follows. All reagents can be purchased from Sigma or Fluka and used without additional purification. Solvents can be dried under standard procedures prior to use. All operations with retinoids may be performed under dim red light unless otherwise specified. B-Ionone can be condensed with triethyl phosphonoacetate in anhydrous tetrahydrofuran in the presence of NaH to give ethyl trans-β-ionylideneacetate. This ester may then be reduced with LiAlH4 to alcohol and reacted overnight with triphenylphosphine hydrobromide to give Wittig salt. Ethyl 4-oxo-3-methylcrotonate can be hydrogenated in methanol with H2 using 10% palladium on carbon as a catalyst to yield ethyl 4-oxo-3-methylbutyrate, which may then be reacted with Wittig salt using t-BuOK as a base in anhydrous CH2Cl2 in the presence of 18-crown-6. The obtained mixture of ethyl 11-cis and all-trans-13,14-dihydroretinoates can be reduced with LiAlH4 to 13,14-dihydroretinols, and all-trans-isomer separated from 11-cis-dihydroretinol by flash chromatography of silica gel using 5% ethyl acetate in hexane. NMR data can be recorded on a Bruker 500-MHz spectrometer using CDCl3 as an internal standard. 1H NMR analysis of synthetic all-trans-13,14-dihydroretinol can yield: NMR (CDCl3, δ, ppm) 6.41 (dd, 1H, H-12, J=11.3, 14.75 Hz), 6.10-6.12 (m, 3H, H-7, H-8, H-10, J=15.7 Hz), 5.6 (dd, 1H, H-11, J=8.34, 14.95 Hz), 3.67 (m, 2H, CH2-15), 2.41 (m, 1H, H-13, J=6.7 Hz), 1.96 (m, 2H, CH2-14), 1.90 (s, 3H, CH3-9), 1.69 (s, 3H, CH3-5), 1.46 (m, 2H, CH2-2), 1.6 (m, 4H, CH2-3, CH2-4), 1.06 (d, 3H, CH3-13 J=6.7 Hz), 1.00 (s, 6H, 2×CH3-1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:28])[C:5]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[CH:6][N:7]2[CH2:16][CH2:17][CH:18]=[O:19].Cl([O-])=[O:30].[Na+].CC(=CC)C.[Na].O.O.P(O)(O)(O)=O>O.ClCCl.C(O)(C)(C)C>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:28])[C:5]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)=[CH:6][N:7]2[CH2:16][CH2:17][C:18]([OH:30])=[O:19]
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCC=O)c12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)(C)O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCC(=O)O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
3-[5-Fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propionaldehyde (1.0 g, 2.61 mmol) was dissolved in water (10 ml), tert-butyl alcohol (20 ml) and dichloromethane (20 ml). Sodium chlorite (3.2 g, 35.4 mmol), 2-methyl-2-butene (19.86 gm, 283 mmol) and sodium-dihydrogenphosphate dihydrate (2 g, 2.61 mmol) were added to the resulting solution, and the solution was stirred at room temperature for 1 hour. Water was added to the reaction mixture, the mixture was extracted with dichloromethane, and then washed with water and dried over anhydrous sodium sulfate. The dried product was concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:ethyl acetate=50:50→0:100). The purified product was concentrated to dryness under reduced pressure, giving a pale yellow powder of 3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propionic acid (710 mg, yield: 68%).