Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([CH3:3])[CH3:2].[CH3:12][C:13]([S@@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14]>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)/[CH:7]=[N:18]/[S@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C=O)c1
Reactant: CC(C)(C)[S@@](N)=O
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: C1CCOC1
Product: CC(C)c1cccc(/C=N/[S@@](=O)C(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a solution of 3-isopropylbenzaldehyde (0.711 g, 4.75 mmol) in THF (5 mL) was added (S)-2-methyl-2-propanesulfinamide (0.534 g, 4.32 mmol) and Ti(OiPr)4 (2.75 mL, 8.64 mmol). The resulting mixture was allowed to stir over night at rt where it was then quenched with aqueous NH4Cl (5 mL) and diluted with EtOAc (100 mL). The mixture was then filtered through celite using excess EtOAc to rinse, concentrated to an oil crude and separated by silica gel (EtOAc:Hexanes) to isolate the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13]CC)=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.CCO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]1([O:19][CH2:18][CH2:17][CH2:16][C:7]2[C:6]3[C:10](=[C:2]([C:5]4[CH:4]=[CH:3][CH:2]=[CH:10][C:6]=4[C:7]#[C:8][CH3:11])[CH:3]=[CH:4][CH:5]=3)[NH:9][C:8]=2[C:11]([OH:13])=[O:12])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCOc1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: CC#Cc1ccccc1-c1cccc2c(CCCOc3cccc4ccccc34)c(C(=O)O)[nH]c12

Procedure:
A suspension of EXAMPLE 1C (0.034 g, 0.075 mmol), EXAMPLE 420B (0.1 g, 0.68 mmol), tetrakis(triphenylphosphine)palladium (0.004 g, 0.006 mmol), and solution of Na2CO3 (2M, 0.5 ml, 1 mmol) in dimethoxyethane/EtOH/H2O (7/2/3) 3 mL was heated under microwave conditions at 150 C for 30 min. The reaction mixture was quenched with aq. HCl (1M, 0.4 mL) and product extracted with ethyl acetate (3×7 mL). The organic phases were filtered through a drying cartridge (MgSO4, Alltech Asoc., 2 g) and concentrated under reduced pressure. The crude product was purified by chromatography on SiO2 using 1% AcOH in EtOAc as eluent. 1H NMR (300 MHz, DMSO-d6) 12.39 (br s, 1H), 10.28 (s, 1H), 8.25 (dd, 1H), 7.87 (d, 1H), 7.71 (d, 1H), 7.38-7.56 (m, 8H), 7.21 (d, 1H), 7.09 (dd, 1H), 6.89 (d, 1H), 4.20 (m, 2H), 3.38 (m, 2H), 2.24 (m, 2H), 1.91 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:11][CH2:10][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C)c(Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CBr)c(Cl)c1
Reaction time: 3 h
Yield: 98 %

Procedure:
Heat a solution of 2-chloro-4-methoxy-1-methyl-benzene (2.0 g, 13 mmol), N-bromosuccinimide (2.7 g, 15 mmol), and benzoyl peroxide (50 mg) in CCl4 (50 mL) to reflux and stir for 3 hr. Cool the reaction to room temperature and quench with water. Extract the aqueous with CH2Cl2, dry over MgSO4, and filter. Remove the solvent to afford 3.0 g (98%) of the desired product.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([CH3:17])[N:16]=1)[C:8](N(OC)C)=[O:9])[CH:2]([CH3:4])[CH3:3].[CH2:18]1COCC1>C[Mg]Br.CCOCC>[CH2:1]([C:5]1[CH:6]=[C:7]([C:8](=[O:9])[CH3:18])[CH:14]=[C:15]([CH3:17])[N:16]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1cc(C)nc(CC(C)C)c1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(=O)c1cc(C)nc(CC(C)C)c1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-isobutyl-N-methoxy-6,N-dimethyl-isonicotinamide (410 mg, 1.74 mmol) in THF (10 mL), methyl magnesium bromide (1.17 mL of a 3 M solution in ether, 3.47 mmol) is added at 5° C. The mixture is stirred at 5° C. for 1.5 h. The reaction is quenched by adding NH4Cl. The mixture is diluted with EA (50 mL), washed with sat. aq. NaHCO3, dried over Na2SO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 1-(2-isobutyl-6-methyl-pyridin-4-yl)-ethanone (280 mg) as a colourless oil. LC-MS: tR=0.84 min.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[O:23][C:14]2=[C:15]3[C:20](=[CH:21][CH:22]=[C:13]2[O:12][CH2:11]1)[N:19]=[CH:18][CH:17]=[CH:16]3)C1C=CC=CC=1.Cl.[C:25]1(C)C=CC=CC=1>>[CH3:25][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]3[O:12][CH2:11][C@H:10]([CH2:9][OH:8])[O:23][C:14]3=2)[N:19]=1
Reactant: c1ccc(COCC2COc3ccc4ncccc4c3O2)cc1
Reactant: Cc1ccccc1
Agent: Cl
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CO)O3
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
A mixture of crude (2S)-2[(benzyloxy)methyl-2,3-dihydro[1,4]dioxino [2,3-f]-quinoline product mixture (57.6 g, 0.179 mol) from example 7 in toluene (300 mL) was mixed with 20% HCl (436 g, 3.59 mol) and heated at 80° C. After 30 min, the reaction mixture was cooled to room temperature. The two layers were separated. A 30% NH4OH solution (400 mL) was added to the aqueous layer at 10–20° C. to pH 10. This was stirred for 30 min, the solid was filtered, washed with water and recrystallized from CH3OH (200 mL) to give 25.7 g (61.9%) of the title alcohol as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)O)[CH:7]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([CH2:8][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:14][CH:15]=2)[CH:7]=1
Reactant: OC(c1ccc(OC(F)(F)F)cc1)c1cc(Br)ccc1Cl
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: FC(F)(F)Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reaction time: 16 h
Yield: 71.4 %

Procedure:
(5-bromo-2-chloro-phenyl)-[4-(trifluoromethoxy)phenyl]methanol 6g (4.37 g, 11.5 mmol) was dissolved in 35 mL dichloromethane, followed by addition of triethyl silane (5.49 mL, 34.4 mmol) and dropwise addition of boron trifluoride etherate (2.9 mL, 22.9 mmol). The reaction mixture was stirred for 16 hours. Thereafter, the reaction mixture was concentrated under reduced pressure and partitioned after 20 mL saturated sodium bicarbonate solution were added. The aqueous phase was extracted with dichloromethane (25 mL×3) and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography with elution system C to obtain the title compound 4-bromo-1-chloro-2-[[4-(trifluoro-methoxy)phenyl]methyl]benzene 6h (3.0 g, colourless grease), yield: 71.6%. 1H NMR (400 MHz, CDCl3): δ 7.33-7.29 (m, 2H), 7.26-7.24 (m, 1H), 7.21-7.18 (m, 2H), 7.15 (d, 2H), 4.06 (s, 2H).
Reaction SMILES: [O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][N:29]2C(=O)C3=CC=CC=C3C2=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.NN.C(OCC)C>C(O)C>[O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][NH2:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[Si:2]([C:15]([CH3:17])([CH3:18])[CH3:16])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)[Si](OCCC1(CCN2C(=O)c3ccccc3C2=O)CCCCC1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CC(C)(C)[Si](OCCC1(CCN)CCCCC1)(c1ccccc1)c1ccccc1
Yield: 104 %

Procedure:
To a solution of N-[2-[1-[2(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]-ethyl]phthalimide (1.52 g) dissolved in ethanol (30 mL) was added hydrazine monohydrate. The reaction solution was heated under reflux for 4 hours. To this was added diethyl ether and the insolbles were filtered off. The solvent was then distilled off under reduced pressure. To this was added chloroform, and the solution was made basic by addition of a 1N aqueous hydroxide solution. The solution was then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then, the solvent was distilled off under reduced pressure to give the title compound (1.20 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:12]([NH2:14])=[O:13].[CH:15]1([CH2:21][C:22](OC)=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(O)C.[H-].[Na+]>O>[CH:15]1([CH2:21][C:22]2[NH:14][C:12](=[O:13])[C:3]3[CH:4]=[N:5][N:6]([CH:7]4[CH2:11][CH2:10][CH2:9][CH2:8]4)[C:2]=3[N:1]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC(=O)c1cnn(C2CCCC2)c1N
Reactant: COC(=O)CC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=c1[nH]c(CC2CCCCC2)nc2c1cnn2C1CCCC1

Procedure:
Under argon, 75 mg (0.39 mmol) of 5-amino-1-cyclopentyl-1H-pyrazole-4-carbox-amide and 183 mg (1.16 mmol, 3 equiv.) of methyl cyclohexylacetate are introduced into 1.5 ml of absolute ethanol. At 0° C., 54 mg of sodium hydride (60% dispersion in mineral oil; 1.35 mmol, 3.5 equiv.) are slowly added in a countercurrent of argon. The resulting mixture is slowly heated and stirred under reflux for 18 h. For workup, 20 ml of water are added, and the mixture is extracted several times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. The crude product is purified by preparative HPLC.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:19][CH:20]=[CH2:21])[C:15]([NH:17][CH3:18])=O)=[CH:10][CH:9]=1.O.[OH-].[Na+]>CCOCC>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH2:19][CH:20]=[CH2:21])[CH2:15][NH:17][CH3:18])=[CH:12][CH:13]=1
Reactant: C=CCC(C(=O)NC)c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: C=CCC(CNC)c1ccc(F)cc1
Yield: 85.4 %

Procedure:
Lithium aluminium hydride (0.11 g, 2.9 mmol) was slurried in ether (15 mL) under nitrogen with stirring. A solution of 2-(4-fluorophenyl)-N-methylpent-4-enamide (0.20 g in 5 mL of ether, 0.97 mmol) was added carefully and the mixture was then stirred at room temperature overnight. Water (0.11 mL) was added dropwise followed by a solution of NaOH (0.11 mL of a 15% aqueous solution) and then water (0.33 mL) again. The mixture was stirred for 10 min and then filtered. The filter cake was washed with ether and the combined solutions were washed several times with water. The organic solution was dried over MgSO4 and the solvent was removed by evaporation. There was obtained 0.16 g (86%) of [2-(4-fluorophenyl)pent-4-en-1-yl]methylamine as an oil. 1H NMR (400 MHz, CDCl3): 2.4-2.6 (m, 5H), 2.7-2.9 (m, 3H), 4.9-5.0 (m, 2H), 5.6-5.8 (m, 1H), 7.0 (m, 2H), 7.1 (m, 2H); LCMS: m/z 194 (M+1)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[N:8]([CH3:17])[C:7]=1[C:18]([F:21])([F:20])[F:19])=[O:5])C.[OH-].[K+].Cl>C1COCC1.CO.O>[CH3:16][O:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:18]([F:20])([F:21])[F:19])[N:8]2[CH3:17])=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)n(C)c2cc(OC)ccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc2c(C(=O)O)c(C(F)(F)F)n(C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
To a solution of 6-methoxy-1-methyl-2-trifluoromethyl-1H-indole-3-carboxylic acid ethyl ester 76e (1.5 g, 4.98 mmole) in 10 ml THF and 5 ml MeOH was added a solution of KOH (2.8 g, 50 mmole) in 5 ml water with ice bath cooling. The mixture was warmed to room temperature and stirred overnight. Concentrated aqueous HCl solution was added to adjust the pH to 1. The mixture was extracted with EtOAc and the combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was further purified by column chromatography (eluting with 1-5% MeOH in CH2Cl2) to give 880 mg product (65% yield). 1H NMR (300 MHz, CD3OD) δ7.90 (1H, d, J=9.0 Hz), 7.01 (1H, d, J=2.1 Hz), 6.91 (1H, dd, J=2.1, 9.0 Hz), 3.90 (3H, s), 3.88 (3H, s).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.S(Cl)(Cl)=O.[CH3:14]O>>[CH3:14][O:8][C:7]([C@H:4]1[CH2:5][CH2:6][C@@H:2]([NH2:1])[CH2:3]1)=[O:9]
Reactant: N[C@@H]1CC[C@H](C(=O)O)C1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1S,3R)-3-aminocyclopentanecarboxylic acid (1.0 g, 7.4 mmol) in dry MeOH (10 mL) under N2 at 0° C. was added thionyl chloride (2.7 mL, 36.8 mmol) dropwise. The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction was concentrated in vacuo. The resultant residue was washed with anhydrous diethyl ether (3×30 mL) and dried under high vacuum to afford 1.87 g of (1S,3R)-3-amino-cyclopentanecarboxylic acid methyl ester as the HCl salt that was used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.[F:23][C:24]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[C:28]([F:40])=[CH:27][C:25]=1[NH2:26]>>[CH2:8]([NH:9][C:11](=[O:12])[NH:26][C:25]1[C:24]([F:23])=[CH:30][C:29]([C:2]2[N:3]=[C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]3[CH3:22])[C:5]3[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=3[N:7]=2)=[C:28]([F:40])[CH:27]=1)[CH3:6]
Reactant: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Reactant: CC1(C)OB(c2cc(F)c(N)cc2F)OC1(C)C
Product: CCNC(=O)Nc1cc(F)c(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)OCC)C3)cc1F
Yield: 13 %

Procedure:
Method as described for example 47 using (S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11) and 2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as starting materials. The mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and the solvent removed in vacuo. The residue was purified by prep. HPLC at low pH, yielding the title compound (25 mg, 0.06 mmol, 13%).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:9][C:10]1[CH:30]=[CH:29][C:13]([O:14][C@@H:15]([CH:26]([CH3:28])[CH3:27])[C@H:16]([OH:25])[CH2:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][CH:11]=1.O.CCOCC>CN(C)C=O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH:15]([CH:26]([CH3:27])[CH3:28])[CH:16]([O:25][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)[C@H](Oc1ccc(Br)cc1)[C@H](O)CCc1cccnc1
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(Oc1ccc(Br)cc1)C(CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.3 %

Procedure:
Solid tert-butyldimethylsilyl chloride (0.46 g) was added to a solution of (3R, 4S)-4-(4-bromophenoxy)-5-methyl-1-pyridin-3-yl-3-hexanol (0.93 g) andimidazole (0.26 g) in dry dimethylformamide (12 ml) and the resulting solution stirred at room temperature for 3 days. Water (100 ml) and ether (100 ml) were added. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluting with dichloromethane then dichloromethane: hexane (1:1) to give the sub-title compound as an oil (0.70 g).
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH3:20])=[O:18]>O>[O:9]=[C:6]1[CH2:7][CH2:8][N:3]([C:17]([O:19][CH3:20])=[O:18])[CH2:4][CH2:5]1
Reactant: COC(=O)Cl
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)N1CCC(=O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a solution of 4-piperidone monohydrate hydrochloride (3.07 g, 20.0 mmol) in water (12 mL) cooled to 0° C. was added a cooled solution (also at 0° C.) of potassium carbonate (6.97 g, 50.4 mmol) in water (40 mL). Methyl chloroformate (2.80 g, 29.6 mmol) was added, and the mixture was allowed to stir for 2 h, still at 0° C. Then, the mixture was extracted with dichloromethane (3×40 mL), and the extract was dried over MgSO4, and concentrated. The obtained residue was chromatographed (silica gel, dichloromethane to 95:5 dichloromethane/methanol) to give the title compound (2.96 g, 94%) as a viscous clear liquid:
Reaction SMILES: CC[O:3][C:4](/[CH:6]=[C:7](/[CH:9]=[CH:10]/[CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]1[C:17]([CH3:26])=[CH:18][C:19]([O:24][CH3:25])=[C:20]([CH3:23])[C:21]=1[CH3:22])\[CH3:13])\[CH3:8])=[O:5].[OH-].[K+].CC(C)=O.Cl>C(O)C>[CH3:26][C:17]1[C:16](/[CH:15]=[CH:14]/[C:12](/[CH3:13])=[CH:11]/[CH:10]=[CH:9]/[C:7](/[CH3:8])=[CH:6]/[C:4]([OH:5])=[O:3])=[C:21]([CH3:22])[C:20]([CH3:23])=[C:19]([O:24][CH3:25])[CH:18]=1
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(C)/C=C/c1c(C)cc(OC)c(C)c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Product: COc1cc(C)c(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)c(C)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 69 %

Procedure:
Acitretin was obtained by stirring the contents of thirty 25 mg capsules of etretinate in ethyl acetate for 4 days, filtering and concentrating to dryness to give recovery of greater than 90% of the theoretical quantity of etretinate. This etretinate was then dissolved in 20 ml of ethanol, 3 ml of 4N KOH, and enough acetone to make the solution one phase. The solution was stirred at room temperature for 2 1/2 days, acidified to pH 3 with 3N HCl, and extracted with ethyl acetate. The ethyl acetate was washed with brine, dried over Na2SO4, filtered and concentrated to give a 69% yield of acitretin.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Cc1cc(Cl)nc(N2CCCC2)n1
Product: COc1cc(Nc2cc(C)nc(N3CCCC3)n2)ccc1-n1cnc(C)c1
Yield: 58 %

Procedure:
The title compound was prepared from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.30 mmol) and 4-chloro-6-methyl-2-pyrrolidin-1-yl-pyrimidine (65 mg, 0.33 mmol, example 95a) in analogous manner as described in example 90. The crude product was purified by stirring with diethyl ether. It was obtained in 58% yield as a light brown solid. MS ISP (m/e): 365.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.30 (s, 1H), 8.06 (s, 1H), 7.65 (s, 1H), 7.21 (d, 1H), 7.15 (d, 1H), 7.02 (s, 1H), 5.91 (s, 1H), 3.81 (s, 3H), 3.50 (br m, 4H), 2.15 (s, 3H), 2.14 (s, 3H), 1.90 (br m, 4H).
Reaction SMILES: [N:1]([CH2:4][C:5]([N:7]1[CH2:12][CH2:11][O:10][CH:9]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:8]1)=[O:6])=[N+:2]=[N-:3].O.O=[C:25]1O[C@H:30]([C@H:32](CO)O)[C:28]([O-])=[C:26]1O.[Na+].C#CCCC>CC(O)(C)C.CCOC(C)=O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:28]([C:26]1[N:3]=[N:2][N:1]([CH2:4][C:5]([N:7]2[CH2:12][CH2:11][O:10][CH:9]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:8]2)=[O:6])[CH:25]=1)[CH2:30][CH3:32]
Reactant: [N-]=[N+]=NCC(=O)N1CCOC(C(=O)OCc2ccccc2)C1
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Cu+2]
Agent: C#CCCC
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: CCCc1cn(CC(=O)N2CCOC(C(=O)OCc3ccccc3)C2)nn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 875 %

Procedure:
In a sealable vessel, benzyl 4-(2-azidoacetyl)morpholine-2-carboxylate (0.096 g, 0.32 mmol) was suspended in t-BuOH (1 mL) and water (1 mL) was added. An aqueous solution of sodium ascorbate (1.0 M, 0.032 ml, 0.032 mmol) and an aqueous solution of copper(II) sulfate pentahydrate (0.30 M, 0.079 ml, 0.024 mmol) were added, followed by pent-1-yne (0.040 ml, 0.41 mmol). The vessel was sealed and placed in a 65 deg oil bath, whereupon the mixture was stirred for 14 h. The reaction mixture was cooled to RT, taken up in EtOAc (60 mL), and the organic layer was extracted with dilute sodium bicarbonate (5 mL), dilute brine (5 mL), and saturated brine (5 mL), then was dried over sodium sulfate and concentrated. The residue was purified through silica gel (25 mL) eluting with EtOAc, affording the title compound (105 mg, 0.28 mmol). MS m/z 373 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][C@H:14]1[CH2:19][O:18][CH2:17][CH2:16][NH:15]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:13][C@H:14]1[CH2:19][O:18][CH2:17][CH2:16][N:15]1[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C[C@H]1COCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1cc(N2CCOC[C@@H]2C)ccc1N
Temperature: 100 °C
Yield: 42.7 %

Procedure:
4-chloro-2-(methyloxy)-1-nitrobenzene (6.71 g, 29.7 mmol), (3S)-3-methylmorpholine (Synthetech Inc., 2.0 g, 19.8 mmol), cesium carbonate (13.0 g, 40 mmol), Pd2dba3 (1.83 g, 2.0 mmol), and XANTPHOS (1.73 g, 3.0 mmol) were added to degassed dioxane (200 mL) and heated to 100° C. under a water cooled reflux condenser for 12 hours. The dioxane was removed under reduced pressure and the solids were partitioned between methylene chloride (500 mL) and water (500 mL). The organic layer was dried over sodium sulfate, taken to a residue under reduced pressure, and purified by chromatography on SiO2to give 4-[(3S)-3-methyl-4-morpholinyl]-2-(methyloxy)aniline as a yellow solid (2.46 g, 8.45 mmol, 43% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.22 (dd, J=6.41, 4.58 Hz, 3 H), 3.22-3.29 (m, J=12.11, 8.03, 4.03, 4.03 Hz, 1 H), 3.31-3.37 (m, 1 H), 3.59-3.69 (m, 1 H), 3.78 (d, J=2.93 Hz, 2H), 3.92 (d, J=4.21 Hz, 4 H), 4.02 (s, 1 H), 6.25 (s, 1 H), 6.32-6.39 (m, 1 H), 7.98 (dd, J=9.34, 4.21 Hz, 1 H).
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].C([Li])CCC.[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=O>O1CCCC1.CCCCCC>[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[C:2]([CH3:4])[CH3:3]
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCCCCCCCCCCBr
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)=CCCCCCCCCCCBr
Temperature: -40 °C

Procedure:
Isopropyltriphenylphosphonium iodide (6 g, 14 mmoles) was suspended in tetrahydrofuran (120 ml), stirred at -40° C. and treated with n-butyllithium (14 mmoles) dissolved in hexane (2.5M). The mixture was stirred at -40° C. for 15 minutes, cooled to -75° C. and treated with a solution of 1-bromo-11-oxoundecane (2.8 g, 11.5 mmoles) in tetrahydrofuran (30 ml). The mixture was stirred at -75° C. for 15 minutes, allowed to warm to 25° C. and concentrated in vacuo. The residue was triturated with hexane, filtered and the filtrate concentrated in vacuo. The residue was chromatographed on silica gel eluted with hexane to afford 1-bromo-12-methyl-11-tridecene.