Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[CH:11]12[CH2:17][CH2:16][CH:15]1[C:14](=[O:18])[O:13][C:12]2=[O:19]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[Cl:10][C:4]1[CH:3]=[C:2]([NH:1][C:14]([CH:15]2[CH2:16][CH2:17][CH:11]2[C:12]([OH:19])=[O:13])=[O:18])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: O=C1OC(=O)C2CCC12
Reactant: N#Cc1ccc(N)cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(NC(=O)C2CCC2C(=O)O)cc1Cl
Yield: 35.4 %

Procedure:
A solution of 4-amino-2-chlorobenzonitrile (1229 mg, 8.06 mmol), 3-oxabicyclo[3.2.0]heptane-2,4-dione (1016 mg, 8.06 mmol) and TEA (1.123 mL, 8.06 mmol) in toluene (10 mL) was stirred at 80° C. for 14 hr. To the reaction mixture was added brine at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by COOH-silica gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane), and crystallized from ethyl acetate to give 2-((3-chloro-4-cyanophenyl)carbamoyl)cyclobutanecarboxylic acid (795 mg, 2.85 mmol, 35.4%) as colorless crystals.
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29]([NH:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])=S)[CH:26]=5)[N:21]=[CH:20][N:19]=4)=[CH:13][C:12]=3[CH3:37])=[CH:6][C:5]=12.[OH-].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>O1CCCC1>[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29]6[O:34][CH2:33][C:32]([CH3:36])([CH3:35])[N:31]=6)[CH:26]=5)[N:21]=[CH:20][N:19]=4)=[CH:13][C:12]=3[CH3:37])=[CH:6][C:5]=12
Reactant: Cc1cc(Nc2ncnc3ccc(NC(=S)NC(C)(C)CO)cc23)ccc1Oc1ccn2ncnc2c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Nc2ncnc3ccc(NC4=NC(C)(C)CO4)cc23)ccc1Oc1ccn2ncnc2c1

Procedure:
The synthesis of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is described in WO 2007/059257. Generally, N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine may be prepared by coupling (E)-N′-(2-cyano-4-(3-(1-hydroxy-2-methylpropan-2-yl)thioureido)phenyl)-N,N-dimethylformimidamide with 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline in isopropyl acetate:acetic acid (65:35 v/v) at 45° C. to yield 1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea. The 1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea may then be agitated in tetrahydrofuran under basic conditions (2.5N NaOH), followed by the addition of p-toluenesulfonyl chloride. Water may then be charged to yield N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine as a mixture of polymorphs (generally a mixture containing one or more of Form C, Form G hemi-THF, Form G mono-THF, Form M or Form P). The final crystallizations or isolations will determine the polymorphic form, which are further detailed in the Examples section.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C(OC([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25]([NH:27][CH2:28][C:29](OC)=O)=[O:26])[CH2:20][CH2:19]1)=O)(C)(C)C>C1(C)C=CC=CC=1.ClCCl>[NH:18]1[CH2:19][CH2:20][CH:21]([N:24]2[CH:29]=[CH:28][NH:27][C:25]2=[O:26])[CH2:22][CH2:23]1
Reactant: COC(=O)CNC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=c1[nH]ccn1C1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diisobutylaluminum hydride (1M, 0.875 μL, 0.875 mmol) was added to a solution of methyl N-{[(1-(tert-butoxycarbonyl)piperidin-4-yl)amino]carbonyl}glycinate (230 mg, 0.729 mmol) in toluene (5 μL) and dichloromethane (5 mL) at −78° C. and stirred for 30 min and then warmed to ambient temperature. After 30 min at room temperature, the reaction was quenched with 1 N saturated potassium sodium tartrate solution (15 mL) and extracted with dichloromethane (2×). The combined organic extracts were dried over sodium sulfate, filtered, concentrated. The crude material was dissolved in dichloromethane (10 μL) and treated with trifluoroacetic acid (5 mL). After 25 min, the reaction was concentrated to give the title compound. MS 168.3 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14]([N+:18]([O-])=O)=[CH:13][CH:12]=3)[N:9]=[C:8]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:5]2=[N:6][CH:7]=1.[H][H]>N1C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[CH:13][CH:12]=3)[N:9]=[C:8]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:5]2=[N:6][CH:7]=1
Reactant: [H][H]
Reactant: Nc1nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: c1ccncc1
Product: Nc1ccc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc1N

Procedure:
300 mg (0.785 mmol) of the compound from example 39A were initially charged in pyridine (35 ml), then 119 mg of palladium (10% on charcoal) were added and the mixture was hydrogenated at standard hydrogen pressure overnight. The reaction mixture was filtered through kieselguhr and washed through with ethanol, and the filtrate was concentrated. This gave 219 mg (92% purity, 73% of theory) of the title compound in solid form.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+].O>CN(C)C=O>[N:19]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][NH:11][C:12](=[O:13])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N+:20]=[N-:21]
Reactant: CC(C)(C)OC(=O)NCCOCCOS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCOCCN=[N+]=[N-]
Temperature: 90 °C
Reaction time: 5 h
Yield: 100.8 %

Procedure:
A stirred solution of 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate (63.5 g, 0.224 mol) in 400 mL of N,N-dimethylformamide (DMF) was treated with NaN3 (16.1 g, 0.247 mol) and the reaction mixture was heated to 90° C. under N2. After 5 h, the solution was cooled to room temperature and treated with 500 mL of cold H2O. The reaction mixture was then extracted with Et2O (3×300 mL). The combined organic extracts were washed with H2O (4×100 mL) and brine (2×100 mL). The organic portion was dried over MgSO4 and concentrated to give 52.0 g of tert-butyl 2-(2-azidoethoxy)ethylcarbamate as a light brown oil.
Reaction SMILES: [CH2:1]([C:5]1[CH2:10][CH:9]([CH3:11])[C:8]([CH3:14])([CH:12]=[O:13])[CH2:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:15][Mg+].[Br-].Cl>C(OCC)C>[CH2:1]([C:5]1[CH2:10][CH:9]([CH3:11])[C:8]([CH:12]([OH:13])[CH3:15])([CH3:14])[CH2:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: C[Mg+]
Reactant: CC(C)CC1=CCC(C)(C=O)C(C)C1
Agent: Cl
Agent: [Br-]
Solvent: CCOCC
Product: CC(C)CC1=CCC(C)(C(C)O)C(C)C1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
4-Isobutyl-1,6-dimethylcyclohex-3-enecarbaldehyde 3c (4.5 g, 23 mmol) was dissolved in diethyl ether (40 ml). The solution was cooled to 0-5° C. under nitrogen and MeMgBr (3M, 12 ml, 35 mmol) added over 40 min with stirring. The temperature was allowed to rise to room temperature and stirring continued for 30 min. The reaction mixture was poured slowly onto a vigorously stirred mixture of 2M HCl and ice. After stirring for 10 min the phases were separated and the lower aqueous layer extracted twice with MTBE. The organic phases were combined and washed with sat. NaHCO3 solution and brine to pH 7. After drying (MgSO4) the organic phase was concentrated in vacuo to give 4.6 g of a light yellow oil. The crude oil was purified by flash chromatography (MTBE/hexane 3:7) to give 4d as a 1:2:3:5 mixture of diastereomers (2.7 g, 55% yield, >98% pure). Distillation of a 0.7 g sample gave 0.6 g of 4d (colorless oil, >99% pure) for olfactory assessment.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[N:9]=[C:10]([CH:18]4[CH2:20][CH2:19]4)[CH:11]=[C:12]([C:13]([O:15]CC)=[O:14])[C:7]=3[C:6]([CH3:21])=[N:5]2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([N:4]2[C:8]3[N:9]=[C:10]([CH:18]4[CH2:19][CH2:20]4)[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:7]=3[C:6]([CH3:21])=[N:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C2CC2)c2nc(C3CC3)cc(C(=O)O)c12

Procedure:
To a solution of ethyl 1,6-dicyclopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (310 mg, 1.086 mmol) in ethanol (30 mL) was added sodium hydroxide (4.35 mL, 4.35 mmol) and the mixture heated at reflux for 2 hours. The solvent was removed in vacuo, the residue suspended in water (20 mL), and acidified by addition of acetic acid. The contents were extracted with EtOAc (4×30 mL). The combined EtOAc extracts were washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo. The product was collected as 250 mg. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88-1.31 (m, 8 H), 2.21-2.42 (m, 1 H), 3.83 (m, J=7.39, 7.39, 3.79, 3.66 Hz, 1 H), 7.44 (s, 1 H), 13.72 (br. s., 1 H). LCMS(ES) [M+H]+ 258.2
Reaction SMILES: Br[C:2]1[S:23][C:5]2[C:6](=[O:22])[NH:7][C:8]([C:18]([O:20][CH3:21])=[O:19])=[C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=3)[C:4]=2[CH:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>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]>[Cl:17][C:12]1[CH:11]=[C:10]([C:9]2[C:4]3[CH:3]=[C:2]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[S:23][C:5]=3[C:6](=[O:22])[NH:7][C:8]=2[C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: C1COCCN1
Reactant: COC(=O)c1[nH]c(=O)c2sc(Br)cc2c1-c1ccc(Cl)c(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1[nH]c(=O)c2sc(N3CCOCC3)cc2c1-c1ccc(Cl)c(Cl)c1
Temperature: 140 °C
Yield: 6.3 %

Procedure:
A mixture of methyl 2-bromo-4-(3,4-dichlorophenyl)-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-5-carboxylate (0.081 g, 0.19 mmol), morpholine (0.0489 g, 0.561 mmol), tris(dibenzylideneacetone)dipalladium(0) (17.1 mg, 0.0187 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (21.6 mg, 0.0374 mmol) and cesium carbonate (183 mg, 0.561 mmol) in 1,4-dioxane (3.0 mL, 38 mmol) was heated to 140° C. for 20 min, and then to 150° C. for another 90 min by microwave irradiation. The mixture was concentrated and purified by chromatography and then preparative HPLC to afford the product as a white solid (5.3 mg, 6.4%). LCMS (FA) ES+: 439.4, 441.4. 1H NMR (400 MHz, DMSO) δ 11.30 (s, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.54 (d, J=1.9 Hz, 1H), 7.25 (dd, J=8.2, 2.0 Hz, 1H), 5.76 (s, 1H), 4.09 (d, J=5.1 Hz, 2H), 3.76-3.63 (m, 4H), 3.59 (s, 3H), 3.23-3.06 (m, 4H).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([SH:16])=[N:13][C:12]=12)C.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[F:36]>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[F:36])[S:16][C:14]1[S:15][C:11]2[CH2:10][CH2:9][C:8]3[C:17](=[CH:18][CH:19]=[CH:20][C:7]=3[O:6][CH2:5][C:4]([OH:3])=[O:21])[C:12]=2[N:13]=1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Reactant: Fc1ccccc1C(Br)c1ccccc1F
Product: O=C(O)COc1cccc2c1CCc1sc(SC(c3ccccc3F)c3ccccc3F)nc1-2
Yield: 58 %

Procedure:
Using ethyl[(2-mercapto-4,5-dihydronaphto[1,2-d]thiazol-6-yl)oxy]acetate and bis(2-fluorophenyl)methylbromide, the procedure of Example 63 was otherwise repeated to synthesize the title compound. Yield 58%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][N:31]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:33]=[CH:32][N:31]=[C:30]([O:29][CH3:28])[CH:35]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: COc1cc(B(O)O)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: COc1cc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one and 2-methoxypyridin-4-ylboronic acid following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.9 min, m/z=447 (M+1); 1H NMR (CDCl3) 8.29 (1H, d, J=5.5 Hz), 7.34 (2H, m), 7.21-7.15 (m, 3H), 7.02-6.93 (5H, m), 5.67-5.61 (1H, m), 4.05 (3H, s), 3.53 (1H, t, J=6.41 Hz), 2.97-2.93 (1H, m), 2.33-2.11 (3H, m), 2.06-1.83 (3H, m), 1.67-1.57 (1H, m), 1.50 (3H, d, J=7.03), 1.36-1.26 (1H, m).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:14][C:15]3[S:19][C:18]([C:20]4([C:25]([OH:27])=[O:26])[CH2:24][CH:23]=[CH:22][CH2:21]4)=[CH:17][CH:16]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:5]2=[C:4]([CH3:28])[CH:3]=1.[CH:29]1(C2NC3C(N=2)=NC(C)=CC=3C)C[CH2:30]1>>[CH2:29]([O:26][C:25]([C:20]1([C:18]2[S:19][C:15]([CH2:14][N:8]3[C:6]4=[N:7][C:2]([CH3:1])=[CH:3][C:4]([CH3:28])=[C:5]4[N:10]=[C:9]3[CH:11]3[CH2:13][CH2:12]3)=[CH:16][CH:17]=2)[CH2:24][CH:23]=[CH:22][CH2:21]1)=[O:27])[CH3:30]
Reactant: CCCc1nc2c(C)cc(C)nc2n1Cc1ccc(C2(C(=O)O)CC=CC2)s1
Reactant: Cc1cc(C)c2[nH]c(C3CC3)nc2n1
Product: CCOC(=O)C1(c2ccc(Cn3c(C4CC4)nc4c(C)cc(C)nc43)s2)CC=CC1

Procedure:
Alkylation was performed on (11) as described in Example 1, Step 5, using 2-cyclopropyl-5,7-dimethylimidazo[4,5-b]pyridine (13) to obtain the title compound (12).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)(C)C.[C:13]1(I)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>O.C(OCC)C.[Cu]I.C(O)CO>[CH2:20]([NH:24][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: OCCO
Solvent: CC(C)O
Product: CCCCNc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-butylaniline (6a) Was synthesized in an analogous manner previously reported (Org Lett, 4, 581).11 Briefly, CuI (19 mg, 0.1 mmol) and freshly ground K3PO4 (849 mg, 4 mmol) were placed in a sealed tube followed by sequential addition of isopropanol (2 mL), ethylene glycol (0.222 mL, 4.0 mL), phenyl-iodide (0.224 mL, 2.0 mmol) and n-butylamine (0.237 mL, 2.4 mmol). The tube was then sealed and stirring commenced at 80° C. for 18 h. After cooling to room temperature the reaction was diluted with water:ethyl ether (1:1, 10 mL). The aqueous layer was extracted with ether (3×5 mL), washed with brine (15 mL), dried over sodium sulfate and concentrated in vacuo. Purification via flash chromatography afforded the title compound as a yellow oil (235 mg, 79%). 1H NMR (400 MHz, CDCl3) δ 7.19 (m, 2H), 6.70 (t, J=7.2 Hz, 1H), 6.61 (d, J=8.4 Hz, 2H), 3.60 (br, 1H), 3.12 (t, J=7.2 Hz, 2H), 1.62 (m, 2H), 1.44 (m, 2H), 0.98 (t, J=7.2 Hz, 3H). Spectra matches that reported in Okano et al., “Synthesis of secondary arylamines through copper-mediated intermolecular aryl amination,” Org Lett 2003, 5(26):4987-4990.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][C:7]#[N:8])=[O:5].[C:9]1(C=CC(O)=CC=1)O.N1CCCCC1.C=O>[Pd].O.C(O)(=O)C.C1(C)C=CC=CC=1>[C:7]([CH:6]([CH3:9])[C:4]([O:3][CH2:2][CH3:1])=[O:5])#[N:8]
Reactant: CCOC(=O)CC#N
Reactant: Oc1ccc(O)cc1
Agent: [Pd]
Agent: C=O
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(C)C#N

Procedure:
904 Parts of ethyl cyano acetate, 10 parts of hydroquinone, 4.3 parts of piperidine, 45 parts of 3% palladium on charcoal catalyst and 6,500 parts of toluene are mixed at 60°C under an atmosphere of hydrogen maintained at 30 p.s.i.g., 1,000 Parts of a solution made from 1,000 parts of formalin (36%), 75 parts of acetic acid, 86 parts of piperidine and water to give a total of 1,500 parts are added at a uniform rate over 3 hours the temperature being maintained at 60°-65°C. The reaction mixture is cooled, filtered and the toluene layer separated. Distillation under reduced pressure of the toluene layer yields 374.7 parts of ethyl 2-cyanopropionate boiling point 91°-118°C/20 mm. of mercury.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([CH:10]([CH2:14][CH2:15][CH2:16][CH3:17])[C:11]([OH:13])=[O:12])[CH3:9].[Cl-].[Cr+2:19].[Cl-]>CCCCCCC>[CH2:8]([CH:10]([CH2:14][CH2:15][CH2:16][CH3:17])[C:11]([O-:13])=[O:12])[CH3:9].[CH2:8]([CH:10]([CH2:14][CH2:15][CH2:16][CH3:17])[C:11]([O-:13])=[O:12])[CH3:9].[Cr+2:19]
Reactant: CCCCC(CC)C(=O)O
Agent: [Cr+2]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: CCCCC(CC)C(=O)[O-]

Procedure:
Chromium (II) bis(2-ethylhexanoate) is prepared by the addition of an equimolar mixture of triethylamine and 2-ethylhexanoic acid in heptane to a suspension of 0.5 mole anhydrous chromium (II) chloride in heptane. A slow reaction results in the formation of a deep purple solution and the precipitation of triethylammonium hydrochloride. The product is isolated as a purple oil after removal of the precipitate by filtration and the volatiles under vacuum.
Reaction SMILES: [Na+].[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O-:15])=[O:14])=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Cl>CN(C)C=O>[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][O:14][C:13](=[O:15])[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:2][CH:3]([CH3:5])[CH3:4])=[CH:11][CH:10]=1
Reactant: CC(C)Cc1ccc(CC(=O)[O-])cc1
Reactant: ClCc1ccccc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Cc1ccc(CC(=O)OCc2ccccc2Cl)cc1
Yield: 73.4 %

Procedure:
To a solution of 3.5 g of p-isobutylphenylacetic acid sodium salt in 20 ml of dimethylformamide was added 5.9 g of o-chlorobenzyl chloride, and the mixture was heated under reflux for 5 hours. After the reaction was complete, the mixture was cooled to produce an inorganic substance, which was then removed by filtration. The filtrate was freed of dimethylformamide by distillation in vacuo to give an oily product. Distillation of this product in vacuo yielded 3.8 g of p-isobutylphenylacetic acid-2-chlorobenzyl ester as a colorless oil, boiling at 145°-147° C/1 mmHg. Analysis-Calculated for C19H21ClO2 : C, 72.03; H, 6.68. Found: C, 71.98; H, 6.51. Mass spectrum: parent ion 316 m/e.
Reaction SMILES: O[CH:2]1[O:6][C:5](=[O:7])[CH:4]=[C:3]1[CH3:8].C(N(CC)CC)C.[CH3:16][C:17]([CH:39]=[CH:40][C:41]1[C:46]([CH3:48])([CH3:47])[CH2:45][CH2:44][CH2:43][C:42]=1[CH3:49])=[CH:18][CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[Mg+2].[Cl-]>CCCCCCC.CN(C)C(=O)C>[CH3:49][C:42]1[CH2:43][CH2:44][CH2:45][C:46]([CH3:47])([CH3:48])[C:41]=1/[CH:40]=[CH:39]/[C:17](/[CH3:16])=[CH:18]/[CH:19]=[CH:2]/[C:3](/[CH3:8])=[CH:4]\[C:5]([OH:6])=[O:7]
Reactant: CC1=CC(=O)OC1O
Reactant: CC(C=CC1=C(C)CCCC1(C)C)=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C\C(=O)O)C(C)(C)CCC1
Temperature: 15 °C
Reaction time: 17 h

Procedure:
N,N-dimethylacetamide (300 milliliters (mL)) , 5-hydroxy-4-methyl-2[5H]-furanone (26.81 grams (g)), 235 millimoles (mmol), 1.2 equivalents), and triethylamine (164 mL,1.2 moles, 6 equivalents) were added to 107.26 g (197 mmol) of [3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienyl] triphenyl phosphonium salt. The resulting mixture was cooled to 15° C. prior to addition of magnesium chloride (30.03 g, 315 mmol, 1.6 equivalents). The reaction mixture was allowed to stir at room temperature for 17 hours. The reaction solution was washed with 200 mL of heptane. Toluene (100 mL) was added and the solution was acidified with 280 mL of 20% by volume HCl . The aqueous layer was back-extracted three times, each time with 200 mL of a 9:1 heptane:toluene mixture. The combined organic layers were washed with aqueous methanol, water, and then concentrated to give an orange solid. Heptane (250 mL) was added to the crude solid and the slurry was cooled to 0° C. and then filtered. Acetone (200 mL) and heptane (800 mL) were added to the solid and the resulting mixture was stirred at 25° C. Filtration of this slurry provided isotretinoin with >98% purity as a solid. 1H NMR: (300 MHz, CDCl3):δ 1.03(s,6; H), 1.44-1.68(m,4H), 1.72(s,3H), 1.88-2.05(m,2H), 2.0(s,3H), 2.11 (d,3H), 5.67(s,1H), 6.15-6.32(m,3H), 7.03 (dd,1H), 7.76 (d,1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19]>>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)(=[O:20])=[O:19])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=S(=O)(Cl)c1ccccn1
Product: O=S(=O)(Nc1cccc2cccnc12)c1ccccn1
Yield: 66 %

Procedure:
In a similar fashion using route 14 general procedure 26, 8-aminoquinoline (100 mg, 0.69 mmol), pyridine-2-sulfonyl chloride (Intermediate 18) (196 mg, 1.107 mmol) gave the title compound (130 mg, 65%) after purification by column chromatography with n-hexane/EtOAc (17:3) as the eluent.
Reaction SMILES: [H][H].[CH2:3]([CH:5]1[CH:31]=[C:30]([CH3:32])[CH2:29][CH:28]([CH3:33])[CH2:27][CH:26]([O:34][CH3:35])[CH:25]2[O:36][C:21]([OH:40])([CH:22]([CH3:39])[CH2:23][CH:24]2[O:37][CH3:38])[C:20](=[O:41])[C:19](=[O:42])[N:18]2[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[C:12](=[O:43])[O:11][CH:10]([C:44]([CH3:60])=[CH:45][CH:46]2[CH2:51][CH2:50][CH:49]([O:52][CH2:53][CH:54]=[CH2:55])[CH:48]([O:56][CH2:57][CH:58]=[CH2:59])[CH2:47]2)[CH:9]([CH3:61])[CH2:8][CH2:7][C:6]1=[O:62])[CH3:4]>[Rh]>[CH2:3]([CH:5]1[CH:31]=[C:30]([CH3:32])[CH2:29][CH:28]([CH3:33])[CH2:27][CH:26]([O:34][CH3:35])[CH:25]2[O:36][C:21]([OH:40])([CH:22]([CH3:39])[CH2:23][CH:24]2[O:37][CH3:38])[C:20](=[O:41])[C:19](=[O:42])[N:18]2[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[C:12](=[O:43])[O:11][CH:10]([C:44]([CH3:60])=[CH:45][CH:46]2[CH2:51][CH2:50][CH:49]([O:52][CH2:53][CH2:54][CH3:55])[CH:48]([O:56][CH2:57][CH2:58][CH3:59])[CH2:47]2)[CH:9]([CH3:61])[CH2:8][CH2:7][C:6]1=[O:62])[CH3:4]
Reactant: C=CCOC1CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CC1OCC=C
Reactant: [H][H]
Agent: [Rh]
Product: CCCOC1CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CC1OCCC
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 65.9 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3",4"-diallyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (6.8 mg in 600 μl ethyl acetate) was added 4 mg of 5% rhodium on carbon catalyst. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 25 minutes, the mixture was filtered over Celite, concentrated and purified by flash chromatography on silica gel (ethyl acetate:hexane (1:3)+1% methanol) to give the title compound (4.5mg).