Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=NC(N2C3C(=CC=C(C(N4CCOCC4)=O)C=3)C(CO)=C2)=NC=1.Br[C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=1.FC1C=CC=CC=1C1C=NC(N2C3C(=CC=C(C(N4CCOCC4)=O)C=3)C(C=O)=C2)=NC=1.FC1C=CC=CC=1[C:74]1[CH:75]=[N:76][C:77]([N:80]2[C:88]3[C:83](=[CH:84][CH:85]=[C:86]([C:89]([N:91]4[CH2:96][CH2:95][O:94][CH2:93][CH2:92]4)=[O:90])[CH:87]=3)[C:82]([CH:97]([OH:99])[CH3:98])=[CH:81]2)=[N:78][CH:79]=1>>[OH:99][CH:97]([C:82]1[C:83]2[C:88](=[CH:87][C:86]([C:89]([N:91]3[CH2:92][CH2:93][O:94][CH2:95][CH2:96]3)=[O:90])=[CH:85][CH:84]=2)[N:80]([C:77]2[N:78]=[CH:79][C:74]([C:28]3[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=3)=[CH:75][N:76]=2)[CH:81]=1)[CH3:98]
Reactant: CC(O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reactant: Cc1ccnc(Br)c1
Agent: O=C(c1ccc2c(CO)cn(-c3ncc(Br)cn3)c2c1)N1CCOCC1
Agent: O=Cc1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Product: Cc1ccnc(-c2cnc(-n3cc(C(C)O)c4ccc(C(=O)N5CCOCC5)cc43)nc2)c1

Procedure:
(1-(5-Bromopyrimidin-2-yl)-3-(hydroxymethyl)-1H-indol-6-yl)(morpholino)methanone (intermediate 27c) was converted into a boronic ester that was subsequently reacted with 2-bromo-4-methylpyridine under Suzuki conditions. The resulting product was oxidized to the corresponding aldehyde and then submitted to a Grignard reaction analogously to the protocols 28a) and 28b), respectively. Light yellow solid. Yield: 70 mg
Reaction SMILES: Cl[C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:7])=[CH:4][N:3]=1.[CH3:25][C:26]1[CH:39]=[CH:38][C:29]([C:30]([NH:32][N:33]2[NH:37][CH:36]=[CH:35][S:34]2)=[O:31])=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1>>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:6](=[O:7])[C:5]2[CH:23]=[CH:24][C:2]([C:27]3[CH:28]=[C:29]([C:30](=[O:31])[NH:32][N:33]4[NH:37][CH:36]=[CH:35][S:34]4)[CH:38]=[CH:39][C:26]=3[CH3:25])=[N:3][CH:4]=2)[CH2:17][CH2:18]1
Reactant: Cc1ccc(C(=O)NN2NC=CS2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN1CCN(Cc2ccccc2NC(=O)c2ccc(Cl)nc2)CC1
Product: Cc1ccc(C(=O)NN2NC=CS2)cc1-c1ccc(C(=O)Nc2ccccc2CN2CCN(C)CC2)cn1

Procedure:
N-[2-(4-Methylpiperazin-1-ylmethyl)phenyl]-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide (Intermediate 5) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B. LCMS: retention time 2.43 min, MH+ 528. NMR: δH [2H6]-DMSO 13.07,(1H, b), 11.74,(1H, s), 9.26,(1H, s), 9.21, (1H, s), 8.43,(1H, d), 8.34,(1H, d), 8.29,(1H, s), 8.12,(1H, d), 7.93,(1H, d), 7.56,(1H, d), 7.36,(1H, t), 7.29,(1H, d), 7.11,(1H, t), 3.78,(2H, s), 2.67–2.26,(11H, m), 2.11,(3H, s).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1.[C:19]([C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30]Cl)=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].[Cl-].[NH4+]>CN(C)C=O>[C:19]([C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][N:15]2[C:14](=[O:16])[O:13][N:12]=[C:11]2[C:7]2[CH:6]=[C:5]([C:4]([F:3])([F:17])[F:18])[CH:10]=[CH:9][N:8]=2)=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Reactant: CC(C)(C)c1ccc(C(=O)OCCl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(C(=O)OCn2c(-c3cc(C(F)(F)F)ccn3)noc2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.1 %

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.07 g of sodium hydride (60% oily), and 0.3 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at room temperature. After stirring for 15 minutes, 0.35 g of chloromethyl 4-t-butylbenzoate was added, and the mixture was stirred at 70° C. for 4 hours. The reaction solution was allowed to cool to room temperature, and poured into an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.23 g of [3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-on-4-yl]methyl 4-t-butylbenzoate (present compound 36)).
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:7]([NH:14][CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCc1ccccc1
Reactant: C[Si](C)(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[Si](C)(C)CNCc1ccccc1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
A mixture of chloromethyltrimethylsilane (325g, 370 ml, 2.65 mole) and benzylamine (835 g, 850 ml, 7.78 mole) was heated at 120° C. (oil bath temperature) for 2 h. A white solid began appearing after only 10 minutes and a viscous mixture eventually resulted. The reaction mixture was allowed to cool, then basified with potassium carbonate solution and extracted twice with ether. The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a yellow oil, which was purified by distillation. The excess benzylamine was removed in the first fractions (b.p. 47°-62° C. at 2 mmHg). The title compound (D10) was obtained as a colourless oil (380 g, 74%) b.p. 75°-80° C. at 2 mmHg.
Reaction SMILES: Cl.Cl.Cl.Cl.[N:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])[NH2:13])=[CH:7][CH:6]=1.[Cl:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:39](O)=[O:40])=[CH:33]2>>[Cl:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:39]([NH:13][C@@H:12]([C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH2:18][CH2:17]1)=[O:15])[CH2:11][C:8]1[CH:7]=[CH:6][N:5]=[CH:10][CH:9]=1)=[O:40])=[CH:33]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CN1CCC(N2CCN(C(=O)[C@H](N)Cc3ccncc3)CC2)CC1
Agent: Cl
Product: CN1CCC(N2CCN(C(=O)[C@@H](Cc3ccncc3)NC(=O)c3cc4cc(Cl)ccc4[nH]3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the titled compound was prepared from 1-[β-(4-pyridinyl)-D-alanyl]-4-(1-methylpiperidin-4-yl)piperazine tetrahydrochloride and 5-chloroindole-2-carboxylic acid (47%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([N:13]1[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]1=[O:23])[CH2:7][CH2:6]2.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([N:13]1[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]1=[O:23])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(N1C(=O)c3ccccc3C1=O)C2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1C1CCc2cc(O)ccc2C1
Temperature: -60 °C
Reaction time: 4 h
Yield: 91.8 %

Procedure:
To 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)isoindole-1,3-dione (29 g; 94.3 mmol) dissolved in anhydrous CH2Cl2 (500 mL), cooled to −60° C., is added a 1.0 M solution of boron tribromide-CH2Cl2 (471 mL), dropwise to maintain reaction temperature between −50 to −60° C. Upon completion of the addition, the reaction mixture is allowed to warm to RT and stirred for an additional 4 h. The reaction is cooled to 0° C., quenched with saturated NaHCO3 (400 mL) and stirred for an additional 0.5 h at RT. The precipitate is filtered, washed thoroughly with H2O, suspended in ether, filtered and dried under vacuo to afford 25.4 g (92%) of 2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)isoindole-1,3-dione as an off-white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15]C(=O)C)=[CH:7][C:6]=1[CH3:19])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O.Cl>CO>[C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[CH:7][C:6]=1[CH3:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C)c(OC(C)=O)c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=O)Oc1c(C)cc(O)c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.3 %

Procedure:
To a solution of 4-(acetyloxy)-2-methyl-1-naphthyl acetate (25 g, 96.8 mmol) in methanol (300 mL) was added potassium carbonate (58.1 g, 420 mmol), and the mixture was stirred under argon atmosphere at room temperature for 15 minutes. Water was poured into the mixture, which was neutralized with hydrochloric acid and then extracted with ethyl acetate. The extract was washed with a saturated brine and dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 21 g (yield: quantitative) of the title compound. Oily matter.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[CH:11]=2)[N:4]=1.Br[C:27]1[N:32]=[C:31]([CH2:33][CH2:34][C:35]([O:37][CH2:38]C)=[O:36])[CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[C:14]([C:27]3[N:32]=[C:31]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:30]=[CH:29][CH:28]=3)[CH:13]=[C:12]([CH3:25])[CH:11]=2)[N:4]=1
Reactant: CCOC(=O)CCc1cccc(Br)n1
Reactant: COc1ccnc(Nc2cc(C)cc(B3OC(C)(C)C(C)(C)O3)c2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)CCc1cccc(-c2cc(C)cc(Nc3nccc(OC)n3)c2)n1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
A mixture of 4-methoxy-N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine (0.045 g, 0.13 mmol), ethyl 3-(6-bromopyridin-2-yl)propanoate (0.037 g, 0.15 mmol), PdCl2(dppf)-CH2Cl2 (0.016 g, 0.020 mmol), and Na2CO3 (2.0 M in water, 0.13 mL, 0.26 mmol) in dioxane (0.75 mL) was purged with argon and heated to 110° C. for 12 hours. Upon cooling, NaOH (1.0 M in water, 0.50 mL) and MeOH (0.50 mL) were added to the reaction mixture and irradiated in a microwave reactor for 10 minutes at 110° C. Silica Supported-DMT (0.088 g, 0.13 mmol, 0.57 mmol/g) was added to the reaction mixture and shaken for 5 hours at ambient temperature. The reaction was passed through a syringe filter and the eluent was evaporated under reduced pressure. The residue was suspended in DMSO (1.5 mL) and was purified by reverse phase preparative HPLC (0:100 to 95:5 acetonitrile:water: 0.1% v/v formic acid modifier) to afford methyl 3-(6-(3-((4-methoxypyrimidin-2-yl)amino)-5-methylphenyl)pyridin-2-yl)propanoate. LRMS (ESI) calc'd for C20H21N4O3 [M+H]+: 365. Found: 365. 1H NMR (600 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.33 (s, 1H), 8.18 (d, J=5.6, 1H), 7.73 (t, J=7.7, 1H), 7.64 (d, J=7.8, 1H), 7.61 (s, 1H), 7.44 (s, 1H), 7.19 (d, J=7.6, 1H), 6.25 (d, J=5.6, 1H), 3.93 (s, 3H), 2.99 (t, J=7.4, 2H), 2.71 (t, J=7.4, 2H), 2.33 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:30])[C:5]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:6][N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22](I)[CH:21]=[N:20]2)=[CH:15][CH:14]=1.[CH:31]([B-](F)(F)F)=[CH2:32].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:30])[C:5]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:6][N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22]([CH:31]=[CH2:32])[CH:21]=[N:20]2)=[CH:15][CH:14]=1
Reactant: C=C[B-](F)(F)F
Reactant: CCOC(=O)c1cn(Cc2ccc(-n3cc(I)cn3)cc2)c2cccc(F)c2c1=O
Agent: CC(C)(C)[PH]([Pd][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C=Cc1cnn(-c2ccc(Cn3cc(C(=O)OCC)c(=O)c4c(F)cccc43)cc2)c1
Temperature: 100 °C
Reaction time: 14 h

Procedure:
To a solution of ethyl 5-fluoro-1-[4-(4-iodo-1H-pyrazol-1-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.080 g, 0.15 mmol), potassium vinyltrifluoroborate (0.013 g, 0.19 mmol), and 1 N cesium carbonate (0.31 mL, 0.31 mmol) in 2 mL of acetonitrile under nitrogen was added bis(tri-tert-butylphosphoranyl)palladium (10 mol %). The reaction mixture was stirred at 100° C. for 14 hours, cooled to room temperature, and concentrated in vacuo to provide the title compound (crude) which gave a mass ion (ES+) of 417.9 for M+H+. This compound could be further hydrolyzed to the corresponding carboxylic acid, as described in Example 1.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:41]([OH:43])=[O:42])[CH2:20][S:21]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]>C(Cl)Cl>[C:1]([NH:18][C@H:19]([C:41]([OH:43])=[O:42])[CH2:20][SH:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: O=C(N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Product: O=C(N[C@@H](CS)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 76 %

Procedure:
A solution of Fmoc-S-trityl-L-cysteine (10.0 g, 17.1 mmol), in DCM containing 15% trifluoroacetic acid (TFA) and 5% TES (total volume 150 mL) was stirred at room temperature. After 10 min the reaction was evaporated to dryness, the solid residue was washed three times with 150 mL n-pentane and then dried under high vacuum. 4.46 g of Fmoc-L-cysteine was obtained as a colorless solid. This material was dissolved in DCM (20 mL) containing 7% TFA. 1.0 g Trityl chloride resin (Novabiochem, loading 2.05 mmol of active chlorine) was added in one portion. The solution was slowly agitated overnight (orbital shaker, or slow stirring on a magnetic stirrer). The resin was isolated on a sintered glass funnel, washed with DCM (5×40 mL), methanol (1×40 mL) and again with DCM and dried overnight in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1)[CH2:7][CH:6]([NH2:18])[CH2:5]2.ON1C2C=CC=NC=2N=N1.[C:29]1([C:39](O)=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.C(N(C(C)C)CC)(C)C.[ClH:51].CN(C)CCCN=C=NCC>CN(C)C=O.C(Cl)(Cl)Cl>[ClH:51].[ClH:51].[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1)[CH2:7][CH:6]([NH:18][C:39]([C:29]1[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=1)=[O:40])[CH2:5]2
Reactant: NC1Cc2cc(Br)ccc2N(Cc2c[nH]cn2)C1
Reactant: O=C(O)c1cccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ncccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(NC1Cc2cc(Br)ccc2N(Cc2c[nH]cn2)C1)c1cccc2ccccc12
Reaction time: 18 h

Procedure:
To a solution of 6-Bromo-1,2,3,4-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-quinolinamine (30 mg, 0.072 mmol) in dimethyl formamide (1 mL) were sequentially added 1-hydroxyazabenzotriazole (19 mg, 0.15 mmol), 1-naphthoic acid (25 mg, 0.15 mmol), diisopropylethyl amine (0.7 mL, 0.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28 mg, 0.15 mmol). After 18 hours, the mixture was diluted with chloroform (10 mL) and washed with saturated NaHCO3 solution (10 mL). The organic layer was separated, dried and concentrated. Purification by silica gel flash column chromatography eluting with 50% ethyl acetate in hexanes followed by 1:9 methanol in chloroform afforded two fractions. More polar fraction 2 (14 mg) was the desired product and the less polar fraction 1 (35 mg) was diacylated product. Fraction 1 was dissolved in methanol (1 mL) and treated with NaOH solution (1 N, 0.2 mL). After 30 minutes, the mixture was concentrated and mixed with fraction 2 obtained above. The resulting mixture was dissolved in chloroform (10 mL) and washed with water (10 mL). The organic layer was dried (MgSO4), concentrated and purified by silica gel flash column eluting with 5% methanol in chloroform to afford the free base of the title compound (20 mg, 60%). The solid was dissolved in chloroform and HCl gas was bubbled for 30 seconds. The mixture was then concentrated in vacuo to afford the title compund (23 mg). MS: (M+H)+=461, 463 (1:1 ratio), 1 Br pattern.
Reaction SMILES: [CH2:1]([C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15]C(C)(C)C)=[O:14])=[CH:11][CH:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>ClCCl.FC(F)(F)C(O)=O>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:20][CH:21]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(CCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To a solution of tert-butyl 4-phenethylbenzoate (50 mg, 0.18 mmol) in dichloromethane (8 mL), trifluoroacetic acid (2 mL) was added. The mixture was stirred 0.5 hour. Once the start material has been consumed, the resultant mixture was concentrated to give 4-phenethylbenzoic acid (36 mg, 90%).
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[N:11]=[C:10]([NH2:12])[CH:9]=[N:8]1.[C:15]1([C:21]2[O:25][CH:24]=[N:23][C:22]=2[C:26](O)=[O:27])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[N:11]=[C:10]([NH:12][C:26]([C:22]2[N:23]=[CH:24][O:25][C:21]=2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:27])[CH:9]=[N:8]1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC(F)(F)CCCCn1ncc(N)n1
Product: CC(F)(F)CCCCn1ncc(NC(=O)c2ncoc2-c2ccccc2)n1

Procedure:
Following general procedure A, starting from 2-(5,5-difluoro-hexyl)-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[S:15][CH:14]([N:16]2[CH:31]=[CH:30][C:20]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:19][C:17]2=[O:18])[CH2:13][O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[C:1]([O:9][CH2:10][C@H:11]1[S:15][C@@H:14]([N:16]2[CH:31]=[CH:30][C:20]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:19][C:17]2=[O:18])[CH2:13][O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccn(C2CO[C@@H](COC(=O)c3ccccc3)S2)c(=O)n1)c1ccccc1
Solvent: CO
Product: O=C(Nc1ccn([C@H]2CO[C@@H](COC(=O)c3ccccc3)S2)c(=O)n1)c1ccccc1
Reaction time: 8 h

Procedure:
To the crude (R)-benzoyloxymethyl-4-(R,S)-(N-benzoylcytosin-1-yl)-1,3-oxathiolane (8.0 g) in a 100 mL round bottom flask, was added approximately 14.0 times (by volume) methanol (112 mL) and the mixture was refluxed till a clear solution could be seen. This was then allowed to cool without stirring overnight. The resulting crystallized product was then filtered, followed by washing with methanol (50 mL). Once all the mother liquor and the subsequent washing had passed through, the resulting crystallized white product was re-washed slowly with methanol (2×100 mL) and dried under vacuum. The resulting white crystalline solid on analyzing with NMR showed that it is >99% the cis isomer. Isolated yield, 3.36 g (42% yield for the recrystallization, based on the crude). Optical purity: RR/SS: 98.1/1.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][N:21]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCNCC3)nc2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCN(S(C)(=O)=O)CC3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(piperazin-1-yl)quinoxaline-6-carboxylate (180 mg, 0.59 mmol) in dichloromethane (10 ml) was added Et3N (202 mg, 2 mmol) and methanesulfonyl chloride (110 mg, 0.98 mmol). The resulting solution was stirred for 1 hour at room temperature. The reaction was then quenched by the addition of ice-water (20 ml) and extracted with dichloromethane (3×15 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford methyl 2-(4-fluorophenyl)-3-(4-(methylsulfonyl)piperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid (0.14 g, 70%).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([OH:20])=O.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[NH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1>N1C=CC=CC=1.O.C(OCC)(=O)C>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([NH:37][C:38]1[CH:39]=[CH:40][C:41]([OH:44])=[CH:42][CH:43]=1)=[O:20]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Reactant: Nc1ccc(O)cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)Nc2ccc(O)cc2)C(C)(C)CCC1
Temperature: 5 °C
Reaction time: 3.5 h
Yield: 123.4 %

Procedure:
To a 5-Liter 4 neck round bottom flask equipped with a mechanical stirrer, temperature probe, addition funnel, and nitrogen inlet adapter was added 100.0 grams (333.3 mmol) of retinoic acid and 1.0 liter of ethyl acetate (EtOAc). The slurry was cooled to an internal temperature of 5° C. Triethylamine (50.7 milliliters, 366 mmol) was added all at once via graduated cylinder. To the thin slurry was then added trimethylacetyl chloride (45.1 milliliters, 366 mmol) via addition funnel over 23 minutes at an internal temperature of less than 5° C. After 3.5 hours, the reaction was judged to be complete by HPLC analysis. To the bright yellow slurry of the mixed anhydride was added a thin suspension of 4-aminophenol (76.3 grams, 700 mmol) in 500 milliliters of pyridine over 30 minutes at an internal temperature of 3-5° C. After 2 hours, the reaction was judged to be complete by HPLC analysis. To the slurry was added 500 milliliters of water over 10 minutes at an internal temperature of 4-8° C. After stirring for 30 minutes the layers were separated and the aqueous layer was extracted with 500 milliliters of EtOAc. The combined organic layers were washed with 3M HCl (3×700 milliliters). The pH of the last wash was 1-2 as determined by pH paper. The organic layer was then washed with 30% aqueous K2CO3 (3×600 milliliters) and brine (2×600 milliliters). The organic layer was held overnight at 0-10° C. The next morning the solution was dried with 50 grams of Na2SO4. After filtration of the drying salts, the amber solution was concentrated to a final volume of about 250 milliliters via rotary evaporation at an external temperature of 45-50° C. The thick slurry was allowed to cool to ambient temperature and 700 milliliters of heptane was added via addition funnel over about 45 minutes. The slurry was cooled to an internal temperature of 0-5° C. and held at this temperature for about 2 hours. The slurry was filtered and washed with a 0-10° C. 5/1 (v/v) mixture of heptane/EtOAc (1×200 milliliters, 1×150 milliliters) to give 161 grams of crude fenretinide wet cake (LOD=25%, 93% yield based on LOD, 98% pure by area percent).