Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:26])([CH3:25])[O:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([NH:16][C:17]2[S:18][C:19]([CH:23]=[O:24])=[C:20]([Cl:22])[N:21]=2)=[O:15])[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[Mn]([O-])(=O)(=O)=[O:28].[K+]>C(O)(C)(C)C.O>[C:1]([Si:5]([CH3:26])([CH3:25])[O:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([NH:16][C:17]2[S:18][C:19]([C:23]([OH:28])=[O:24])=[C:20]([Cl:22])[N:21]=2)=[O:15])[CH:10]=[CH:11][CH:12]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CC(=O)Nc2nc(Cl)c(C=O)s2)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(CC(=O)Nc2nc(Cl)c(C(=O)O)s2)c1
Yield: 84.8 %

Procedure:
To a solution of 2-[3-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-N-(4-chloro-5-formyl-thiazol-2-yl)-acetamide (590 mg, 1.436 mmol) in t-butanol (15 mL) stirred at 60° C. was added drop wise potassium permanganate (405 mg, 2.56 mmol) in water (5 mL) over 15 minutes. The resultant reaction mixture was heated at 80′C for 2 h. The reaction mixture was filtered hot through celite and washed with hot 1/1 t-butanol/water. The filtrate was acidified to pH 1 with aqueous 2N HCl and extracted with 9:1 Methylene chloride/methanol (3×75 mL). The organic layers were combined, washed with brine (50 mL), dried over MgSO4, filtered, concentrated under reduced pressure and dried to give 2-{2-[3-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-acetylamino}-4-chloro-thiazole-5-carboxylic acid (0.52 g, 84.8%) as a pale yellow solid. MS m/e 428.0 (M+H+).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH2:7])[CH2:2][CH3:3].Cl[C:12]1[N:13]=[N+:14]([O-:25])[C:15]2[CH:24]=[C:23]3[C:19]([CH2:20][CH2:21][CH2:22]3)=[CH:18][C:16]=2[N:17]=1>COCCOC>[O-:25][N+:14]1[C:15]2[CH:24]=[C:23]3[C:19](=[CH:18][C:16]=2[N:17]=[C:12]([NH:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][CH3:10])[CH2:1][CH2:2][CH3:3])[N:13]=1)[CH2:20][CH2:21][CH2:22]3
Reactant: CCCN(CCC)CCN
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Solvent: COCCOC
Product: CCCN(CCC)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Yield: 75.9 %

Procedure:
N1,N1-Dipropyl-1,2-ethanediamine (297) (0.27 g, 1.9 mmol) was added to a stirred solution of chloride 21 (298 mg, 1.3 mmol) in DME (50 mL) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 28 (325 mg, 74%) as a yellow powder: mp (MeOH/EtOAc) 95-97° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.39 (s, 1H, H-5), 5.80 (br s, 1H, NH), 3.46-3.53 (m, 2H, CH2N), 2.96-3.03 (m, 4H, 2×CH2N), 2.68 (dd, J=6.0, 5.8 Hz, 2H, CH2N), 2.38-2.45 (m, 4H, H-6, H-8), 2.10-2.18 (m, 2H, H-7), 1.41-1.51 (m, 4H, 2×CH2), 0.87 (t, J=7.1 Hz, 6H, 2×CH3); 13C NMR δ 158.7, 154.4, 148.8, 143.0, 129.8, 120.5, 114.7, 55.9 (2), 52.6, 38.9, 31.1, 32.3, 25.7, 20.3 (2), 11.9 (2). Anal. calcd for C18H27N5O: C, 65.6; H, 8.3; N, 21.3. Found: C, 65.4; H, 8.4; N, 21.3%.
Reaction SMILES: [C:1](=[O:19])([O:17][CH3:18])[O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([F:12])=[CH:5][C:4]=1[C:13]([CH3:16])([CH3:15])[CH3:14].C([O-])=O.[NH4+]>CCO.[Pd]>[C:1](=[O:19])([O:17][CH3:18])[O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([F:12])=[CH:5][C:4]=1[C:13]([CH3:14])([CH3:15])[CH3:16]
Reactant: COC(=O)Oc1c([N+](=O)[O-])cc(F)cc1C(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)Oc1c(N)cc(F)cc1C(C)(C)C
Yield: 27 %

Procedure:
To a refluxing solution of 2-tert-butyl-4-fluoro-6-nitrophenyl methyl carbonate (250 mg, 0.92 mmol) and ammonium formate (250 mg, 4 mmol) in EtOH (10 mL) was added 5% Pd—C (170 mg). The mixture was refluxed for additional 1 h, cooled and filtered through Celite. The solvent was removed by evaporation and the residue was purified by column chromatography (0-15%, EtOAc-Hexane) to give 2-tert-butyl-4-fluoro-6-aminophenyl methyl carbonate (C-6) (60 mg, 27%). HPLC ret. time 3.35 min, 10-99% CH3CN, 5 min run; ESI-MS 242.0 m/z (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8]([CH2:13][NH:14][OH:15])=[C:7]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])[C:6]=2[CH:23]=1.C[Si]([N:28]=[C:29]=[S:30])(C)C.O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:11])([CH3:12])[C:8]([CH2:13][N:14]([OH:15])[C:29]([NH2:28])=[S:30])=[C:7]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])[C:6]=2[CH:23]=1
Reactant: CC1(C)Oc2ccc(Br)cc2C(n2ccccc2=O)=C1CNO
Reactant: C[Si](C)(C)N=C=S
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(Br)cc2C(n2ccccc2=O)=C1CN(O)C(N)=S
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-bromo-2,2-dimethyl-3-(hydroxyamino)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran in tetrahydrofuran was added dropwise trimethylsilyl isothiocyanate at room temperature. The reaction mixture was stirred at room temperature for two hours. Water was added, and the organic layer separated, dried and evaporated. The residue was triturated with diethyl ether to give 0.18 g of 6-bromo-2,2-dimethyl-3-(N-hydroxythioureido)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 219° C.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:14]=1C=O>ClCCl>[Cl:12][C:13]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:14]=1[OH:6]
Reactant: COc1cccc(C=O)c1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cccc(O)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
3-Chloroperoxybenzoic acid (760 mg, 4.396 mmol) was added portionwise to a solution of 2-Chloro-3-Methoxybenzaldehyde (500 mg, 2.931 mmol) in dichloromethane (12 ml) and the mixture was stirred for 3 hours at room temperature. Further 3-chloroperoxybenzoic acid (760 mg, 4.396 mmol) was added and mixture allowed to stir for 18 hrs. The solution was diluted with 12 ml dichloromethane and washed with saturated sodium sulphite solution (15 ml) and saturated sodium hydrogen carbonate solution (15 ml). The organic layer was dried over sodium sulphate and concentrated in vacuo to a yellow gum. The residue was dissolved in methanol (12 ml), triethylamine (0.05 ml) was added and the mixture stirred for 18 hours at room temperature. The solution was concentrated in vacuo, dissolved in diethyl ether (20 ml) and extracted with 1N sodium hydroxide (20 ml). The aqueous layer was acidified to pH1 by dropwise addition of 2N hydrochloric acid and extracted with diethyl ether (2×25 ml). These combined organic layers were dried over sodium sulphate and concentrated in vacuo to afford the title compound as a brown gum in 70% yield, 325 mg.
Reaction SMILES: [C:1]([C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15]2[S:16][C:17]([C:24]#[N:25])=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:31][OH:32].CCN(C(C)C)C(C)C>C(O)C.C(OCC)(=O)C>[C:1]([C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15]2[S:16][C:17](/[C:24](/[NH2:25])=[N:31]/[OH:32])=[C:18]([C:20]([F:22])([F:23])[F:21])[N:19]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc(C(F)(F)F)c(C#N)s1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc(C(F)(F)F)c(/C(N)=N/O)s1
Temperature: 60 °C

Procedure:
A mixture of 2-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-4-(trifluoromethyl)thiazole-5-carbonitrile (Example 404, 177 mg, 0.42 mmol), hydroxylamine hydrochloride salt (145 mg, 2.1 mmol), DIPEA (732 μL, 4.2 mmol) in ethanol (5 mL) was heated at 60° C. for 5 h. The reaction was diluted with ethyl acetate and washed with brine. The organic layer was separated and evaporated to give the crude product. Purification of the crude product by flash chromatography (silica, 0-80% EtOAc/hexane gradient) gave Example A53a (120 mg) as white crystals. (M+H)+=452.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[C:25]3[C:24]([NH2:26])=[N:23][CH:22]=[N:21][C:20]=3[N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35]Cl)[CH:28]=3)[CH:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:37]1[CH:41]=[CH:40][N:39]=[CH:38]1.[Na]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[C:25]3[C:24]([NH2:26])=[N:23][CH:22]=[N:21][C:20]=3[N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][N:37]4[CH:41]=[CH:40][N:39]=[CH:38]4)[CH:28]=3)[CH:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(-c2cn(-c3cccc(OCCCl)c3)c3ncnc(N)c23)cc1OCc1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.1 g of 5-(3-benzyloxy-4-methoxyphenyl)-7-[3-(2-chloro-1-ethoxy)phenyl]-4-aminopyrrolo-[2,3-d]pyrimidine and 0.3 g of sodium imidazole are heated to 85° C. in 30 ml of DMF and the mixture is stirred for 8 h. It is then cooled to RT and concentrated. After chromatography on silica gel, 5-(3-benzyloxy-4-methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-amino-pyrrolo[2,3-d]pyrimidine having an m.p. of 150° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:3]=1
Reactant: Clc1ccnc2ccccc12
Reactant: FC(F)(F)c1ccc(Br)cc1
Product: FC(F)(F)c1ccc(-c2cc(Cl)c3ccccc3n2)cc1

Procedure:
The title compound, m. p. 53-55° C., MS: m/e=307 (M+), was prepared from 4-chloro-quinoline and 4-bromo-benzotrifluoride.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]4[C:20](B5OC(C)(C)C(C)(C)O5)=[CH:21][CH:22]=[CH:23][C:17]=4[CH:16]=3)[C:12]([F:33])=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1.Br[C:35]1[CH:36]=[C:37]([F:44])[CH:38]=[C:39]2[C:43]=1[NH:42][CH:41]=[CH:40]2.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].[F-].[Cs+]>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].O.CS(C)=O.O1CCOCC1.CN(C=O)C>[N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]4[C:20]([C:35]5[CH:36]=[C:37]([F:44])[CH:38]=[C:39]6[C:43]=5[NH:42][CH:41]=[CH:40]6)=[CH:21][CH:22]=[CH:23][C:17]=4[CH:16]=3)[C:12]([F:33])=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: Fc1cc(Br)c2[nH]ccc2c1
Reactant: CC1(C)OB(c2cccc3cc(-c4nc(NCCn5ccnn5)ncc4F)sc23)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: Fc1cc(-c2cccc3cc(-c4nc(NCCn5ccnn5)ncc4F)sc23)c2[nH]ccc2c1
Temperature: 80 °C
Yield: 43.1 %

Procedure:
Combine N-(2-(1H-1,2,3-triazol-1-yl)ethyl)-5-fluoro-4-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)pyrimidin-2-amine (0.12 g, 0.26 mmol), 7-bromo-5-fluoro-1H-indole (64 mg, 0.28 mmol, synthesized based on reference: Manfred S.; Assunta G.: Frédéric L., Eur. J. Org. Chem. 2006, 2956-2069), barium hydroxide octahydrate (0.24 g, 0.77 mmol, alternatively sodium carbonate, potassium carbonate, cesium fluoride), Pd(dppf)Cl2 (20 mg, 0.03 mmol) in 2 mL of mixed solvent of DMF (alternatively dioxane, DMSO) and water (4/1, v/v). Purge the mixture with N2 three times. Heat the reaction mixture to 80° C. for 4 h (HPLC monitor) (or microwave reactor). Cool to RT. Dilute with chloroform/IPA (3:1, v/v) 50 mL. Wash with water, aqueous saturated sodium chloride and dry over magnesium sulfate. Remove the organic solvent to give the crude product. Purify the residue by column chromatography (hexane to ethyl acetate, or methylene chloride and methanol) to give the title compound (0.053 g, 43%). MS (ES) m/z 474 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13].C(OC(=O)C)(=O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:13][CH2:12][C:11]([OH:15])=[O:14]
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: C=CC(=O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)CCc1c[nH]c2ccc(Cl)cc12
Temperature: 100 °C
Reaction time: 48 h
Yield: 24.4 %

Procedure:
A mixture of 5-chloro-1H-indole (2.5 g; 16.49 mmol), acrylic acid (2.49 mL; 36.28 mmol) and acetic anhydride (3.09 mL; 32.98 mmol) in acetic acid was stirred at 100° C. for 48 hours, concentrated under reduced pressure and diluted in NaOH 3N (water), the precipitate was filtered off and the solution acidified to pH 2 and extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure and the crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) and (eluent: 15 to 60% of ethyl acetate in heptane) to give 0.900 g (24%) of 3-(5-chloro-1H-indol-3-yl)propanoic acid as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([N:19]3[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]3)[CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:27][C:28]1[N:33]=[C:32]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:31]=[CH:30][N:29]=1.[P:40]([OH:43])([OH:42])[OH:41]>CO>[P:40]([OH:7])([OH:43])([OH:42])=[O:41].[CH3:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[C:11]([N:19]3[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]3)[CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:27][C:28]1[N:33]=[C:32]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:31]=[CH:30][N:29]=1
Reactant: OP(O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Solvent: CO
Product: O=P(O)(O)O
Temperature: 64 °C
Reaction time: 0.5 h

Procedure:
To a 1 L round-bottom flask equipped with a mechanical stirrer, a thermometer, and a condenser, 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide free base and 500 mL of methanol were charged. The slurry was stirred and heated to 64° C. and held at that temperature for ˜30 minutes. To the resulting clear solution, 7.5 mL of 1 M phosphorous acid solution (in methanol) was added. The mixture was stirred at 64° C. for one hour, cooled down to room temperature by natural cooling (cooling rate ˜0.5° C./min) and held at room temperature for 3-4 hours. The solid was collected by filtration and was dried at 50-55° C./10-20 torr for 8-16 hours to obtain 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide monophosphate salt (3.25 g) as a white solid. Melting point=˜208° C. (dec.); x-ray diffraction pattern showing maxima at 2θ=6.1°, 7.5°, 9.1°, 15.8°, 17.5°, 18.3°, 21.8°, 23.1°, 24.9°, 26.6°.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:31])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][C:16]([CH2:21][O:22]CC3C=CC=CC=3)=[N:15][C:14]=2[N:13]([CH3:30])[C:11]1=[O:12])(=[O:3])[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[C:1]([O:4][C@H:5]([CH3:31])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][C:16]([CH2:21][OH:22])=[N:15][C:14]=2[N:13]([CH3:30])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]c(COCc3ccccc3)nc2n(C)c1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]c(CO)nc2n(C)c1=O
Yield: 88.7 %

Procedure:
To a solution of (R)-1-(5-acetoxyhexyl)-8-benzoxymethyl-3-methylxanthine (4.0 g, 9.33 mmol) in acetic acid (40 ml) was added 10% palladium on carbon (0.52 g). The mixture was treated with hydrogen gas (50 psi) on a Parr shaker for 18 hours. After removing catalyst by filtration, evaporation of the solvent under reduced pressure provided (R)-1-(5-acetoxyhexyl)-8-hydroxymethyl-3-methylxanthine (2.8 g, 88% yield) as a white solid.
Reaction SMILES: [C:1]1(=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:12][CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[C:1]1([NH:12][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C1CCCCCCCCC1
Reactant: CCOC(=O)C(=CN)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)C(=CNC1=CCCCCCCCC1)C(=O)OCC

Procedure:
A mixture of 25.0 g of cyclodecanone, 60.7 g of diethyl aminomethylenemalonate, 1.54 g of p-toluenesulfonic acid monohydrate in 500 ml xylene is refluxed 2 weeks under argon, collecting the distillate in a Dean-Stark trap. The solution is then decanted and solvent is removed. The residual oil is triturated twice with hexane and the combined hexane extract is concentrated to yield an oil which is flash chromatographed on 600 g of silica gel using 99:1 methylene chloride ethyl acetate as eluent. A forerun containing cyclodecanone is discarded and the fractions containing the product are combined and concentrated to dryness to give diethyl N-(1-cyclodecenyl)-aminomethylenemalonate as an oil.
Reaction SMILES: C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:24]1([S:30][C:31]2[C:32]3[CH:47]=[C:46]4[C:41]([CH:42]=[CH:43][CH:44]=[CH:45]4)=[CH:40][C:33]=3[S:34][C:35]=2[Si](C)(C)C)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[C:24]1([S:30][C:31]2[C:32]3[CH:47]=[C:46]4[C:41]([CH:42]=[CH:43][CH:44]=[CH:45]4)=[CH:40][C:33]=3[S:34][CH:35]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[Si](C)(C)c1sc2cc3ccccc3cc2c1Sc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(Sc2csc3cc4ccccc4cc23)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
At −40° C., a THF solution (5 ml, 5 mmol) of 1 M tetra-n-butyl ammonium fluoride was added to THF (50 ml) and water (0.3 ml) of 3-(phenylsulfenyl)-2-trimethylsilylnaphtho[2,3-b]thiophene (550 mg, 1.5 mmol). After the mixture was stirred for 4 hours at room temperature, the reaction liquid was poured into water (50 ml). The precipitated solid was filtered and washed with ethanol and hexane. Purification was implemented by column chromatography (silica gel, CHCl3, Rf: 0.9), so that a white solid was quantitatively produced.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:22](=[O:24])[CH3:23].Cl>O1CCCC1>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:22](=[O:24])[CH3:23])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])=[CH:14][CH:15]=1
Reactant: CCCc1c(OCc2ccc([N+](=O)[O-])cc2)ccc(C(C)=O)c1O
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(OCc2ccc(N)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-[2-Hydroxy-4-(4-nitro-benzyloxy)-3-propyl-phenyl]-ethanone (1.0 g, 3.0 mmol) in tetrahydrofuran (13 mL) is added concentrated hydrochloric acid (2.7 mL) and stannous chloride dihydrate (2.2 g, 9.9 mmol). The reaction mixture is stirred at room temperature overnight. The reaction mixture is quenched into saturated aqueous NH4Cl (100 mL). The resulting emulsion is filtered and the filtrate extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with brine, dried over sodium sulfatesodium sulfate, and concentrated to provide the title compound in crude form (980 mg,). LC-MS (m/z): 298 (M−1).
Reaction SMILES: [In].[F:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[C:4]=1[C:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6]>CC(O)=O.CCOC(C)=O>[NH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:3]([F:2])[C:4]=1[C:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6]
Reactant: O=C(O)CNC(=O)c1c(F)cccc1[N+](=O)[O-]
Agent: [In]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cccc(F)c1C(=O)NCC(=O)O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a suspension of indium powder (237 mg, 2.07 mmol) in AcOH (2 mL) was added 2-(2-fluoro-6-nitrobenzamido)acetic acid (50 mg, 0.21 mmol) at rt and stirred at 60° C. for 30 min. The reaction mixture was attained to rt and diluted with EtOAc (20 mL). The solution was stirred for 5 min and filtered through celite. The celite bed was washed with EtOAc (10 mL) and the combined organic layer was evaporated under reduced pressure. The residue was chromatographed over silica gel column using chloroform:methanol (70:30) as eluents to give the product as a pale brown color solid (32 mg, 73%), mp 188-192° C. 1H NMR (400 MHz, CDCl3+DMSO-d6): δ 7.80 (2H, br s), 7.04 (1H, dd, J=15.0, 7.8 Hz), 6.50 (1H, d, J=8.4 Hz), 6.27 (1H, t, J=9.4 Hz), 6.26 (1H, br s, exchangeable with D2O), 3.74 (2H, d, J=3.6 Hz); 13C NMR (100 MHz, CDCl3+DMSO-d6): δ 172.7, 164.3, 160.7 (d, J=242 Hz), 150.1 (d, J=6 Hz), 130.9 (d, J=12 Hz), 111.5, 106.4 (d, J=18 Hz), 101.2 (d, J=24 Hz), 43.0; LC-MS (negative ion mode): m/z 211 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH3:19])[N:8]2[CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1.[Cl-].[Cl-].C([Al+2])C.[CH3:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([C:36](Cl)=[O:37])=[CH:28][CH:27]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:36]([C:29]3[C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]([CH3:25])=[CH:27][CH:28]=3)=[O:37])=[C:7]([CH3:19])[N:8]2[CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: Cc1cc2ccc(Cl)cc2n1CCN1CCOCC1
Reactant: Cc1ccc(C(=O)Cl)c2ccccc12
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2c(C)n(CCN3CCOCC3)c3cc(Cl)ccc23)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-(6-chloro-2-methyl-1H-indol-1-yl)ethyl)morpholine (48 mg, 0.17 mmol) in 0.5 mL CH2Cl2 at 0° C. was added dropwise ethyl aluminum dichloride (0.14 mL, 0.26 mmol, 1.8 M in toluene). The reaction mixture was stirred at 0° C. for 30 min, then a solution of 4-methyl-1-naphthoyl chloride (43 mg, 0.21 mmol) in 0.5 mL CH2Cl2 was added and stirred at 0° C. for 1 h, then allowed to slowly warm to room temperature overnight. The reaction stirred at room temp for 3 d. The reaction mixture was then poured into ice cold 1M HCl and extracted three times with CH2Cl2. The combined organic extract was washed three times with a saturated solution of sodium bicarbonate, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 5% MeOH in CH2Cl2 to give CBX004 (23 mg, 0.052 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.46 (s, 3H), 2.48-2.59 (m, 4H), 2.71 (t, J=6.9 Hz, 2H), 2.80 (s, 3H), 3.71 (t, J=4.6 Hz, 4H), 4.20 (t, J=6.9 Hz, 2H), 7.02 (dd, J=8.6 Hz, 1.8 Hz, 1H), 7.25 (d, J=8.6 Hz, 1H), 7.33 (d, J=1.7 Hz, 1H), 7.37 (d, J=7.2 Hz, 1H), 7.44-7.53 (m, 2H), 7.58 (td, J=7.6 Hz, 1.1 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H). 13C NMR (500 MHz, CDCl3, δ): 12.62, 19.93, 41.40, 54.10, 57.36, 66.88, 109.40, 115.34, 122.34, 122.49, 124.40, 125.72, 125.76, 126.03, 126.08, 126.21, 126.66, 128.25, 130.43, 132.91, 136.51, 137.22, 138.35, 146.00, 193.43. MS m/z 447.6 [M+H]+.