Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][CH:9]([CH2:12][OH:13])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[OH:13][CH2:12][CH:9]1[O:8][C:7]2[C:2]([O:1][CH3:14])=[CH:3][CH:4]=[CH:5][C:6]=2[O:11][CH2:10]1
Reactant: OCC1COc2cccc(O)c2O1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1cccc2c1OC(CO)CO2
Temperature: 45 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A mixture of 5.52 g of 8-hydroxy-2-hydroxymethyl-1,4-benzodioxan (prepared as described in EP 210581), 4.2 g of anhydrous potassium carbonate and 2.06 ml of methyl iodide in 75 ml of anhydrous dimethylformamide was stirred at 45° C. for 8 hours. Methyl iodide (1 ml) was added to the mixture and stirring continued at the same temperature. After 8 hours, 1 ml of methyl iodide and 2.1 g of potassium carbonate were further added, and the reaction mixture was stirred at 45° C. for 6 hours. Thereafter, the mixture was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was washed with 6N aqueous sodium hydroxide solution, water, then dried on sodium sulfate. Evaporation of the organic layer to dryness in vacuo afforded 5.35 g of 2-hydroxymethyl-8-methoxy- 1,4-benzodioxan, which was used in the next step without further purification.
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][CH2:3][CH2:2]2.[OH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[O:18][CH3:19].B(F)(F)F.CCOCC>C1C=CC=CC=1.C(OCC)(=O)C>[OH:6][C@@H:1]1[CH2:2][CH2:3][CH2:4][C@H:5]1[O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[O:18][CH3:19]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: C1CC2OC2C1
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(O[C@@H]2CCC[C@H]2O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Oxabicyclo[3.1.0]hexane (2.43 g, 2.50 mL, 28.9 mmol) was added dropwise to a stirred solution of methyl 4-hydroxy-3-methoxy-benzoate (5.26 g, 28.9 mmol) and BF3.OEt2 (410 mg, 369 μL, 2.89 mmol) in benzene (10 mL) at ambient temperature. The mixture was stirred at room temperature overnight before it was diluted with ethyl acetate and was washed with 1N NaOH. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with 0-100% EtOAc in hexanes to give methyl 4-((1R,2R)-2-hydroxycyclopentyloxy)-3-methoxybenzoate. ESI-MS m/z talc. 266.1, found 267.1 (M+1)+; Retention time: 1.16 minutes (3 min run).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:20]1[C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[CH:17]=[CH:18][CH:19]=1
Reactant: C#CCCc1nc2cccc(Cl)c2o1
Reactant: Brc1ccccn1
Product: Clc1cccc2nc(CCC#Cc3ccccn3)oc12
Yield: 45 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (32 mg, 0.20 mmol) and 2-(but-3-ynyl)-7-chlorobenzo[d]oxazole (42 mg, 0.20 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 25 mg (90 μmol, 44%) of 7-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11])([O-])=O>C(OCC)(=O)C.C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(O)cc1F
Yield: 980 %

Procedure:
A mixture of 4-nitro-3-fluorophenol (0.314 g, 2 mmol) and iron (0.56 g, 10 mmol) in ethyl acetate (4 ml) and acetic acid (2 ml) was refluxed for 3 hour. The solid particles were filtered off. The filtrate was washed with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated to yield 4-amino-3-fluorophenol (53a) (0.25 g, 19.6 mmol, 98%) as a brown solid. 1H NMR (CDCl3, 400 MHz) δ 6.48-6.58 (m, 2H), 6.61-6.70 (m, 1H), 7.87 (bs, 3H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][OH:14])[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=2)[N:6]=1)(=O)=O.[C-:23]#[N:24].[Na+].C(OCC)(=O)C>CS(C)=O>[OH:14][CH2:13][CH2:12][CH2:11][C:9]1[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=2)[N:6]=[C:5]([C:23]#[N:24])[N:10]=1
Reactant: Cc1ccc(-c2cc(CCCO)nc(S(C)(=O)=O)n2)cc1C
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cc(CCCO)nc(C#N)n2)cc1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the solution of 2-methylsulfanyl-4-(3-hydroxypropyl)-6-(3,4-dimethyl-phenyl)pyrimidine (5.8 g) in a mixed solvent of methanol and water (110 ml, 10:1) was added OXONE (35 g). The mixture was stirred at room temperature for 3 hours, then diluted with ethyl acetate (500 ml). The mixture was washed with water (3×500 ml). Organic layer dried over sodium sulphate, solvent removed under reduced pressure to give 2-methanesulphonyl-4-(3-hydroxypropyl)-6-(3,4-dimethylphenyl)-pyrimidine as crude product. To a stirred solution of above 2-methylsulphonyl-4-(3-hydroxypropyl)-6-(3,4-dimethylphenyl)pyrimidine in dimethylsulfoxide (50 mL), was added sodium cyanide (2.9 g). The mixture was stirred at room temperature for 4 hours, then poured into ethyl acetate (300 mL) and washed with water (2×200 mL). The organic layer was dried over sodium sulphate, solvent evaporated at reduced pressure, the above residue was flashed on silica gel using Petrol/EtOAc (1:1) as eluent to give 4-(3-Hydroxy-propyl)-6-(3,4-dimethylphenyl)-pyrimidine-2-carbonitrile as product (4.8 g).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=[C:6]2[N:5]=[C:4]([CH3:17])[C:3]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20].CC[N:25]([CH:29]([CH3:31])C)[CH:26]([CH3:28])C.CN1C(=O)[CH2:36][CH2:35][CH2:34]1>>[CH3:34][C:35]1([CH3:36])[CH2:28][CH2:26][N:25]([C:2]2[N:7]3[N:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:10]=[C:6]3[N:5]=[C:4]([CH3:17])[C:3]=2[CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:29][CH2:31]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN1CCCC1=O
Reactant: COC(=O)Cc1c(C)nc2nc(-c3ccccc3)nn2c1Cl
Product: COC(=O)Cc1c(C)nc2nc(-c3ccccc3)nn2c1N1CCC(C)(C)CC1
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of methyl 2-(7-chloro-5-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)acetate (100 mg, 0.316 mmol) and 4,4-dimethylpiperidine, HCl (47.3 mg, 0.316 mmol) in NMP (Volume: 3 mL) was added DIEA (0.220 mL, 1.263 mmol). The resulting mixture was stirred at r.t for 3 hrs. then purified by Pre-HPLC to afford methyl 2-(7-(4,4-dimethylpiperidin-1-yl)-5-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)acetate (108 mg, 0.269 mmol, 85% yield). 1H-NMR (500 MHz, CDCl3) δ 1.14 (6 H, s), 1.68 (2 H, t), 2.63 (3 H, s), 3.62 (2 H, t), 3.82 (3 H, s), 7.55-7.57 (3 H, m), 8.24-8.26 (2 H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[F:38][C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C1(C)C=CC=CC=1>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(O)C.O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:42]1[CH:43]=[CH:44][C:39]([F:38])=[CH:40][CH:41]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: OB(O)c1ccc(F)cc1
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: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)c1c(-c2ccc(F)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 58.7 %

Procedure:
A mixture of 2-benzyl-6-chloro-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg), sodium carbonate (45 mg), 4-fluorophenylboronic acid (35 mg), tetrakis(triphenylphosphine)palladium(0) (12 mg), toluene (2.0 ml), water (0.4 ml) and ethanol (0.4 ml) in a pear shape flask with dimroth was deaerated in a vacuum line, substituted with argon and stirred at 80° C. for 12 hrs. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (52 mg) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[CH2:16][C:17](Cl)=[O:18].[CH2:20]([CH2:22][NH2:23])[OH:21]>C1COCC1>[OH:18][CH2:17][CH2:16][NH:23][CH2:22][C:20]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:21]
Reactant: NCCO
Reactant: Nc1cccnc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CNCCO)Nc1cccnc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 31.7 %

Procedure:
To a stirred solution of 3-aminopyridine (2.0 g, 21 mmol) and triethylamine (4 mL, 29 mmol) in THF (25 mL) under an inert atmosphere and precooled to 0–5° C., was added chloroacetyl chloride (2.2 mL, 26 mmol) dropwise over 10 min. After a further 15 min. the mixture was allowed to return to ambient temperature. Ethanolamine (5.4 mL, 87 mmol) was added and the dark solution warmed to 60° C. for 3 h. Solvents were removed in vacuo and DCM:MeOH (80:20) added to the resultant residue. This was filtered directly onto a column of silica gel, eluting with DCM:MeOH (90:10) to afford the title compound (1.3 g, 32%) isolated as an oil. 1H NMR (400 MHz, d6-DMSO) δ 2.67 (2H, t, J=5.5 Hz), 3.32 (1H, br s), 3.40 (2H, s), 3.50 (2H, t, J=5.4 Hz), 4.70 (1H, br s), 7.33–7.37 (1H, m), 8.06–8.10(1H, m), 8.26–8.28 (1H, m), 8.77–8.79 (1H, m), 10.20 (1H, br s). MS (ES+) 196 (M+1).
Reaction SMILES: [CH2:1]=[O:2].[CH3:3][OH:4].[CH3:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]=1>CC[O-].[Na+]>[OH:2][CH2:1][CH:5]([CH2:3][OH:4])[C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]=1
Reactant: C=O
Reactant: CO
Reactant: COc1cc2c(cc1OC)C(C)=NCC2
Agent: CC[O-]
Agent: [Na+]
Product: COc1cc2c(cc1OC)C(C(CO)CO)=NCC2
Yield: 90 %

Procedure:
To a suspension of 2.5 moles of paraformaldehyde in 300 ml of methanol 1 mole (205.3 g) of 1-methyl-6,7-dimethoxy-3,4-dihydroisoquinoline and subsequently freshly prepared sodium ethylate (1 g of sodium+50 ml of ethanol) are added at room temperature, with stirring. The reaction mixture is stirred for 5 to 6 hours, whereupon it is kept at 40° to 50 C.° for half an hour. The mixture is evaporated under reduced pressure and the obtained crystalline material is recrystallized from a mixture of acetone and ether. The aimed compound is obtained with a melting point of 129° to 131 C.°
Reaction SMILES: ClC(OCC)=O.[C:7]([O:11][C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].I.[NH:20]=[C:21]1[N:25]([CH3:26])[CH2:24][CH2:23][S:22]1>C(Cl)Cl.C(N(CC)CC)C>[CH3:26][N:25]1[CH2:24][CH2:23][S:22][C:21]1=[N:20][C:16](=[O:18])[CH2:15][NH:14][C:12]([O:11][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:13]
Reactant: CN1CCSC1=N
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCOC(=O)Cl
Agent: I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCSC1=NC(=O)CNC(=O)OC(C)(C)C
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
Ethyl chloroformate (0.25 ml.) at -5° C. was added to a solution of 350 mg. of t-butoxycarbonylaminoacetic acid and 0.4 ml. of triethylamine in 10 ml. of methylene chloride at -5° C. After stirring 5 minutes at -5° C. there was added a solution of 610 mg. of 2-imino-3-methylthiazolidine hydrogen iodide and 1.0 ml. of triethylamine in 10 ml. of methylene chloride also at -5° C. Stirring was continued at -5° C. for 15 minutes and one hour at room temperature. The reaction mixture was washed with 40 ml. of 20% (w/v) citric acid solution, sodium bicarbonate solution, and water, dried and concentrated to dryness. The residue was triturated with ether, petroleum ether and ether and finally collected to give pure N-(3-methylthiazolidin-2-ylidene)-t-butoxycarbonylaminoacetamide.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.CCN(CC)CC.[Br:22][CH:23]([CH3:27])[C:24](Br)=[O:25]>C(Cl)Cl.O>[Br:22][CH:23]([CH3:27])[C:24]([N:8]([CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:25]
Reactant: CN1CCC(Nc2ccccc2)CC1
Reactant: CC(Br)C(=O)Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Br)C(=O)N(c1ccccc1)C1CCN(C)CC1
Reaction time: 1 h
Yield: 87.8 %

Procedure:
A solution of compound 1-methyl-N-phenylpiperidin-4-amine (1.0 g, 5.255 mmol) in dry CH2Cl2 (10 mL) was treated with Et3N (2.19 mL, 15.766 mmol) followed by 2-bromopropionyl bromide (0.61 mL, 5.780 mmol) at 0° C. and stirred at same temperature for 1 h. The reaction was diluted with water (25 mL) and product was extracted into CH2Cl2 (2×25 mL). The combined CH2Cl2 layer was washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (MeOH:CH2Cl2, 5:95) to obtain compound 2-Bromo-N-(1-methylpiperidin-4-yl)-N-phenylpropanamide (1.5 g, 88%) as a solid. 1H NMR (DMSO-d6) δ: 1.09-1.33 (m, 2H), 1.59 (d, 3H, J=6.3 Hz), 1.66-1.74 (m, 2H), 1.89-1.98 (m, 2H), 2.09 (s, 3H), 2.68-2.74 (m, 2H), 4.01 (q, 1H), 4.28-4.36 (m, 1H), 7.26-7.30 (m, 2H), 7.46-7.50 (m, 3H); ESI-MS (m/z, %) 327 and 325 (MH+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-])=O)[CH2:9][C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.C(O)C.[ClH:28]>[Fe].O>[ClH:1].[ClH:28].[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:8]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)[C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9]1
Reactant: O=[N+]([O-])c1ccccc1N1CC2(CCNCC2)c2ccc(Cl)cc21
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccccc1N1CC2(CCNCC2)c2ccc(Cl)cc21

Procedure:
A mixture of 2.1 g of 6-chloro-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine], free base of Example 33, 95 ml of 95% ethyl alcohol, 7.5 ml of water and 4.4 g of iron powder is acidified with 0.2 ml of concentrated hydrochloric acid and then refluxed under nitrogen for 10 minutes. Thereafter, the mixture is permitted to cool before being filtered through celite. The filtrate is concentrated under vacuum leaving an oily residue which is basified. The alkaline mixture is extracted with ether and then dried. The product is converted to a solid dihydrochloric acid salt which is recrystallized from a methyl alcohol-ether mixture to provide off-white prisms, mp 270°-273° C. (after darkening) of 1-(2-aminophenyl)-6-chlorospiro[indoline-3,4'-piperidine]dihydrochloride.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:10][N:11]([CH3:16])[S:12](Cl)(=[O:14])=[O:13].C(Cl)Cl.C(N(CC)CC)C>O>[CH2:1]([C:5]1[N:9]([S:12]([N:11]([CH3:16])[CH3:10])(=[O:14])=[O:13])[CH:8]=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc[nH]1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCCc1nccn1S(=O)(=O)N(C)C
Temperature: 40 °C
Reaction time: 2 h
Yield: 103.6 %

Procedure:
12.4 g of butylimidazole and 13.3 g of N,N-dimethylsulfamoyl chloride were introduced into 200 ml of methylene chloride, and 9.7 g of triethylamine was added at room temperature. The mixture was stirred for 20 hours at room temperature and for 2 hours at 40° C., 200 ml of water was added and the phases were separated. The organic phase was washed with water, dried with Na2SO4 and concentrated by evaporation to give 22.2 g of product in the form of a red oil. The yield was 96 percent. Other data concerning the product was:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].CC1C=C[C:9]([O:12]C)=CC=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]>Cl>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:9]=[O:12])=[CH:17][C:16]=1[CH3:21]
Reactant: COc1ccc(C)cc1
Reactant: Cc1ccccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C=O)ccc1F
Temperature: 30 °C
Yield: 131.4 %

Procedure:
229.30 g of aluminum chloride (mol. Wt. 133.34; 1,719.7 mmol), 110.0 g (4-Methylanisole (mol. Wt. 122.17; 900.4 mmol), and about 500 g of 2-fluorotoluene (mol. Wt. 110.13; 4,540.1 mmol) were charged to a 2 liter Parr®-brand 4522 stainless steel reaction vessel. To this mixture was added 5 drops of concentrated HCl. The vessel was sealed, heated to 30° C., and purged three times with carbon monoxide with the pressure of the vessel increased to 100 psi for each purging. After the third purge, the vessel was vented and a final introduction of CO was made at a pressure of about 550 psi, the pressure at which the reaction was maintained for the total reaction time of about 66 hours (the reaction temperature was maintained at 30° C. for the duration as well). Once the reaction was complete, the resultant mixture (exhibiting a greenish-brown color) was poured into about 500 mL of ice water (which turned the solution a yellow color), to which was added 500 mL of cyclohexane. The top, organic layer was removed and washed three times with water using a separatory funnel and dried over magnesium sulfate. The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 2-fluorotoluene, and left about 98.01 g of 4-fluoro-3-methylbenzaldehyde product (mol. Wt. 138.14; 709.5 mmol; yield of approximately 86.7%). The 4-fluoro-3-methylbenzaldehyde product may then be easily separated from any residual 4-methylanisole by conversion into its corresponding bisulfite adduct, filtration, and decomposition of the bisulfite adduct under acidic or basic conditions.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17](O)[C:16]3[C:11](=[CH:12][C:13]([O:20][CH3:21])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:17]1[C:16]2[C:11](=[CH:12][C:13]([O:20][CH3:21])=[CH:14][CH:15]=2)[N:10]=[C:9]([C:6]2[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)[CH:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(Cl)cc(-c3nc(C(C)C)cs3)nc2c1
Temperature: 100 °C
Yield: 62 %

Procedure:
2-(4-Isopropylthiazol-2-yl)-7-methoxyquinolin-4-ol, prepared as described in WO00/59929, (3.6 g) was mixed with 20 ml of phosphorus oxychloride and heated at 100° C. for 40 min. Reaction was monitored by LC-MS. After 40 min of heating the excess of phosphorus oxychloride was removed by rotary evaporation. The residual oil was mixed with sat. sodium bicarbonate solution and extracted into ether (3×70 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate, concentrated by rotary evaporation and passed through short pad of silica (hexane) to give the title compound as a white powder 3.6 g (yield 62%).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14]>C1COCC1>[CH:2]([C:1]([O:8][CH3:9])=[O:7])([C:3]([O:5][CH3:6])=[O:4])[CH2:14][CH2:13][C:12]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: COC(=O)CC(=O)OC
Reactant: C=CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCC(C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
To a solution of dimethyl malonate (2.5 g, 18.9 mmol) in anhydrous THF (20 mL) was added NaH (0.038 g, 0.95 mmol, 60% in mineral oil). The reaction was stirred at ambient temperature for 15 minutes. In a separate flask, ethyl acrylate was dissolved in anhydrous THF (1 mL) and then added dropwise over 30 minutes to the dimethyl malonate solution. The reaction was stirred at ambient temperature for 16 h and then concentrated under vacuum. The residue was dissolved in EtOAc (ethyl acetate) and washed with saturated NH4Cl solution and brine. The organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by column chromatography (silica gel) using an EtOAc/hexanes gradient to yield the desired compound as a colorless oil (1.68 g, 77%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47](O)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.ON1C2C=CC=CC=2N=N1.[CH3:61][NH:62][CH3:63]>C1COCC1>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([N:62]([CH3:63])[CH3:61])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Reactant: CNC
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)N(C)C)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (60 mg, 0.09 mmol) in THF (2 mL) was added polystyrene-carbodiimide (156 mg, 0.18 mmol), 1-hydroxybenzotriazole hydrate (18 mg, 0.13 mmol) and dimethylamine (0.09 mL, 0.13 mmol). The reaction mixture was stirred at room temperature under nitrogen for 4 h. The reaction was filtered through a micro filter and concentrated. The crude material was purified by preparative TLC (9:1, methylene chloride/methanol) to afford (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-N,N,3-trimethyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide as a mixture of diastereomers (8.0 mg, 13%) and as a red solid: 1H NMR (500 MHz, CDCl3) δ 14.18 (s, 1H), 8.16 (s, 1H), 6.85 (d, J=9.0 Hz, 0.8H), 6.57 (s, 1H), 6.28-6.24 (m, 0.2H), 6.20 (s, 0.2H), 5.87 (s, 0.8H), 5.14-5.08 (m, 1H), 5.00-4.94 (m, 1H), 4.71-4.66 (m, 1H), 4.62-4.56 (m, 1H), 3.79 (s, 3H), 3.75-3.68 (m. 2H), 3.61 (s, 3H), 3.59-3.52 (m, 3H), 3.41 (s, 3H), 3.38-3.28 (m, 2H), 3.13 (t, J=9.0 Hz, 1H), 2.92 (s, 6H), 2.14 (s, 3H), 3.14 (d, J=6.0 Hz, 3H); MS (ESI−) m/z 709 (M−H); HPLC 95.6% (AUC), tR 11.51 min.