Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[O:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([NH:26][NH2:27])=[O:25])(=[O:20])=[O:19])[CH2:14][CH2:13]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](/[C:8](=[N:27]/[NH:26][C:24](=[O:25])[C:23]2[CH:28]=[CH:29][CH:30]=[C:21]([S:18]([N:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)(=[O:19])=[O:20])[CH:22]=2)/[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 31.2 %

Procedure:
1-(5-Chloro-2-hydroxyphenyl)ethanone (20 mg, 0.117 mmol) and 3-(morpholinosulfonyl)benzohydrazide (33.5 mg, 0.117 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound (16 mg) as a solid. 1H NMR (400 MHz, CD3OD): δ 8.26 (m, 1H), 8.17 (d, 1H, J=8.0 Hz), 7.92 (d, 1H, J=8.0 Hz), 7.72 (t, 1H, J=8.0 Hz), 7.48 (d, 1H, J=2.0 Hz), 7.22 (m, 1H), 6.91 (d, 1H, J=8.8 Hz), 3.72 (m, 4H), 3.01 (m, 4H), 2.43 (s, 3H). ESI-MS: 438.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[CH2:9][CH2:8][C:7](=O)[C:6](=O)[C:5]=2[C:4]([CH3:14])([CH3:13])[CH:3]1[CH3:15].CC1(C)C2CCCC(=O)C=2C(C)(C)C1C.[CH2:32]([NH2:35])[CH2:33][NH2:34].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>COCCOCCOC>[CH3:1][C:2]1([CH3:16])[C:10]2[CH2:9][CH2:8][C:7]3[N:35]=[CH:32][CH:33]=[N:34][C:6]=3[C:5]=2[C:4]([CH3:14])([CH3:13])[CH:3]1[CH3:15]
Reactant: CC1C(C)(C)C2=C(C(=O)C(=O)CC2)C1(C)C
Reactant: NCCN
Agent: CC1C(C)(C)C2=C(C(=O)CCC2)C1(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: COCCOCCOC
Product: CC1C(C)(C)C2=C(c3nccnc3CC2)C1(C)C
Temperature: 130 °C
Reaction time: 24 h

Procedure:
1,1,2,3,3-Pentamethyl-2,3,6,7-tetrahydro-1H-indene-4,5-dione is first prepared with 1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-inden-4-one (Cashmeran®) (commercially available at IFF) via oxidation with (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO) (prepared as described by Barton in Tetrahedron Letters, 1984, 25(6), pages: 603-606). A 100 mL reaction flask is charged with 1,1,2,3,3-pentamethyl-2,3,6,7-tetrahydro-1H-indene-4,5-dione (10 g, 0.04 mol), ethylene diamine (NH2CH2CH2NH2) (2.5 g, 0.04 mol), and diglyme (50 mL). The reaction mixture is heated to 130° C. and stirred for 24 hours. The reaction mixture is then cooled to 25° C. and further oxidized with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (10 g, 0.045 mol) for another 8 hours. The crude mass is washed once with aqueous sodium carbonate (10%, 100 mL) followed by twice with brine (30 mL). Diglyme is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product 7,7,8,9,9-pentamethyl-5,7,8,9-tetrahydro-6H-cyclopenta[f]quinoxaline (˜10 g) is obtained.
Reaction SMILES: [N:1]1[C:2]([C:6]2[CH:11]=[N:10][CH:9]=[CH:8][N:7]=2)=[N:3][CH2:4][CH:5]=1.[H-].[Na+].Cl[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[CH3:20][Si:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][O:16][CH2:15][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: C1=NC(c2cnccn2)=NC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccnc1-c1cnccn1
Temperature: 40 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
To a solution of 2-(4H-imidazol-2-yl)pyrazine (0.75 g, 5.1 mmol) in DMF (7 mL) was added sodium hydride (60% dispersion in oil, 0.42 g, 10.3 mmol) and the reaction stirred at 40° C. for 2 hours. [2-(chloromethoxy)ethyl](trimethyl)silane (1.71 g, 10.3 mmol) was added and the reaction was stirred at 40° C. for a further 3 hours The reaction mixture was partitioned between EtOAc and water and the layers separated. The aqueous layers was extracted with EtOAc (×2) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified using column chromatography (gradient 20-60% EtOAc in hexane) to give the title compound (0.88 g, yellow oil). 1H NMR (400 MHz, CDCl3) δ ppm: 9.47 (d, J=1.0 Hz, 1 H), 8.36-8.59 (m, 2 H), 7.26-7.28 (m, 1 H), 7.24 (d, J=1.3 Hz, 1 H), 5.96-6.00 (m, 2 H), 3.53-3.61 (m, 2 H), 0.86-0.94 (m, 2 H), −0.10-−0.05 (m, 9 H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][NH:32][C:33]([NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]1[CH:48]=[CH:47][C:46]([CH2:49]O)=[CH:45][CH:44]=1)=[O:34]>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:49][C:46]2[CH:45]=[CH:44][C:43]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[CH2:36][NH:35][C:33]([NH:32][CH3:31])=[O:34])=[CH:48][CH:47]=2)[C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)NCc1ccccc1-c1ccc(CO)cc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1
Product: CNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1

Procedure:
Prepared from 3-benzyloxycarbonylamino-3-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]butanamide (Step D) and 2'-[[(methylamino)carbonyl]amino]methyl-1,1'-biphenyl-4-methanol, methanesulfonate ester (Step I) according to the procedure described in Example 35, Step H. 1H NMR (200 MHz, CDCl3): δ 1.33 (s,6H), 1.78 (m, 1H), 2.37-2.63 (m, 3H), 2.60 (d, 5 Hz, 3H), 4.20 (d, 6 Hz, 2H), 4.52 (m, 2H), 4.72 (t, 6 Hz, 1H), 4.86 (d, 16 Hz, 1H), 4.89 (s, 2H), 5.10 (d, 15 Hz, 1H), 5.69 (s, 1H), 6.73 (d, 7.5 Hz, 1H), 7.08-7.35 (m, 16H) 7.40 (m, 1H). FAB-MS: calculated for C39H43N5 O5 661; found 662 (M+H, 40%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:21](=[O:23])[CH3:22])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC1CCN(Cc2ccccc2)CC1
Reaction time: 5 h

Procedure:
To a solution of 1-benzylpiperidin-4-amine (10 g) in dichloromethane (80 ml), cooled to 5° C., was added pyridine (5.1 ml) followed by acetyl chloride (4.5 ml) and the resulting mixture was stirred for 5 hours. The reaction mixture was washed with 1N NaOH (×2) and then the organic layers were dried and evaporated to dryness to give a solid which was recrystallised from ethyl acetate to give N-(1-benzylpiperidin-4-yl)acetamide. Yield 8.8 g. NMR (d6 DMSO): 1.4 (m, 2H), 1.7 (m, 2H), 1.8 (s, 3H), 2.0 (m, 2H), 2.75 (m, 2H), 3.45 (s, 2H), 3.55 (m, 1H), 7.3 (m, 5H), 7.75 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)c(C)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(Cc2ccc(OC)cc2)c(C)c(C)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a mixture of methyl 2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.40 g), 1-(chloromethyl)-4-methoxybenzene (0.21 g) and sodium carbonate (0.28 g) in 1,2-dimethoxyethane (6.00 mL)-water (2.00 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.08 g), and the mixture was stirred overnight at 80° C. under argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.30 g).
Reaction SMILES: [CH2:1]1[O:7][P:5]([OH:8])(=[O:6])[CH2:4][O:3][C@H:2]1[CH2:9][N:10]1[C:15](=[O:16])[N:14]=[C:13]([NH2:17])[CH:12]=[CH:11]1.C1(NC(N2CCOCC2)=NC2CCCCC2)CCCCC1.Br[CH2:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]>>[CH3:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][CH2:40][O:6][P:5]1([O:7][CH2:1][C@H:2]([CH2:9][N:10]2[C:15](=[O:16])[N:14]=[C:13]([NH2:17])[CH:12]=[CH:11]2)[O:3][CH2:4]1)=[O:8]
Reactant: CCCCCCCCCCCCCCCCOCCCBr
Reactant: Nc1ccn(C[C@H]2COP(=O)(O)CO2)c(=O)n1
Agent: C1CCC(N=C(NC2CCCCC2)N2CCOCC2)CC1
Product: CCCCCCCCCCCCCCCCOCCCOP1(=O)CO[C@@H](Cn2ccc(N)nc2=O)CO1
Temperature: 80 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a heterogeneous solution of cyclic cidofovir (39 g, 0.131 mol., 1 equiv, purchased from Gilead Sciences) in N,N-DMF (2.0 L) under a nitrogen atmosphere was added N,N′-dicyclohexyl-4-morpholinecarboxamidine (DCMC) (0.131 mol, 38.51 g, 1 equiv.). This was stirred overnight. This dissolved most of the solid in the reaction mixture. To this solution was added 1-bromo-3-hexadecyloxypropane (238.45 g, 0.656 mol, 5 equiv.). The reaction mixture was heated to 80° C. and stirred for 6 hours. The crude reaction mixture was concentrated in vacuo at 80° C. The crude reaction mixture was absorbed on silica gel (300 g) and purified via column chromatography (800 g SiO2). The column was eluted with dichloromethane (6 L) to remove the excess 1-bromo-3-hexadecyloxypropane. The solvent phase was then switched to 9:1 CH2Cl2:EtOH (32 L). The product came off with this solvent system. Fractions 30-39 were combined to give hexadecyloxypropyl-cyclic cidofovir (17.8 g) in a 25% yield.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH:13]=[CH2:14].C(N(CC)CC)C.[C:22]([Si:26]([CH3:29])([CH3:28])Cl)([CH3:25])([CH3:24])[CH3:23]>ClCCl.CN(C)C1C=CN=CC=1>[Si:26]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH:13]=[CH2:14])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:29])[CH3:28]
Reactant: C=CCc1cc(C(=O)OC)ccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCc1cc(C(=O)OC)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5.168 g (26.9 mmol) of the product of Step B in 50 mL of dichloromethane was added 4.40 mL (2.95 mmol) of triethylamine, 4.46 g (2.95 mmol) of tert-butyldimethylchlorosilane, 0.100 g of 4-dimethylaminopyridine, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was then diluted with 50 mL dichloromethane, washed with 100 mL 1N hydrochloric acid, dried (MgSO4), filtered and evaporated. The residual oil (7.993 g, 97%) was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[OH:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(OCc2ccc(C#N)cc2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of 4-cyanobenzyl bromide (40 mmol, 7.84 g), methyl 3-hydroxybenzoate (40 mmol, 6.08 g) and potassium carbonate (60 mmol, 8.29 g) in 50 mL DMF was stirred at 60° C. overnight and the solution was cooled to room temperature. To it was added dilute citric acid followed by ethyl acetate. The organic layer was separated, washed with brine, NaHCO3 and brine, dried (MgSO4), and concentrated to give a solid. The solid was washed with ether two times to give 6.2 g (60%) product. NMR (DMSO-d6): δ7.88 (d,2H);7.66(d,2H);7.58 (m, 2H); 7.46 (t, 1H); 7.32 (dd, 1H); 5.30 (s, 2H); 3.84 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.[CH2:10](O)[CH3:11]>OS(O)(=O)=O.C(OCC)(=O)C.[Cl-].[Na+].O>[CH2:10]([O:8][C:7]([C:4]1[CH:3]=[C:2]([Br:1])[S:6][CH:5]=1)=[O:9])[CH3:11]
Reactant: O=C(O)c1csc(Br)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1csc(Br)c1

Procedure:
5-bromo-thiophene-3-carboxylic acid (18.2 g, 0.09 mol) was dissolved in absolute ethanol (150 ml) and H2SO4 (5 ml), and the mixture was refluxed for 5 hours. The mixture was concentrated under vacuum to give a yellow oil, then diluted with a mixture of ethyl acetate (100 ml) and saturated brine (200 ml), and mixed, let standing for layer separation. The aqueous layer was washed with ethyl acetate (25 ml twice). The extract and the organic layer was adjusted with Na2CO3 (10%) to pH=8, and the organic phase was separated and washed with saturated brine to pH=7□ dried over anhydrous Na2SO4 over night. The organic layer was concentrated under reduced pressure to give 5-bromo-thiophene-3-carboxylic acid ethyl ester as yellow oil (15 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[C:5]([CH3:11])[CH:4]=1)#[CH:2].[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1)[CH3:13]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:19]2[CH:20]=[CH:21][C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:23])=[CH:17][CH:18]=2)=[CH:4][C:5]=1[CH3:11]
Reactant: C#Cc1ccc(CO)c(C)c1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(CO)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
Using General Procedure F; (4-ethynyl-2-methyl-phenyl)-methanol (Intermediate 136, 100.0 mg, 0.44 mmol) and ethyl-4-iodo benzoate (Reagent A, 125.0 mg, 0.45 mmol) in triethyl amine (4 mL) was treated with copper(I)iodide (29 mg, 0.15 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (102 mg, 0.15 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (20-40% EtOAc-hexanes) afforded 130.0 mg (99%) of the title compound as an orange solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([Br:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:24]([CH3:31])([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[CH2:28]([O:27][C:25](=[O:26])[C:24]([O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[Br:16])([CH3:31])[CH3:30])[CH3:29]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc(OCc2ccccc2)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1Br
Temperature: 55 °C
Yield: 34.7 %

Procedure:
A mixture of 4-benzyloxy-2-bromo-phenol (9.37 g, 33.6 mmol) and Cs2CO3 (21.9 g, 67.2 mmol) in DMF (80 mL) was treated with ethyl bromoisobutyrate (15 mL, 100 mmol) and heated at 55° C. for 18 h. The reaction mixture was cooled and partitioned between ethyl acetate (250 mL) and H2 (100 mL). The organic layer was washed with brine (75 mL), dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography using CH2Cl2:hexanes (2:3 to 3:2) to give a pale yellow oil (4.58 g, 35%): 1H NMR (400 MHz, CDCl3) δ1.29 (t, 3H, J=7.1 Hz), 1.57 (s, 6H), 4.25 (q, 2H, J=7.1 Hz), 4.98 (s, 2H), 6.79 (dd, 1H, J=3.2, 9.1 Hz), 6.89 (d, 1H, J=8.8 Hz), 7.17 (d, 1H, J=3.4 Hz), 7.32-7.40 (m, 5H); MS (ES) m/e #[M+1].
Reaction SMILES: C([C:3]1[C:4](=[O:11])[NH:5][CH:6]=[CH:7][C:8]=1[O:9]C)#N.C(O)(=O)C.[N+:16]([O-])([OH:18])=[O:17]>O>[OH:11][C:4]1[C:3]([N+:16]([O-:18])=[O:17])=[C:8]([OH:9])[CH:7]=[CH:6][N:5]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc[nH]c(=O)c1C#N
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(O)ccnc1O
Temperature: 177.5 °C
Reaction time: 2 h

Procedure:
86% phosporic acid (90 mL, 151.3 g) and 3-cyano-4-methoxy-2(1H)-pyridinone (Compound X) (30.0 g, 0.20 mole) are combined under argon in a 500 mL flask equipped with a mechanical stirrer, reflux condensor. The mixture is heated in an oil bath at 175-180° C. for 23 hours. The reaction mixture is cooled to 71° C. and glacial acetic acid (90 mL, 94.5 g) added and the mixture heated at 90° C. for about 90 minutes. Fuming nitric acid (density=1.52) (12.6 g, 8.3 ml) is then added carefully over a period of 15 minutes (giving a mild exotherm), and the mixture heated at 90-95° D. for 2 hours. Water (90 mL) is then added to the mixture and heating at 90° C. continued for 1 hour. The mixture is then cooled slowly with stirring to room temperature, filtered through a sintered glass funnel and the residue washed with water to give Compound XII, m.p. 268° C.; NMR (DMSO) δ7.44 (1H, d); 6.0 (1H, d); 3.5 (2H).
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([F:17])[CH:9]=1.CI>C(#N)C>[CH3:1][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([F:17])[CH:9]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1ccc([N+](=O)[O-])c(F)c1
Reaction time: 5 h

Procedure:
A 2 L round bottom flask equipped with a stir bar and reflux condenser was charged with acetonitrile (1 L), K2CO3 (263 g, 1.9 mol) and 4-hydroxy-2-fluoro-1-nitrobenzene (100 g, 0.64 mol). Methyl iodide (271 g, 1.9 mol) was added to the reaction mixture and heated at reflux temperatures with vigorous stirring for 5 h. The acetonitrile was removed and ethyl acetate (1 L) and H2O (700 mL) were added. The heterogeneous mixture was transferred to a separatory funnel where the aqueous phase was separated and re-extracted with ethyl acetate (2×200 mL). The organic phases were combined and washed with H2O (2×500 mL), brine (500 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give the desired product as a slightly yellow solid (107 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=1.[Br-:18].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>CO.C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[Br:18])[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=1
Reactant: [Br-]
Reactant: CC1C(=O)NN=C2COc3ccc(N)cc3N21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: CC1C(=O)NN=C2COc3cc(Br)c(N)cc3N21
Reaction time: 1 h
Yield: 29.9 %

Procedure:
To a 30° C. solution of 6-amino-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #2, Step E, 3.0 g, 12.92 mmol) in MeOH (15 mL) and DCM (7.5 mL) was added tetrabutylammonium tribromide (3.31 g, 12.92 mmol) in portions and the resulting black solution was stirred for 1 h. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1-50% EtOAc in petroleum ether) to give 6-amino-7-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (1.2 g, 3.86 mmol, 30%). LC/MS (Table 1, Method 4) Rt=1.337 min.; MS m/z: 311/313 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5](N)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.N([O-])=O.[Na+].[Cu]C#N.[ClH:20]>C(O)(=O)C.O>[Cl:20][C:5]1[C:4]([N+:10]([O-:12])=[O:11])=[CH:3][C:2]([CH3:1])=[CH:8][C:7]=1[CH3:9]
Reactant: Cl
Reactant: Cc1cc(C)c(N)c([N+](=O)[O-])c1
Agent: N#C[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C)c(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of 4,6-dimethyl-2-nitroaniline (3 g, 18.07 mmol) in acetic acid (20 mL) and 6 N HCl (60 mL) at 0° C. was added a solution of sodium nitrite (2.18 g, 31.62 mmol) in water (5 mL). The reaction mixture was stirred at 0° C. for 30 min after completion of addition and copper (I) cyanide (3.24 g, 3 mmol) was added pinch by pinch. The resulting mixture was stirred at 0° C. for 5 h and at room temperature for an additional 2 h. The mixture was passed through a Celite pad, extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford a solid residue. The solid was further purified by column (SiO2, hexanes/EtOAc=7:1) to yield 2-chloro-1,5-dimethyl-3-nitro-benzene (2.6 g, 81%) as a light yellow solid. A solution of 2-chloro-1,5-dimethyl-3-nitro-benzene (2.6 g, 15.7 mmol) and copper (I) cyanide (7.05 g, 78.3 mmol) in DMAC (20 mL) was stirred at reflux for 14 h. The reaction mixture was cooled to room temperature, quenched by adding water (30 mL), filtered through a Celite pad, extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford a solid residue. The solid was further purified by column (SiO2, hexanes/EtOAc=6:1) to yield 0.64 g of 2,4-dimethyl-6-nitro-benzonitrile (23%). A solution of 2,4-dimethyl-6-nitro-benzonitrile (1.1 g, 6.24 mmol) in MeOH (20 mL) and water (10 mL) was mixed with hydrogen peroxide (10 mL), DMSO (10 mL) and potassium hydroxide (0.636 g, 11.36 mmol). The reaction mixture was stirred at 60° C. for 3 h, diluted with water (100 mL), extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford 4,6-dimethyl-2-nitrobenzamide (0.52 g, 43%). A solution of 4,6-dimethyl-2-nitrobenzamide (0.52 g, 2.68 mmol) in MeOH (30 mL) was mixed with palladium carbon (0.25 g). The resulting suspension was stirred at room temperature under hydrogen for 14 h. The mixture was passed through a Celite pad, concentrated using a rotary evaporator to afford 2-amino-4,6-dimethylbenzamide (0.42 g, 95%).
Reaction SMILES: CO.C[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1>O>[OH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1
Reactant: COc1ccc(C=O)cc1
Solvent: CO
Solvent: O
Product: O=Cc1ccc(O)cc1

Procedure:
The reactions are carried out in a manner similar to Examples 1 to 19. However, water is added but no methanol. The starting material and reaction product and the blanketing stream of nitrogen are passed downward over the fixed-bed catalyst by the co-current method. With the aid of this downward-flow procedure, it is also possible to convert liquid phases. At 200° C., for example, the water will be in the form of steam but p-methoxybenzaldehyde (boiling point 248° C.) will still be substantially in the form of a liquid. In this case too, the desired p-hydroxybenzaldehyde is obtained.