Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[C:12]([F:15])([F:14])[F:13])(=[O:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>OS(O)(=O)=O>[C:1]([NH:4][C:5]1[C:10]([N+:16]([O-:18])=[O:17])=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[C:12]([F:15])([F:13])[F:14])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(Cl)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1c([N+](=O)[O-])cc(Cl)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-acetamido-5-chlorobenzotrifluoride (890 mg, 3.74 mmol) in concentrated H2SO4 (4 mL) at 0° C. was added dropwise 70% HNO3 (0.5 mL, Baker). The mixture was stirred at 0° C. for 0.5 h, then at room temperature for 3 h and it was poured into ice water (15 g). The precipitate was collected by filtration, affording 700 mg of crude 2-acetamido-5-chloro-3-nitrobenzotrifluoride. It was crystallized from EtOH/H2O to give 559 mg of pure 2-acetamido-5-chloro-3-nitrobenzotrifluoride as yellow needles. Mp 190°-2° C., 1H NMR (CDCl3): δ2.210 (s, 3H), 7.357 (s, 1H), 7.896 (d, 1H, J=2.1 Hz), 8.105 (d, 1H, J=2.1 Hz).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:14]4[CH2:19][CH2:18][CH2:17][CH:16]([N:20]5[CH:24]=[CH:23][N:22]=[N:21]5)[CH2:15]4)[N:12]=3)[C:7](=[O:26])[C:6]([C:27]([O:29]CC)=[O:28])=[CH:5]2)[CH2:3][CH2:2]1.Cl>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:14]4[CH2:19][CH2:18][CH2:17][CH:16]([N:20]5[CH:24]=[CH:23][N:22]=[N:21]5)[CH2:15]4)[N:12]=3)[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(N3CCCC(n4ccnn4)C3)c(F)cc2c1=O
Agent: Cl
Product: O=C(O)c1cn(C2CC2)c2nc(N3CCCC(n4ccnn4)C3)c(F)cc2c1=O
Yield: 35.9 %

Procedure:
A mixture of ethyl 1-cyclopropyl-6-fluoro-7-[3-(1,2,3-triazol-1-yl)piperidin-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (90 mg, 0.21 mmol) and 6N-HCl (5 ml) was heated to 100°-110° C. for 6 hrs. The mixture was concentrated and the residue was diluted with water. The pH of aqueous solution was adjusted to 7 by the addition of NH4OH and thus separated solid was filtered, washed with water, acetonitrile and dried to give 30 mg of desired product. m.p. 251°-254° C.; 1H NMR (TFA) δ: 9.25 (s, 1H), 8.65 (s, 1H), 8.55 (s, 1H), 8.22 (d, 1H), 5.37 (m, 1H), 5.15 (m, 1H), 4.38-4.75 (m, 2H), 4.10 (m, 2H), 2.45-2.85 (m, 2H), 2.00-2.40 (m, 2H), 1.22-1.65 (m, 4H).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1[C:35](OC)=[O:36].C(OCC)(OCC)OCC.COC1C=CC=C(N)C=1>C(O)(=O)C>[CH3:35][O:36][C:3]1[CH:2]=[C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COc1cccc(N)c1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: COc1cccc(-n2cnc3c(-c4ccccc4)csc3c2=O)c1
Yield: 83 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (70 mg, 0.30 mmol), triethyl orthoformate (0.57 ml), m-anisidine (0.063 ml, 0.56 mmol), and acetic acid (0.07 ml) were used to give 83 mg (0.25 mmol, 83% yield) of the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[N:9]=[C:4]2[CH:3]1[OH:33].[C:34](N1C=CN=C1)(N1C=CN=C1)=[S:35]>O1CCCC1>[S:35]=[C:34]1[O:33][CH:3]2[C:4]3[C:5]([N:24]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:25][CH:2]2[O:1]1)=[N:6][C:7]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)=[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[N:9]=3
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(C(=O)OC(C)(C)C)CC(O)C3O)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(C(=O)OC(C)(C)C)CC2OC(=S)OC32)cc1
Temperature: 25 °C

Procedure:
tert-Butyl 7,8-di hydroxy-2,3-d i-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 2) (1.28 g, 2.86 mmol) was dissolved in tetrahydrofuran (50 ml). 1,1′-Thiocarbonyl diimidazole (1.019 g, 5.72 mmol) was added and the solution heated at reflux for 3 h. The reaction mixture was cooled to room temperature and evaporated to dryness. Water and DCM (300 ml) were added. The organic layer was separated and evaporated to dryness. Ethyl acetate (5 ml) was added to the dark residue and the resulting solid filtered off. The solid was washed twice with EtOAc (5 ml) to afford the titled compound;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17](C=O)=[CH:16][CH:15]=1.OOS([O-])=O.[K+].CC[O:30][C:31](C)=[O:32]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH:31]([O:32][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:21][CH:20]=1)=[O:30]
Reactant: CCOC(C)=O
Reactant: COc1ccc(C=O)cc1
Agent: COc1ccc(C(=O)O)cc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(OC=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To prepare 4-methoxybenzoic acid, 4-methoxybenzaldehyde (100 mg) was dissolved in DMF (10 mL), and OXONE (0.451 g) was added and stirred at room temperature for 3 hours with the reaction having a final volume (11 mL). The reaction was monitored by TLC or GC analysis. EtOAc was added to extract the products and 1N HCl was used to dissolve the salts. The organic extract was washed with 1N HCl (30 mL×3) and brine (30 mL), dried over Na2SO4, and the solvent was removed under reduced pressure to obtain 4-methoxybenzoic acid in 31% yield and 4-methoxyphenol formate in 58% yield after purification by silica gel column chromatography. 4-Methoxyphenyl Formate: 1H NMR (CDCl3, 300 MHz): δ8.26 (s, 1H), 7.03 (d, 2H, J=9.0), 6.89 (d, 2H,J=8.9), 3.78 (s, 3H); 13C NMR (CDCl3, 75 MHz): 8176.7, 170.5, 79.9, 74.3, 31.4, 30.4, 28.2, 24.8, 23.9, 22.4, 20.9, 13.9.
Reaction SMILES: [BrH:1].[O:2]([CH2:20][CH:21]([CH3:30])[CH2:22][CH2:23][CH2:24][C:25]([CH3:29])(O)[CH:26]=[CH2:27])[Si:3]([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+]>CCOCC>[O:2]([CH2:20][CH:21]([CH3:30])[CH2:22][CH2:23][CH2:24][C:25]([CH3:29])=[CH:26][CH2:27][Br:1])[Si:3]([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=CC(C)(O)CCCC(C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(=CCBr)CCCC(C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 0 °C

Procedure:
A solution of 2.25 N hydrogen bromide in ether (1.8 ml) is added to 8-t-butyldiphenylsiloxy-3,7-dimethyl-1-octen-3-ol (1.64 g) in ether (15 ml) dropwise at -70° C. The solution is warmed at 0° C. for 2 hours followed by the addition of solid sodium bicarbonate and then aqueous sodium bicarbonate to pH 7. The layers are separated, the aqueous layer re-extracted with ether and the combined ether extracts are washed with aqueous sodium bicarbonate, brine and dried (Na2SO4). The solids are filtered and the filtrate is evaporated in vacuo to give 8-t-butyldiphenylsiloxy-1-bromo-3,7-dimethyl-oct-2-ene as a yellow oil (1.66 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26]([OH:28])=O)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.[F:30][C:31]1[CH:39]=[C:38]2[C:34]([CH2:35][CH2:36][NH:37]2)=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:30][C:31]1[CH:39]=[C:38]2[C:34]([CH2:35][CH2:36][N:37]2[C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[CH:21]=2)=[O:28])=[CH:33][CH:32]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Reactant: Fc1ccc2c(c1)NCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5ccc(F)cc54)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
100 mg (0.25 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 35 mg (0.26 mmol) 6-fluoro-2,3-dihydro-1H-indole in 0.10 mL (0.71 mmol) TEA and 1.5 mL DMF were combined with 90 mg (0.28 mmol) TBTU and stirred for 1 h at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:36])[C@:7]1([O:31][CH2:32][O:33][CH2:34][CH3:35])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@:21](Br)([C@@H:22]([OH:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:28])[CH:17]=[CH:18]2)[C@@H:13]([CH3:29])[CH2:12]3)[CH2:9][C@@H:8]1[CH3:30])(=[O:3])[CH3:2].C([SnH](CCCC)CCCC)CCC>>[C:1]([O:4][CH2:5][C:6](=[O:36])[C@:7]1([O:31][CH2:32][O:33][CH2:34][CH3:35])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([OH:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:28])[CH:17]=[CH:18]2)[C@@H:13]([CH3:29])[CH2:12]3)[CH2:9][C@@H:8]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CCOCO[C@]1(C(=O)COC(C)=O)[C@@H](C)C[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@@]3(Br)[C@@H](O)C[C@@]21C
Agent: CCCC[SnH](CCCC)CCCC
Product: CCOCO[C@]1(C(=O)COC(C)=O)[C@@H](C)C[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Yield: 68.6 %

Procedure:
Analogously to Example 1(G), 2.2 g of 21-acetoxy-9α-bromo-17α-ethoxymethoxy-11β-hydroxy-6α,16β-dimethyl-1,4-pregnadiene-3,20-dione is dehalogenated with tributyltin hydride, worked up, and purified, thus obtaining 1.3 g of 21-acetoxy-17α-ethoxymethoxy-11β-hydroxy-6α,16β-dimethyl-1,4-pregnadiene-3,20-dione, mp 137°-139° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]1[O:21][CH2:20]1>O>[OH:21][CH2:20][CH2:19][N:15]1[CH2:16][CH2:17][CH2:18][CH:14]1[C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1
Reactant: c1ccc(Oc2ccc(C3CCCN3)cc2)cc1
Reactant: C1CO1
Solvent: O
Product: OCCN1CCCC1c1ccc(Oc2ccccc2)cc1

Procedure:
12 parts of 2-(4-phenoxyphenyl) pyrrolidine, 2.2 parts of ethylene oxide and 1 part of water were heated at 80° C. for 5 hours. After cooling, there were obtained 8 parts of 1-β-hydroxyethyl-2-(4-phenoxyphenyl) pyrrolidine, B.P./0.3 mm Hg: 179°-180° C.
Reaction SMILES: [C:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:23][C:24]1([CH3:32])[CH2:29][C@@H:28]([CH3:30])[CH2:27][C@H](O)[CH2:25]1>CCCCCCC>[C:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][C:12]([CH3:18])([CH3:17])[C:13]([O:15][C@H:16]3[CH2:27][C@H:28]([CH3:30])[CH2:29][C:24]([CH3:32])([CH3:25])[CH2:23]3)=[O:14])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(-c2ccccc2)cc1
Reactant: C[C@H]1C[C@H](O)CC(C)(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Product: C[C@H]1C[C@H](OC(=O)C(C)(C)Oc2ccc(-c3ccccc3)cc2)CC(C)(C)C1
Reaction time: 4.5 h

Procedure:
27 g of methyl 2-(4-phenylphenoxy)-2-methylpropionate (0.1 mol) and 0. 3 g of sodium hydride as a 60% dispersion in oil are added to 14.2 g of (trans) 3,3,5-trimethylcyclohexanol (0.1 mol) dissolved in 500 ml of heptane. The stirred mixture is brought to the boil in a distillation apparatus appropriately equipped for progressively separating the binary heptane/methanol mixture, which boils at 59° C.; the operation requires 4 to 5 hours; the mixture is cooled and then washed carefully with an alkaline aqueous solution, then an acidic aqueous solution and finally pure water. After chromatography on a silica column with a mixture of ethyl acetate and petroleum ether and recrystallization from 90% isopropanol, the title derivative is obtained in the form of silky crystals melting at 96° C. TLC performed under the previous conditions gives a single spot of Rf 0. 90. The IR spectrum has characteristic bands at 2950-2850, 1745 and 1640 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:16]([O-])=O)=[C:5]([NH:11][CH2:12][C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>[Pd].CO>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[C:4]2[C:5]([NH:11][CH2:12][C:13](=[O:14])[NH:16]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(NCC(=O)O)c([N+](=O)[O-])c1OC
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1OC)NC(=O)CN2
Reaction time: 16 h
Yield: 51.5 %

Procedure:
10% Palladium on activated carbon (0.22 g, 2.06 mmol, 0.48 eq) is added at room temperature to a stirred solution of (3,4-dimethoxy-2-nitro-phenylamino)-acetic acid (1.1 g, 4.29 mmol, 1.0 eq) in methanol (30 mL). The mixture is hydrogenated for 16 hours, then filtered through decalite. Solvent is removed to afford 7,8-dimethoxy-3,4-dihydro-1H-quinoxalin-2-one as an off-white solid (0.46 g, 52% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH:10]C(=O)C.C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:26](OCCC(C)C)=O>C(OCC)(=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[NH:10][N:26]=[CH:9]2
Reactant: COc1cccc(C)c1NC(C)=O
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: COc1cccc2cn[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
To a solution of N-(2-methoxy-6-methylphenyl)acetamide (9.28 g, 51.8 mmol) in ethyl acetate (100 ml) are added acetic anhydride (14.7 mL, 156 mmol), tetrabutylammonium bromide (0.84 g, 2.61 mmol), potassium acetate (10.16 g, 104 mmol), and isoamyl nitrite (9.1 mL, 67.7 mmol), and the mixture is refluxed for 9 hours. After the reaction is completed, the solvent is evaporated under reduced pressure, and to the obtained residue is added 6N aqueous sodium hydroxide solution (100 mL). The mixture is stirred at room temperature for 1 hour. After the reaction is completed, the pH value of the mixture is adjusted to pH 7–8 with 3N hydrochloric acid, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue is purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1→1/1) to give the title compound (3.95 g, yield: 51%).
Reaction SMILES: Br[CH:2]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=O.[C:20]([NH2:23])(=[S:22])[CH3:21].C(Cl)Cl.CCCCCC>C(O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:2]2[S:22][C:20]([CH3:21])=[N:23][C:3]=2[C:5]2[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: CC(N)=S
Reactant: CSc1ccc(C(=O)C(Br)c2ccc(F)cc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCO
Product: CSc1ccc(-c2nc(C)sc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To a solution of 2-bromo-2-(4-fluorophenyl)-1-(4-methylthiophenyl) ethanone from Step 2 (0.70 g, 2.10 mmol) in ethanol (20 mL) in a 50 mL round bottom flask was added thioacetamide (0.16 g, 2.10 mmol) and the mixture heated to reflux for 20 hours. The reaction was cooled to room temperature and concentrated in vacuo and dissolved in methylene chloride. This solution was washed with NaHCO3 saturated solution and dried over Na2SO4, filtered and reconcentrated in vacuo yielding a white crystalline solid. Flash chromatography of this solid (2:1 methylene chloride: hexane) yielded 5-(4-fluorophenyl)-4-(4-methylthiophenyl) -2-methylthiazole as a white solid (0.45 g, 68%): mp 104°-105° C. 1H NMR (CDCl3) 400 mHz δ7.39 (d, J=8.32, 2H), 7.28 (dd, J=8.80, 5.14, 2H), 7.15 (d, J=8.32, 2H), 7.00 (t, J=8.80, 2H), 2.74 (s, 3H), 2.47 (s, 3H). MS (EI): m/z 316 (M+H). HRMS Δ=0.000 mmu.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Br:25][C:26]1[CH:34]=[CH:33][C:29]2[O:30][CH2:31][O:32][C:28]=2[C:27]=1[C:35](Cl)=[O:36].O=C1CC(=O)N(C2C=CC(C(O)=O)=CC=2)C2C=CC3C(C=2N1)=CC=CC=3>>[Br:25][C:26]1[C:27]([C:35]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:36])=[C:28]2[O:32][CH2:31][O:30][C:29]2=[CH:33][CH:34]=1
Reactant: O=C(Cl)c1c(Br)ccc2c1OCO2
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3c(Br)ccc4c3OCO4)cc2)c2ccc3ccccc3c2N1
Yield: 64 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 5-bromo-1,3-benzodioxol-4-carbonyl chloride, the title compound (yield 64%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: C([NH:9][C:10]([NH:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>O>[CH2:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:21][CH:13]1[NH:12][C:10]([NH2:9])=[S:11]
Reactant: O=C(NC(=S)NC1Cc2ccccc2C1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=S)NC1Cc2ccccc2C1

Procedure:
1-Benzoyl-3-(2-indanyl)thiourea (0.931 g.) and sodium hydroxide (0.500 g.) were refluxed in water (6 ml.) for 10 minutes. The mixture was cooled, extracted into chloroform and the chloroform extracts washed with water, dried (MgSO4) and evaporated to give a white solid. Recrystallisation from ethanol/water afforded the title compound as platelets (0.647 g.), m.p. 155.0° C.
Reaction SMILES: C(O)=[O:2].[CH:4]1([N:10]=[C:11]=[N:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:11]([NH:10][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)([NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:2]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=CO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of formic acid (0.026 g, 0.556 mmol) in chloroform (1.5 mL) was added dropwise dicyclohexylcarbodiimide (DCC) (0.114 g, 0.56 mmol) in chloroform (1.5 mL) at 0° C. After 5 min the above solution was added to the compound 9 (0.10 g, 0.28 mmol) in pyridine (2 mL). The mixture was then stirred for 1 hours at room temperature. Evaporation of solvent was followed by addition of ether gave dicyclohexylurea which was removed via filtration and the solid was washed with ether. The combined filtrate was concentrated and purified by flash column chromatography to give the product 11, (EM 347) (0.075 g, 70%); 1H NMR (CDCl3): δ 0.66 (s,3H), 0.74-1.42 (m, 11H), 1.2-2.08 (m, 19H), 2.37-2.48 (m, 2H), 2.87 (s, 3H), 3.04 (dd, 1H, J=4, 13 Hz), 3.2-3.4 (m, 3H),8.12 (s, 0.8H), 8.24 (s, 0.2H); 13C NMR (CDCl3) δ 170.56, 164.54, 162.97, 68.59, 65.62, 51.99, 51.71, 44.11 ,36.85, 36.40, 34.12, 32.88, 30.64, 29.68, 29.04, 28.96, 25.20, 24.37, 22.86, 20.55, 20.21, 13.77, 12.34:. HRMS: calcd for C24H40N2O2, 388.3089; found 388.3147. ##STR12##
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][C:3]=1[F:21].N1C=CC=CC=1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30].CCOC(C)=O>C(Cl)Cl>[CH:16]1([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:19]=[CH:20][C:2]([NH:1][C:29](=[O:30])[O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[C:3]([F:21])[CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:18][CH2:17]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)C3CC3)c2)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Oc2ccnc(NC(=O)C3CC3)c2)cc1F)Oc1ccccc1
Temperature: 2.5 °C
Yield: 102.5 %

Procedure:
Mix N-[4-(4-amino-3-fluoro-phenoxy)-2-pyridyl]cyclopropanecarboxamide (500 mg, 1.7 mmol), DCM (8 mL) and pyridine (345 mg) and cool to 0-5° C. Add a solution of phenyl chloroformate (350 mg, 2.2 mmol) in DCM (1 mL). Stir the reaction at room temperature for 1.5 hrs. TLC (EtOAc:PE=1;1) shows the reaction is complete. Quench the reaction with water (5 mL). Wash the organic layer with 1N HCl solution, saturated NaHCO3 solution and brine respectively. Dry the organic layer with anhydrous Na2SO4. Filter and concentrate to give the crude product (710 mg) which is used without further purification. MS: (M+1): 408.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[Cl-].[Ca+2].[Cl-].C(O)C>C(OCC)(=O)C.[Fe]>[NH2:13][C:11]1[CH:10]=[CH:9][C:3]([C:4]([NH:6][CH2:7][CH3:8])=[O:5])=[C:2]([Cl:1])[CH:12]=1
Reactant: CCNC(=O)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCNC(=O)c1ccc(N)cc1Cl
Temperature: 25 °C
Yield: 89.2 %

Procedure:
2-Chloro-N-ethyl-4-nitrobenzamide (2.00 g) obtained in Example 66a), iron powder (2.43 g) and calcium chloride (0.48 g) were suspended in an aqueous solution (30 ml) of 85% ethanol, and the mixture was refluxed for 1 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 ml), and the insoluble material was removed by filtration through celite. The filtrate was concentrated, and the residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate) to give the title compound as a yellow powder (1.55 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22]C)[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[OH:22])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:11][CH2:12][CH2:13][CH2:14]1)=[O:9]
Reactant: COc1ccc(Cl)cc1-c1ccc(C(=O)N2CCCC2)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccc(-c2cc(Cl)ccc2O)cc1Cl)N1CCCC1
Reaction time: 1 h

Procedure:
The product from step b) (0.6 g) was dissolved in DCM (20 ml) and treated with boron tribromide (7 ml) and stirred for 1 h. Ice was added and a solid formed, which was filtered to give the sub-title compound. Yield 0.46 g.