Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.[Mg].[CH2:11]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1)[CH2:12][CH3:13].Cl>C1COCC1>[OH:20][C:17]1([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[CH2:18][CH2:19][CH:14]([CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16]1
Reactant: CCCC1CCC(=O)CC1
Reactant: Fc1cc(F)cc(Br)c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCC1CCC(O)(c2cc(F)cc(F)c2)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 132.1 %

Procedure:
In a nitrogen atmosphere, a solution prepared by dissolving 75.85 g of 3,5-difluorobromobenzene in 150 mL of THF was added at a rate that caused gentle reflux to a solution prepared by suspending 10.03 g of magnesium in 50 mL of THF, followed by stirring at 40° C. for 1 hour. After the resultant mixture was allowed to cool to room temperature, a solution prepared by dissolving 60.62 g of 4-propylcyclohexanone in 120 mL of THF was added to the mixture at such a rate that the inside temperature did not exceed 35° C., followed by stirring at room temperature for 2 hours. Then, 10% hydrochloric acid was added until the reaction system became acidic, and an organic layer was separated from the mixture. Further, an aqueous layer was subjected to extraction with toluene, and the toluene extract was combined with organic layer and washed with saturated brine. The resultant mixture was dried by adding sodium sulfate, and then the solvent was distilled off under reduced pressure to yield 132 g of crude 1-(1-hydroxy-4-propylcyclohexyl)-3,5-difluorobenzene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21](O)=[O:22])[C:17]=3[O:19][CH3:20])[NH:12][N:11]=2)=[CH:4][CH:3]=1.[NH2:24][CH2:25][CH:26]([OH:34])[CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[OH:34][CH:26]([CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[CH2:25][NH:24][C:21]([C:16]1[C:17]([O:19][CH3:20])=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2/[CH:9]=[CH:8]/[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:22]
Reactant: NCC(O)CN1CCOCC1
Reactant: COc1c(C(=O)O)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Product: COc1c(C(=O)NCC(O)CN2CCOCC2)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Yield: 45.4 %

Procedure:
100 mg of 3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic acid obtained by Example 234 and 130 mg of 1-amino-3-(morpholine-4-yl)propane-2-ol were condensed in the similar method as described in Example 44, to afford 66 mg of the title compound as colorless needle crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]([C:12](=O)[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[C:30](O)(=O)C>>[C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]([C:12]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]2[CH:16]=[CH:17][C:18]([CH3:30])=[CH:19][C:14]=2[N:13]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1NCc1ccccc1
Reactant: CC(=O)O
Product: Cc1ccc2c(c1)nc(C(NC(=O)OC(C)(C)C)C(C)C)n2Cc1ccccc1
Yield: 90 %

Procedure:
A solution of [1-(2-benzylamino-phenylcarbamoyl)-2-methyl-propyl]-carbamic acid tert-butyl ester (453 mg, 1.14 mmol) in acetic acid (4 ml) was heated at 100° C. for 2 hours. The solvent was removed in vacuo and the resulting solid was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography to give of [1-(1-benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-carbamic acid tert-butyl ester (389 mg, yield 90%).
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([CH3:27])([C:23]([F:26])([F:25])[F:24])[O:18][CH2:17][CH2:16]2.O.[C:29]([O:33]C)(C)(C)C>FC(F)(F)C(O)=O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[CH:29]=[O:33])[C:19]([CH3:27])([C:23]([F:26])([F:24])[F:25])[O:18][CH2:17][CH2:16]2
Reactant: COc1ccc2c(c1)CCOC2(C)C(F)(F)F
Reactant: COC(C)(C)C
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc2c(cc1C=O)C(C)(C(F)(F)F)OCC2
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To hexamethylenetetramine (31.3 g, 223 mmol) was added trifluoroacetic acid (400 mL) and the mixture was heated to 70° C. for 90 minutes. A solution of 6-methoxy-1-methyl-1-trifluoromethyl-isochroman (50.0 g, 203 mmol) in trifluoroacetic acid (100 mL) was then added to the reaction mixture over 40 minutes. The solution was stirred for 3 hours and water was added (450 mL). The reaction mixture was stirred 16 hours, cooled to room temperature, and poured into methyl tert-butyl ether (500 mL). The organic layer was separated and washed with water (3×300 mL). The organic layer was poured into a round bottom flask and cooled to 0° C. 6N Sodium hydroxide was added in portions until the pH raised to 10 (˜500 mL). The organic layer was separated, washed with water (200 mL), dried over magnesium sulfate, filtered, and concentrated to afford 6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7-carbaldehyde as an oil (54.2 g of a 12:1 mixture of regioisomers, 97%). 1H NMR (400 MHz, CDCl3) δ1.71 (s, 3), 2.95 (dt, 2, J=2.6, 5.3), 3.90-3.97 (m, 1), 3.97 (s, 3), 4.19 (dt, 1, J=11.2, 5.6), 6.81 (d, 1, J=1.2), 10.4 (s, 1). 13C NMR (75 MHz, CDCl3) δ23.07, 29.98, 55.73, 60.83, 76.03 (q, J=27.4), 111.81, 112.50, 123.65, 125.32, 125.64 (q, J=287), 127.06, 160.89, 188.92. IR 1683, 1616, 1498, 1296, 1271, 1163, 1149, 1120, 1096, 874 cm−1. Analysis calculated for C13H13F3O3: C, 57.13; H, 5.05. Found: C, 56.94; H, 4.78.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:22]=[CH:23][C:24]([N:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)=[N:25][CH:26]=3)[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[N:25][C:24]([N:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)=[CH:23][CH:22]=3)[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3noc([C@H](CCCC4CCCCC4)CC(=O)NO)n3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(-c2ccc(N3CCNCC3)nc2)no1)NO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 9.7 %

Procedure:
To a solution of the title compound from Example 32 (0.37 g, 0.7 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and the reaction was stirred at room temperature for 1.5 hours. The solvent was removed in vacuo and the residue was azeotroped with toluene. The residue was then dissolved in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate solution (30 mL) followed by 10% aqueous citric acid solution (30 mL). The acidic aqueous layer was basified to pH 7 with saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water (30 mL), dried (MgSO4) and the solvent was removed in vacuo to give the title compound as a viscous oil (0.03 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[N:29]=3)[C:13]=2[C:14]([O:16]CC2C=CC=CC=2)=[O:15])[N:4]=1.[H][H]>C(OCC)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[N:29]=3)[C:13]=2[C:14]([OH:16])=[O:15])[N:4]=1
Reactant: [H][H]
Reactant: COc1cccc(-c2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)OCc2ccccc2)n1
Agent: [Pd]
Solvent: CCOCC
Product: COc1cccc(-c2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)O)n1

Procedure:
1.57 g of benzyl 2-(4,6-dimethoxypyrimidin-2-yloxy)-6-(6-methoxypyridin-2-yl)benzoate and 560 mg of palladium on active carbon (10%) in 100 ml of diethyl ether are hydrogenated at room temperature for 10 h at a hydrogen pressure of 50 bar. A further 300 mg of catalyst are then added and the mixture is hydrogenated at room temperature for another 10 h at a hydrogen pressure of 50 bar. The mixture is filtered through Celite® (Aldrich) and concentrated under reduced pressure. Yield: 0.99 g of a solid of m.p. 158°-160° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].[I:14]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>C(Cl)(Cl)Cl.CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([I:14])[C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(I)c(O)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
Methyl 3-cyano-4-hydroxybenzoate (6.47 g) was dissolved in chloroform (80 mL) and methanol (10 mL), and N-iodosuccinimide (8.63 g) and trifluoromethanesulfonic acid (2.5 mL) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and the obtained residue was washed with water to obtain the title compound (11.29 g) as a pale yellow crystal.
Reaction SMILES: Cl[CH2:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[I:11][C:12]1[CH:13]=[N:14][C:15](=[O:18])[NH:16][CH:17]=1.C(N(CC)CC)C>ClCCl>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:2][N:16]2[CH:17]=[C:12]([I:11])[CH:13]=[N:14][C:15]2=[O:18])=[CH:5][CH:6]=1
Reactant: O=c1ncc(I)c[nH]1
Reactant: ClCOc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1ncc(I)cn1COc1ccc(Cl)cc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 6, by adding a solution of 1-chloromethoxy-4-chlorobenzene (see Preparation 3) (10 mmol) in dichloromethane (10 ml) to a solution of 5-iodopyrimidin-2-one (10 mmol) and triethylamine (10 mmol) in dichloromethane (50 ml), and heating the resultant mixture under reflux for 3 h. The product, 2.05 g (56%), consisted of the N- and O-isomers in the ratio 4:1. The O-isomer was removed from the product by extraction with acetone and the remaining N-isomer was recrystallized from EtOAc; m.p. 216° C. (Found C36.64; H2.24 Calc. for C11H8ClIN2O2 : C36.44; H2.23) 1H NMR (DMSO-d6 /CDCl3); δ 5.85 (CH2), 6.9-7.5 (Ph), 8.68 and 8.82 (H-4 and H-6, respectively, J 3 Hz). IR (KBr) 1650 cm-1 (CO). MS (70 eV, m/z (% rel. int.)): 362 (37,M) 235 (100), 222 (6), 108 (22).
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[OH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:16]([O:28][CH3:29])[CH:15]=1>ClCCl>[CH:13]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[C:16]([O:28][CH3:29])[CH:15]=1)=[O:12]
Reactant: COc1cc(CO)ccc1NC(=O)OC(C)(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1cc(C=O)ccc1NC(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of finely ground PCC (80 mg, 0.56 mmol) and Celite (80 mg) in dry dichloromethane (2 ml) at room temperature was added drop wise a solution of the alcohol 8 (92.9 mg, 0.37 mmol) in dichloromethane (1 ml followed by 0.7 ml rinse). The mixture was stirred in the dark for 20 minutes. The reaction mixture was adsorbed on silica gel and purified by normal phase MPLC, eluting with hexanes/ethyl acetate 20-40% gradient. GC-MS EI+: m/z 251 (M+); LC-MS ESI+: m/z 252 (M+H+). Yield: 72.7 mg (78%). H-NMR (400 MHz, CD2Cl2): 9.06 (1H, brs) 8.02 (1H, d, J=8 Hz) 7.65 (1H, s) 6.92 (1H, dd, J=8 Hz, 0.4 Hz) 4.67 (1H, s) 1.22 (9H, s).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.Br[CH:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C>C(#N)C>[CH2:27]([O:26][C:24]([C@H:23]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]1[C:35](=[O:44])[C:36]2=[CH:43][CH:42]=[CH:41][CH:40]=[C:37]2[C:38]1=[O:39])=[O:25])[CH3:28]
Reactant: CCOC(=O)C(Br)CCCCCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)[C@@H](CCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Yield: 25.3 %

Procedure:
In 100 ml of acetonitrile are dissolved 2 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 7.4 g of ethyl 2-bromo-7-phthalimidoheptanoate, and 0.85 g of triethylamine is added to the solution. After the mixture is heated at 80°-100° C. for 2 days, the mixture is concentrated under reduced pressure, diluted with 100 ml of water and extracted with 200 ml of ethyl acetate. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily substance is separated and purified by silicagel column chromatography (hexane:ethyl acetate=2:1) to give from the first fraction 1.0 g of tert-butyl 3(R)-[1(R)-ethoxycarbonyl6-phthalimidohexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=2)=[CH:6][CH:5]=1
Reactant: OCCc1ccc(O)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc(CCO)cc2)nc1
Temperature: 120 °C
Yield: 48.1 %

Procedure:
Combine 4-(2-hydroxy-ethyl)-phenol (2.0 g, 14.5 mmol), 6-chloronicotinamide (2.3 g, 14.5 mmol) and K2CO3 (5.0 g, 36.2 mmol) in DMF (40 mL) under nitrogen, stir and heat at 120° C. overnight. Cool to ambient temperature and pour into water, extract the aqueous layer with ethyl acetate. Combine the organic layers and dry over Na2SO4. Eliminate the solvent and purify by flash chromatography on silica gel (eluent: CHCl3/7% EtOH/0.7% NH4OH) to give the title compound (1.8 g, 49%). Electrospray MS M+1 ion=259, 1H-NMR (DMSO-d6, 400 MHz): 8.58 (d, 1H, J=2.7 Hz), 8.22 (dd, 1H, J=2.7 and 8.8 Hz), 8.00 (bs, 1H), 7.46 (bs, 1H), 7.25 (m, 2H), 7.05-7.02 (m, 3H), 4.65 (t, 1H, J=5.3 Hz), 3.63-3.58 (m, 2H), 2.72 (t, 2H, J=6.9 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27])[CH3:25]>>[C:1]([O:5][C:6]([N:8]1[CH:13]=[CH:12][C:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([N:32]4[CH2:31][CH2:30][N:29]([S:26]([CH2:24][CH3:25])(=[O:27])=[O:28])[CH2:34][CH2:33]4)[CH:21]=[C:16]3[CH2:15]2)=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CCS(=O)(=O)N1CCN(c2cc3c(cn2)OC(C2=CCN(C(=O)OC(C)(C)C)C=C2)C3)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-(ethylsulfonyl)piperazine following a procedure analogous to that described in Example 79. LC (method 10): tR=1.45 min;
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-])=O.C(=O)([O-])O.[Na+].[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[H][H]>C(O)C.[C].[Pd].O1CCCC1.O>[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:4][C:3]=2[NH2:17])=[CH:28][CH:27]=1
Reactant: Nc1ccc(F)cc1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2nc3ccccc3o2)ccc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.8 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.16 mmol) in ethanol (5 mL) was added sodium hydrogen carbonate (195 mg, 2.32 mmol) and 4-fluoroaniline (322 mg, 2.90 mmol), and this was heated to reflux with stirring for 4 hours. After the reaction was complete, this was cooled to room temperature, water was added, and this was extracted with chloroform. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The crystals obtained were added to a tetrahydrofuran (5 mL) solution containing 10% palladium-carbon (50 mg), a hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature for 4 hours. After the reaction was complete, this was filtered through Celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (40.0 mg, 11% yield) as brown crystals.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)[N:10]=[N:9][C:8]=1[C:23]([NH:25][CH:26]1[CH2:28][CH2:27]1)=[O:24])(=O)=O.[O:29]=[C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[N-:31]1.[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:26]1([NH:25][C:23]([C:8]2[N:9]=[N:10][N:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=3)[C:7]=2[CH2:6][N:31]2[C:32](=[O:39])[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:30]2=[O:29])=[O:24])[CH2:27][CH2:28]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COS(C)(=O)=O)cc1
Reactant: O=C1[N-]C(=O)c2ccccc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
(4-[(Cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)methyl methanesulfonate (1.02 g, 2.5 mmol) obtained in Example 126a) and potassium 1,3-dioxo-1,3-dihydroisoindol-2-ide (463 mg, 2.5 mmol, 1.0 eq.) were dissolved in DMF (10 ml), and the mixture was stirred at 50° C. for 30 min. The reaction mixture was diluted with ethyl acetate (20 ml), and the precipitate was collected by filtration, washed with water and dried to give the title compound as a white powder (1.0 g, 87.7%).
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:19]=[CH:18][C:9]([O:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1.Br[C:21]1([CH2:30][CH2:31][O:32][CH2:33][CH3:34])[C:26](=[O:27])[NH:25][C:24](=[O:28])[NH:23][C:22]1=[O:29].CCCCC=CCCCC.C1(F)(C2(F)OC(C(F)(F)F)(C(F)(F)F)OC2(F)F)OC(C(F)(F)F)(C(F)(F)F)OC1(F)F>C(O)(=O)C.CO.C(#N)C>[CH2:33]([O:32][CH2:31][CH2:30][C:21]1([O:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][C:9]3[CH:18]=[CH:19][C:6]([C:2]4[O:1][CH:5]=[N:4][N:3]=4)=[CH:7][CH:8]=3)=[CH:12][CH:13]=2)[C:22](=[O:29])[NH:23][C:24](=[O:28])[NH:25][C:26]1=[O:27])[CH3:34]
Reactant: CCOCCC1(Br)C(=O)NC(=O)NC1=O
Reactant: Oc1ccc(Oc2ccc(-c3nnco3)cc2)cc1
Agent: CCCCC=CCCCC
Agent: FC(F)(F)C1(C(F)(F)F)OC(F)(F)C(F)(C2(F)OC(C(F)(F)F)(C(F)(F)F)OC2(F)F)O1
Solvent: CO
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOCCC1(Oc2ccc(Oc3ccc(-c4nnco4)cc3)cc2)C(=O)NC(=O)NC1=O
Temperature: 23 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
A mixture of 4-(4-[1,3,4]oxadiazol-2-yl-phenoxy)-phenol (0.90 g, 2.5 mmol), 5-Bromo-5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-trione (1.0 g, 3.6 mmol), 1,5,7-trazabicyclo[4.4.0]dec-5-ene bound to polystyrene crosslinked with 2% DVB (PTBD, Fluka, 2.4 g, 6.1 mmol) and 11.7 mL of acetonitrile was shaken at 23° C. for 24 hours. The mixture was diluted with 30 mL of 25% acetic acid in methanol, filtered, and the solids were washed twice with methanol-acetic acid. The filtrate was concentrated in vacuo and purified by radial chromatography (2:1 to 1:1 hexane-ethyl acetate), affording 600 mg of 5-(2-Ethoxy-ethyl)-5-[4-(4-[1,3,4]oxadiazol-2-yl-phenoxy)-phenoxy]-pyrimidine-2,4,6-trione as a colorless solid.
Reaction SMILES: BrCC(C1C=CC([N+]([O-])=O)=CC=1)=O.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22](=[S:24])[NH2:23].[C:25]1([CH2:31][C:32](=[S:34])[NH2:33])C=C[CH:28]=[CH:27][CH:26]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]1[S:24][CH:28]=[C:27]([C:26]2[S:34][C:32]([NH2:33])=[CH:31][CH:25]=2)[N:23]=1
Reactant: NC(=S)Cc1ccccc1
Reactant: NC(=S)Cc1ccccc1Cl
Agent: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Product: Nc1ccc(-c2csc(Cc3ccccc3Cl)n2)s1

Procedure:
The title compound was prepared as described in Example 806A, substituting 2-bromo-1-(5-nitrothiophen-2-yl)ethanone for 2-bromo-1-(4-nitrophenyl)ethanone and 2-(2-chlorophenyl)ethanethioamide for 2-phenylethanethioamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=2[S:6][C:7]=1[C:8](O)=[O:9].S(Cl)([Cl:17])=O>CN(C)C=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]2[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=2[S:6][C:7]=1[C:8]([Cl:17])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C(=O)O)sc2ccccc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C(=O)Cl)sc2ccccc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
An ice-cooled suspension of 3-methoxybenzo[b]thiophene-2-carboxylic acid (0.62 g, 0.003 m) and dried methylene chloride (25 ml) was treated under nitrogen with thionyl chloride (2.0 ml) and dimethylformamide (1 drop). After stirring overnight two times at ambient temperatures, the volatiles were removed in vacuo, and the solid residue washed twice by addition and removal in vacuo of small portions of benzene. The resultant off-white solid was used without further purification in the next step.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[C:4]=1[NH2:11].[OH:12][CH:13](O)[C:14](=O)[CH3:15]>O>[NH2:9][C:7]1[N:8]=[C:3]([NH2:2])[C:4]2[C:5](=[N:10][CH:15]=[C:14]([CH2:13][OH:12])[N:11]=2)[N:6]=1
Reactant: Nc1nc(N)c(N)c(N)n1
Reactant: CC(=O)C(O)O
Agent: Cl
Solvent: O
Product: Nc1nc(N)c2nc(CO)cnc2n1

Procedure:
reacting tetraaminopyrimidinehydrochloride with dihydroxyacetone in the presence of air and water and at a pH in the range of 5.5±0.2 to give 2,4-diamino-6-hydroxymethylpteridine;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:16][CH:18]2[CH2:19][O:20]2)=[CH:7][CH:6]=1
Reactant: ClCC1CO1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCC2CO2)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (2.71 g) in dimethylformamide (20 mL) under argon was treated with 55% sodium hydride (0.65 g) , stirred for 15 minutes and treated with epichlorohydrin (12 mL). The mixture was heated at 60° C. for four hours and worked up as in Example 20. The material was purified by HPLC (dichloromethane-diethyl ether; 50:1) to provide 2.4 g of 4-(oxiranylmethoxy)alpha-oxobenzeneacetic acid methyl ester, as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][N:6]=[CH:5]2.BrC1C=C2C(=CC=1F)NN=C2.C([Li])(C)(C)C.[C:28](=[O:30])=[O:29]>>[CH3:11][C:10]1[CH:9]=[C:8]2[C:4]([CH:5]=[N:6][NH:7]2)=[CH:3][C:2]=1[C:28]([OH:30])=[O:29]
Reactant: Cc1cc2[nH]ncc2cc1Br
Reactant: O=C=O
Agent: Fc1cc2[nH]ncc2cc1Br
Agent: [Li]C(C)(C)C
Product: Cc1cc2[nH]ncc2cc1C(=O)O

Procedure:
This compound was prepared in a manner similar to that shown in Scheme 3, using 5-bromo-6-methyl-1H-indazole as the starting material, which was prepared in a manner similar to that of 5-bromo-6-fluoro-1H-indazole. The starting material was treated with t-butyl lithium and carbon dioxide to yield 6-methyl-1H-indazole-5-carboxylic acid, which was in turn treated with thiosemicarbazide and polyphosphoric acid to form 94.