Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9](Br)[C:8]([Cl:12])=[CH:7][C:6]=1[O:13][CH3:14])[CH3:2].[Cu][C:17]#[N:18].CN(C)C=O.Cl>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([C:17]#[N:18])[C:8]([Cl:12])=[CH:7][C:6]=1[O:13][CH3:14])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1cc(Br)c(Cl)cc1OC
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(C#N)c(Cl)cc1OC

Procedure:
14.7 g (0.05 mol) of 5-bromo-4-chloro-2-methoxybenzoic acid ethyl ester, 5.4 g (0.06 mol) of copper(I) cyanide and 8 ml of dimethylformamide are heated at 190° for three hours while stirring under a nitrogen atmosphere. After cooling, the reaction mixture is stirred well with 250 ml of methylene chloride and 250 ml of 2N hydrochloric acid. The insoluble portions are filtered off with suction and the layers are separated in a separating funnel. The methylene chloride solution is washed neutral with water and then concentrated by evaporation. 4-Chloro-5-cyano-2-methoxybenzoic acid ethyl ester is obtained as residue which, after recrystallisation from methylene chloride/hexane, melts at 102°-103°.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13](Br)[CH:14]=3)[N:9]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>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.C1(C)C=CC=CC=1.C(O)C>[C:1]1([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:31]4[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=4)[CH:14]=3)[N:9]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccccc1B(O)O
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccccc2)c2cc(Br)cnc21
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cnc3c(c2)c(-c2ccccc2)cn3S(=O)(=O)c2ccccc2)cc1
Temperature: 85 °C
Yield: 98 %

Procedure:
To a solution of 3-phenyl-5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (309 mg, 0.75 mmol) in a 3:1 toluene/ethanol mixture (24 ml) are added 2-methoxy-benzene boronic acid (125 mg, 0.83 mmol), K2CO3 (2.4 ml of 2 M solution in water, 4.5 mmol), Pd(PPh3)4 (1.5 mol %), and the mixture is heated at 85° C. for 2 hours under argon. The mixture is cooled to room temperature, concentrated under a vacuum and redissolved in a water/CH2Cl2 mixture. The aqueous phase is extracted several times with CH2Cl2 and the combined organic phases are dried on MgSO4. The solvent is evaporated under reduced pressure and the residue purified by flash chromatography on silica gel (100% CH2Cl2) to yield the purified product in the form of a colorless oil with a yield of 98%.
Reaction SMILES: [C:1]([CH:4]([NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)(=O)[CH3:2].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Br:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH2:5][C:4]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[O:15][C:1]=2[CH3:2])[CH:7]=1
Reactant: CC(=O)C(Cc1cccc(Br)c1)NC(=O)c1ccc(C)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc(Cc3cccc(Br)c3)c(C)o2)cc1
Yield: 86.2 %

Procedure:
1-[2-Acetyl-2-(p-toluoylamino)ethyl]-3-bromobenzene (13.26 g) was dissolved in 260 ml of toluene, and 6.8 ml of phosphorus oxychloride was added and heated to reflux for 3 hours. The reaction solution was cooled, poured into ice-cold water and extracted with ethyl acetate. The resulting solution was washed with aqueous solution of saturated sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=4:1) to provide 10.86 g of the objective compound as yellowish crystals. M.p. 74–75° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][N:3]=1.[NH2:18][C:19]1[CH:33]=[CH:32][C:22]2[N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:24]=[N:25][C:21]=2[CH:20]=1>CC(O)C>[C:26]1([N:23]2[C:22]3[CH:32]=[CH:33][C:19]([NH:18][C:2]4[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)=[N:4][N:3]=4)=[CH:20][C:21]=3[N:25]=[CH:24]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Reactant: Nc1ccc2c(c1)ncn2-c1ccccc1
Solvent: CC(C)O
Product: c1ccc(-c2nnc(Nc3ccc4c(c3)ncn4-c3ccccc3)c3ccccc23)cc1
Yield: 99.6 %

Procedure:
A solution of 1-chloro-4-phenylphthalazine (156 mg, 0.65 mmol) and 5-amino-1-phenylbenzimidazole (4) (105 mg, 0.5 mmol) in i-PrOH (10 mL) is stirred at 95° C. under argon for 2 h. The reaction mixture is concentrated, diluted with sat. NaHCO3 (15 mL), and extracted with CHCl3 (100 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is purified on silica gel (1% to 9% methanol/ethyl acetate) to give 206 mg (99%) of 5 as an orange solid, mp 265° C. IR 3285, 2842, 1615, 1476 cm−1; 1H NMR (CDCl3) δ 7.45-7.61 (m, 5H, 1-PhH), 7.62-7.77 (m, 6H, 4′-C6H5, 7-BenzimidH), 7.82 (dd, J=8.7, 2.1 Hz, 1H, 6-BenzimidH), 7.86-7.90 (m, 1H, 5′-PhthH), 7.91-7.98 (m, 1H, 6′-PhthH), 8.00-8.08 (m, 1H, 7′-PhthH), 8.50 (d, J=2.1 Hz, 1H, 4-BenzimidH), 8.56 (s, 1H, 2-BenzimidH), 8.72 (d, J=8.7 Hz, 1H, 8′-PhthH), 9.37 ppm (s, 1H, NH).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.CN(C)C=O.N1C=CN=C1.Cl[Si:21]([CH3:27])([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>O>[CH3:26][Si:21]([CH3:27])([C:22]([CH3:25])([CH3:24])[CH3:23])[O:9][CH2:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ncccc1CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cccnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a solution of 6.2 parts of 2-amino-3-pyridinemethanol in 23.5 parts of N,N-dimethylformamide there were added 6.8 parts of 1H-imidazole and 7.5 parts of chlorodimethyl(1,1-dimethylethyl)silane. The whole was cooled for 10 min in an ice-bath and was stirred overnight at room temperature. The reaction mixture was diluted with 100 parts of water and the product was extracted with 1,1'-oxybisethane (2x). The combined extracts were washed with water and NaCl (sat.), dried, filtered and evaporated, yielding 11.1 parts (93.1% ) of 3-[[dimethyl(1,1-dimethylethyl)silyloxy]methyl]-2-pyridinamine (interm. 1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[OH:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: OC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 8 h
Yield: 100.6 %

Procedure:
(1-(4-Fluorophenyl)-1H-indazol-5-yl)(phenyl)methanol (Example 1(f)) (2.4 g, 7.54 mmol) was dissolved in 50 mL of DCM and treated with Dess Martin periodinane (3.2 g, 7.54 mmol) and stirred overnight. The next day, the reaction was extracted from 2 M NaOH with DCM (vigorous shaking)×3, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was filtered through a silica gel pad using EtOAc and concentrated to give (1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methanone (2.4 g, 100%). MS found: (M+H)+=340.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[Br:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[Cl:19])[NH:15][N:14]=[C:13]2[NH:20][C:21](=[O:25])[CH2:22][CH2:23][CH3:24].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[Br:9][C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([N+:7]([O-:8])=[O:6])[C:18]=1[Cl:19])[NH:15][N:14]=[C:13]2[NH:20][C:21](=[O:25])[CH2:22][CH2:23][CH3:24]
Reactant: O=[N+]=O
Reactant: CCCC(=O)Nc1n[nH]c2cc(Cl)c(Br)cc12
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCC(=O)Nc1n[nH]c2c([N+](=O)[O-])c(Cl)c(Br)cc12
Reaction time: 4 h
Yield: 1.8 %

Procedure:
418 mg of nitronium tetrafluoroborate are added to 4 g of N-(5-bromo-6-chloro-1H-indazol-3-yl)butanamide, described in Example 58, in 50 cm3 of acetonitrile at 0° C., and the mixture is stirred for 4 hours. 200 cm3 of ethyl acetate and 100 cm3 of saturated sodium hydrogen carbonate solution are added to the reaction medium. The organic phase is washed with 2×40 cm3 of saturated sodium hydrogen carbonate solution and then with 40 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.) to give 840 mg of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) and then dried (90 Pa; 45° C.) to give 20 mg of N-(5-bromo-6-chloro-7-nitro-1H-indazol-3-yl)butanamide in the form of a yellow solid melting above 260° C.
Reaction SMILES: [NH:1]=[C:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:6]=1[NH:15][C:16]([NH:18][C:19]([O:21][CH3:22])=[O:20])=[S:17])[CH2:3][CH3:4].[OH-].[Na+].[CH3:25]I>CC(C)=O.O>[NH:1]=[C:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:6]=1[NH:15][C:16](=[N:18][C:19]([O:21][CH3:22])=[O:20])[S:17][CH3:25])[CH2:3][CH3:4]
Reactant: CCCSc1ccc(C(=N)CC)c(NC(=S)NC(=O)OC)c1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCSc1ccc(C(=N)CC)c(NC(=NC(=O)OC)SC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a suspension of 1-iminopropyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (1 g.; 0.00295 mole) in acetone (30 ml.) and water (15 ml.) there is added 50.8% aqueous sodium hydroxide (0.23 g.; 0.00295 mole). The solution that forms is stirred at room temperature for one hour and to it there is added methyl iodide (0.42 g.; 0.00295 mole). The turbid solution formed is stirred at room temperature for 30 minutes and is poured into water (500 ml.). The suspension formed is stirred at room temperature for one hour and is vacuum filtered. The filter cake is dried to afford 1-iminopropyl-2-(3-carbomethoxy-S-methylisothioureido)-4-propylthiobenzene (0.85 g.; 81.5%), m.p. 85°-90° C. (dec.).
Reaction SMILES: [H-].[Li+].[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([NH:8][CH:9]=[N:10]2)=[C:6]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:5]=1.CS(O[C@H:23]1[CH2:27][CH2:26][C@H:25]([CH2:28][O:29][Si:30]([C:43]([CH3:46])([CH3:45])[CH3:44])([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:24]1[CH2:47][O:48][Si:49]([C:62]([CH3:65])([CH3:64])[CH3:63])([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)(=O)=O.P([O-])([O-])([O-])=O>CN(C=O)C.CO>[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@@H:23]2[CH2:27][CH2:26][C@H:25]([CH2:28][O:29][Si:30]([C:43]([CH3:45])([CH3:44])[CH3:46])([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@H:24]2[CH2:47][O:48][Si:49]([C:62]([CH3:65])([CH3:64])[CH3:63])([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[C:6]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:5]=1
Reactant: CC(C)(C)[Si](OC[C@H]1CC[C@H](OS(C)(=O)=O)[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Reactant: COCCOc1nc(N)nc2nc[nH]c12
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: COCCOc1nc(N)nc2c1ncn2[C@@H]1CC[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 1 h
Yield: 28.7 %

Procedure:
In an atmosphere of argon gas, lithium hydride (8.4 mg, 1.06 mmoles) was added to a suspension of 2-amino-6-(2-methoxyethoxy)purine (221 mg, 1.06 mmoles) in DMF (7 ml). After stirring the mixture for one hour, (1S,2S,3S)-2,3-bis(t-butyldiphenylsilyloxymethyl)-1-cyclopentyl methanesulfonate (370 mg, 0.53 mmole) was added, and the resulting mixture was stirred at 140° C. for one hour. After cooling the mixture, 0.2M phosphate buffer (pH 7) was added, and the product formed was extracted with ethyl acetate. The extract solution was washed with water, washed with saturated aqueous solution of sodium chloride and dried on anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (methylene chloride:methanol=50:1, v/v) to obtain 2-amino-9-[(1R,2R,3S)-2,3-bis(t-butyldiphenylsilyloxymethyl)-1-cyclopentyl]-6-(2-methoxyethoxy)purine (124 mg, Yield 29%).
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([N+:14]([O-])=O)[CH:8]=1)(=[O:5])=[O:4]>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:14][C:9]1[CH:8]=[C:7]([NH:6][S:3]([CH2:2][Cl:1])(=[O:4])=[O:5])[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: O=[N+]([O-])c1cc(NS(=O)(=O)CCl)ccc1F
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cc(NS(=O)(=O)CCl)ccc1F
Temperature: 80 °C
Yield: 93.9 %

Procedure:
A mixture of 12.5 g of iron powder (223 mmol) and 16 mL of an aqueous solution of acetic acid (8%) was heated to 80° C., and a solution of 6 g of 1-chloro-N-(4-fluoro-3-nitrophenyl)methanesulfonamide (22.3 mmol) in 20 mL of glacial acetic acid and 22 mL ethyl acetate was added dropwise to the mixture. After heating for 1.5 h the reaction mixture was filtered through a pad of Celite® and washed with 200 mL of ethyl acetate and water (twice with 25 mL). The organic phase was separated, dried (MgSO4), filtered and concentrated under reduced pressure to yield 5 g (94%) of the title compound as a solid melting at 128-129° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[O:16][CH3:17])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:20][C:21]1[C:22]([CH3:37])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:25][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:20][C:21]2[C:22]([CH3:37])=[N:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)=[CH:11][C:10]=1[O:16][CH3:17])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1OC
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1OC

Procedure:
In analogy to the procedures described in examples 8A] and 31B], 2-(4-hydroxy-2-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester was reacted with 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 1N]) to give 2-{2-methoxy-4-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow solid.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][N:17]([CH3:36])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:35])[C:24]2[C:34]3[CH2:33][CH2:32][CH2:31][O:30][C:29]=3[CH:28]=[CH:27][C:25]=2[N:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[O-:35][N+:23]1[C:24]2[C:34]3[CH2:33][CH2:32][CH2:31][O:30][C:29]=3[CH:28]=[CH:27][C:25]=2[N+:26]([O-:4])=[C:21]([NH:20][CH2:19][CH2:18][N:17]([CH3:36])[CH3:16])[N:22]=1
Reactant: CN(C)CCNc1nc2ccc3c(c2[n+]([O-])n1)CCCO3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCNc1n[n+]([O-])c2c3c(ccc2[n+]1[O-])OCCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 53.9 %

Procedure:
H2O2 (70%, 0.16 mL, ca. 3.2 mmol) was added dropwise to a stirred solution of TFAA (0.45 mL, 3.2 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 236 (50 mg, 0.17 mmol) and TFA (0.12 mL, 1.6 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 237 (28 mg, 54%) as a red gum: 1H NMR δ 8.11 (d, J=9.5 Hz, 1H, H-5), 7.36 (d, J=9.5 Hz, 1H, H-6), 7.23 (br s, 1H, NH), 4.21-4.25 (m, 2H, H-8), 3.61 (br t, J=5.8 Hz, 2H, CH2N), 3.56 (br t, J=6.5 Hz, 2H, H-10), 2.62 (br t, J=6.0 Hz, 2H, CH2N), 2.31 [s, 6H, N(CH3)2], 2.00-2.07 (m, 2H, H-9); 13C NMR δ 154.0, 148.4, 135.8, 130.6, 128.9, 116.0, 114.9, 66.2, 57.5, 45.1 (2), 38.7, 24.5, 21.9; MS (FAB+) m/z 306 (MH+, 60%), 290 (20), 176 (100); HRMS (FAB+) calcd for C14H20N5O3 (MH+) m/z 306.1566, found 306.1568. Anal. calcd for C14H19N5O3.½H2O.½MeOH: C, 52.7; H, 6.7; N, 21.2. Found: C, 52.8; H, 6.7; N, 21.2%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][CH3:15])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[C:5]([O:14][CH3:15])=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:12]([N+:16]([O-:18])=[O:17])[CH:13]=1)[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOc1ccc(C(=O)OC)cc1OC
Solvent: CC(=O)O
Product: CCOc1cc([N+](=O)[O-])c(C(=O)OC)cc1OC
Temperature: 50 °C

Procedure:
Dissolved 5.00 g (23.7 mmol) methyl 4-ethoxy-3-methoxybenzoate in 25 ml acetic acid under N2 and added 6.1 ml (95.1 mmol) 69% nitric acid dropwise over 30 minutes. Heated to 50° C. for 1.5 hours and poured onto ice bath. Extracted with chloroform, washed with dilute sodium hydroxide solution and filtered through magnesium sulfate. Stripped solvent and dried in vacuo, giving 5.268 of off-white solid: mass spectrum (electrospray m/e): M+H=255.8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C)C=O.O>[CH:12]1([NH:15][C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:14][CH2:13]1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(F)cc1)NC1CC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 74.3 %

Procedure:
To a solution of 4-fluorophenylacetic acid (4.5 g) and cyclopropylamine (1.7 g) in N,N-dimethylformamide (60 mL) was added 1-Hydroxybenzotriazole (4.4 g), followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (WSC) hydrochloride (6.2 g) on an ice bath. This solution was stirred for 4.5 hours while gradually warming to room temperature. The reaction solution was poured into water (120 mL) on an ice bath, and the resulting solid was collected by filtration, washed with water, then dried, and the title compound (4.19 g) was obtained as a colorless solid.
Reaction SMILES: [OH:1][C:2](CC1C=CC=CC=1)([C:19]1[CH:24]=[CH:23][C:22]([O:25]CC2C=CC=CC=2)=[CH:21][CH:20]=1)[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[NH:10][CH2:9]1.[H][H].C([O-])=O>CO.[Pd]>[OH:1][CH:2]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[NH:10][CH2:9]1
Reactant: O=C1NCN(CCCNCC(O)(Cc2ccccc2)c2ccc(OCc3ccccc3)cc2)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Agent: O=C[O-]
Solvent: CO
Product: O=C1NCN(CCCNCC(O)c2ccc(O)cc2)c2ccccc21
Yield: 78.9 %

Procedure:
15.5 gm of 1-{-[2-hydroxy-2-(4-benzyloxy-phenyl)benzylethylamino]-propyl}-1,2,3,4-tetrahydro-4-quinazolone (m.p. 119°-121° C.) were dissolved in 250 ml of methanol and debenzylated by hydrogenation at 60° C. and 6 bars pressure in the presence of palladium as the catalyst. After 2 mols of hydrogen had been taken up, the hydrogenation was complete, yielding of 8 gm of 1-{3-[2-hydroxy-2-(4-hydroxyphenyl)ethylamino]-propyl}-1,2,3,4-tetrahydro-4-quinazolone, whose formate of the formula ##STR75## had a melting point of 174°-176° C. The yield was 61.5% of theory.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[O:29]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[N:19]1[CH2:18][C@@H:17]([NH:16][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)[CH:4]=1)=[O:9])[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1
Reactant: N[C@@H](Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1sc(C(=O)O)cc1-c1ccnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)N[C@@H](Cc2ccc(F)cc2)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
To a 50 mL round-bottomed flask was added 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (200 mg, 0.90 mmol) [Prepared according to the procedure of Example 151], 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (288 mg, 0.86 mmol) [Prepared according to Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (512 mg, 1.09 mmol) in Chloroform (9 mL). DIEA (790 μL, 4.52 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (162 mg, 32%): LC-MS (ES) m/z=503 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:12](Cl)=[O:13])[CH:9]=[N:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[NH2:15][C:16]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl>[C:29]1([C:27]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])=[C:16]([NH:15][C:12]([C:8]3[CH:9]=[N:10][CH:11]=[C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[CH:2]4)[CH:7]=3)=[O:13])[CH:28]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Cl)c1cncc(-n2cccc2)c1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cncc(-n2cccc2)c1
Reaction time: 2 h

Procedure:
0.062 mL of triethylamine and 69 mg of 5-(1H-pyrrol-1-yl)pyridine-3-carbonyl chloride were added to 5.0 mL of methylene chloride solution containing 60 mg of tert-butyl 2-amino-4-phenylbenzoate at room temperature sequentially and stirred at the same temperature for 2 hours. 0.031 mL of triethylamine and 23 mg of 5-(1H-pyrrol-1-yl)pyridine-3-carbonyl chloride were added to the reaction mixture at room temperature sequentially and stirred at the same temperature for 1 hour. 0.62 g of aminomethylated polystyrene was added to the reaction mixture and stirred at room temperature overnight. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 4-phenyl-2-(5-(1H-pyrrol-1-yl)pyridine-3-carboxamido)benzoate.