Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[S:5])[NH2:3].[C:13]1(=[O:23])[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>CN(C)C=O>[C:16]([C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[C:13]([NH:3][N:2]([CH3:1])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[S:5])=[O:23])([OH:18])=[O:17]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CN(N)C(=S)Nc1ccccc1
Solvent: CN(C)C=O
Product: CN(NC(=O)c1ccccc1C(=O)O)C(=S)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Methyl-4-phenyl-3-thiosemicarbazide (0.2 mole) was dissolved in about 75 ml of dimethylformamide and placed in a 3-necked round-bottomed flask equipped with magnetic stirrer, condenser, additional powder funnel and thermometer. Phthalic anhydride (0.2 mole) was added in portions at 20°. The contents were stirred overnight at room temperature, then poured into ice water the following morning. The resulting solid title product was recrystallized from a mixture of hexane and ethanol. (m.p. 155°-156°) yield, 70%
Reaction SMILES: [CH3:1][N:2]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)[C:3](=[O:26])[CH2:4][N:5]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6](=[O:19])[CH2:7][N:8]1C(=O)C2=CC=CC=C2C1=O.O.NN.[CH3:37][C:38]1[CH:39]=[C:40]([N:44]=[C:45]=[O:46])[CH:41]=[CH:42][CH:43]=1>>[CH3:1][N:2]([C:27]1[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=1)[C:3](=[O:26])[CH2:4][N:5]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6](=[O:19])[CH2:7][NH:8][C:45]([NH:44][C:40]1[CH:41]=[CH:42][CH:43]=[C:38]([CH3:37])[CH:39]=1)=[O:46]
Reactant: Cc1cccc(N=C=O)c1
Reactant: Cc1ccc(N(C)C(=O)CN(C(=O)CN2C(=O)c3ccccc3C2=O)c2ccccc2)cc1
Agent: NN
Solvent: O
Product: Cc1ccc(N(C)C(=O)CN(C(=O)CNC(=O)Nc2cccc(C)c2)c2ccccc2)cc1
Yield: 69.9 %

Procedure:
The procedure is analogous to that described in Example 23, but 1.6 g of N-methyl-N-(4-methylphenyl)-2-(N-phenyl-2-phthalimidoacetamido)acetamide, 0.36 g of hydrazine hydrate and 0.3 g of 3-methylphenyl isocyanate are used as the starting material. The product obtained is purified by chromatography on 80 g of silica gel (0.065-0.200 mm) contained in a column 2.5 cm in diameter [eluent: methylene chloride], collecting 20 cm3 fractions. Fractions 10 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from a mixture of ethyl acetate and diethyl ether (40-60 by volume), 0.7 g of N-methyl-N-(4-methylphenyl)-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetamide melting at 162° C. is obtained.
Reaction SMILES: [Cl:1][CH:2](OC)[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].CC(C)(CO)[CH2:17][OH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([O:18][CH3:17])=[CH:11][CH:12]=1)=[O:6]
Reactant: COC(Cl)CCC(=O)c1ccccc1
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COc1ccc(C(=O)CCCCl)cc1
Yield: 30.9 %

Procedure:
A solution of 45.96 g. (0.217 mole) of 4-chloro-4 -methoxybutyrophenone [prepared in (a), above], 28 g. (0.27 mole) of 2,2-dimethyl-1,3-propanediol and 0.53 g. of p-toluenesulfonic acid in 425 ml. of benzene is heated at reflux under a Dean-Stark trap for about 20 hours. The solution is allowed to cool, washed successively with aqueous sodium bicarbonate solution, water and brine and then evaporated to dryness. The residue is distilled at 174° C. at 1.5 mm. of mercury pressure and then recrystallized from petroleum ether to give 19.97 g. (30.9% yield) of 4-chloro-4'-methoxybutyrophenone, 2,2-dimethylpropylene ketal, having a melting point of 51.5 ° to 53.5° C.
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]1.[CH3:15][C:16]1[O:17][C:18]([C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[C:19]([C:21](O)=[O:22])[N:20]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH:12][C:21]([C:19]2[N:20]=[C:16]([CH3:15])[O:17][C:18]=2[C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[O:22])[CH:9]=[N:8]1
Reactant: CC(F)(F)CCCCn1cc(N)cn1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Product: Cc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(CCCCC(C)(F)F)c2)c1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-4-ylamine and 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.18 min; [M+H]+=403.28.
Reaction SMILES: CN1C(=O)CCC1.Cl[C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[CH:17]=2)[C:12]([C:24]([NH2:26])=[O:25])=[CH:11][N:10]=1.Cl.[Cl:28][C:29]1[CH:30]=[C:31]([CH2:36][CH2:37][NH2:38])[CH:32]=[CH:33][C:34]=1[OH:35].C(N(C(C)C)CC)(C)C>O>[Cl:28][C:29]1[CH:30]=[C:31]([CH2:36][CH2:37][NH:38][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[CH:17]=3)[C:12]([C:24]([NH2:26])=[O:25])=[CH:11][N:10]=2)[CH:32]=[CH:33][C:34]=1[OH:35]
Reactant: CCc1cccc(Nc2nc(Cl)ncc2C(N)=O)c1
Reactant: NCCc1ccc(O)c(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1cccc(Nc2nc(NCCc3ccc(O)c(Cl)c3)ncc2C(N)=O)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 37242.5 %

Procedure:
A 6 ml portion of NMP solution containing 533 mg of 2-chloro-4-[(3-ethylphenyl)amino]pyrimidine-5-carboxamide was mixed with 0.624 mg of 2-(3-chloro-4-hydroxyphenyl)ethylamine hydrochloride and 0.87 ml of diisopropylethylamine, followed by stirring at 80° C. for 4 hours. The reaction mixture was cooled down to room temperature, and then mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, the solvent was evaporated, and then the resulting residue was recrystallized (methanol-THF) to obtain 460 mg of 2-{[2-(3-chloro-4-hydroxyphenyl)ethyl]amino}-4-[(3-ethylphenyl)amino]pyrimidine-5-carboxamide as colorless crystals.
Reaction SMILES: C(=O)(O[CH2:10][C:11]1([Si](C)(C)C)[C:23]2[CH:22]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][C:14]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:15][CH:16]=2)NC1C=CC=CC=1.O.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[C:24]([C:21]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:15][CH:16]=3)[CH:11]([CH2:10][N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[C:23]=2[CH:22]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: C1CCNCC1
Reactant: CC(C)(C)c1ccc2c(c1)C(COC(=O)Nc1ccccc1)([Si](C)(C)C)c1cc(C(C)(C)C)ccc1-2
Solvent: O
Product: CC(C)(C)c1ccc2c(c1)C(CN1CCCCC1)c1cc(C(C)(C)C)ccc1-2
Reaction time: 0.17 h
Yield: 100 %

Procedure:
Piperidine Cleavage of 2,7-Di-tert-butyl-9-trimethylsilyl-9-fluorenylmethyl Carbanilate: A solution of 0.4 g of DT-Fmoc-analine in 8.0 mL of piperidine was stirred at room temperature for 22 hours. The mixture was poured into 50 mL of cold water and stirred for 10 minutes. The precipitate was removed by filtration, rinsed with water (2×5 mL), and dried in air to afford 0.30 g (100%) of crude N-(2,7-di-tert-butyl-9-fluorenylmethyl)piperidine as an off-white solid. Recrystallization from CH3OH--CHCl3 (2:1) gave 0.248 g (82.53%) of the pure amine as white crystals, m.p. 159°-160° C., identified by mixture melting point, and IR and NMR spectral comparison with a sample obtained by piperidine cleavage of DT-Fmoc-PCA.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13]1[NH:14][C:15]3[C:20]([C:21]=1[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7]2.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>>[CH3:32][O:31][C:29](=[O:30])[CH2:28][O:12][C:11]1[CH:10]=[CH:9][C:8]2[C:3](=[CH:4][CH:5]=[C:6]([C:13]3[NH:14][C:15]4[C:20]([C:21]=3[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:7]=2)[C:2]=1[Br:1]
Reactant: CCCCCc1c(-c2ccc3c(Br)c(O)ccc3c2)[nH]c2ccccc12
Reactant: COC(=O)CBr
Product: CCCCCc1c(-c2ccc3c(Br)c(OCC(=O)OC)ccc3c2)[nH]c2ccccc12

Procedure:
The title compound was prepared as a solid (0.410 g, 58%) from 2-(5-bromo-6-hydroxy-2-naphthyl)-3-pentyl-1H-indole using methyl bromoacetate and the procedure from step 3 of Example 2; 1H NMR (DMSO-d6) δ 0.82 (t, J=7.0 Hz, 3H), 1.27-1.39 (m, 4H), 1.64-1.74 (m, 2H), 2.93 (t, J=7.3 Hz, 2H), 3.73 (s, 3H), 5.12 (s, 2H), 7.02 (t, J=7.5 Hz, 1H), 7.12 (t, J=7.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.48 (d, J=9.2 Hz, 1H),7.57 (d, J=7.9 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H), 8.03 (d, J=9.0 Hz, 1H), 8.14 (d, J=1.6 Hz, 1H), 8.22 (d, J=8.9 Hz, 1H), 11.26 (s, 1H); mass spectrum [(+) ESI], m/z 480/482 (M+H)+and [(−) ESI], m/z 478/480 (M−H)−.
Reaction SMILES: [NH2:1][C@H:2]([C:7](=[O:9])[NH2:8])[CH2:3][C:4]([OH:6])=[O:5].[N+:10]([C:13]1[CH:23]=[CH:22][CH:21]=[C:15]2[C:16](O[C:19](=O)[C:14]=12)=[O:17])([O-:12])=[O:11]>C(O)(=O)C>[N+:10]([C:13]1[CH:23]=[CH:22][CH:21]=[C:15]2[C:14]=1[CH2:19][N:1]([CH:2]([C:7](=[O:9])[NH2:8])[CH2:3][C:4]([OH:6])=[O:5])[C:16]2=[O:17])([O-:12])=[O:11]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: NC(=O)[C@@H](N)CC(=O)O
Solvent: CC(=O)O
Product: NC(=O)C(CC(=O)O)N1Cc2c(cccc2[N+](=O)[O-])C1=O

Procedure:
A mixture of isoaspargine (10 mmol) and 3-nitrophthalic anhydride (10 mmol) in 15 ml of acetic acid is heated to reflux. The cooled reaction mixture is concentrated and the residue is purified by chromatography to afford 3-(4-nitro-1-oxoisoindolin-2-yl)-3-carbamoylpropanoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][C@@:11]([CH2:17][CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:13][CH2:12][C@@:11]([CH2:17][CH3:18])([C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:25]3[CH:24]=[C:23]([C:22]([F:36])([F:21])[F:35])[CH:28]=[CH:27][N:26]=3)[CH2:30][CH2:31]2)=[O:16])[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@@]1(C(=O)O)CC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a solution of (1R,3S)-3-[(tert-butoxycarbonyl)amino]-1-ethylcyclopentanecarboxylic acid (0.30 g, 1.2 mmol) and 1-[4-(trifluoromethyl)pyridin-2-yl]piperazine dihydrochloride (0.39 g, 1.3 mmol) in DMF (10 mL) under N2 was added triethylamine (0.65 mL, 4.7 mmol) and O-(Benzotriazol-1-yl)-N,N,N′,N-tetramethyluronium hexafluorophosphate (0.663 g, 1.75 mmol). After being stirred at room temperature overnight, the reaction was quenched with saturated NaHCO3 and extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, concentrated and purified by flash column chromatography to yield the desired product (400 mg, 72.9%). MS calculated for C23H34F3N4O3: (M+H) 471.3; found 371.2 (M+H-Boc).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:5][NH:6][C:7]1[C:8]2[N:23]([CH3:24])[N:22]=[C:21]([CH2:25][CH2:26][CH3:27])[C:9]=2[N:10]=[C:11]([CH2:13][O:14][CH2:15][C:16]([O:18]CC)=[O:17])[N:12]=1.[OH-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:5][NH:6][C:7]1[C:8]2[N:23]([CH3:24])[N:22]=[C:21]([CH2:25][CH2:26][CH3:27])[C:9]=2[N:10]=[C:11]([CH2:13][O:14][CH2:15][C:16]([OH:18])=[O:17])[N:12]=1
Reactant: CCCc1nn(C)c2c(NCc3ccc(OC)c(Cl)c3)nc(COCC(=O)OCC)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1nn(C)c2c(NCc3ccc(OC)c(Cl)c3)nc(COCC(=O)O)nc12
Reaction time: 8 h

Procedure:
1.6 4.3 g of ethyl [7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]acetate are dissolved in 30 ml of tetrahydrofuran (THF), 10 ml of 10% NaOH are added, and the mixture is stirred at 60° for 8 hours. After 10% HCl has been added, the deposited crystals are separated off and recrystallised from methanol, giving 3.7 g of [7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]acetic acid.
Reaction SMILES: [OH:1][C@@:2]1([CH3:15])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:3]1[CH3:14].O.I([O-])(=O)(=O)=[O:18].[Na+]>C(OCC)(=O)C.O.[Ru](=O)=O>[OH:1][C@@:2]1([CH3:15])[CH2:6][C:5](=[O:18])[N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:3]1[CH3:14]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C[C@@H]1N(C(=O)OC(C)(C)C)CC[C@]1(C)O
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H]1N(C(=O)OC(C)(C)C)C(=O)C[C@]1(C)O
Temperature: 25 °C
Reaction time: 40 h
Yield: 34.2 %

Procedure:
To a solution of tert-butyl(2S,3S)-3-hydroxy-2,3-dimethylpyrrolidine-1-carboxylate (3.05 g) in ethyl acetate (45 mL) were successively added water (68 mL), ruthenium dioxide monohydrate (566 mg) and sodium periodate (4.57 g) at room temperature. The mixture was stirred at room temperature for 40 hr, the organic layer and the aqueous layer were separated, and the aqueous layer was extracted with ethyl acetate. The obtained organic layers were mixed, isopropanol (0.7 mL) was added, and the mixture was stirred at room temperature for 5 min. The reaction solution was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/10→4/10) to give the title compound as a white powder (yield: 1.11 g, 34%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH2:17])=[CH:11][C:10]=1[O:18][CH3:19])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:11][C:10]=1[O:18][CH3:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=Cc1cc(CNC(=O)OC(C)(C)C)c(OC)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1cc(CNC(=O)OC(C)(C)C)c(OC)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
To a ice-cooled solution of (4-amino-2-methoxy-5-vinyl-benzyl)-carbamic acid tert-butyl ester (220 mg, 0.79 mmol) in methylene chloride was added triethylamine (132 L) followed by methanesulfonyl chloride (72 L). The mixture was warmed up to room temperature and stirred for 4 hrs. The reaction was quenched with water, and the reaction solution was extracted with methylenechloride, washed with water and brine, dried over anhyd. MgSO4, filtered and concentrated under reduced pressure. The resulting residue was treated with 1N NaOH/MeOH/THF (1/2/1) for 2 hrs, and then neutralized by adding 1N HCl. After evaporating methanol, water was added to the residue. The resulting mixture was extracted with EtOAc, and the combined organic layer was washed with brine, dried over anhyd. MgSO4, filtered, and concentrated under reduced pressure. The crude residue was column-chromatographed (hexane/ethylacetate=1/1) to yield a white solid (260 mg, 92%).
Reaction SMILES: C1([C:7]2[NH:11][C:10]3[C:12]([C:16]([O:18]C)=[O:17])=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)C=CC=CC=1.[OH-].[Na+].Cl>C1COCC1>[C:9]1([N:11]2[C:10]3[C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[CH:7]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:10]=1
Reactant: COC(=O)c1cccc2nc(-c3ccccc3)[nH]c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cccc2ncn(-c3ccccc3)c12
Temperature: 0 °C
Yield: 175.9 %

Procedure:
A mixture of 540 mg (2.1 mmol) of methyl 2-phenyl-1H-benzo[d]imidazole-7-carboxylate 9z and 3 mL (9 mmol) of 3N aqueous NaOH was refluxed in 8 mL of THF overnight. After cooling, the mixture was poured into ice water and acidified with conc. HCl. The resulting solid was filtered and dried to give 440 mg (86%) of phenyl-1H-benzo[d]imidazole-7-carboxylic acid, 9aa. MS m/z (M+H+) 238.9.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([I:15])[C:3]=1[C:4]([O:6]/[N:7]=[C:8](\[NH2:10])/[CH3:9])=O.[C:16]([O-:19])(=[O:18])[CH3:17].[Na+].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=C(I)[C:23]=1[C:29]1[O:33][N:32]=[C:31]([CH3:34])[N:30]=1.C([Mg]Cl)(C)C.C(=O)=O>C1COCC1.C(O)(C)(C)C>[F:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([I:15])[C:3]=1[C:4]1[O:6][N:7]=[C:8]([CH3:9])[N:10]=1.[F:21][C:22]1[C:23]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[N:30]=2)=[C:17]([CH:25]=[CH:26][CH:27]=1)[C:16]([OH:19])=[O:18]
Reactant: C/C(N)=N/OC(=O)c1c(F)cccc1I
Reactant: CC(=O)[O-]
Agent: CC(C)[Mg]Cl
Agent: Cc1noc(-c2c(F)cccc2I)n1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: Cc1noc(-c2c(F)cccc2C(=O)O)n1

Procedure:
Alternately, acid (XXXIXa) is prepared by first converting 2-fluoro-6-iodobenzoic acid to the acid chloride by reaction with a chlorinating agent such as oxalyl chloride, in a solvent such as DCM, with a catalytic amount of DMF, at a temperature of 0° C. Subsequent reaction of the acid chloride with N-hydroxyacetamide in a solvent such as CH2Cl2 provides (Z)—N′-((2-fluoro-6-iodobenzoyl)oxy)acetimidamide. 5-(2-Fluoro-6-iodophenyl)-3-methyl-1,2,4-oxadiazole is prepared by reacting (Z)—N′-((2-fluoro-6-iodobenzoyl)oxy)acetimidamide with sodium acetate, in a solvent such as tert-butanol, at temperatures ranging from 100° C. to 110° C. 3-Fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (XXXIXa) is prepared by reacting 5-(2-fluoro-6-iodophenyl)-3-methyl-1,2,4-oxadiazole with a grignard reagent such as i-PrMgCl, in a suitable solvent such as THF and the like, at a temperature of −78° C. Subsequent addition of CO2 gas, at a temperature of −78° C. provides 3-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (XXXIXa).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[CH3:33][C:34]1[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=1[NH2:36]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:36][C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[CH3:33])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][C:21]4([C:27]5[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=5[O:25][CH2:24]4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cc1ccccc1N
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CC3)COc3ccc(F)cc34)cnc12
Product: CCOC(=O)c1cnn2c(Nc3ccccc3C)c(C(=O)N3CCC4(CC3)COc3ccc(F)cc34)cnc12
Yield: 50.1 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(5-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.260 g, 0.569 mmol) obtained in step 2 and 2-methylaniline (0.091 mL, 0.853 mmol), the title compound (0.151 g, 50%) was obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)=[N:6][N:5]=[C:4]1[S:13][CH2:14][C:15]1[N:19]=[C:18]([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=2F)[C:23]#[N:24])[O:17][N:16]=1)[CH3:2].[H-].[Na+].CN(C=[O:35])C>>[CH2:1]([N:3]1[C:7]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)=[N:6][N:5]=[C:4]1[S:13][CH2:14][C:15]1[N:19]=[C:18]([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=2[OH:35])[C:23]#[N:24])[O:17][N:16]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCn1c(SCc2noc(-c3cc(C#N)ccc3F)n2)nnc1-c1ccco1
Agent: [H-]
Agent: [Na+]
Product: CCn1c(SCc2noc(-c3cc(C#N)ccc3O)n2)nnc1-c1ccco1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 41 %

Procedure:
The title compound was prepared using the general procedure of Rogers et al., Tetrahedron Letters (2002) 43: 3585-3587. To a stirring solution of 3-[3-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-4-fluoro-benzonitrile (20 mg, 0.050 mmol), 2-(methylsulfonyl-ethanol) (9.38 mg, 0.075 mmol), and DMF (0.05 M) at 0° C. was added NaH (5.8 mg, 0.150 mmol). Stirred for 20 min and removed the ice bath. Stirred an additional 20 min while warming to room temperature. The reaction mixture was quenched with 1 N HCl solution and partitioned between ethyl acetate and brine. The organic layer was dried (Na2SO4), filtered and concentrated to dryness. The crude organics were purified by flash column chromatography using ethyl acetate followed by 5% methanol in ethyl acetate to give the title compound (8.1 mg, 41%, white solid). 1H NMR (CDCl3), δ (ppm): 8.25 (m, 1H), 7.75 (m, 1H), 7.60 (s, 1H), 7.18 (m, 2H), 6.60 (m, 1H), 4.64 (s, 2H), 4.25 (q, 2H), 1.38 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH:16]1(C)CCC(C(C)C)C(O)C1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:16])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CC1CCC(C(C)C)C(O)C1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
To a solution of 2-(4-bromophenyl)acetic acid (10 g, 46.7 mmol) in menthol was added thionyl chloride (8.34 g, 70.07 mmol) dropwise. The mixture was then stirred at room temperature for 18 hours. The reaction mixture was concentrated, and obtained methyl 2-(4-bromophenyl)acetate (10.5 g, 99.8%).
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:24][OH:25].C([O-])(O)=O.[Na+]>>[C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8]/[C:9](/[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:24]\[OH:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CC(c1ccccc1)c1ccccc1)c1ccncc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O/N=C(\CC(c1ccccc1)c1ccccc1)c1ccncc1

Procedure:
In analogy to example 1, step 2, from 3,3-diphenyl-1-pyridin-4-yl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white solid, MS (ESI+): m/z=303.1 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[CH2:15](O)[CH3:16].S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5]2
Reactant: CCO
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C

Procedure:
To a solution of 6-bromo-2-naphthalenecarboxylic acid (Compound M) 3.1 g, (12.43 mmol) in ethanol (30 ml, 23.55 g, 511.0 mmol) was added 18M sulfuric acid (2 ml). The solution was refluxed for 30 minutes, cooled to room temperature, and the reaction mixture partitioned between pentane (100 ml) and water (100 ml). The aqueous phase was extracted with pentane (100 ml) and the combined organic layers washed with saturated aqueous NaCl (100 ml), dried (MgSO4), and concentrated to yield an off-white solid. Purification by flash chromatography (silica, 10% EtOAc-hexane) afforded the title compound as a white solid. 1H NMR (CDCl3): δ 8.58 (1H, br s), 8.10 (1H, dd, J=1.7, 9 Hz), 8.06 (1H, d, J=2 Hz), 7.83 (1H, d, J=9 Hz), 7.80 (1H, d, J=9 Hz), 7.62 (1H, dd, J=2, 9 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:8]=1[C:17]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:18]=1[F:24].C(=O)([O-])[O-].[Cs+].[Cs+].[F:32][C:33]([F:37])([F:36])[CH2:34]I>CN(C=O)C.O>[CH3:1][C:2]1([CH3:25])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:8]=1[C:17]1[CH:22]=[C:21]([O:23][CH2:34][C:33]([F:37])([F:36])[F:32])[CH:20]=[CH:19][C:18]=1[F:24]
Reactant: FC(F)(F)CI
Reactant: COC(=O)c1ccc(-c2cc(O)ccc2F)c(C2CCCC2(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cc(OCC(F)(F)F)ccc2F)c(C2CCCC2(C)C)c1
Reaction time: 5 h
Yield: 91.8 %

Procedure:
To a flask containing 66.23A (0.100 g, 0.29 mmol) and cesium carbonate (0.29 g, 0.88 mmol) in DMF (2 mL) was added 1,1,1-trifluoro-2-iodoethane (0.12 g, 0.58 mmol) (commercially available from Aldrich), and stirring was continued for 5 hours. The reaction was diluted with water and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield 66.23B as a colorless oil (0.113 g, 91% yield).