Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[Cl-].[NH2:3][C:4]([NH2:6])=[NH2+:5].[CH:7]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH:16]([CH2:20][C:21](OCC)=[O:22])[N:15]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:14]2=[O:30])([CH3:9])[CH3:8]>C(O)C>[CH2:26]([N:15]1[C:14](=[O:30])[C:13]2[C:17](=[CH:18][CH:19]=[C:11]([O:10][CH:7]([CH3:8])[CH3:9])[CH:12]=2)[CH:16]1[CH2:20][C:21]([NH:5][C:4]([NH2:6])=[NH:3])=[O:22])[CH:27]([CH3:29])[CH3:28]
Reactant: NC(N)=[NH2+]
Reactant: CCOC(=O)CC1c2ccc(OC(C)C)cc2C(=O)N1CC(C)C
Agent: [Cl-]
Agent: [Na]
Solvent: CCO
Product: CC(C)CN1C(=O)c2cc(OC(C)C)ccc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 18 h
Yield: 4 %

Procedure:
N-[2-(2-Isobutyl-5-isopropoxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-acetyl]-guanidine is prepared as described in Example 9, starting with 20 cm3 of absolute ethanol, 0.086 g of sodium, 0.36 g of guanidinium chloride and 0.42 g of ethyl (5-isopropyloxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 18 hours and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is then taken up in 50 cm3 of ethyl acetate and the organic phase is washed twice with 30 cm3 of aqueous 1N sodium hydroxide solution and then twice with 50 cm3 of aqueous 1N hydrochloric acid solution. The acidic aqueous phase is treated with aqueous 30% sodium hydroxide solution to pH 14, and then extracted with 3 times 30 cm3 of ethyl acetate. The organic extracts are combined, washed with 50 cm3 of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is triturated with diethyl ether and then filtered and dried in a desiccator under reduced pressure (2 Pa) at a temperature in the region of 40° C. for 2 hours. 0.0175 g of N-[2-(2-Isobutyl-5-isopropoxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-acetyl]-guanidine is thus obtained in the form of a white powder melting at 208° C. 1H NMR (300 MHz, d6-(CD3)2SO, δ in ppm): 0.75 (d, J=6.5 Hz: 3H); 0.90 (d, J=6.5 Hz: 3H); 1.30 (mt: 6H); 2.01 (mt: 1H); 2.40 (dd, J=15 and 6.5 Hz: 1H); 2.65 (dd, J=15 and 6.5 Hz: 1H); 3.00 (dd, J=13.5 and 5.5 Hz: 1H); 3.53 (dd, J=13.5 and 10 Hz: 1H) 4.68 (mt: 1H); 4.96 (broad t, J=6.5 Hz: 1H); from 6.40 to 7.10 (broad multiplet: 2H); 6.98 (dd, J=8.5 and 2 Hz: 1H); 7.09 (d, J=2 Hz: 1H); 7.54 (d, J=8.5 Hz: 1H); from 7.60 to 8.20 (broad multiplet: 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:11][C:12]([NH:14][CH3:15])=[O:13])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[OH:16][C:17]([C:20]1[CH:44]=[CH:43][C:23]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29](B3OC(C)(C)C(C)(C)O3)[C:28]=2[CH3:42])=[O:25])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].C(=O)([O-])[O-].[Na+].[Na+]>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.C(COC)OC>[OH:16][C:17]([C:20]1[CH:44]=[CH:43][C:23]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:2]3[CH:3]=[C:4]([NH:11][C:12]([NH:14][CH3:15])=[O:13])[C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[CH:7]=3)[C:28]=2[CH3:42])=[O:25])=[CH:22][CH:21]=1)([CH3:18])[CH3:19]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)O)cc2)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CNC(=O)Nc1cc(Br)cn2ccnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CNC(=O)Nc1cc(-c2cccc(NC(=O)c3ccc(C(C)(C)O)cc3)c2C)cn2ccnc12
Yield: 13.8 %

Procedure:
A 5 mL Microwave Reactor Vessel was charged with 1-(6-Bromo-imidazo[1,2-a]pyridin-8-yl)-3-methyl-urea (85 mg, 0.317 mmol), 4-(1-Hydroxy-1-methyl-ethyl)-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (125 mg, 1 eq), tetrakis(triphenylphosphine)palladium (37 mg, 0.1 eq), 1M sodium carbonate (1 mL) and dimethoxyethane (2 mL). The reaction mixture was irradiated for 10 minutes at 150° C. on the Microwave Reactor. The reaction mixture was then partitioned between ethyl acetate (150 mL) and water (50 ml). Separated the layers and washed the organic layer with water (4×50 mL), then finally washed with brine (1×50 mL). The ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by Preparative Thin Layer Chromatography, eluting with 50% acetone in hexanes to give 4-(1-Hydroxy-1-methyl-ethyl)-N-{2-methyl-3-[8-(3-methyl-ureido)-imidazo[1,2-a]pyridin-6-yl]-phenyl}-benzamide as an off-white powder (20 mg), ((M+H)+=458).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[CH:4][C:3]=1[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[CH:16]=1.[OH2:20].N>S(=O)(=O)(O)O>[CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]([NH2:10])=[O:20])=[CH:4][C:3]=1[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[CH:16]=1
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccc2nccn2c1
Reactant: O
Agent: N
Agent: O=S(=O)(O)O
Product: Cc1[nH]c(=O)c(C(N)=O)cc1-c1ccc2nccn2c1

Procedure:
In 15 ml of conc. sulfuric acid, 3 g of 1,2-dihydro-6-methyl-5-(imidazo[1,2-a]pyridin-6-yl)-2-oxo-3-pyridinecarbonitrile was stirred at 90° C. for 40 minutes. After cooling, the reaction mixture was poured into ice and conc. ammonia water was added thereto to render the mixture alkaline. Crystals prepcipitated were taken by filtration. After washing with water and drying, the crystals were recrystallized from N,N-dimethylformamide to obtain 2.5 g of 1,2-dihydro-6-methyl-5-(imidazo[1,2-a]pyridin-6-yl)-2-oxo-3-pyridinecarboxamide.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2([C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH3:27])=[C:21]([F:28])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH3:27])=[C:21]([F:28])[CH:20]=1)[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:33]2[CH:34]=[N:29][CH:30]=[N:31][CH:32]=2)[CH:7]=1
Reactant: OB(O)c1cncnc1
Reactant: COc1c(C)cc(C2(c3ccnc(Br)c3)N=C(N)c3c(F)cccc32)cc1F
Product: COc1c(C)cc(C2(c3ccnc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc1F
Yield: 11 %

Procedure:
The title compound was synthesized as described in Example 33 in 11% yield starting from 1-(2-bromopyridin-4-yl)-4-fluoro-1-(3-fluoro-4-methoxy-5-methylphenyl)-1H-isoindol-3-amine (330 mg, 0.74 mmol) and pyrimidin-5-ylboronic acid (101 mg, 0.82 mmol).
Reaction SMILES: C[O:2][CH:3]=[C:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1.Cl.CCCCCC>C1COCC1>[CH:3]([CH:4]1[CH2:5][CH2:6][CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:9]1)=[O:2]
Reactant: COC=C1CCC(C(=O)OC)CC1
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
103 g of methyl 4-methoxymethylidene-cyclohexane carboxylate was dissolved in 350 mL of THF, and 100 mL of 10% hydrochloric acid was added dropwise thereto at 11 to 13° C. for 10 minutes. The solution was further stirred at room temperature for 3 hours, and then 80 mL of hexane was added. The aqueous layer was extracted with ethyl acetate, and then the organic layers were combined and washed with water and saturated saline in this order. The resultant product was dried over anhydrous magnesium sulfate, and then concentrated, to obtain 92.4 g of methyl 4-formylcyclohexane carboxylate in the form of an oil-like product. The obtained product was analyzed by gas chromatography, and was found to be a mixture of cis-form:trans-form at a ratio of 64:36.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([CH3:11])=[CH:6][C:5]=1[NH:12][C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>CN(C)C=O>[CH2:28]([N:12]([C:5]1[CH:6]=[C:7]([CH3:11])[C:8]([Cl:10])=[CH:9][C:4]=1[Br:3])[C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1cc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(Br)cc1Cl
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(N(Cc2ccccc2)C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(Br)cc1Cl
Temperature: 25 °C

Procedure:
Sodium hydride (193 mg, 8.06 mmol) was added to a stirred solution of tert-butyl 4-{[(2-bromo-4-chloro-5-methylphenyl)amino]carbonyl}piperidine-1-carboxylate 2-5 (2.90 g, 6.72 mmol) in N,N-dimethylformamide (40 mL) at approximately 0° C. The reaction mixture was warmed to ambient temperature and aged for 30 min. Benzyl bromide (1.20 mL, 10.1 mmol) was added and after 1 h, the reaction mixture was poured into aqueous 2 N hydrochloric acid and extracted with diethyl ether. The organic phase was washed with saturated aqueous sodium bicarbonate, brine, dried (sodium sulfate) and concentrated in vacuo to give a crude residue. Purification of the crude residue by flash chromatography over silica gel (gradient elution; 0%-20% acetone/methylene chloride as eluent) afforded 2-6 as a white solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH:7]1[C:19]2[NH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.C1OCCOCCOCCOCCOCCOC1.I[C:39]1[CH:40]=[C:41]([CH3:45])[CH:42]=[CH:43][CH:44]=1>ClC1C=CC=CC=1Cl>[CH3:45][C:41]1[CH:40]=[C:39]([N:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3[C:19]2=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:44]=[CH:43][CH:42]=1
Reactant: Cc1cccc(I)c1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Product: Cc1cccc(-n2c3ccccc3c3ccccc32)c1

Procedure:
Activated Cu, (4.2 g (65.8 mmol, 1.1 eq)), 12.4 g (89.7 mmol, 1.5 eq) of K2CO3, 10 g (59.8 mmol) of carbazole, 0.47 g (3 mol %) of 18-crown-6 and 13.7 g (62.8 mmol, 1.05 eq) of 3-iodotoluene were added into 100 ml of dried 1,2-dichlorobenzene and reacted at 180° C. for 24 hours. Then, the reaction mixture was filtered to remove un-reacted Cu and salts. The filtrate was distilled under reduced pressure to remove the solvent and purified by silica gel chromatography. The product was obtained as a colorless liquid at 88.3% (15.5 g) yield. 1H-NMR (300 MHz, CDCl3): δ 8.17 (2H, d), 7.51-7.27 (10H, m), 2.51 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([CH3:29])[CH:3]=1.Cl.[NH2:31][OH:32].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH2:9]/[C:10](=[N:31]\[OH:32])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([CH3:29])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1

Procedure:
In analogy to example 1, step 2, from 4-[1-(4-chloro-2-methyl-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-benzoic acid (example 332, step 2) and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a light yellow oil, MS (ESI+): m/z=425.1 ([M+H]+).
Reaction SMILES: [Na].[CH2:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])[CH2:3][CH3:4].Cl.[CH:14]([N:17]([CH2:21][CH2:22]Cl)[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15]>C(O)C>[CH2:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:22][CH2:21][N:17]([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])[CH2:3][CH3:4]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: CCCOc1ccccc1O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCCOc1ccccc1OCCN(C(C)C)C(C)C

Procedure:
The compound was prepared as described in Example 1, using sodium (3.45 g; 150 mole), 0-propoxyphenol (11.4 g; 75 mmole) and diisopropylaminoethylchloride hydrochloride (15.0 g; 75 mmole) in 200 ml of ethanol. Yield 12.7 g (64%) of product, boiling at 109°-110° C under a pressure of 0.001 mm.Hg, nD25 : 1.4961. Calcd. for C17H29NO2 : C 73.07%, H 10.46%, N 5.01%. Found C 73.2% H 10.5%, N 4.96%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH3:17])[NH:14][C:13](=[O:15])[NH:12][C:11]3=[O:16])=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:24]([O:31][C:32]([C:41]1[N:46]=[CH:45][C:44]([N:47]2[CH2:52][CH2:51][N:50]([C:53](=[O:56])[CH2:54]Br)[CH2:49][CH2:48]2)=[C:43]([CH2:57][CH2:58][CH3:59])[CH:42]=1)([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O>[CH2:24]([O:31][C:32]([C:41]1[N:46]=[CH:45][C:44]([N:47]2[CH2:52][CH2:51][N:50]([C:53](=[O:56])[CH2:54][N:12]3[C:11](=[O:16])[C:10]([C:8]4[CH:7]=[CH:6][C:5]5[O:1][CH2:2][CH2:3][C:4]=5[CH:9]=4)([CH3:17])[NH:14][C:13]3=[O:15])[CH2:49][CH2:48]2)=[C:43]([CH2:57][CH2:58][CH3:59])[CH:42]=1)([C:33]([F:34])([F:35])[F:36])[C:37]([F:38])([F:40])[F:39])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC1(c2ccc3c(c2)CCO3)NC(=O)NC1=O
Reactant: CCCc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ncc1N1CCN(C(=O)CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ncc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc4c(c3)CCO4)C2=O)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.3 %

Procedure:
5-(2,3-Dihydrobenzofuran-5-yl)-5-methylimidazolidine-2,4-dione (5.6 mg, 0.0240 mmol) was dissolved in N,N-dimethylformamide (500 μL), and potassium carbonate (7.5 mg, 0.0545 mmol) was added under ice-cold conditions. The mixture was stirred at room temperature for 5 minutes. Then, under ice-cold conditions, 1-(4-{6-[2-(benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-4-propylpyridin-3-yl}piperazin-1-yl)-2-bromoethanone (13 mg, 0.0218 mmol) was added and stirred at room temperature for 18 hours. Under ice-cold conditions, the reaction solution was added water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone), and the title compound (13 mg (yield 78%)) was obtained as a yellow oil.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](O)=[O:20])=[N:10][N:11]3[CH2:15][CH2:14][S:13][C:12]=23)=[CH:4][CH:3]=1.[C:25]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>S(Cl)(Cl)=O.C(OCC)(=O)C>[C:25]([C:29]1[CH:30]=[CH:31][C:32]([NH:33][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([C:9]3[C:8]([C:5]4[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=4)=[C:12]4[S:13][CH2:14][CH2:15][N:11]4[N:10]=3)[CH:17]=2)=[CH:34][CH:35]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)c1cccc(-c2nn3c(c2-c2ccncc2)SCC3)c1
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CC(C)(C)c1ccc(NC(=O)c2cccc(-c3nn4c(c3-c3ccncc3)SCC4)c2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
3-(7-Pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazol-6-yl)-benzoic acid hydrochloride (45 mg, 0.125 mmol) was dissolved in thionylchloride (1 mL) and stirred at 60° C. for 1 hour. The solvent was distilled and the residue was taken up with toluene, evaporated to dryness and dried under high vacuum for 1 h. The acid chloride was then dissolved in dry pyridine (1 mL) under nitrogen and 4-tert-butylaniline (0.030 mL, 0.187 mmol, 1.5 eq) was added. The mixture was stirred at room temperature for 1 h and then diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (eluant DCM/EtOH 95:5 to give 44 mg of N-(4-tert-butyl-phenyl)-3-(7-pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazol-6-yl)-benzamide as a white solid (77%).
Reaction SMILES: Br[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.[CH3:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.CN1CCCC1=O>O>[CH3:13][C:14]1[CH:18]=[CH:17][N:16]([C:2]2[N:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6](=[O:12])[NH:7]3)[N:15]=1
Reactant: O=c1ccc2c(Br)nccc2[nH]1
Reactant: Cc1cc[nH]n1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccn(-c2nccc3[nH]c(=O)ccc23)n1
Temperature: 200 °C

Procedure:
A stirred mixture containing 13.5 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 18 ml of 3-methyl-1H-pyrazole and 75 ml of N-methylpyrrolidinone was heated in an oil bath at 170°-180° C. for 18 hours, after which a tlc analysis indicated some remaining starting material. The temperature of the oil bath was raised to 200° C.; and, the reaction mixture was heated for an additional 5 hours and then poured into water. The solid that separated was collected, dried and combined with 1.7 g of corresponding material obtained in another run starting with 2.25 g of 5-bromo-1,6-naphthyridin-2(1H)-one. The combined solids were recrystallized from dimethylformamide and dried in an oven for three days at 100° C. to yield 6.6 g of 5-(3-methyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. >300° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)=[O:7].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)=[O:7]
Reactant: [H][H]
Reactant: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)c2cccc(N)c2)cc1OC
Yield: 38.9 %

Procedure:
To a solution of 3,4-dimethoxy-3'-nitrobenzophenone (0.5 g, 1.7 mmol) in 40 mL of ethyl acetate was added 0.05 g of 10% palladium on carbon catalyst. The mixture was hydrogenated in a Parr-Shaker apparatus at 55-60 psi of hydrogen for 1.5 hours. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford the crude product. The crude product was purified by flash column chromatography (silica gel, 10% ethyl acetate/methylene chloride) to afford 0.17 g (38%) of the product as a yellow solid: mp 157-175° C.; 1H NMR (CDCl3) δ 7.56-6.80 (m, 7 H); 3.95 (s, 3 H), 3.94 (s, 3 H); 13C NMR (CDCl3) δ 195.7, 152.9, 148.9, 146.4, 139.3, 130.3, 128.9, 125.4, 120.1, 118.4, 115.6, 112.1, 109.7, 56.0, 56.0; Anal. Calcd for C15H15NO3. Theoretical: C, 70.02; H, 5.88; N, 5.44. Found: C, 70.00; H, 6.10; N, 5.13.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7])=[CH:4][CH:3]=1.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:7])=[CH:23][CH:24]=1
Reactant: O=C(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccccc12
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccc(OCCCCBr)cc1)c1c(-c2ccccc2)oc2ccccc12

Procedure:
A mixture of 3.0 g. (9.5 mmol.) of 3-(4-hydroxybenzoyl)-2-phenylbenzofuran, 6.2 g. (0.029 mol.) of 1,4-dibromobutane and 3.9 g. (0.029 mol.) of potassium carbonate in 100 ml. of dry acetone is refluxed for 18 hours. The reaction mixture is cooled, filtered and the filtrate is concentrated under reduced pressure then heated on a steam bath in vacuo to remove excess 1,4-dibromobutane and leave 3-[4-(4-bromobutoxy)benzoyl]-2-phenylbenzofuran as a residue.
Reaction SMILES: [C:1]([NH:5][C:6]([CH:8]1[CH2:13][CH:12]([O:14][CH3:15])[CH2:11][CH2:10][CH:9]1[CH2:16][CH:17]([OH:47])[CH:18]([NH:26][C:27](=[O:46])[CH:28]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH2:29][S:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:56])C=1>ClCCl>[C:1]([NH:5][C:6]([CH:8]1[CH2:13][CH:12]([O:14][CH3:15])[CH2:11][CH2:10][CH:9]1[CH2:16][CH:17]([OH:47])[CH:18]([NH:26][C:27](=[O:46])[CH:28]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH2:29][S:30]([C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)=[O:56])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC1CCC(CC(O)C(Cc2ccccc2)NC(=O)C(CSc2ccc3ccccc3c2)NS(C)(=O)=O)C(C(=O)NC(C)(C)C)C1
Solvent: ClCCl
Product: COC1CCC(CC(O)C(Cc2ccccc2)NC(=O)C(CS(=O)c2ccc3ccccc3c2)NS(C)(=O)=O)C(C(=O)NC(C)(C)C)C1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-{2-Hydroxy-3-[2-methanesulfonylamino-3-(naphthalen-2-ylsulfanyl)-propionylamino]-4-phenyl-butyl}-5-methoxy-cyclohexanecarboxylic acid tert-butylamide (80 mg, 0.117 mmol) in dichloromethane (3 ml) was cooled to −10° C. A solution of meta-chloroperbenzoic acid in dichloromethane (2 ml) was added and the mixture stirred at −10° C. for 30 minutes. The solution was then washed with 5% aqueous sodium hydrogen carbonate solution, dried (anhydrous magnesium sulfate) and concentrated in vacuo to give, after purification by flash chromatography on silica gel (dichloromethane/methanol: 97/3 2-{2-Hydroxy-3-[2-methanesulfonylamino-3-(naphthalen-2-sulfinyl)-propionylamino]-4-phenyl-butyl}-5-methoxy-cyclohexanecarboxylic acid tert-butylamide (65 mg, 70%) as a white solid. Mass spectrum, 701 [M+H]+. The following compounds were prepared in a similar manner, by oxidation of the appropriate sulphide:
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[O:20]C.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[Cl:12][C:13]1[C:18]([Cl:19])=[C:17]([C:1](=[O:10])[C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH:16]=[CH:15][C:14]=1[OH:20]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1cccc(Cl)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(c1ccc(O)cc1)c1ccc(O)c(Cl)c1Cl
Temperature: 5 °C
Reaction time: 48 h
Yield: 58.7 %

Procedure:
A mixture of 15.4 g of p-anisoyl chloride and 17.7 g of 2,3-dichloroanisole in 80 ml of dry benzene is cooled at 5° C. After adding 13.3 g of anhydrous aluminum chloride in portions at 5° to 10° C. over a period of five minutes, the cloudy greenish mixture is warmed up to room temperature and then stirred for 48 hours. It is then cooled at 15° C. and 25 ml more of dry benzene is added, followed by the addition of 26.6 g of anhydrous aluminum chloride in portions at 15° C. over a period of five minutes. After the addition is completed, the mixture is stirred at room temperature for 21/2 hours, heated to 45° C. for 90 minutes and to 75° C. to 80° C. for one hour. The reaction mixture is then treated with ice and concentrated hydrochloric acid. The organic phase is separated, and the solid residue is washed with boiling dichloroethane to yield 15 g (53% of theory) of crude 2,3-dichloro-4-(4-hydroxybenzoyl)phenol, melting at 208° to 210° C.