Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.Br.[NH2:15][C:16]1[C:24](O)=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.CN(C=O)C.O>[CH3:1][CH:2]1[CH2:4][CH:3]1[C:5]1[O:7][C:24]2[C:16](=[C:17]([C:18]([OH:20])=[O:19])[CH:21]=[CH:22][CH:23]=2)[N:15]=1
Reactant: CC1CC1C(=O)O
Reactant: Nc1c(O)cccc1C(=O)O
Agent: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1CC1c1nc2c(C(=O)O)cccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To an ice-cold solution of 2-methylcyclopropanecarboxylic acid (214 mg, 2.14 mmol) in dichloromethane (10 mL) was added oxalyl chloride (0.19 mL, 2.14 mmol) dropwise and a few drops of DMF. The ice bath was removed and stirring was continued for 1 h. 2-Amino-3-hydroxybenzoic acid hydrobromide (500 mg, 2.14 mmol) was added followed by triethylamine (0.90 mL, 6.42 mmol). The resulting reaction mixture was stirred at room temperature overnight. The reaction was quenched with aqueous 1 N HCl (25 mL) until the solution reached pH 1. The reaction mixture was extracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated to a brown solid. The crude was dissolved in toluene (10 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (574 mg, 3.0 mmol). The reaction mixture was then heated to reflux for 5 h. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was separated then washed with water (5×150 mL), brine, dried (Na2SO4), filtered and concentrated to afford 2-(2-methylcyclopropyl)benzoxazole-4-carboxylic acid (409 mg, 88%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 12.92 (br s, 1H), 7.84 (dd, J=8.1, 1.0 Hz, 1H), 7.81 (dd, J=7.8, 1.0 Hz, 1H), 7.38 (t, J=7.9 Hz, 1H), 2.10-2.05 (m, 1H), 1.62-1.57 (m, 1H), 1.41-1.34 (m, 1H), 1.28 (d, J=6.5 Hz, 3H), 1.08-1.02 (m, 1H); MS (ESI+) m/z 218 (M+H).
Reaction SMILES: [CH:1]1([S:7]([C:10]([C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])[N:16]=[C:15]([C:26]3[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=3)[N:14]=2)([CH3:12])[CH3:11])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].Cl[C:39]([O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:40]>O1CCOCC1>[CH:1]1([S:7]([C:10]([C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])[N:16]=[C:15]([C:26]3[CH:32]=[CH:31][C:29]([NH:30][C:39](=[O:40])[O:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[CH:28][CH:27]=3)[N:14]=2)([CH3:11])[CH3:12])(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C2CCCCC2)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C2CCCCC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a solution of 4-[4-(2-cyclohexylsulfonylpropan-2-yl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (1.1 g, 2.40 mmol) in 1,4-dioxane (12 mL) was added sodium bicarbonate (0.302 g, 3.60 mmol). Phenyl chloroformate (0.316 mL, 2.52 mmol) was then added dropwise and the resulting mixture was stirred at RT for 3 hours. The resulting mixture was evaporated to dryness and the residue partitioned between water (10 mL) and DCM (10 mL). The organic layer was separated and evaporated to dryness. The residue was triturated with diethyl ether to give the desired material as a solid (1.328 g).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([O:15]C(C)(C)C)=[O:14])=[N:5][CH:4]=1)=[O:2].Cl.CCOCC>C(Cl)Cl>[CH:1]([C:3]1[S:7][C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([OH:15])=[O:14])=[N:5][CH:4]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1c1ncc(C=O)s1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1cnc(N2CCC[C@H]2C(=O)O)s1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Following the procedure as described in Example 68, except using material from Example 79 (33.4 mg, 0.118 mmol), anhydrous CH2Cl2 (3 mL), HCl, 1.0M in Et2O (6 mL, 6.0 mmol) stirring at room temp for 48 h, the title compound (quantitative yield) is isolated as an HCl salt that is used directly “as is” in the next step. LC/MS (Condition A): ret. T=1.88 min, (M+H)+ 227.05.
Reaction SMILES: [O:1]1[CH2:5][CH:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][CH:8]=2)[C:3]2[CH:22]=[CH:23][CH:24]=[CH:25][C:2]1=2.I[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[NH2:36])[N:29]([C@H:37]2[CH2:42][CH2:41][C@@H:40]([N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)[CH2:39][CH2:38]2)[N:28]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[O:1]1[CH2:5][CH:4]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([C:27]3[C:35]4[C:30](=[N:31][CH:32]=[N:33][C:34]=4[NH2:36])[N:29]([C@H:37]4[CH2:38][CH2:39][C@@H:40]([N:43]5[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]5)[CH2:41][CH2:42]4)[N:28]=3)=[CH:11][CH:12]=2)[C:3]2[CH:22]=[CH:23][CH:24]=[CH:25][C:2]1=2
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2ccc(NC3COc4ccccc43)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(NC5COc6ccccc65)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Yield: 20.2 %

Procedure:
A mixture of N-(2,3-dihydrobenzo[b]furan-3-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.080 g, 0.000237 mol), cis-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.087 g, 0.000198 mol), tetrakis-(triphenylphosphine)palladium (0.014 g, 0.000012 mol) and sodium carbonate monohydrate (0.061 g, 0.000495 mol) was heated in a mixture of ethylene glycol dimethyl ether (5 mL) and water (3 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1 M ammonium acetate over 25 min, 21 mL/min). Subsequently, the crude product was dissolved in dichloromethane, loaded onto Trikonex column (7 cm) and eluted with dichloromethane (5 mL). The desired band was cut, the product was extracted with a mixture of dichloromethane/methanol/triethylamine in a ratio of 90:5:5 (10 mL) and the solvents were removed under reduced pressure. The residue was triturated in diethyl ether and the precipitate was collected by filtration and dried to yield cis-3-[4-(2,3-dihydrobenzo[b]furan-3-ylamino)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.021 g, 0.00004 mol) as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[CH:35]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[N:8]2[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C@@H:2]([NH:1][CH2:35][C:34]3[CH:37]=[C:38]([O:42][CH3:43])[C:39]([O:40][CH3:41])=[C:32]([O:31][CH3:30])[CH:33]=3)[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:10][CH2:9]2)=[CH:17][CH:16]=1
Reactant: CC(C)C[C@H](N)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(CN[C@@H](CC(C)C)C(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
(S)-2-Amino-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-4-methyl-pentan-1-one (0.500 g, 1.25 mmol, Example 53) and 3,4,5-trimethoxybenzaldehyde (0.244 g, 1.25 mmol, Aldrich, Milwaukee, Wis.) were mixed in CH2Cl2 (6 mL). After stirring at ambient temperature under nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.396 g, 1.87 mmol). The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. and 12 hours at ambient temperature. Twenty milliliters of saturated aqueous NaHCO3 solution was added to the reaction mixture and the resulting mixture was stirred for 15 minutes. The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic solution was dried over Na2SO4. TLC (50% EtOAc in Hexanes as the eluant) showed two spots with Rf values 0.46 and 0.15. The solution was concentrated in vacuo affording a viscous oil. The lower spot on TLC (Rf=0.15) was isolated by flash chromatography (50% EtOAc in hexanes). Eighty-four percent (0.61 g) of the pure titled compound was obtained as a white foam: mp 58-62° C. APCI-MS m/z 582.4 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br.Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)=[O:29]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH2:27][C:28](=[O:29])[C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[O:17])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccncc1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: O=C(Cc1ccc(OCc2ccccc2)cc1)OCC(=O)c1ccncc1
Reaction time: 1 h
Yield: 49.8 %

Procedure:
To a 10° C. stirred solution of 2-(4-(benzyloxy)phenyl)acetic acid (5.0 g, 0.02 mol) in MeOH (50 mL) was added a solution of potassium tert-butoxide (2.43 g, 0.02 mol) in MeOH (50 mL) under an inert atmosphere. The reaction mixture was stirred for 1 h, concentrated in vacuo and the residue was dissolved in DMF (30 mL). Potassium tert-butoxide (3.6 g, 0.03 mmol) was then added followed by 2-bromo-1-(pyridin-4-yl)ethanone hydrobromide (10.3 g, 0.05 mol), and the reaction mixture at RT. The reaction mixture was then stirred for an additional 16 h at RT, quenched with water, stirred for an additional 10 min and the precipitated solid was filtered. The crude solid was dissolved in EtOAc (200 mL) and washed with water, dried over Na2SO4, filtered and concentrated in vacuo to afford 2-oxo-2-(pyridin-4-yl)ethyl 2-(4-(benzyloxy)phenyl)acetate (3.6 g, 48%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[Cl:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>C(Cl)(Cl)Cl>[Cl:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:12]([C:9]2[C:8](=[O:15])[N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[N:11][CH:10]=2)=[O:14])=[CH:31][CH:30]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc2ncc(C(=O)Nc3ccc(Cl)cc3)c(=O)n12
Reaction time: 0.08 h
Yield: 73.7 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at a temperature between -10° C. and -12° C. during 20 minutes. After stirring for 5 minutes, 11.23 g (0.088 mol) of 4-chloroaniline dissolved in 80 ml of chloroform are dropped to the above solution at -10° C. during 35 minutes. The reaction mixture is stirred below -10° C. for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to yield 18.5 g (73.7%) of the named compound as yellow crystals after recrystallization from ethanol, m.p.: 202°-204° C.
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]([O:8]C)=O)[CH2:3][CH2:2]1.C1(NN)C=CC=CC=1.[CH:19]1([C:22]2[N:26]([CH:27](C)C)[N:25]=[CH:24][C:23]=2C=O)[CH2:21][CH2:20]1>>[CH:1]1([C:4]2[N:25]([C:24]3[CH:20]=[CH:21][CH:19]=[CH:22][CH:23]=3)[N:26]=[CH:27][C:5]=2[CH:6]=[O:8])[CH2:2][CH2:3]1
Reactant: COC(=O)CC(=O)C1CC1
Reactant: CC(C)n1ncc(C=O)c1C1CC1
Solvent: NNc1ccccc1
Product: O=Cc1cnn(-c2ccccc2)c1C1CC1

Procedure:
5-Cyclopropyl-1-phenyl-1H-pyrazole-4-carbaldehyde was prepared from methyl 3-cyclopropyl-3-oxo-propionate and phenyl hydrazine in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][C:7](=[O:9])[NH:6][N:5]=[C:4]1[C:10]1[CH:28]=[CH:27][C:13]2[N:14]=[C:15]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][CH:23]=O)=[CH:19][CH:18]=3)[O:16][C:12]=2[CH:11]=1)[CH3:2].C(O)(=O)C.[CH3:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CN(C=O)C>[CH2:1]([CH:3]1[C:4]([C:10]2[CH:28]=[CH:27][C:13]3[N:14]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH2:23][N:37]5[CH2:38][CH2:39][CH:34]([CH3:33])[CH2:35][CH2:36]5)=[CH:25][CH:26]=4)[O:16][C:12]=3[CH:11]=2)=[N:5][NH:6][C:7](=[O:9])[CH2:8]1)[CH3:2]
Reactant: CC1CCNCC1
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCC=O)cc3)oc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCCN4CCC(C)CC4)cc3)oc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
11 mg (29 μmol) {4-[6-(4-ethyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-benzoxazol-2-yl]-phenoxy}-acetaldehyde are placed in 2 mL DCM and 250 μL DMF. 1.70 μL (29 mmol) acetic acid and 3 μL (42 μmol) 4-methylpiperidine are added and the mixture is stirred for 20 min at RT. Then 9 mg (42 μmol) sodium triacetoxyborohydride are added and the mixture is stirred overnight at RT. The reaction mixture is diluted with DCM and extracted successively with 10% sodium carbonate solution and sat. saline solution. The solv. of the organic phase is eliminated i.V. and the residue is purified through KG. (DCM/MeOH+ammonia) the solv. of the corresponding fractions is eliminated i.V. and the residue is crystallised from EN petroleum ether.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12](O)=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].B>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][CH2:12][OH:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)CCc1cccc([N+](=O)[O-])c1
Agent: B
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(CCCO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
3-(3-Nitrophenyl)propanoic acid (3.0 g, 15 mmol) was dissolved in dry tetrahydrofuran (7.6 mL) in a flame-dried flask and cooled in an ice bath. A solution of borane in tetrahydrofuran (20 mL, 20 mmol, 1.0 M) was added dropwise over a period of 30 minutes. The reaction mixture was stirred for an additional 2 hours at rt, then quenched slowly with ice water, and followed by an addition of ether (40 mL). The ether layer was washed with water and saturated aqueous solution of NaHCO3 successively, dried, and concentrated to give the desired product as a yellow gel (2.7 g, 97%).
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]3[O:11][CH2:12][O:13][C:8]3=[CH:7][C:5]=2[N:6]=1.N(OC(C)(C)C)=O.O.C(OCC)C.[ClH:27]>C(#N)C.[Cu](Cl)Cl>[Cl:27][C:2]1[S:3][C:4]2[CH:10]=[C:9]3[O:11][CH2:12][O:13][C:8]3=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2cc3c(cc2s1)OCO3
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: Clc1nc2cc3c(cc2s1)OCO3
Temperature: 25 °C

Procedure:
The product from Step 1 (1.7 g) was partially dissolved in dry acetonitrile (50 cm3) and added in portions to a stirred suspension of copper(II) chloride (1.41 g) and tert-butyl nitrite (1.56 cm3) in dry acetonitrile (15 cm3) at 60° C. The mixture was heated for 1 hr., cooled to ambient temperature, poured into water/diethyl ether and acidified with aqueous 2M hydrochloric acid. The aqueous fraction was separated and extracted with diethylether (3×100 cm3) and the combined organic fractions washed with water (3×50 cm3) and dried (magnesium sulphate). The solution was evaporated under reduced pressure to give a brown solid. The solid was fractionated by absorbing it onto silica and eluting with hexane/ethyl acetate (50:1 by volume) to give the required product as a colourless solid, M+ =213; 1NMR (CDCl3): δ7.36(1H,s): 7.14(1H,s); 6.08(2H,s); mp 131°-2° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:10][CH2:9]1)(C)(C)C.[ClH:22]>O1CCOCC1>[ClH:22].[ClH:22].[CH3:20][S:17]([CH2:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]1)(=[O:19])=[O:18]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCCS(C)(=O)=O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)CCCN1CCC(N)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cooled (0 degrees) mixture of 3.6 g (0.0113 mole) of [1-(3-methanesulfonyl-propyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and 30 mL of dioxane, was added 14.1 mL of 4M HCl in dioxane. The mixture was stirred 18 hours at room temperature, and the solid collected by filtration to give 2.3 g of 1-(3-methanesulfonyl-propyl)-piperidin-4-ylamine dihydrochloride.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Cl-].[Cl-].[Cl-].[Al+3]>C1C=CC=CC=1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:2]2[CH:10]=[CH:9][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(I)c([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1ccc(I)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.3 g (17 mmol) of 4-iodo-3-nitrobenzoic acid and 8.0 g (60 mmol) of aluminium trichloride are added successively to 70 ml of benzene while cooling with an ice bath. Then the mixture is stirred for 2 hours at ambient temperature, then poured into ice water, extracted with methylene chloride, dried with sodium sulphate and concentrated in vacuo.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[N:4]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:3]=1.[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1B(O)O.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC>[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[N:4]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:3]=1
Reactant: CCOC(=O)c1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: OB(O)c1cc2ccccc2o1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: CCOC(=O)c1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Temperature: 90 °C
Reaction time: 8 h
Yield: 363.3 %

Procedure:
A solution of ethyl 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylate (500 mg, 1.41 mmol), 2-benzofuran boronic acid (454 mg, 2.82 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) complex with dichloromethane (163 mg, 0.141 mmol), and potassium phosphate (1.5 g, 7.05 mmol) in ethylene glycol dimethyl ether (12 mL) was allowed to stir under a nitrogen atmosphere at 90° C. overnight. The reaction was extracted with ethyl acetate and purified by silica gel chromatography to yield the title compound (2.0 g, 90% yield). ES-MS (m/z) 391 [M+1]+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[CH2:8][CH2:7][O:6][CH2:5]1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:18]([CH2:28][C:29]([N:31]3[CH2:36][CH2:35][N:34]([C:37]4[CH:42]=[C:41](Cl)[N:40]=[CH:39][N:38]=4)[CH2:33][CH2:32]3)=[O:30])[N:17]=2)=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:18]([CH2:28][C:29]([N:31]3[CH2:36][CH2:35][N:34]([C:37]4[CH:42]=[C:41]([N:2]([CH3:1])[CH2:3][CH:4]5[CH2:8][CH2:7][O:6][CH2:5]5)[N:40]=[CH:39][N:38]=4)[CH2:33][CH2:32]3)=[O:30])[N:17]=2)=[CH:12][CH:11]=1
Reactant: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCN(c2cc(Cl)ncn2)CC1
Reactant: CNCC1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CN(CC1CCOC1)c1cc(N2CCN(C(=O)Cn3nc(-c4ccc(F)cc4)nc3-c3ccc(F)cc3)CC2)ncn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
58 mg methyl-(tetrahydro-furan-3-ylmethyl)-amine was added to 50 mg 2-(3,5-Bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-1-(4-(6-chloro-pyrimidin-4-yl)-piperazin-1-yl)-ethanone and 35 μl DIPEA in 1 mL DMSO. The reaction was stirred 3 h at 80° C. The mixture was purified by HPLC to give 44 mg of the desired product. Rt: 2.13 min (method M), (M+H)+: 575
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]2=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:7][N:8]=[C:4]2[CH:3]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:16]=[CH:15][C:5]2=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:7][N:8]=[C:4]2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(-c3ccccc3)onc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2c(-c3ccccc3)onc2c1

Procedure:
A mixture of 13.3 g (0.064 mole) of 6-methyl-3-phenyl-2,1-benzisoxazole, 11.3 g (0.064 mole) of N-bromosuccinimide, 0.1 g of dibenzoylperoxide and 225 ml of carbon tetrachloride was heated at reflux under illumination by a flood lamp for 2.5 hr. The mixture was filtered and the filtrate was washed with 100 ml of 5% sodium bicarbonate, dried over sodium sulfate, and concentrated to give a solid as residue. The solid was recrystallized from 2-propanol to give 12.9 g (71%) predominantly the title compound as a tan solid. A reference sample, m.p. 127°-128° C. was recrystallized thrice from 2-propanol, but a satisfactory analysis could not be obtained. A TLC of the solid showed one spot and the H1 and C13NMR and mass spectrum were consistent with the assigned structure.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+].[N+:15]([O-:18])([O-:17])=[O:16].[Ag+:19]>O>[N+:15]([O-:18])([O-:17])=[O:16].[Ag+:19].[C:1]([O-:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:8])([CH3:9])[CH3:10].[Ag+:19]
Reactant: CC(C)(C)CCCCCC(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)CCCCCC(=O)[O-]

Procedure:
Sodium neodecanoate is formed by reacting 31.1 gm of neodecanoic acid with 7.2 gm of sodium hydroxide. The solution is diluted to 500 ml. with water. An aqueous solution of silver nitrate is prepared by dissolving 30.6 gm of silver nitrate in distilled water the diluting with water to a total volume of 500 ml. The two aqueous solutions are mixed, resulting in the formation of silver neodecanoate, which precipitates from the solution. The solids are filtered, washed with distilled water, and dried. Thereafter, they are used to prepare silver catalysts following the methods of the previous examples.