Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:15][C:14]2[CH:16]=[CH:17][C:11]([Cl:10])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: Nc1ccc(Cl)cc1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(NCc2ccc(Br)cn2)cc1

Procedure:
To 5-Bromo-pyridine-2-carbaldehyde (52, 1.00 g, 5.38 mmol) in acetonitrile (50.0 mL) were added p-chloroaniline (53, 0.686 g, 5.38 mmol), triethylsilane (6.00 mL, 0.0376 mol) and trifluoroacetic acid (3.00 mL, 0.0389 mol). The reaction was heated to reflux for 3 hours. The reaction was concentrated, poured into water and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid (54, 0.75 g, 47.0%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([N:20]3[CH2:24][C:23](=[O:25])[NH:22][S:21]3(=[O:27])=[O:26])=[C:14]([OH:19])[CH:15]=2)[CH:10]=1)[CH3:2].[CH3:29]C([O-])(C)C.[K+]>CC(O)C>[CH:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([N:20]3[CH2:24][C:23](=[O:25])[NH:22][S:21]3(=[O:26])=[O:27])=[C:14]([OH:19])[CH:15]=2)[CH:10]=1)([CH3:29])[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)CCCCc1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)cc2c1
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)OC(=O)CCCCc1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)cc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of 5-[6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-naphthalen-2-yl]-pentanoic acid ethyl ester (0.003 g, 0.007 mmol) in iPrOH (1 mL) is added t-BuOK (1M in THF, 0.044 mL). The mixture is stirred for 18 h at room temperature. The reaction is quenched with 1 N HCl (1.5 mL) and extracted with EtOAc (3×10 mL). The organic layers are dried and concentrated. The residue is passed through a short column of reverse phase silica gel eluting with 40% MeOH/H2O to afford 5-[6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-naphthalen-2-yl]-pentanoic acid isopropyl ester: Retention time=1.17 min (Method A); (M−H)−=419.
Reaction SMILES: O1CCOC1C([O-])=O.[C:9]([OH:17])(=[O:16])[C@H:10]([CH2:12][C:13]([OH:15])=O)[OH:11].O1C[CH2:21][CH2:20][CH2:19]1>COC(OC)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:15][CH2:13][CH2:12][C@@H:10]1[O:11][C:20]([CH3:21])([CH3:19])[O:17][C:9]1=[O:16]
Reactant: C1CCOC1
Reactant: O=C(O)C[C@H](O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])C1OCCO1
Solvent: COC(C)(C)OC
Product: CC1(C)OC(=O)[C@H](CCO)O1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
In a 500 mL flame-dried round bottom flask fitted with a septum and under argon was placed 11.0 g (63.2 mmol) of the dioxolanate of (S)-malic acid (prepared by reaction of commercially available (S)-malic acid with excess dimethoxypropane and p-toluenesulfonic acid as a catalyst) dissolved in 200 mL anhydrous tetrahydrofuran. The reaction was cooled (-20° C. to -30° C.) and 70 mL of 1M borane-tetrahydrofuran complex was added dropwise over 2 hours. Following addition the reaction vessel was placed in a refrigerator at 4° C. for 11 hours, warmed to room temperature, stirred at room temperature for 9 hours and chromatographed (silica gel) using acetone as eluant. Following evaporation under reduced pressure, the residue was chromatographed as before to generate 9.1 g (90%) of the alcohol as a colorless unstable liquid which was dried under reduced pressure and utilized as such in the next reaction: IR (neat, cm-1) 3480 (br), 2994, 2940, 2888, 1791, 1220; 1H NMR (CDCl3) δ 4.58 (dd, J=5.1, 7.0 Hz, 1H), 3.91-3.79 (m, 2H), 2.28-2.13 (m, 1H), 2.13-1.97 (m, 1H), 1.64 (s, 3H), 1.57 (s, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)=[CH:7][CH:6]=1.[O-:29][C:30]#[N:31].[K+]>C(O)(=O)C>[CH3:25][C:21]1[CH:20]=[C:19]([NH:18][C:16]2[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([CH2:4][NH:3][C:30]([NH2:31])=[O:29])=[CH:6][CH:7]=3)[N:17]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: N#C[O-]
Reactant: Cc1cccc(Nc2nc(Nc3ccc(CN)cc3)ncc2C(N)=O)c1
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1cccc(Nc2nc(Nc3ccc(CNC(N)=O)cc3)ncc2C(N)=O)c1
Reaction time: 6 h
Yield: 32.3 %

Procedure:
A 20 ml acetic acid-10 ml THF mixed solution containing 500 mg of 2-{[4-(aminomethyl)phenyl]amino}-4-[(3-methylphenyl)-amino]pyrimidine-5-carboxamide dihydrochloride was mixed with 5.76 g of potassium cyanate, which was added by dividing into 6 portions, at room temperature, followed by stirring for 6 hours. The reaction mixture was concentrated and then poured into water, and the precipitated solid was collected by filtration and washed with acetonitrile. The resulting solid was purified by a silica gel column chromatography (chloroform:methanol) to obtain 150 mg of 4-[(3-methylphenyl)amino]-2-[(4-ureidomethylphenyl)amino]pyrimidine-5-carboxamide as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].Cl[C:18]1[C:19]([N+:45]([O-:47])=[O:46])=[C:20]([C:30]2[C:35]([N+:36]([O-:38])=[O:37])=[CH:34][C:33]([N+:39]([O-:41])=[O:40])=[CH:32][C:31]=2[N+:42]([O-:44])=[O:43])[C:21]([N+:27]([O-:29])=[O:28])=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25].CO>CC(C)=O>[N+:8]([C:7]1[CH:6]=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=[C:3]([N+:14]([O-:16])=[O:15])[C:2]=1[CH2:1][C:22]1[C:21]([N+:27]([O-:29])=[O:28])=[C:20]([C:30]2[C:31]([N+:42]([O-:44])=[O:43])=[CH:32][C:33]([N+:39]([O-:41])=[O:40])=[CH:34][C:35]=2[N+:36]([O-:38])=[O:37])[C:19]([N+:45]([O-:47])=[O:46])=[CH:18][C:23]=1[N+:24]([O-:26])=[O:25])([O-:10])=[O:9]
Reactant: Cc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(-c2c([N+](=O)[O-])cc([N+](=O)[O-])c(Cl)c2[N+](=O)[O-])c([N+](=O)[O-])c1
Solvent: CC(C)=O
Solvent: CO
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cc2c([N+](=O)[O-])cc([N+](=O)[O-])c(-c3c([N+](=O)[O-])cc([N+](=O)[O-])cc3[N+](=O)[O-])c2[N+](=O)[O-])c([N+](=O)[O-])c1

Procedure:
The reaction of 4.5 g (0.02 mole) of TNT with 4.6 g, (0.01 mole) of 3-chloro-2,2',4,4',6,6'-hexanitrobiphenyl was carried out as above. After extracting the crude reaction product with methanol until the extracts were light colored, the somewhat gummy residue was dissolved in acetone, an equal volume of methanol was added and the solution was heated, with magnetic stirring, on a hot plate. A light yellow crystalline material separated, was filtered off and dried. It weighed 1.7 g, 25% of the theoretical yield. Recrystallized from acetone methanol formed faintly yellow rod-like crystals, mp 255°-256°. Anal. Calcd for C19H7N9O18 : C, 35.1; H, 1.1; N, 19.4. Found: C, 34.9, 34.2; H, 1.6, 1.2; N, 19.2, 18.8.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[CH3:13]I>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([CH3:13])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)Cc1cccs1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)c1cccs1
Temperature: -30 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
A solution of methyl 2-(thiophen-2-yl)acetate (4.90 g, 31.4 mmol) in THF (25 ml) was added dropwise to a suspension of sodium hydride (1.20 g, 31.4 mmol, 60%) in THF (25 ml) at −50° C. under an atmosphere of nitrogen. After the reaction mixture was stirred for 1 h, methyl iodide was added (1.76 ml, 28.2 mmol) as solution in THF (25 ml) slowly at −50° C. over a period of 15 min. The reaction mixture was warmed up to −30° C. and continued to stir for another 2 h. It was quenched with aqueous ammonium chloride, extracted with DCM (2×30 ml) and washed with brine (30 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuo. The crude was purified by column chromatography over silica gel (100-200 mesh) using ethyl acetate (5%) in petroleum ether as eluent to get 2.2 g (41.7%) of methyl 2-(thiophen-2-yl)propanoate as a colorless liquid.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH:15]=O)[C:10]([O:12]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24](=[NH:26])[NH2:25])[CH:21]=[CH:20][N:19]=1>C(O)C>[CH2:1]([O:8][C:9]1[C:10]([OH:12])=[N:25][C:24]([C:22]2[CH:21]=[CH:20][N:19]=[C:18]([Cl:17])[CH:23]=2)=[N:26][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N=C(N)c1ccnc(Cl)c1
Reactant: CCOC(=O)C(C=O)OCc1ccccc1
Solvent: CCO
Product: Oc1nc(-c2ccnc(Cl)c2)ncc1OCc1ccccc1
Yield: 66 %

Procedure:
A mixture of crude ethyl 2-(benzyloxy)-3-oxopropanoate (all from previous step), 2-chloropyridine-4-carboximidamide (9.57 g, 50 mmol) and 100 mL of anhydrous ethanol was refluxed for 4 h under nitrogen. The mixture was then cooled and the volatile solvents were removed by rotary-evaporator. The residue was re-dissolved in water and filtered. The filtrate was acidified by HCl (4N aq) in an ice bath and the white precipitate was filtered, washed with water, and dried to give 5-(benzyloxy)-2-(2-chloropyridin-4-yl)pyrimidin-4-ol (10.4 g, 66%). 1H NMR δ (400 MHz, d6-DMSO): 13.12 (s, 1H), 8.58 (d, J=5.2 Hz, 1H), 8.12 (s, 1H), 8.04 (d, J=5.2 Hz, 1H), 7.94 (s, 1H), 7.51-7.34 (m, 5H), 5.20 (s, 2H); MS (ESI) m/z (M++H)+ 314.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH:18]([C:24]([CH3:26])=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)(O)[O-].[Na+].C(COC)OC>CCCCCC>[CH2:22]([O:21][C:19]([C:18]1[N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:2]2=[N:1][C:24]=1[CH3:26])=[O:20])[CH3:23]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1ncccc1OCc1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: COCCOC
Product: CCOC(=O)c1c(C)nc2c(OCc3ccccc3F)cccn12
Reaction time: 0.5 h

Procedure:
A mixture of 25.0 g of 2-amino-3-(2-fluorobenzyloxy)pyridine, 20.5 g ethyl 2-chloroacetoacetate, 10.0 g of sodium bicarbonate and 250 ml dimethoxyethane was heated under reflux for 48 hrs. An additional 5.0 g ethyl 2-chloroacetonacetate was added and refluxed for another 24 hrs., followed by another 5.0 g and refluxed for a further 66 hrs. The mixture was cooled and suctionfiltered. The solids collected were washed with tetrahydrofuran, and the combined filtrate and washings were evaporated invacuo to leave a dark-colored oil. Hexane (200 ml) was added to the oil with vigorous stirring, and the resulting precipitate filtered off. To this solid was added (with vigorous stirring) acetonitrile (50 ml) and diisopropyl ether (200 ml) and stirring was continued for 0.5 hr. The suspended solid was filtered and crystallized from acetonitrile to give the desired ester.
Reaction SMILES: [CH3:1][N:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[C:3]#[N:4].Cl.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O.C(=O)(O)[O-].[Na+]>C1C(O)=CC=CC=1C>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([N:2]([CH3:1])[C:3]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[NH:4])=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C#N)c1ccc(OCc2ccccc2)cc1
Reactant: Nc1ccccc1-c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(O)c1
Solvent: O
Product: CN(C(=N)Nc1ccccc1-c1ccccc1)c1ccc(OCc2ccccc2)cc1

Procedure:
N-Methyl-4-benzyloxyphenylcyanamide (3.6 g) was added to a suspension of 2-aminobiphenyl hydrochloride (3 g) in m-cresol (8 ml) and the mixture was heated at 90°-95° C. for 3 hours and then added to water. The aqueous layer was basified with solid sodium bicarbonate and extracted with ether. The extract was dried (Na2SO4) and the solvent removed to give a residue which was extracted into boiling hexane to yield N-(4-benzyloxyphenyl)-N'-(2-biphenylyl)-N-methylguanidine.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[NH:11]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19](O)=O)=[N:12]1.N>>[NH:11]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[C:18]([C:19]3[O:1][N:2]=[C:3]([C:4]4[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=4)[N:10]=3)[CH:22]=[CH:23][CH:24]=2)=[N:12]1
Reactant: O=C(O)c1cccc(-c2cc[nH]n2)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: c1cncc(-c2noc(-c3cccc(-c4cc[nH]n4)c3)n2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-(1H-pyrazol-3-yl)benzoic acid (Maybridge). 1H NMR (300 MHz, DMSO-d6) δ 6.91 (d, J=2.4 Hz, 1H), 7.62-7.69 (m, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.79-7.92 (m, 1H), 7.82-7.88 (m, 1H), 8.10-8.20 (m, 3H), 8.49 (dt, J=8.2, 1.9, 1.7 Hz, 1H), 8.64 (s, 1H), 8.83 (dd, J=4.7, 1.7 Hz, 1H), 9.29 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 290 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:23][O:24][CH2:25][CH2:26][NH2:27].O>CN1CCCC1=O>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C:13]([NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[NH:27][CH2:26][CH2:25][O:24][CH3:23])=[O:22]
Reactant: O=C(Nc1cccc2c(Cl)ccnc12)c1c(Cl)cccc1Cl
Reactant: COCCN
Solvent: CN1CCCC1=O
Solvent: O
Product: COCCNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 120 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A mixture of 4-chloro-8-(2,6-dichlorobenzoylamino)quinoline (100 mg) and 2-methoxyethylamine (314 mg) in N-methylpyrrolidone (1 ml) was heated at 120° C. overnight. Water (3 ml) was added thereto under ice-cooling, and the mixture was stirred for 1 hour. The resulting precipitate was collected by filtration, and the residue was purified by preparative thin layer chromatography (methanoldichloromethane) to give 8-(2,6-dichlorobenzoylamino)-4-(2-methoxyethylamino)quinoline (65 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH3:13])([CH3:12])[OH:11])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:17][CH2:18][OH:19].[I-].[Na+]>O>[OH:19][CH2:18][CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([CH3:13])([CH3:12])[OH:11])=[CH:6][CH:7]=1
Reactant: CC(C)(O)CCc1ccc(O)cc1
Reactant: OCCBr
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(O)CCc1ccc(OCCO)cc1
Yield: 114.1 %

Procedure:
To a suspension of 4-hydroxy-α,α-dimethylbenzenepropanol (15 g, 0.083 m) in water, was added a solution of sodium hydroxide (5 g, 0.125 m) in water (50 ml). 2-Bromoethanol (11.4 g, 0.091 m) and sodium iodide (6.3 g) were successively added and the solution stirred and heated under reflux for 3 hours. The reaction mixture was then diluted with more water and extracted with ethyl acetate. Evaporation of the ethyl acetate gave a cream solid (21.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:34]2[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(Cl)cc3)c3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-chlorophenol: ESMS m/e: 568.7 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9]([O:11]CC)=[O:10].O.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)CCCOc1cccc(Br)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCOc1cccc(Br)c1
Temperature: 50 °C

Procedure:
Ethyl 4-(3-bromophenoxy)butanoate 6 from Example 5 was taken up in 100 mL THF and 50 mL water and treated with lithium hydroxide LiOH (hydrate, 4.9 g). see FIG. 1. The whole was heated at 50° C. for 2 days. The mixture was cooled to room temperature and acidified to pH 1 with 2N HCl. The aqueous was extracted with ethylacetate. The combined organics were washed with brine and dried over sodium sulfate to give crude 4-(3-Bromophenoxy)butanoic acid as a sticky solid. 1H NMR (DMSO-d6, 500 MHz) 7.24 (m, 1H), 7.13 (m, 1H), 7.11 (m, 1H), 6.95 (m, 1H), 3.99 (m, 2H), 2.37 (m, 2H), 1.94 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19](O)=[O:20])=[O:5].[CH2:30]([NH2:34])[CH:31]([CH3:33])[CH3:32]>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:16])([CH3:17])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([NH:34][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:20])=[O:5]
Reactant: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)O
Reactant: CC(C)CN
Product: CC(C)CNC(=O)c1c(NC(=O)c2c(F)cccc2C(F)(F)F)sc2c1C(C)(C)OC2(C)C

Procedure:
The title compound was prepared from the product of Example 45A and commercially available isobutylamine using the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 0.85 (d, J=6.8 Hz, 6H), 1.45 (s, 6H), 1.48 (s, 6H), 1.76 (sept, J=6.8 Hz, 1H), 2.99 (t, J=6.4 Hz, 2H), 7.67-7.81 (m, 3H), 8.05 (t, J=5.9 Hz, 1H), 11.49 (br s, 1H). MS (ESI+) m/z 487 (M+H)+. Anal. calcd. for C23H26F4N2O3S: C, 56.78; H, 5.39; N, 5.76. Found: C, 57.06; H, 5.57; N, 5.68.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([OH:18])([CH3:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:5]=[CH:4][N:3]=1.[C:19]([N:27]=C=O)(=[O:26])C1C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[OH:18][C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:19]([NH2:27])=[O:26])[CH:7]=1)([CH3:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Cc1ccccc1CC(C)(O)c1ccnc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccccc1CC(C)(O)c1ccnc(NC(N)=O)c1
Temperature: 50 °C
Yield: 19.2 %

Procedure:
2-(2-Amino-pyridin-4-yl)-1-o-tolyl-propan-2-ol (37 mg, 0.15 mmol) is dissolved in DCM (1 mL) and benzoyl isocynate (27 mg, 0.18 mmol) is added. The reaction is sealed and heated at 50° C. for 16 hrs. Then the solvent is removed and to the residue are added ethanol (1 mL) and potassium carbonate (32 mg, 0.23 mmol). The mixture is heated at 80° C. for 55 min. The solvent is removed and the residue is partitioned between water (25 mL) and EtOAc (35 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) followed by Gilson preparative HPLC affords 8.2 mg of the titled product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[CH:14]=[N:13][N:12](CC3C=CN=CC=3)[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].[Se](=O)=[O:23]>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccncc2)c1
Reactant: O=[Se]=O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2[nH]ncc2c1O

Procedure:
3 g of 4-hydroxy-1-(4-picolyl-1H-pyrazolo[3,4-b]pyridine- 5-carboxylic acid ethyl ester (0.01 mol) is dissolved in 20 ml of acetic acid, 2.2 g of selenium dioxide (0.02 mol) and 2-3 drops of water are added. The mixture is refluxed for 30 minutes and then filtered off. 4-Hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester precipitates on cooling. Recrystallization from acetic acid yields 1.8 g (87%), m.p. 275°.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7](B(O)O)[CH:6]=1.I[C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.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>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)[CH:6]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: COCOc1ccc(C)c(B(O)O)c1
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
Product: CCOC(=O)c1ccc(-c2cc(O)ccc2C)cc1

Procedure:
In a manner similar to that of Example 11(d), by reaction of 3.7 g (18.8 mmol) of 4-methoxymethoxy-1-methylbenzene-2-boronic acid described in Example 16(c) with 4.7 g (17 mmol) of ethyl 4-iodobenzoate, 17 mL of 2.0M potassium carbonate solution and 1 g (0.8 mmol) of tetrakis(triphenylphosphine)palladium, followed by deprotection in ethanol, the desired product is obtained in the form of a colourless oil (m=3.07 g; Y=71%).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>ClCCl.N1C=CC=CC=1>[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:30][CH:29]=2)=[O:13])=[CH:27][CH:26]=1)(=[O:23])=[O:24]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: CS(=O)(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(NC(=O)c2ccccc2SSc2ccccc2C(=O)Nc2ccc(S(C)(=O)=O)cc2)cc1
Yield: 56 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 4-aminophenyl methyl sulfone (2.00 g, 11.7 mmol) in 16 mL of pyridine. The crude product was recrystallized from acetonitrile-DMF to yield 2.0 g of the title compound, mp 236°-238° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=C(C)O[N:11]=2)=[CH:6][C:5]=1[NH:16][CH2:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19].[C:28](O)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:28]([NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[NH:11])[NH2:14])=[CH:6][C:5]=1[NH:16][CH2:17][C:18]([OH:20])=[O:19])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1nc(-c2ccc(CN)c(NCC(=O)OCc3ccccc3)c2)no1
Agent: Cl
Product: N=C(N)c1ccc(CNC(=O)c2ccccc2)c(NCC(=O)O)c1

Procedure:
Compound 58d was reacted with benzoic acid and subsequently hydrogenated according to the the procedure described in Example 58, to give Example 62. ESI-MS m/e 327.5 (M+1).