Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1.[N:10]([CH:13]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:14]1[CH:15]=[C:16]([CH:28]=[CH:29][CH:30]=1)[O:17][CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)=[N+:11]=[N-:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[N:10]([CH:13]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:14]1[CH:15]=[C:16]([CH:28]=[CH:29][CH:30]=1)[O:17][CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:25][CH2:2][CH2:3][CH2:4][CH:5]2[O:9][CH2:8][CH2:7][O:6]2)=[O:24])=[CH:21][CH:20]=1)=[N+:11]=[N-:12]
Reactant: ClCCCC1OCCO1
Reactant: [N-]=[N+]=NC(c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(c1ccccc1)c1cccc(OCc2ccc(C(=O)OCCCC3OCCO3)cc2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
To a stirred solution of 3-chloropropyl-1,3-dioxolane (0.2 g, 1.35 mmol) in dimethyl formamide (14 mL), was added 4-((3-(azido(phenyl)methyl)phenoxy)-methyl)benzoic acid (Example 51 Step 3) (0.5 g, 1.39 mmol) and potassium carbonate (0.38 g, 2.78 mmol). The reaction was allowed to stir at 80° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (×3). The organic extracts were washed with brine, dried (sodium sulphate), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0-100% ethyl acetate in iso-hexane to afford the title compound (0.63 g, 96%).
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])=[S:12])/[N:7]([CH2:22][C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2C(OC(C)(C)C)=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:36]>CO.O1CCOCC1>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[S:12])[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])/[N:7]([CH2:22][C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3].[ClH:36]
Reactant: COc1ccc(Cl)cc1C(=S)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(Cl)cc1C(=S)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 112C (160 mg, 0.306 mmol) in methyl alcohol (2 mL) added hydrogen chloride (4 M) in dioxane (1 mL) and stirred at rt for 2 hr. The reaction concentrated to give the title compound as HCl salt. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.27 (m, 1H) 1.34-1.38 (m, 1H) 1.40 (s, 9H) 1.61 (m, 2H) 1.81 (m, 2H) 2.53-2.63 (m, 1H) 3.02 (m, 1H) 3.13 (m, 1H) 3.81 (s, 3H) 4.03-4.09 (m, 1H) 4.33 (m, 1H) 6.85 (d, J=8.73 Hz, 1H) 6.93 (s, 1H) 7.21-7.24 (m, 1H) 7.53 (d, J=2.78 Hz, 1H); MS (DCI/NH3) m/z 438 (M+H)+.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH3:7])[C:3](Br)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[OH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[NH:21][C:20](=[O:23])[CH:19]=[CH:18]2>C(=S)=S>[Br:1][CH:2]([CH2:6][CH3:7])[C:3]([C:16]1[CH:15]=[CH:14][C:13]([OH:12])=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20](=[O:23])[NH:21]2)=[O:4]
Reactant: O=c1ccc2cccc(O)c2[nH]1
Reactant: CCC(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(Br)C(=O)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 50 °C
Yield: 70.1 %

Procedure:
50 g of α-bromobutyric acid bromide (V), 50 g of anhydrous aluminum chloride and 400 ml of carbon disulfide were added to 20 g of 8-hydroxycarbostyril (VI). The resulting mixture was heated at a temperature of 50° C for 13 hours and the carbon disulfide layer was removed by decantation. Crushed ice was added to the residue to crystallize the product, and the crystals thus formed were filtered, washed with water and then recrystallized from methanol to obtain 27 g of 5-(α-bromobutyryl)-8-hydroxycarbostyril (VI) having a melting point of 218°-219° C (with coloring and decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[C:24]([Cl:28])=[N:25][O:26][CH3:27]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:21][C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[C:24]([Cl:28])=[N:25][O:26][CH3:27]
Reactant: CON=C(Cl)c1ccccc1CCl
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CON=C(Cl)c1ccccc1COc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 91.2 %

Procedure:
3-Chlorophenol (3.09 g, 0.024 mol), dimethyl-formamide (20 ml) and potassium carbonate (4.15 g, 0.03 mol) were added to 2-chloromethyl-α-methoxyiminobenzyl chloride (4.36 g, 0.02 mol), and the mixture was stirred at room temperature for 4 days. After completion of the reaction, ether (250 ml) was added, and the mixture was washed with brine (200 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(3-chlorophenoxymethyl)-α-methoxyiminobenzyl chloride (5.66 g, 91.2%) as a colorless oil.
Reaction SMILES: [CH3:1][Si:2]([O:5]S(C(F)(F)F)(=O)=O)([CH3:4])[CH3:3].[CH2:13]([C:15]([C:34]1[CH:39]=[CH:38][C:37]([C:40]#[C:41][C:42]2(O)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[C:36]([CH3:50])[CH:35]=1)([C:18]1[CH:23]=[CH:22][C:21]([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)=[C:20]([CH3:33])[CH:19]=1)[CH2:16][CH3:17])[CH3:14].N1C=CC=CC=1.[Cl-].[NH4+]>ClCCl>[CH2:13]([C:15]([C:18]1[CH:23]=[CH:22][C:21]([B:24]2[O:25][C:26]([CH3:32])([CH3:31])[C:27]([CH3:29])([CH3:30])[O:28]2)=[C:20]([CH3:33])[CH:19]=1)([C:34]1[CH:39]=[CH:38][C:37]([C:40]#[C:41][C:42]2([O:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[C:36]([CH3:50])[CH:35]=1)[CH2:16][CH3:17])[CH3:14]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCCCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reaction time: 1.5 h
Yield: 30.3 %

Procedure:
Trifluoromethanesulfonic acid trimethylsilyl ester (0.37 mL, 2.04 mmol) was added to a solution of the mixture containing 1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenylethynyl)-cycloheptanol (529 mg) and pyridine (0.42 mL, 5.19 mmol) in dichloromethane (4.0 mL) at 0° C., and the mixture was stirred at the same temperature for 90 minutes. An ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 80:20) to give the target compound as a colorless oil (183 mg, 28% in three steps).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:4]=1[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][C:12]2[CH2:13][NH:14][CH2:15][CH2:16][C:17]=2[N:18]=1)=[NH:8].[C:25](Cl)(=[O:27])[CH3:26].C(N(CC)CC)C>C1COCC1>[C:25]([N:14]1[CH2:15][CH2:16][C:17]2[N:18]=[C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]3[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:3]=3[O:2][CH3:1])=[NH:8])[S:11][C:12]=2[CH2:13]1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: COc1cccc(OC)c1CNC(=N)Nc1nc2c(s1)CNCC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(OC)c1CNC(=N)Nc1nc2c(s1)CN(C(C)=O)CC2

Procedure:
Acetylation of 110 mg N-(2,6-dimethoxybenzyl)-N′-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-yl)guanidine (0.26 mmol, Example 221.3) under standard conditions with acetylchloride and triethylamine in 15 ml THF followed by purification, yielded 16 mg of the desired product as a white solid; ESI-MS [M+H+]=390.15.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20][CH:19]=1>>[N:18]1([C:13]2[N:12]=[C:11]([NH:10][C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[CH3:9])[CH:16]=[N:15][CH:14]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1ccc(Br)cc1
Reactant: c1ccc2[nH]cnc2c1
Product: C[C@H](Nc1cncc(-n2cnc3ccccc32)n1)c1ccc(Br)cc1
Yield: 41.8 %

Procedure:
In a procedure analogous to example 25, reaction of N-[(1S)-1-(4-bromophenyl)ethyl]-6-chloropyrazin-2-amine (125 mg, 0.40 mmol) and benzimidazole (52 mg, 0.44 mmol) furnished the product (66 mg, 42%).
Reaction SMILES: [C:1]1([N:7]=[N:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH2:19])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([O:27][C:28]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32](O)=[O:33])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]1([N:7]=[N:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH:19][C:32](=[O:33])[C@@H:31]3[CH2:35][CH2:36][CH2:37][N:30]3[C:28]([O:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:29])=[CH:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(N=Nc2ccccc2)c2ccccc12
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Product: O=C(Nc1ccc(N=Nc2ccccc2)c2ccccc12)[C@@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
4-Phenylazo-1-naphthylamine (4.9 g, 0.02 mole) and N-benzyloxylcarbonyl-L-proline (5.0 g, 0.02 mole) were coupled and the reaction mixture was worked up as in Example 6. The final product was obtained as crystals.
Reaction SMILES: [Na].[F:2][C:3]([F:25])([F:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:15]3[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]3[N:13]=[CH:12][CH:11]=2)[CH:5]=1.[CH3:26][O:27]CCO>>[CH3:26][O:27][CH2:23][CH2:22][O:21][C:19]([C:18]1[CH:17]=[N:16][N:15]2[C:10]([C:6]3[CH:5]=[C:4]([C:3]([F:24])([F:2])[F:25])[CH:9]=[CH:8][CH:7]=3)=[CH:11][CH:12]=[N:13][C:14]=12)=[O:20]
Reactant: CCOC(=O)c1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Reactant: COCCO
Agent: [Na]
Product: COCCOC(=O)c1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
One hundred milligrams of metallic sodium is added to 50 ml. of 2-methoxyethanol and after it has dissolved, 3.35 g. of ethyl 7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate is added and the mixture is refluxed for one hour. On cooling, the desired compound crystallizes from the solution and is removed by filtration. Recrystallization from methylene chloride-hexane affords the product as crystals, m.p. 111°-112° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:10]=2[Cl:17])=[C:4]([CH2:18][O:19]C)[N:3]=1.C[Si](I)(C)C>S1(CCCC1)(=O)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:10]=2[Cl:17])=[C:4]([CH2:18][OH:19])[N:3]=1
Reactant: COCc1nc(N)nc(N)c1-c1cc(Cl)cc(Cl)c1Cl
Agent: C[Si](C)(C)I
Solvent: O=S1(=O)CCCC1
Product: Nc1nc(N)c(-c2cc(Cl)cc(Cl)c2Cl)c(CO)n1

Procedure:
This compound was made from the compound of Example 2 by reaction with trimethylsilyl iodide in sulpholane at 80° C. mp. 101°-105° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:22][OH:23])[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(CO)cc(Br)cc3c2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2oc3c(COS(C)(=O)=O)cc(Br)cc3c2C1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
To a mixture of the product of Example 74, step E (300 mg, 0.78 mmol) in dichloromethane (4 mL) at 0° C. was added triethylamine (93 mg, 0.92 mmol) followed by methanesulfonyl chloride (100 mg, 0.88 mmol). The reaction mixture was allowed to warm to ambient temperature over 2 h, then treated with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic extracts were dried over sodium sulphate, filtered, and concentrated in vacuo. Purification by flash chromatography (SiO2, 95:5 hexanes/ethyl acetate) provided tert-butyl 8-bromo-6-((methylsulfonyloxy)methyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (340 mg, 94%) as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 7.59 (s, 1H), 7.44 (s, 1H), 5.47 (s, 2H), 4.52 (s, 2H), 3.83 (t, J=5.1 Hz, 2H), 3.02 (s, 3H), 2.88 (s, 2H), 1.51 (s, 9H).
Reaction SMILES: [C:1]([C:3](=[C:8]([OH:19])[C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[C:10]=1[F:18])C(OC)=O)#[N:2].[Na].Cl>O>[F:18][C:10]1[C:11]([F:17])=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=1[C:8]([CH2:3][C:1]#[N:2])=[O:19]
Reactant: COC(=O)C(C#N)=C(O)c1cc(F)c(F)c(F)c1F
Agent: Cl
Agent: [Na]
Solvent: O
Product: N#CCC(=O)c1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 26 h
Yield: 88.9 %

Procedure:
Methyl 2-cyano-3-hydroxy-3-(2,3,4,5-tetrafluorophenyl)acrylate (75.1 g) is added to a solution of sodium hydroxyde (110 g) in water (1.1 liter) and the mixture is stirred at room temperature for 26 hours. To the reaction mixture is added ice (1.3 Kg) and conc. HCl. After 1 hour, the precipitate is filtered and washed with dil. HCl to yield 2-(2,3,4,5-tetrafluorobenzoyl)acetonitrile (52.7 g) as a light cream colored powder, m.p. 60°-61° C.
Reaction SMILES: [CH2:1]([C:10]1[CH:11]=[C:12]([CH3:17])[C:13]([OH:16])=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:18](OC(=O)C)(=[O:20])[CH3:19]>S(=O)(=O)(O)O.CCCCCCC>[C:18]([O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:11][C:12]=1[CH3:17])(=[O:20])[CH3:19]
Reactant: CCCCCCCCCc1ccc(O)c(C)c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Product: CCCCCCCCCc1ccc(OC(C)=O)c(C)c1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
4-Nonyl-2-cresol (1a) (934 g, 3.99 mol) was treated with acetic anhydride (456.6 g, 4.42 mol) in the presence of a few drops of concentrated sulfuric acid at 110° C. for 1 h. After cooling to ambient temperature, the reaction mixture was transferred into a 4-I separatory funnel with aid of heptane (400 mL). The resulting organic phase was washed with aqueous sodium bicarbonate solution and water until the pH became 6 or so. The heptane phase was dried over sodium sulfate and concentrated to obtain 4-nonyl-2-methylphenyl acetate (1098.3 g) in 99.7% yield.
Reaction SMILES: [CH2:1]([O:8][N:9]([C:20](=[O:40])[CH2:21][CH2:22][C:23](=[O:39])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:41]1(=[O:47])[O:46][C:44](=[O:45])[CH2:43][CH2:42]1>N1C=CC=CC=1>[CH2:32]([O:31][N:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][NH:24][C:23](=[O:39])[CH2:22][CH2:21][C:20](=[O:40])[N:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:41](=[O:47])[CH2:42][CH2:43][C:44]([OH:46])=[O:45])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C1CCC(=O)O1
Reactant: COCCOCCOCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCNOCc1ccccc1
Solvent: c1ccncc1
Product: COCCOCCOCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)O
Yield: 95 %

Procedure:
5,16-Bis (benzyloxy)-4,12,15-trioxo-5,11,16-triaza-19,22,25-trioxahexacosanoic acid (19) was synthesized by reacting compound (18) (3.40 g, 6.07 mmol) with succinic anhydride in pyridine following the procedure of (16) to produce 3.81 g (95%) of (19) as an oil: NMR δ 1.2-1.8 (m, 6 H) t 2.38-2.91 (m, 8 H) t 3.07-3.83 (m, 19 H) t 4.79 (s, 2 H), 4.88 (s, 2 H), 5.7 (br s, 1 H), 6.62 (br s, 1 H), 7.33 (s, 10 H). Analysis: (C34H49N3O10) C, H, N.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].C(=O)([O-])[O-].[K+].[K+].I[CH:38]([CH3:40])[CH3:39]>CN(C=O)C>[CH:38]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[C:24]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:16][CH:17]=1)=[O:11])([CH3:40])[CH3:39]
Reactant: CC(C)I
Reactant: O=C(c1ccc(Oc2nccnc2N2CCOCC2)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1c(C(=O)c2ccc(Oc3nccnc3N3CCOCC3)cc2)nc2ccccc21
Reaction time: 8 h

Procedure:
A mixture of (1H-benzo[d]imidazol-2-yl)(4-(3-morpholinopyrazin-2-yloxy)-phenyl)methanone (115 mg, 286 μmol), potassium carbonate (79.2 mg, 573 μmol) and 2-iodopropane (97.4 mg, 573 μmol) in DMF (2 mL) was stirred overnight. Additional isopropyl iodide was added until the starting material was consumed. The mixture was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate and the combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by Biotage™, 10-30% acetone/hexanes gradient, to give (1-isopropyl-1H-benzo[d]imidazol-2-yl) (4-(3-morpholinopyrazin-2-yloxy)phenyl)methanone. MS (ESI, pos. ion) m/z: 444.1 (M+1). IC50 (uM) ++++.
Reaction SMILES: [NH2:1][CH:2]([C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Br:15])=[CH:10][N:9]=1)C(OCC)=O>Cl>[ClH:14].[Br:15][C:11]1[CH:12]=[C:13]([Cl:14])[C:8]([CH2:2][NH2:1])=[N:9][CH:10]=1
Reactant: CCOC(=O)C(N)c1ncc(Br)cc1Cl
Agent: Cl
Product: NCc1ncc(Br)cc1Cl
Yield: 182.4 %

Procedure:
A stirred solution of ethyl 2-amino-2-(5-bromo-3-chloropyridin-2-yl)acetate (0.5 g, 1.7 mmol) in 3 N HCl (25 mL) was heated at reflux for 4 h. The reaction mixture was washed with Et2O and water. The combined ether layer was concentrated under reduced pressure to afford the title compound as an off-white solid (400 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.70 (br s, 2H), 8.45 (s, 1H), 4.56 (m, 2H); ESIMS m/z 221.15 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([CH:18]=[CH2:19])=[CH:16][CH:15]=[C:14]([O:20][CH3:21])[C:12]=3[N:13]=2)=[O:7])=[CH:4][CH:3]=1>CO.[Pd]>[CH2:18]([C:17]1[C:11]2[S:10][C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=3)=[N:13][C:12]=2[C:14]([O:20][CH3:21])=[CH:15][CH:16]=1)[CH3:19]
Reactant: C=Cc1ccc(OC)c2nc(NC(=O)c3ccc(F)cc3)sc12
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(OC)c2nc(NC(=O)c3ccc(F)cc3)sc12
Reaction time: 2 h

Procedure:
100 mg of 4-fluoro-N-(4-methoxy-7-vinyl-benzothiazol-2-yl)-benzamide (0.3 mmol) were dissolved in methanol (100 ml) and Pd/C (4 mg) were added. The reaction mixture was hydrogenated for 2 hrs. After filtering and evaporation of the solvent the crude product was subjected to column chromatography (silica gel, eluent MeOH/CH2Cl2 1:9). The title compound was obtained in form of white crystals (79 %); F.p.: 165-167° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:6]1O[CH:8]=[CH:9][C:10](=[O:12])[CH:11]=1)([CH3:5])[CH3:4].[NH4+:15].[OH-]>>[F:1][C:2]([F:14])([F:13])[C:3]([C:6]1[NH:15][CH:8]=[CH:9][C:10](=[O:12])[CH:11]=1)([CH3:5])[CH3:4]
Reactant: CC(C)(c1cc(=O)cco1)C(F)(F)F
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(c1cc(=O)cc[nH]1)C(F)(F)F
Temperature: 90 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A mixture of 2-(1,1,1-trifluoro-2-methylpropan-2-yl)-4H-pyran-4-one (800 mg, 3.88 mmol) in NH4OH (8 mL, 205 mmol) was stirred at 90° C. for 1 h. Then the mixture was concentrated, triturated with MeOH (20 mL) and filtered. The filtrate was concentrated and purified by silica column chromatography (DCM/MeOH=9:1). All fractions found to contain product by TLC (DCM/MeOH=9:1, Rf=0.2) were combined and concentrated to yield a yellow oil of 2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4(1H)-one (700 mg, 2.90 mmol, 74.7% yield): 1H NMR (400 MHz, CD3OD): δ 7.87 (d, J=7.2 Hz, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.54 (dd, J=2.4, 7.2 Hz, 1H), 1.60 (s, 6H). ES-LCMS m/z 206.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.I[C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[OH:19].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[C:13]([OH:19])=[CH:14][CH:15]=[C:16]([CH3:18])[N:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)c(I)n1
Reactant: OB(O)c1ccc(Br)cc1
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: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(O)c(-c2ccc(Br)cc2)n1
Yield: 22.8 %

Procedure:
A solution of 4-bromobenzeneboronic acid (2.0 g) in ethanol (10 ml) was added over a period of 15 minutes to a stirred mixture of 6-iodo-2-picolin-5-ol (2.35 g), saturated aqueous sodium carbonate solution (5.0 ml), tetrakis(triphenylphosphine)palladium [0] (280 mg) and toluene (10 ml) under an atmosphere of argon. The mixture was stirred at reflux for 6 hours. The mixture was evaporated and the residue was treated with water (20 ml). The mixture was filtered and the yellow solid collected was purified by flash column chromatography on alumina (1CN Biomedicals Alumina N32-63) using 50% n-pentane/ethyl. acetate as eluent to give 2-(4-bromophenyl)-3-hydroxy-6-methylpyridine (600 mg), m.p. 196°-199° C.; NMR: 2.42(3H,s), 7.09(1H,d), 7.25(1H,d), 7.62(2H,d), 8.02(2H,d), 9.98(1H,s); m/z 264 & 266 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH3:9])[CH2:3][C:4]1[NH:8][CH:7]=[N:6][CH:5]=1.[CH3:11][N:12]([CH3:17])[S:13](Cl)(=[O:15])=[O:14].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][C:2]([CH3:10])([CH3:9])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:13]([N:12]([CH3:17])[CH3:11])(=[O:15])=[O:14])[CH:5]=1
Reactant: CC(C)(C)Cc1cnc[nH]1
Reactant: CN(C)S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)n1cnc(CC(C)(C)C)c1

Procedure:
To a solution of 5-(2,2-dimethylpropyl)-1H-imidazole, dimethylsulfamoyl chloride (25 mL), Et3N (45 mL) in CH2Cl2 (300 mL) was added DMAP (0.8 g). The reaction mixture was refluxed overnight. The solvent was concentrated and the residue was purified by silica gel chromatography to give the title compound as a white solid.
Reaction SMILES: [CH:1]1([NH:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH:24]3[CH2:25][CH2:26][CH2:27][CH:20]2[C:21](=[CH:29]O)[C:22](=O)[CH2:23]3)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([N:19]2[CH:24]3[CH2:25][CH2:26][CH2:27][CH:20]2[C:21]2[CH:29]=[N:8][N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[C:22]=2[CH2:23]3)(=[O:18])=[O:17])=[CH:14][CH:15]=1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: NNC1CCCCC1
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cnn(C3CCCCC3)c1C2

Procedure:
Prepared as described in Example 5 using cyclohexylhydrazine and 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34.