Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[C:10]1([CH:17]=[CH:16][C:14]([OH:15])=[CH:13][CH:12]=1)[OH:11]>CS(C)=O.O.C1OCCOCCOCCOCCOCCOC1>[Cl:8][C:7]1[C:2]([O:11][C:10]2[CH:17]=[CH:16][C:14]([OH:15])=[CH:13][CH:12]=2)=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Oc1ccc(O)cc1
Reactant: Clc1cnc(Cl)c(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: O
Solvent: CS(C)=O
Product: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
2,3,5-Trichloropyridine (69.32 g, 0.38 mol) and 18-crown-6 (4.0 g, 0.015 mol) are added to a mixture of the dipotassium salt of hydroquinone (prepared from hydroquinone (44.0 g, 0.4 mol) and potassium hydroxide (45.0 g, 0.8 mol)) in dimethyl sulfoxide (700 mL). The reaction mixture is stirred overnight at room temperature, heated at 60° C. for 21/2 hours, diluted with water and extracted with ether. The combined organic extracts are washed with water, treated with charcoal, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain the title product as a white solid (47.23 g, mp 122°-123.5° C.)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1>>[N:11]1([C:2]2[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: c1c[nH]cn1
Product: CC(=O)c1ccc(-n2ccnc2)nc1
Temperature: 125 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
To a 25 mL vial which contained 1-(6-chloro-pyridin-3-yl)-ethanone (1.5 g, 10 mmol.) was added 1H-imidazole (3 g, 50 mmol.) at rt. The mixture was stirred at 120-130° C. for 2 h and cooled to rt. The contents were poured into 150 mL ice-water solution and extracted with EtOAc (3×100 mL). The combined organic layers was washed with water (3×50 mL), brine (50 mL) and dried over Na2SO4. The solvent was removed under vacuum to yield the crude which was purified by column to afford desired 1-(6-imidazol-1-yl-pyridin-3-yl)-ethanone (1.25 g, 67%).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[NH2:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=[C:19]([NH2:26])[C:18]=2[N:17]=[C:16]1[CH3:27]>>[NH2:26][C:19]1[C:18]2[N:17]=[C:16]([CH3:27])[N:15]([CH2:14][CH2:13][NH:12][C:3](=[O:4])[N:2]([CH3:1])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:23]=2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=1
Reactant: Cc1nc(N)c2nc(C)n(CCN)c2c1C
Reactant: CN(C(=O)Cl)c1ccccc1
Product: Cc1nc(N)c2nc(C)n(CCNC(=O)N(C)c3ccccc3)c2c1C

Procedure:
Using the method of Examples 118-133, N-methyl-N-phenylcarbamoyl chloride was reacted with 1-(2-aminoethyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 353.2073.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[C:7]([F:32])=[C:8]([CH:29]=[CH:30][CH:31]=1)[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[CH:18]=2)[N:13]=[CH:12][N:11]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([N:23]1[CH2:24][CH2:25][CH2:26][CH:21]([O:20][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][C:16]=2[O:27][CH3:28])[N:13]=[CH:12][N:11]=[C:10]3[NH:9][C:8]2[CH:29]=[CH:30][CH:31]=[C:6]([Cl:5])[C:7]=2[F:32])[CH2:22]1)(=[O:3])[CH3:2]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCNC1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(C(C)=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.3 %

Procedure:
Acetyl chloride (27 mg) was added to a solution of 4-(3-chloro-2-fluoroanilino)-6-(piperidin-3-yloxy)-7-methoxyquinazoline (starting material described in Example 22; 134 mg) and diisopropylethylamine (65 mg) in methylene chloride (5 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was adsorbed onto silica and purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 95/5). The fractions containing the required product were combined and evaporated to give the title product (0.07 g); 1H NMR Spectrum: (DMSO d6 at 373K) 1.52-1.62 (m, 1H), 1.80-1.94 (m, 2H), 2.00 (s, 3H), 2.06-2.15 (m, 1H), 3.43-3.64 (m, 3H), 3.82-4.04 (m, 4H), 4.58 (m, 1H), 7.20-7.29 (m, 2H), 7.42 (t, 1H), 7.59 (t, 1H), 7.93 (s, 1H), 8.40 (s, 1H), 9.30 (s, 1H); Mass Spectrum: (M+H)+ 445.
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[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:17].[C:18]1([CH2:24][C:25](=[NH:29])OCC)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C.C(Cl)(Cl)Cl>[ClH:17].[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25](=[NH:29])[CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1COc1cccnc1N
Reactant: CCOC(=N)Cc1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Cc1ccccc1COc1cccnc1NC(=N)Cc1ccccc1
Yield: 9.5 %

Procedure:
A mixture of 2-amino-3-(2-methylbenzyloxy)pyridine (5.2 g, 24.2 mmol) and ethyl phenylacetimidate hydrochloride (5.32 g, 26.7 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was taken up in chloroform, filtered to remove an insoluble white solid, and purified by flash chromatography (chloroform/methanol) to obtain the product (0.85 g), m.p. 175°-178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[N+:19]([O-])([OH:21])=[O:20].O>C(O)(=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[C:4]([N+:19]([O-:21])=[O:20])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 50 °C
Yield: 99 %

Procedure:
To a suspension of 4′-chloro-p-toluenesulfonanilide (1100 g (3.90 mol) in acetic acid (2200 ml), fuming nitric acid (273.9 g (4.22 mol) was added dropwise over a period of 40 minutes with stirring at 50° C. After completion of the addition, the reaction mixture was stirred at the same temperature to complete the reaction. After being left to cool to room temperature, the reaction mixture was treated with 7000 ml of water to bring about precipitation of crystals. The crystals were filtered and washed with water to give 1261 g (99%) of 4′-chloro-2′-nitro-p-toluenesulfonanilide as yellow crystals.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([NH2:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([NH:13][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1cc(F)c(F)c2cccnc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cc(F)c(F)c2cccnc12)c1ccccc1
Yield: 34 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5,6-difluoroquinolin-8-amine (Intermediate 49) (120 mg, 0.67 mmol), benzenesulfonyl chloride (141 mg, 0.78 mmol) and DMAP (cat.) gave the title compound (73 mg, 35%) after purification by column chromatography with n-hexane/EtOH (1:1) as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([NH2:20])[N:17]([CH3:19])[N:18]=[C:11]12.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([NH:20][C:28](=[O:31])[CH2:29][CH3:30])[N:17]([CH3:19])[N:18]=[C:11]12
Reactant: CCC(=O)Cl
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3N)c(Cl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine (0.51 g) and triethylamine (0.27 mL) in dichloromethane (40 mL) at 0° C. was added propionyl chloride (0.17 mL) in dichloromethane (10 mL) dropwise over 25 minutes. The resulting mixture was stirred for an additional 1 hour at 0° C., followed by 14 hours at room temperature. The reaction mixture was then stirred with an aqueous 5% citric acid solution (40 mL) for 10 minutes. The layers were separated, and the aqueous layer was further extracted with dichloromethane (50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, then decanted from the desiccating agent and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a dichloromethane/methanol gradient to afford N-[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]propionamide (0.49 g) as an off white solid, ms m/z 347 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([C:15](=O)[CH2:16][CH3:17])[C:11](=[O:14])[CH2:12][CH3:13])=[CH:5][CH:4]=1.Cl.[NH2:20]O>N1C=CC=CC=1>[CH2:16]([C:15]1[C:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:11]([CH2:12][CH3:13])[O:14][N:20]=1)[CH3:17]
Reactant: NO
Reactant: CCC(=O)C(Cc1ccc(OC)cc1)C(=O)CC
Agent: Cl
Solvent: c1ccncc1
Product: CCc1noc(CC)c1Cc1ccc(OC)cc1

Procedure:
3,5-Diethyl-4-[(4-methoxyphenyl)methyl]isoxazole [I; Ar is 4-CH3OC6H4, Y is CH2, R is C2H5 ] was prepared from 41.1 g. of 4-(4-methoxyphenylmethyl)-3,5-heptanedione and 12.0 g. of hydroxylamine hydrochloride in 100 ml. of pyridine according to the procedure of Example 2, part (b), and was obtained in the form of a colorless oil, b.p. 145°-146° C. (0.1 mm.); MIC=25 μg/ml (herpes 2).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:13]2[CH2:14][O:15]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(O)cc1
Reactant: ClCC1CO1
Product: CC(C)c1ccc(OCC2CO2)cc1

Procedure:
The title compound was prepared from 4-isopropyl-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@:4](C)([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1.[Cl-].[NH4+].CO>[Zn].O>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: COC(=O)[C@](C)(Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 100.2 %

Procedure:
To a mixture of methyl (S)-3-[4-nitrophenyl]-2-tert-butoxycarbonylamino-propionic acid methyl ester (72 g, 222 mmol), zinc dust (˜325 mesh, 145.2 g, 2.2 mole, 10 equiv.) and ammonium chloride (178.1 g, 3.3 mole, 15 equiv.) was added methanol (1 L) and water (500 mL) at room temperature. After addition of water, an exothermic reaction ensued and the internal temperature rose to 45 to 50° C. The suspension was stirred for 30 min to 1 h at room temperature, at which time TLC analysis of the mixture indicated the absence of starting material, and the reaction mixture was filtered through a pad of celite and the filtered cake was washed with methanol (1 L) and water (500 mL). Concentration to remove most of the methanol and some water afforded white solids which were collected by filtration and washed with water. After air drying, 65.5 g (100% yield) of (S)-3-[4-aminophenyl]-2-tert-butoxycarbonylamino-propionic acid methyl ester was isolated as a white solid (mp 86-89° C.). ES(+)-HRMS m/e calcd. for C15H22N2O4 (M+H)+ 294.1621, obsd. 294.1614.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[C:3]=1N.C(O)C.[N+]([O-])([O-])=O.[Na+].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[CH:3]=1
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(Cl)cc(Cl)c1
Yield: 84 %

Procedure:
An article in Journal of the American Chemical Society, 72 (1950), 798, discloses that 2,6-dichloro-4-nitroaniline, ethanol and sodium nitrate can be reacted at the boil, in the absence of water and in the presence of concentrated sulfuric acid, to give an 84% yield of 3,5-dichloronitrobenzene. A corresponding reaction to form the 3,5-dibromonitrobenzene proceeds with a yield of 91%. The process is unsatisfactory in respect of the yield and purity of the end product and in respect of simple, reliable and economical operation, particularly on an industrial scale.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14]#[N:15])[N:9]=1)[C:2]([NH2:4])=[NH:3].Cl.[CH3:17][OH:18]>C(Cl)(Cl)Cl>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14](=[NH:15])[O:18][CH3:17])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CO
Reactant: N#CCCSCc1csc(NC(=N)N)n1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=N)CCSCc1csc(NC(=N)N)n1
Temperature: 2 °C
Reaction time: 20 h

Procedure:
3-(2-Guanidino-4-thiazolylmethylthio)propionitrile (12.82 g) was dissolved in a mixture of dry methanol (75 ml) and dry chloroform (150 ml) and the stirred solution was cooled (under nitrogen) in an ice-salt bath to 2° C. Hydrogen chloride gas (dried) was passed through the solution for three hours, keeping the temperature at 0°-10° C. The solution was then allowed to stand in a stoppered flask at ca 0° C. for 20 hours. The solvents were removed at reduced pressure and the oily residue added to ice-water (200 ml) containing potassium carbonate (30 g). The mixture was extracted with chloroform containing 20% methanol (4×150 ml) and the combined organic extracts were dried (MgSO4). The solvent was removed to give methyl 3-(2-guanidino-4thiazolylmethylthio)propionimidate (13.60 g) as a tacky light-brown oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12]>ClCCl>[Br:1][C:15]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10]([F:9])[CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccccc1F
Solvent: ClCCl
Product: Nc1ccc(Br)cc1F
Temperature: 0 °C
Yield: 105.3 %

Procedure:
N-Bromosuccinimide (160.4 g, 0.90 mol) was added in small portions to a stirred, cooled solution of 2-fluoroaniline (100.0 g, 0.90 mol) in dry dichloromethane (400 ml). The stirred mixture was allowed to warm to 0° C. over 45 min, washed with water and dried (MgSO4). The solvent was removed in vacuo to yield a red solid (180 g) which was steam distilled to give a colourless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[C:3]=1[OH:10].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([O:10][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[C:4]([Br:9])[CH:5]=1
Reactant: Oc1c(Br)cc(Br)cc1Br
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2c(Br)cc(Br)cc2Br)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 2,4,6-tribromophenol (3.8 g), 4-fluoronitrobenzene (1:6 g), cesium carbonate (3.7 g) in dimethylformamide (8 mL) was heated at reflux until the starting materials were consumed. The reaction was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate and washed with sodium hydroxide (2 N), hydrochloric acid (2 N) and brine. Concentration of the organic phase gave 1,3,5-tribromo-4-(4-nitrophenoxy)benzene in quantitative yield. The crude product was used directly in the next step.
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([OH:24])=[C:10]2[C:22]([CH3:23])=[N:21][S:20][C:11]2=[C:12]([C:14]#[C:15][Si](C)(C)C)[N:13]=1)=[O:7])CCC.[NH2:25][CH2:26][C:27]([OH:29])=[O:28]>>[C:14]([C:12]1[N:13]=[C:8]([C:6]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:7])[C:9]([OH:24])=[C:10]2[C:22]([CH3:23])=[N:21][S:20][C:11]=12)#[CH:15]
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#C[Si](C)(C)C)c2snc(C)c2c1O
Product: C#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(C)nsc12

Procedure:
The title compound was synthesized in analogy Example 1 from 4-hydroxy-3-methyl-7-trimethylsilanylethynyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester and glycine: MS (m/z) 290.1 (M−1).
Reaction SMILES: [CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:17][C:18]1[CH:26]=[C:22]([C:23]([OH:25])=[O:24])[C:21]([OH:27])=[CH:20][CH:19]=1>C(O)(=O)C>[C:23]([C:22]1[CH:26]=[C:18]([N:17]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[CH:1]=[C:2]2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:19]=[CH:20][C:21]=1[OH:27])([OH:25])=[O:24]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C(CC1CCCCC1=O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCCC3)ccc1O

Procedure:
A solution of 49.7 g. (0.23 mole) of 2-phenacylcyclohexanone, 35.2 g. (0.23 mole) of 5-aminosalicylic acid, and 135 ml. of glacial acetic acid was heated under reflux under nitrogen for 31/2 hours. A solid separated and was collected, washed with water, and recrystallized from acetic acid to provide 46.0 g. (60%) of pale yellow crystals, m.p. 209°-211°.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[CH:5][CH2:4][CH2:3]1>CCOC(C)=O.[Pd]>[CH3:1][C:2]1([CH3:25])[CH2:3][CH2:4][CH2:5][CH:6]1[C:7]1[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:8]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1
Reactant: COC(=O)c1ccc(-c2cccc(OC)c2)c(C2=CCCC2(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cccc(OC)c2)c(C2CCCC2(C)C)c1
Reaction time: 19 h
Yield: 98.5 %

Procedure:
To a stirred solution of 78.5A (0.50 g, 1.5 mmol) in EtOAc (2.00 mL) at 23° C. was added palladium on carbon (0.16 g, 1.5 mmol). The reaction was placed under an atmosphere of hydrogen and stirred for 19 hours. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The product was purified on silica gel (0-10% EtOAc in hexanes) to yield 78.5B as a colorless oil (0.50 g, 99% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9](=[O:17])[N:10]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:11][C:3]=12.Cl.Cl.[CH2:20]([C:22]1[N:23]=[C:24]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[N:25]([CH2:27][CH2:28][OH:29])[CH:26]=1)[CH3:21].C(N(C(C)C)CC)(C)C>CO>[CH2:20]([C:22]1[N:23]=[C:24]([CH:30]2[CH2:31][CH2:32][N:33]([C:2]3[N:7]=[CH:6][N:5]=[C:4]4[NH:8][C:9](=[O:17])[N:10]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:11][C:3]=34)[CH2:34][CH2:35]2)[N:25]([CH2:27][CH2:28][OH:29])[CH:26]=1)[CH3:21]
Reactant: CCc1cn(CCO)c(C2CCNCC2)n1
Reactant: O=C1Nc2ncnc(Cl)c2CN1CC(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCc1cn(CCO)c(C2CCN(c3ncnc4c3CN(CC(F)(F)F)C(=O)N4)CC2)n1
Temperature: 150 °C
Yield: 140.7 %

Procedure:
Add 5-chloro-3-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.28 g, 1.05 mmol), 2-(4-ethyl-2-(piperidin-4-yl)-1H-imidazol-1-yl)ethanol dihydrochloride (0.38 g, 1.3 eq), methanol (15 mL) and diisopropylethylamine (0.91 mL, 5.0 eq) into a 20 mL microwave vial. Seal the tube and heat in a microwave reactor to 150° C., for 1 hour. Filter through silica gel, eluting with 10% ammonia-methanol/dichloromethane. Concentrate the filtrate in vacuo. Purify by silica gel chromatography, eluting with 3:1 ethyl acetate/methanol, to give the title compound as a yellow foam (0.67 g, 70%). MS (ES) m/z=454 [M]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].[CH2:12](I)[CH3:13]>CN(C=O)C>[CH2:12]([N:2]1[CH:3]=[C:4]2[C:9]([CH:8]=[CH:7][CH:6]=[CH:5]2)=[N:1]1)[CH3:13]
Reactant: c1ccc2[nH]ncc2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 30.5 %

Procedure:
To a solution of indazole (6.2 g, 52.5 mmol) in DMF (30 mL) was added sodium hydride (60% dispersion in mineral oil, 3.0 g, 75.0 mmol) at 0° C. After stirring at 0° C. for 20 min., ethyl iodide (5 mL, 62.5 mmol) was added dropwise at 0° C. The mixture was stirred at rt for 1 h, and then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3×). The combined organic phases were washed with brine, and dried over anhydrous magnesium sulfate. TLC indicated that a 2:1 mixture of two isomers was formed. The mixture was purified by flash chromatography (hexanes:ethyl acetate=4:1, then 1:1) to give 2.34 g of the title compound as a viscous oil (slow moving isomer).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C=O)C.C(OCC)(=O)C>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C

Procedure:
To a stirred solution of tert-butyl 4-(2-hydroxyphenyl)-piperazine 20 (1 g, 0.0035 mol.) and cesium carbonate (2.34 g, 0.0071 mol.) in 5 mL of DMF anhydrous was added a solution of ethyl 4-bromobutanoate (6a) at rt. The resulting mixture was heated at 70° C. overnight (12 h). The progress of the reaction was monitored by thin layer chromatography (TLC). After the reaction was complete, the reaction mixture was diluted with 25 mL of ethyl acetate and filtered to remove cesium carbonate. The filtrate was washed with saturated aqueous NaHCO3 solution, dried over Na2SO4 and evaporated to give tert-butyl 4-(2-(4-ethoxy-4-oxobutoxy)phenyl)-piperazine-1carboxylate 21a which was purified by silica gel chromatography using a gradient elution of ethyl acetate and hexane. Colorless oil (1.1 g, 78%). 1H NMR (400 MHz, CDCl3): δ 1.25 (t, J=6.4 Hz, 3H); 1.45 (s, 9H); 2.14 (q, J=7.2 Hz, 2H); 2.53 (t, J=7.2Hz, 2H); 3.00 (br s, 4H); 3.58 (br s, 4H); 4.04 (t, J=6.4 Hz, 2H); 4.12 (q, J=6.4 Hz, 2H); 6.84-6.97 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[C:5]([C:15](N(OC)C)=[O:16])[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=1)#[N:2].O1CCC[CH2:30]1.C[Li]>C(OCC)C>[C:15]([C:5]1[S:6][C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=2)=[C:3]([C:1]#[N:2])[C:4]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28])(=[O:16])[CH3:30]
Reactant: CON(C)C(=O)c1sc(-c2ccnc(F)c2)c(C#N)c1-c1ccc(Cl)cc1Cl
Reactant: C1CCOC1
Agent: [Li]C
Solvent: CCOCC
Product: CC(=O)c1sc(-c2ccnc(F)c2)c(C#N)c1-c1ccc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a flame dried flask were placed 4-cyano-3-(2,4-dichlorophenyl)-5-(2-fluoropyridin-4-yl)-N-methoxy-N-methylthiophene-2-carboxamide (1.45 g, 3.32 mmol) and tetrahydrofuran (90 mL, 1000 mmol) under argon. The solution was cooled to −78° C. and Methyllithium (4.653 mmol, 4.653 mmol) in diethylether (1.6M) solution was added. After addition, the mixture was kept at this temperature for 30 min. The mixture was quenched by ammonium chloride solution. The mixture was extracted with EtOAc and the organic layer was collected and dried over Na2SO4. The solvent was evaporated and the residue was purified using column chromatography. The title compound was collected as a white solid (0.93 g, 71.5%). LCMS: (FA) ES+ 391, 393. 1H NMR (400 MHz, d1-chloroform) δ: 8.43 (1H, d, J=5.28 Hz), 7.67-7.62 (2H, m), 7.48 (1H, dd, J=8.24, 2.01 Hz), 7.38 (1H, s), 7.35 (1H, d, J=8.24 Hz), 2.13 (3H, s)