Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[S:18])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:21][CH2:22][C:23](=O)[CH2:24]Cl>O1CCOCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:18][CH:24]=[C:23]([CH2:22][Cl:21])[N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)CCl
Reactant: CN1Cc2c(C(N)=S)ncn2-c2cccc(Cl)c2C1=O
Solvent: C1COCCO1
Product: CN1Cc2c(-c3nc(CCl)cs3)ncn2-c2cccc(Cl)c2C1=O
Yield: 87.1 %

Procedure:
A yellow suspension of 10.3 g (0.0336 mol) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-thiocarboxamide in 220 ml of dioxan was treated with 4.69 g (0.0370 mol) of 1,3-dichloro-2-propanone. The solution was boiled at reflux for 16 hrs., cooled and suction filtered. There were obtained 11.1 g (87%) of 7-chloro-3-(4-chloromethyl-thiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as brown crystals. An analytical sample was recrystallized from hot acetonitrile. White crystals; m.p. 277°-279°.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:15]([O:32][CH3:33])=[C:16]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([NH2:30])=[O:29])=[C:24]([F:31])[CH:23]=2)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:20][C:18]1[C:17]([CH3:21])=[C:16]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([NH2:30])=[O:29])=[C:24]([F:31])[CH:23]=2)[C:15]([O:32][CH3:33])=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:19]=1
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1-c1ccc(C(N)=O)c(F)c1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1-c1ccc(C(N)=O)c(F)c1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (13 mg, 0.065 mmol), 3′-(1-aminoethyl)-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxamide (20 mg, 0.06 mmol), and N,N-diisopropylethylamine (0.021 mL, 0.12 mmol) in isopropyl alcohol (0.2 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C22H21ClFN6O2 (M+H)+: m/z=455.1. found: 455.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)=O.[BH4-].[Na+].C(O)(=[O:27])C>C(O)CC>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:27])[CH2:10][CH2:11][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1
Reactant: COc1ccc(C(=O)C=Cc2ccc(O)cc2O)cc1OC
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCO
Product: COc1ccc(CCC(O)c2ccc(O)cc2O)cc1OC
Temperature: 80 °C

Procedure:
2,4-Dihydroxy-3′,4′-dimethoxychalcone (4) (40 mg) was dissolved in 1-propanol (5 ml), followed by the addition of sodium borohydride (15 mg) and the mixture was allowed to react at room temperature for 2 hours. Upon completion of the reaction, 20% acetic acid (0.2 ml) was added and the mixture was heated at 80° C. for 5 minutes and cooled down. The mixture was then separated on a pre-packed C18 column eluting with a MeOH/H2O gradient to provide 1-(2,4-dihydroxyphenyl)-3-(3,4-dimethoxyphenyl)-1-propanol (5). The structure of compound (5) was confirmed by MS, UV spectroscopy, 1D and 2D 1H-NMR.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:15][N:14]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([O:21]CC)=[O:20])[CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].O>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:15][N:14]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([OH:21])=[O:20])[CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cccc(N2CC(NC(=O)c3nc(Cl)c(CC)[nH]3)C2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1[nH]c(C(=O)NC2CN(c3cccc(C(=O)O)c3)C2)nc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 13 %

Procedure:
Ethyl 3-(3-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}azetidin-1-yl)benzoate obtained in Example (223c) (84 mg, 0.22 mmol) was dissolved in methanol (2 mL). A 2 N aqueous lithium hydroxide solution (1.11 mL, 2.23 mmol) was added, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction solution, and then the mixture was washed with ethyl acetate. A 1 N aqueous hydrochloric acid solution was added to the aqueous layer, followed by extraction with a chloroform/methanol mixed solvent. The combined organic layers were dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The resulting solid was suspended and washed in diethyl ether to obtain 10 mg of the title compound as a white solid (13%).
Reaction SMILES: [CH3:1][N:2]1[CH2:28][CH2:27][C:5]2[N:6]([CH2:14][CH:15](OS(C)(=O)=O)[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:29]1([NH2:33])[CH2:32][CH2:31][CH2:30]1>O>[CH:29]1([NH:33][CH:15]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)[CH2:14][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:28][CH2:27][C:5]2=3)[CH2:32][CH2:31][CH2:30]1
Reactant: NC1CCC1
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccncc2)CCN(C)C1
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(NC2CCC2)c2ccncc2)CCN(C)C1
Temperature: 100 °C

Procedure:
Methanesulfonicacid2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethylester (300 mg, 0.75 mmol) was dissolved in 70% cyclobutylamine in water (6 mL) and heated at 100° C. for 18 h. The reaction mixture was concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtained 90 mg of cyclobutyl-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethyl]-amine as the TFA salt.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]2N=N[N:11]=[C:7]2[C:6]([CH2:12][CH:13]=[C:14]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[Cl:23])[CH3:15])=[C:5]([CH3:24])[N:4]=1.O>C(O)(=O)C.[Zn]>[NH2:2][C:3]1[N:8]=[C:7]([NH2:11])[C:6]([CH2:12][CH:13]=[C:14]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[Cl:23])[CH3:15])=[C:5]([CH3:24])[N:4]=1
Reactant: CC(=CCc1c(C)nc(N)n2nnnc12)c1cc(Cl)ccc1Cl
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CC(=CCc1c(C)nc(N)nc1N)c1cc(Cl)ccc1Cl
Temperature: 80 °C
Reaction time: 18 h
Yield: 30.9 %

Procedure:
Zinc is activated by treating 2.5 grams (excess) of it with aqueous 10% hydrochloric acid for two minutes. The activated zinc is collected by filtration, washed with water then acetone, and dried in a vacuum oven for one hour. A solution of 1.5 grams (0.004 mole) of 5-amino-7-methyl-8-[3-(2,5-dichlorophenyl)-2-butenyl]tetrazolo[1,5-c]pyrimidine in 35 mL of acetic acid is stirred, and the activated zinc is added portionwise during a 20 minute period. Upon completion of addition, the reaction mixture is warmed to about 80° C. where it is stirred for about 18 hours. After this time, the reaction mixture is stirred with 50 mL of water. The mixture is then extracted with three 30 mL portions of methylene chloride. The combined extracts are washed with two 10 mL portions of an aqueous solution saturated with sodium bicarbonate. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel; using 15% methanol in methylene chloride as the eluant. The product-containing fractions are combined and concentrated under reduced pressure, yielding 0.4 gram of 2,4-diamino-6-methyl-5-[3-(2,5-dichlorophenyl)-2-butenyl]pyrimidine; mp 172°-174° C. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CS(O[CH2:20][C@H:21]1[CH2:26][O:25][CH2:24][CH2:23][O:22]1)(=O)=O>CN(C)C=O.C(OCC)C>[CH2:7]([O:6][C:5](=[O:14])[N:4]([CH2:20][C@H:21]1[CH2:26][O:25][CH2:24][CH2:23][O:22]1)[CH3:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CNC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)OC[C@H]1COCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C[C@H]1COCCO1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (29 mg, 0.74 mmol) was suspended in 2 mL of N,N-dimethylformamide (DMF) and cooled to 0° C. A solution of benzyl methylcarbamate (81 mg, 0.49 mmol) in 2 mL of DMF was added via syringe. After 20 minutes, a solution of (2R)-1,4-dioxan-2-ylmethyl methanesulfonate (191 mg, 0.97 mmol) in 2 mL of DMF was added by syringe and the mixture was heated to 70° C. After 2 h the mixture was cooled to ambient temperature, then diluted in diethyl ether, washed with water and brine, then dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (silica, ethylacetate/hexanes) to afford the title compound. LRMS (APCI) calc'd for (C14H20NO4) [M+H]+, 266.1; found, 266.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CC=CC=1.[CH3:19][C:20](Cl)=[O:21].Cl>C(Cl)Cl.CN(C1C=CC=CN=1)C>[C:20]([O:12][CH2:11][CH:10]=[CH:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:21])[CH3:19]
Reactant: OCC=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCC=Cc1ccc(Cl)c(Cl)c1
Temperature: 23 °C
Yield: 96.8 %

Procedure:
Treat a solution of the product of step 2 (13.2 g, 65 mmol) in CH2Cl2 (250 mL) at 0° C. with pyridine (7.89 mL, 97.5 mmol, 1.5 eq) and dimethylaminopyridine (397 mg, 3.25 0.05 eq), followed by CH3COCl (6.48 mL, 74.75 mmol, 1.1 5 eq). Allow the mixture to warm to 23° C., pour into 1M HCl (100 mL) and wash the resulting organic layer again with 1M HCl (100 mL), followed by water (5×100 mL; pH=6.5-7). Dry the organic layer (Na2SO4) and concentrate to obtain 15.4 g (62.9 mmol, 97%) of 3-(3,4-dichlorophenyl)-2-propene-1-ol acetate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:23]2[O:22][C:9]3[C:10](=[O:21])[N:11]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14](O)=[O:15])[CH2:12][C:8]=3[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:24][C:25]1[S:26][CH:27]=[CH:28][N:29]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[S:26]1[CH:27]=[CH:28][N:29]=[C:25]1[NH:24][C:14](=[O:15])[C@@H:13]([N:11]1[CH2:12][C:8]2[CH2:7][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:23]=3[O:22][C:9]=2[C:10]1=[O:21])[CH2:17][CH:18]([CH3:19])[CH3:20]
Reactant: Nc1nccs1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC2=C(Oc3c(Cl)cccc3C2)C1=O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@@H](C(=O)Nc1nccs1)N1CC2=C(Oc3c(Cl)cccc3C2)C1=O
Yield: 99.1 %

Procedure:
A solution of (S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (130 mg, 0.35 mmol) (Example 22, Step 1c), commercially available 2-aminothiazole (47 mg, 0.36 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (82 mg, 0.43 mmol), and N-hydroxybenzotriazole (HOBt) (57 mg, 0.43 mmol) in methylene chloride (15 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded (S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid thiazol-2-ylamide (145 mg, 58.2%), as a white solid. 1H NMR (DMSO-d6) δ: 12.57 (s, 1H), 7.50 (d, J=3.4 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.20-7.29 (m, 2H), 7.08-7.16 (m, 1H), 5.05 (dd, J=10.8, 4.4 Hz, 1H), 4.39 (d, J=19.1 Hz, 1H), 4.09 (d, J=19.1 Hz, 1H), 3.75-3.91 (m, 2H), 1.80-1.93 (m, 1H), 1.62-1.75 (m, 1H), 1.46 (br. s., 1H), 0.94 (t, J=6.6 Hz, 6H).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH2:16][CH2:17][CH3:18])[C:6]=2[O:5][C:4]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:3]1)[NH:13][C:12]([C:19]([O:21][CH3:22])=[O:20])=[CH:11][C:10]3=O.[C:29]1([CH3:41])[CH:34]=[CH:33][C:32]([S:35]([N:38]=C=O)(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClC(Cl)C>[CH3:22][O:21][C:19]([C:12]1[CH:11]=[C:10]([NH:38][S:35]([C:32]2[CH:33]=[CH:34][C:29]([CH3:41])=[CH:30][CH:31]=2)(=[O:36])=[O:37])[C:9]2[C:14](=[C:15]([CH2:16][CH2:17][CH3:18])[C:6]3[O:5][C:4]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:3][C:2](=[O:1])[C:7]=3[CH:8]=2)[N:13]=1)=[O:20]
Reactant: CCCc1c2[nH]c(C(=O)OC)cc(=O)c2cc2c(=O)cc(C(=O)OCC)oc12
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: CC(Cl)Cl
Product: CCCc1c2nc(C(=O)OC)cc(NS(=O)(=O)c3ccc(C)cc3)c2cc2c(=O)cc(C(=O)OCC)oc12

Procedure:
Ethyl 6,9-dihydro-4,6-dioxo-8-methoxycarbonyl-10-propyl-4Hpyrano[3,2-g]quinoline-2-carboxylate (38.5 g, 0.1 mol) was suspended in dichloroethane (200 ml) and 4-toluene-sulphonyl isocyanate (15.1 ml; 0.1 mol) added at room temperature. The whole was then refluxed for 16 hours, allowed to cool, and filtered, to give the sub-title compound as brillant yellow cubes, 44.0 g (82%), m.p. 219° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[C:23](=[O:25])[CH3:24].[CH2:26](I)[CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:26][CH2:27][CH3:28])=[CH:18][C:17]=1[C:23](=[O:25])[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(O)cc3C(C)=O)c2cc1OC
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-hydroxy-phenyl]-ethanone (compound 176) (75 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Propyl iodide (113 mg) and potassium carbonate (153 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (22 mg, yield 26%).
Reaction SMILES: [CH3:1][C:2]1[C:6](=[CH:7][NH2:8])[C:5](=[O:9])[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.FC(F)(F)C(O)=O.[CH2:23]([O:26][C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1N)[CH2:24][CH3:25]>C(O)C>[CH3:1][C:2]1[C:6](=[CH:7][NH:8][C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[O:26][CH2:23][CH2:24][CH3:25])[C:5](=[O:9])[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: CC1=NN(c2ccccc2)C(=O)C1=CN
Reactant: CCCOc1ccccc1N
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1ccccc1NC=C1C(=O)N(c2ccccc2)N=C1C

Procedure:
2 g of 3-methyl-4-aminomethylene-1-phenyl-4,5-dihydro-5-pyrazolone and 1.6 g of 2-propoxyaniline trifluoroacetate are added to ethanol and boiled under reflux for 1.5 hours. The reaction solution is concentrated. The reaction product is then separated by chromatography on silica gel using a solvent mixture consisting of methyl butyl ketone/hexane 4:1 as eluent and is recrystallized from a methyl butyl ketone/hexane mixture.
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)[CH:8]=1)[C:3](=[O:6])[CH2:4][CH3:5].[CH3:20][NH:21][C:22](=S)[NH:23][NH2:24]>C(O)C>[CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]3[N:15]([C:22]([NH:21][CH3:20])=[N:23][N:24]=3)[N:14]=2)[CH:8]=1)[C:3](=[O:6])[CH2:4][CH3:5]
Reactant: CCC(=O)N(C)c1cccc(-c2ccc(Cl)nn2)c1
Reactant: CNC(=S)NN
Solvent: CCO
Product: CCC(=O)N(C)c1cccc(-c2ccc3nnc(NC)n3n2)c1
Yield: 16 %

Procedure:
A solution of 5.0 g of N-methyl-N-[3-(6-chloro-3-pyridazinyl)phenyl]propanamide and 3.8 g 4-methylthiosemicarbazide in 200 ml ethanol was refluxed for 18 hours. The mixture was then treated and the product chromatographed as described in Example 70. Recrystallization of the product from dichloromethane-hexane afforded 0.9 g yellow powder, mp 212°-213° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[S:38](=[O:40])(=[O:39])[NH:37][C:36](=[O:41])[CH2:35]5)=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:42]4[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]4)=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[N:16]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[S:38](=[O:40])(=[O:39])[NH:37][C:36](=[O:41])[CH2:35]3)=[CH:30][CH:29]=2)[CH:17]=1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cc4)cc3)cc2)S(=O)(=O)N1
Reactant: C1CNCCN1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N5CCNCC5)cc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{4-[2-(4′-Bromo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (268 mg, 0.4 mmol) was treated as described in general procedure R using excess piperazine (346 mg, 4 mmol) to give the desired compound 5-{4-[4-(2,4-dichloro-phenyl)-2-(4′-piperazin-1-yl-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])[CH3:2].[H-].[Na+].[Br:11][C:12]1[C:13]([C:24]([P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])([F:26])[F:25])=[CH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([CH2:22]Br)[CH:16]=2>C1(C)C=CC=CC=1>[CH2:1]([O:3][P:4]([CH2:22][C:17]1[CH:18]=[CH:19][C:20]2[C:15](=[CH:14][C:13]([C:24]([P:27]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:34])([F:26])[F:25])=[C:12]([Br:11])[CH:21]=2)[CH:16]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP([O-])OCC
Reactant: CCOP(=O)(OCC)C(F)(F)c1cc2cc(CBr)ccc2cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ccc2cc(Br)c(C(F)(F)P(=O)(OCC)OCC)cc2c1)OCC
Reaction time: 1 h

Procedure:
To a solution of diethylphosphite (0.22 mL) in toluene (5 mL) at 0° C. was added NaH (60% in mineral oil, 20 mg). The reaction mixture was stirred for 1 hour and then a solution of diethyl [3-bromo-7-(bromomethyl)-2-naphthyl](difluoro)methylphosphonate (220 mg) in toluene (2 mL) was added dropwise. The reaction was stirred for 1 h at 0° C., quenched with a solution of saturated NH4Cl, extracted with EtOAc and dried over Na2SO4. The organic extracts were evaporated to dryness and the residue was purified by flash chromatography eluting with 50% EtOAc/hexanes to afford the titled compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[F:21])[NH:17][C:16]([C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH2:28])[CH:27]=1)=[CH:15]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[F:21])[NH:17][C:16]([C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH:28][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:1]#[N:2])[CH:4]=3)[CH:27]=1)=[CH:15]2
Reactant: N#Cc1cccc(C=O)c1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
3-Cyanobenzaldehyde (0.262 g, 2.0 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.548 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.46 g, 2.0 mmol) was added in one portion, and the resulting homogeneous solution stirred at room temperature for 3 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture stirred for 2 hours. The mixture was shaken, the organic layer separated and dried over Na2S4. The solvent was evaporated to give a white solid. Recrystallization from methanol gave the product (500 mg), mp 154-155° C.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[CH:10]=[CH:11][C:12]([F:21])=[C:13]([CH:20]=3)[C:14]([O:16]C(C)C)=[O:15])[CH:8]=2)[CH2:3][CH2:2]1>Cl>[CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[CH:10]=[CH:11][C:12]([F:21])=[C:13]([CH:20]=3)[C:14]([OH:16])=[O:15])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: CC(C)OC(=O)c1cc(-n2cnc(C3CC3)c2)ccc1F
Agent: Cl
Product: O=C(O)c1cc(-n2cnc(C3CC3)c2)ccc1F
Yield: 100 %

Procedure:
A solution of isopropyl 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluorobenzoate (0.306 g, 1.06 mmol) in 2N hydrochloric acid (10 ml) was heated to 100° C. for 10 hours. The solvent was removed under reduced pressure to afford 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluorobenzoic acid as the hydrochloride salt, as a brown powder. (0.260 g, 1.06 mmol). 100% yield. 247 (M+1).
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[C:8]=2[C:7]([CH:17]=[O:18])=[CH:6][CH:5]=1.S(=O)(=O)([OH:22])N.Cl([O-])=O.[Na+]>CC(C)=O.O>[F:19][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[C:8]=2[C:7]([C:17]([OH:22])=[O:18])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OC(F)F)c2oc3ccncc3c12
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(OC(F)F)c2oc3ccncc3c12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
To a well stirred solution of 6-(difluoromethoxy)[1]benzofuro[3,2-c]pyridine-9-carbaldehyde (500 mg, 1.90 mmol) in acetone (10 mL) was added sulphamic acid (276 mg, 2.85 mmol) at about 10° C. followed by drop wise addition of a solution of sodium chlorite (240 mg, 2.66 mmol) in water (5 mL) at about 0 to 5° C. The mixture was then stirred for about 1-2 hours. Ice cold water (50 mL) was added and the mixture was stirred for about 30 hours. The solid which separated was filtered, washed with water (3×5 mL) and dried at about 60-70° C. to give 6-(difluoromethoxy)[1]benzofuro[3,2-c]pyridine-9-carboxylic acid as a white solid.