Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:16])([O:3][C@@H:4]([C@H:6]([O:12][N+:13]([O-:15])=[O:14])[CH:7]([CH3:11])[CH2:8][CH2:9][OH:10])[CH3:5])=[O:2].Cl[C:18]([O:20][CH:21]([Cl:23])[CH3:22])=[O:19].N1C=CC=CC=1>C(Cl)Cl>[C:18](=[O:19])([O:20][CH:21]([Cl:23])[CH3:22])[O:10][CH2:9][CH2:8][CH:7]([CH3:11])[C@@H:6]([O:12][N+:13]([O-:15])=[O:14])[C@H:4]([O:3][N+:1]([O-:16])=[O:2])[CH3:5]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CC(CCO)[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Cl)OC(=O)OCCC(C)[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2R,3R)-6-hydroxy-4-methylhexane-2,3-diyl dinitrate (Intermediate 2, 0.78 g, 3.26 mmol) in CH2Cl2 (15 mL) cooled at 0° C., 1-chloroethyl chloroformate (0.355 mL, 3.26 mmol) was added. Then a solution of Pyridine (0.263 mL, 3.26 mmol) was added dropwise. The solution was stirred at room temperature overnight. Then it was diluted with CH2Cl2 (25 mL) and washed with HCl 1 N (2×15 mL), a saturated solution of NaHCO3 (15 mL) and brine. The organic layer was dried over Na2SO4 and concentrated affording the title compound as colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[C:6]2[C:5]=1Cl)(=[O:3])[NH2:2].CC[N:21]([CH:25]([CH3:27])[CH3:26])C(C)C.O.CN1C(=O)C[CH2:32][CH2:31]1>>[C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[C:6]2[C:5]=1[NH:21][C@@H:25]([CH:26]1[CH2:32][CH2:31]1)[CH3:27])(=[O:3])[NH2:2]
Reactant: CCOC(=O)c1cc2c(Cl)c(C(N)=O)cnn2c1
Reactant: CN1CCCC1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1cc2c(N[C@H](C)C3CC3)c(C(N)=O)cnn2c1
Reaction time: 0.17 h
Yield: 86 %

Procedure:
A solution of ethyl 3-carbamoyl-4-chloropyrrolo[1,2-b]pyridazine-6-carboxylate (1.0 g, 3.74 mmol), (R)-1-cyclopropylethanamine, HCl (0.500 g, 4.11 mmol) and DIPEA (1.468 mL, 8.41 mmol) in NMP (Volume: 5 mL) was heated to 100° C. for 4 hr. The reaction mixture was added 30 mL of water and stirred for 10 minutes. The solid was collected as the desired product (1.1 g, 86% yield). 1H NMR (400 MHz, CD3OD) δ 8.22 (s, 1H), 8.03 (d, J=1.8 Hz, 1H), 7.34 (d, J=1.8 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 4.08-3.96 (m, 1H), 1.46 (d, J=6.4 Hz, 3H), 1.41 (t, J=7.2 Hz, 3H), 1.22-1.12 (m, 1H), 0.62 (dd, J=10.9, 8.3 Hz, 2H), 0.43-0.36 (m, 2H). MS (ES+) m/z: 317.1 (M+H); HPLC: 92.6%, retention time: 3.080 min (analytical HPLC Method Q).
Reaction SMILES: [H-].[Na+].[N:3]1([C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:7]([CH3:8])[C:5]1=[O:6])[CH3:4].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27].O>CS(C)=O>[CH2:27]([N:12]1[C:13]2[C:14](=[O:15])[N:3]([CH3:4])[C:5](=[O:6])[N:7]([CH3:8])[C:9]=2[N:10]=[CH:11]1)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=[CH2:17]
Reactant: C=CCCCCCCCCCBr
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCCCCCn1cnc2c1c(=O)n(C)c(=O)n2C
Reaction time: 0.33 h
Yield: 94.2 %

Procedure:
This example illustrates a synthesis of 7-(11,10-Oxidondecyl)-1,3-dimethylxanthine (inventive compound no. 1423). Sodium hydride (95%) (0.575 g, 24 mmol) was added to a solution of theophylline (3.6 g, 20 mmol) in dimethylsulfoxide (100 mL). After 20 minutes of stirring, 1-bromoundec-10-ene (4.66 g, 20 mmol) was added and stirred for 12 hours at room temperature. The reaction mixture was then poured into a separatory funnel containing water (300 mL) and extracted with dichloromethane (5×100 mL). The organic extracts were combined, washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 50% hexane/ethyl acetate eluant, yielding 6.26 g (94% yield) of 7-(10-undecenyl)-1,3-dimethylxanthine (inventive compound no. 1420).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:21]=[N:22][C:23]([O:29][CH2:30][CH3:31])=[CH:24][C:25]=3[O:26][CH2:27][CH3:28])=[N:9]2)=[CH:4][CH:3]=1.[C:32](Cl)([Cl:34])=[O:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:32]([Cl:34])=[O:33])[C:10]([C:20]3[CH:21]=[N:22][C:23]([O:29][CH2:30][CH3:31])=[CH:24][C:25]=3[O:26][CH2:27][CH3:28])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(OCC)c(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2)cn1
Product: CCOc1cc(OCC)c(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)cn1

Procedure:
Using the procedure as described in example 1, cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4,6-diethoxy-pyridin-3-yl)-4,5-dihydro-1H-imidazole was reacted with phosgene to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4,6-diethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1-carbonyl chloride. The carbonyl chloride was then coupled with 2-piperazinone (Alfa) to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4,6-diethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one hydrochloride.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11](=O)[C:12](=[N:15][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]#[N:14])[CH2:6][CH2:5]O[CH2:3][CH2:2]1.[OH2:24].[NH2:25][NH2:26].O>CCOCC.C1COCC1>[N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[C:12](=[N:15][NH:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:13]([NH2:14])=[N:25][N:26]=2)[CH2:6][CH2:5][O:24][CH2:3][CH2:2]1
Reactant: NN
Reactant: N#CC(=NNc1ccccc1)C(=O)CCCCN1CCOCC1
Reactant: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC1=NN=C(CCCCN2CCOCC2)C1=NNc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
The powder of 7-morpholin-4-yl-3-oxo-2-(phenylhydrazono)-heptanenitrile (510 mg, 1.6 mmole) and hydrazine hydrate (3.2 mmole) were suspended in 20 mL of ether:THF (1:1) and stirred at ambient temperature overnight. Water was added to the reaction and the mixture was extracted with ethyl acetate. The organic extracts were washed with saline. The volume of the organic solution was reduced which resulted in the precipitation of a yellow solid. The solution was filtered to yield 270 mg (51%) of the title compound as a yellow powder. MS (m/z, ES+): 329 (M+1, 100%); 1H NMR (ppm, 300 MHz, DMSO-d6) δ 11.58 (br s, 1H), 7.66 (m, 2H), 7.44 (m, 2H), 7.30 (m, 1H), 6.98 (br s, 2H), 3.51 (m, 4H), 2.79 (m, 2H), 2.20-2.33 (m, 5H), 1.72 (m, 2H), 1.47 (m, 2H).
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[NH2:7][S:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[N:12]([CH3:20])[C:11]=1[C:21]([O:23]CC)=O)=[O:9]>O.CC(C)=O>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]2[N:12]([CH3:20])[C:11]3[C:21](=[O:23])[NH:7][S:8](=[O:9])(=[O:2])[C:10]=3[C:18]=2[CH:17]=1
Reactant: CCOC(=O)c1c(S(N)=O)c2cc(Cl)ccc2n1C
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cn1c2c(c3cc(Cl)ccc31)S(=O)(=O)NC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 15.8 gm (0.1 mols) of potassium permanganate in 300 ml of water was added dropwise over a period of 2.5 hours to a solution of 37.6 gm (0.125 mols) of ethyl 3-aminosulfinyl-5-chloro-1-methyl-indole-2-carboxylate in 2500 ml of acetone at 20° C. After stirring overnight at room temperature, the precipitate which had formed was filtered off and washed with warm water and acetone. The filtrate then was evaporated in vacuo at 25°-30° C. to a volume of about 350 ml. The crystallized product, ethyl 5-chloro-1-methyl-3-sulfamoyl-indole-2-carboxylate, was filtered off, washed with water and dried. Yield: 30.5 gm (77% of theory); M.p.: 207°-208° C. After acidification of the filtrate to pH 3, another product, 7-chloro-4-methyl-2H-isothiazolo[4,5-b]indole-3-(4H)-one-1,1-dioxide, was obtained, which was filtered off, washed with water and dried. Yield: 3.9 gm (12% of theory); M.p.: 288° C. (decomposition).
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[N:4]1.[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][N:3]([CH2:2][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20])[N:4]=1
Reactant: FC(F)(F)c1ccn(CCl)n1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1ccc(C(F)(F)F)n1
Yield: 35.9 %

Procedure:
1.44 g of 1-(chloromethyl)-3-(trifluoromethyl)-1H-pyrazole and 1.30 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 16 ml of N,N-dimethylformamide. 2.21 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain 0.87 g of {[3-(trifluoromethyl)-1H-pyrazole-1-yl]methyl}(3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (6), hereinafter) shown by below formula.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:24][OH:25].[OH2:26]>>[OH:25][C@H:24]1[CH2:2][CH2:1][N:4]([C:21]2[N:20]=[CH:19][C:16]3[C:17]4[N:11]([CH:10]=[C:9]([C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=5)[N:18]=4)[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[C@@H:8]1[C:9]([NH2:18])=[O:26]
Reactant: CO
Reactant: O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CC[C@H](O)[C@H]3C(N)=O)cc1OCC2
Yield: 39 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and 3-trans-hydroxy-L-prolinamide were reacted and the crude product subjected to RPHPLC (C18 column, gradient 15 to 55% methanol in water+0.1% HCO2H) to give 398 as a white powder (63 mg, 39%). LCMS: RT=2.20 min, [M+H]+ 425. 1H NMR 400 MHz (DMSO-d6) δ: 9.09 (1 H, s), 7.91 (1 H, d, J=0.63 Hz), 7.86 (1 H, s), 7.40 (1 H, br), 7.04 (1 H, br), 5.99 (1 H, m), 5.89 (1 H, s), 5.29 (1 H, d, J=3.76 Hz), 4.53 (4 H, m), 4.29 (1 H, m), 4.21 (1 H, br), 3.66 (1 H, d, J=m) 3.50 (1 H, m), 2.13-2.02 (1 H, m), 1.91 (1 H, dd, J=12.83, 6.39 Hz), 1.50 (6 H, dd, J=6.59, 3.95 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:5]([O:7][CH3:8])=[O:6].[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][C:11]1[C:2]([NH:1][S:38]([C:35]2[CH:36]=[CH:37][C:32]([CH3:31])=[CH:33][CH:34]=2)(=[O:40])=[O:39])=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][C:10]=1[O:21][CH2:22][CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1
Reactant: COC(=O)c1cc(N)c(Oc2ccccc2OC)c(OCCOC2CCCCO2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(C)cc2)c(Oc2ccccc2OC)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.04 g of methyl 3-amino-4-(2-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate were dissolved in pyridine (30 ml), treated dropwise while cooling with ice with a solution of 0.953 g of 4-methyl-benzenesulphonyl chloride in toluene (10 ml) and subsequently stirred at RT for 20 hours. The reaction mixture was poured on to ice/3M HCl, the product was extracted with ethyl acetate and the organic phase was dried over magnesium sulphate. After removing the solvent there was obtained methyl 4-(2-methoxy-phenoxy)-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-5-(toluene-4-sulphonylamino)-benzoate as a yellow solid.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].Cl.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][Cl:17]>C(O)C>[ClH:17].[C:1]1([S:7][CH2:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: c1ccc(SCc2ccccn2)cc1

Procedure:
Thiophenol (21 ml) was added to a solution of sodium (4.6 g) in ethanol (100 ml). To the resulting solution was added 2-picolyl chloride, hydrochloride (15 g) and the mixture was heated at reflux for 2 hours. Precipitated sodium chloride was removed by filtration and the solution was acidified with ethereal HCl. The solvent was removed by evaporation and the residue induced to crystallise by trituration with ether. Recrystallisation from ethanol-ether gave 2-((phenylthio)methylpyridine, hydrochloride (5.0 g) mp 142°-4° C. (Found: C,60.6; H,5.25; N,5.5 C12H11NS,HCl requires C,60.6; H,5.1; N,5.9%).
Reaction SMILES: Br[C:2]1[C:3]([F:25])=[CH:4][C:5]2[O:15][CH2:14][C:13]([OH:19])([CH:16]([CH3:18])[CH3:17])[C:12]3[S:11][C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:9][C:8]=3[C:6]=2[CH:7]=1.[C:26]([C@:28]1([OH:35])[CH2:32][CH2:31][N:30]([CH3:33])[C:29]1=[O:34])#[CH:27]>>[F:25][C:3]1[C:2]([C:27]#[C:26][C@:28]2([OH:35])[CH2:32][CH2:31][N:30]([CH3:33])[C:29]2=[O:34])=[CH:7][C:6]2[C:8]3[N:9]=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:11][C:12]=3[C:13]([OH:19])([CH:16]([CH3:18])[CH3:17])[CH2:14][O:15][C:5]=2[CH:4]=1
Reactant: C#C[C@]1(O)CCN(C)C1=O
Reactant: CCOC(=O)c1nc2c(s1)C(O)(C(C)C)COc1cc(F)c(Br)cc1-2
Product: CCOC(=O)c1nc2c(s1)C(O)(C(C)C)COc1cc(F)c(C#C[C@]3(O)CCN(C)C3=O)cc1-2

Procedure:
Ethyl 9-bromo-8-fluoro-4-oxo-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (133 mg) was reacted with isopropylmagnesium bromide similarly to as described in the synthesis of 4-Hydroxy-9-(3-hydroxy-3-methyl-but-1-ynyl)-4-methyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo {e}azulene-2-carboxylic amide with non-critical modifications to afford ethyl 9-bromo-8-fluoro-4-hydroxy-4-isopropyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate. Ethyl 9-bromo-8-fluoro-4-hydroxy-4-isopropyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (80 mg) was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford ethyl 8-fluoro-4-hydroxy-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-4-isopropyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate which was directed subjected to General Procedure M to afford 12 mg and 13 mg (29% overall yield) after reverse phase purification then chiral separation. The absolute stereochemistry at the 4-hydroxyl substitution position for each isomer was not determined.
Reaction SMILES: [C:1]1([C:7](=[O:17])[CH:8]2[O:10][CH:9]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].O.C(=O)=O>CO.C(O)C>[C:1]1([C:7](=[O:17])[C:8](=[O:10])[CH2:9][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)C1OC1c1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CO
Solvent: CCO
Solvent: O
Product: O=C(Cc1ccccc1)C(=O)c1ccccc1
Reaction time: 0.03 h
Yield: 65 %

Procedure:
To a boiling solution of 30 g 1,3-diphenyl-2,3-epoxy-1-propanone in 500 ml methanol was rapidly added a hot solution of 30 g potassium t-butoxide in 500 ml ethanol. The mixture was kept boiling on a steambath for 2 minutes. It was then diluted with 3 l. water. The aqueous solution was saturated with carbon dioxide by the addition of small pieces of dry ice. The resulting emulsion was extracted with ether. The ether extracts were diluted with benzene, dried over sodium sulfate and evaporated under reduced pressure. The remaining dark oil was distilled in high vacuum to afford 19.5 g 1,3-diphenyl-1,2-propanedione; b.p. 136°-138° /0.1 mm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.N=C=N.[CH:23]1[CH:24]=[CH:25][C:26]2N(O)N=[N:29][C:27]=2[CH:28]=1.CCN(C(C)C)C(C)C.CC1CCCCN1.C(=O)([O-])[O-]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[CH:13][C:14]([C:15]([N:29]3[CH2:25][CH2:24][CH2:23][CH2:28][CH:27]3[CH3:26])=[O:17])=[CH:18][CH:19]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(F)cc2)cc1
Reactant: On1nnc2ccccc21
Agent: CC1CCCCN1
Agent: N=C=N
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCCCN1C(=O)c1ccc(C(=O)Nc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 383.5 %

Procedure:
To a solution of 4-(4-fluorophenylcarbamoyl)benzoic acid (50 mg, 0.19 mmol) in DMF (1 mL) was added PS-Carbodiimide (125 mg, 0.25 mmol), HOBt (26 mg, 0.19 mmol), DIPEA (52 mg, 0.40 mmol) and 2-methylpiperidine (25 mg, 0.25 mmol). The reaction was agitated at room temperature for 18 h. To the reaction was added MP-carbonate and agitated for a further 8 h. The reaction was filtered and concentrated under vacuum to afford diluted with water (10 mL) and isolated the white precipitate by vacuum filtration to afford N-(4-fluorophenyl)-4-(2-methylpiperidine-1-carbonyl)benzamide (248 mg, 95%). 1H-nmr (400 MHz, d6-DMSO) δ 10.37 (br s, 1H), 8.00 (d, J=7 Hz, 2H), 7.83-7.72 (m, 2H), 7.49 (d, J=7 Hz, 2H), 7.21 (t, J=8 Hz, 2H), 3.52-3.01 (m, 3H), 1.75-1.29 (m, 6H), 1.21 (m, 3H); MS (ESI) m/z 341.4.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[NH:16][NH2:17]>C1(C)C=CC=CC=1>[C:20]([O:19][C:15]([NH:16][N:17]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 17 h
Yield: 73.4 %

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (2 g, 10 mmol, 1 eq) in toluene (50 mL) was added tert-butyl carbazate (1.3 g, 10 mmol, 1 eq). The contents were stirred at 70° C. for 17 h. Precipitate was formed upon cooling down to rt. Filtration of the heterogeneous mixture gave a white solid (2.3 g). The filtrate was concentrated to dryness and triturated with ether carefully to collect another crop of solid (400 mg). The two solid product crops were combined (2.7 g, 85%) and used directly in the next step. 1H-NMR (CH3CN-d3) δ 8.11 (s, 1H), 3.49 (m, 4H), 2.34 (m, 4H), 1.47 (s, 9H), 1.45 (s, 9H); LCMS RT=3.04 min; [M+Na]+=336.1.
Reaction SMILES: O.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[CH:8]=[O:9].[CH2:14](O)[CH2:15][OH:16].ClCCl>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:8]2[O:16][CH2:15][CH2:14][O:9]2)[CH:10]=1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cl)cc1C1OCCO1
Yield: 90.2 %

Procedure:
In a flask equipped with a Dean-Stark water separator, 5-chloro-2-nitrobenzaldehyde (12.0 g, 64.7 mmol), ethylene glycol (8.0 g, 129.3 mmol) and p-toluenesulfonic acid (0.2 g) were dissolved in toluene (150 mL). The mixture was stirred at reflux for 8 hours. Dichloromethane was added and the organic phase was washed with saturated sodium bicarbonate and brine, then dried over anhydrous sodium sulfate, evaporated and purified by silica gel chromatography to afford the product 2-(5-chloro-2-nitrophenyl)-1,3-dioxolane (13.4 g, yield 90.0%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2Br)cc1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: CS(=O)(=O)c1ccc(-c2ccccc2-c2ccc(F)c(Cl)c2)cc1
Yield: 89.3 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 6.43 g (20.6 mmol) of 1-bromo-2-[4-(methylsulfonyl)phenyl]benzene (Example 4, Step 2) was reacted with 5.37 g (30.9 mmol) of 3-chloro-4-fluorophenylboronic acid. Purification by silica gel chromatography (Waters Prep-500A) with ethyl acetate/hexane (1:3) gave 6.64 g (89%) of 2-chloro-1-fluoro-4-[2-[4-(methylsulfonyl)phenyl]phenyl]benzene as a colorless solid: mp 179.5-181.1° C.; NMR (CDCl3) δ 3.06 (s, 3H), 6.86-6.93 (m, 1H), 6.98 (t, J=8 Hz, 1H), 7.19 (dd, J=2, 7 Hz, 1H), 7.33 (d, J=8 Hz, 2H), 7.38-7.53 (m, 4H), 7.84 (d, J=9 Hz, 2H). MS (FAB): m/e 367 (M+Li); HRMS Calc'd for C19H14ClFO2S: 360.0387. Found: 360.0401. Anal. Calc'd for C19H14ClFO2S: C, 63.25; H, 3.91; F, 5.27. Found: C, 62.92; H, 4.02; F, 5.19.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=1[OH:20])=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:16][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][C:11]([CH:9]=[O:10])=[C:12]([O:20][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(C(=O)O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)OCc2ccccc2)cc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 95.1 %

Procedure:
Benzyl bromide (2.17 ml, 18.3 mmol) was added to a solution of 4-formyl-3-hydroxy-benzoic acid (1.01 g, 6.10 mmol) and potassium carbonate (3.37 g, 24.4 mmol) in DMF (10 ml), and the mixture was stirred at 50° C. for five hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3-benzyloxy-4-formyl-benzoic acid benzyl ester (2.01 g, 95%).
Reaction SMILES: [CH:1]([N:4]([CH2:8]C)[CH:5](C)C)(C)C.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:38])[CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[C:28]2[C:29]([NH:33][CH2:34][CH2:35][C:36]#[N:37])=[N:30][O:31][N:32]=2)=[CH:13][CH:12]=1.P(Cl)(Cl)(Cl)=O.[Cl-].[NH4+]>CN(C)C=O>[C:36]([CH2:35][CH2:34][NH:33][C:29]1[C:28]([C:20]2[N:19]([CH2:18][C:17]([C:14]3[CH:13]=[CH:12][C:11]([N:10]=[CH:1][N:4]([CH3:8])[CH3:5])=[CH:16][CH:15]=3)=[O:38])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=2)=[N:32][O:31][N:30]=1)#[N:37]
Reactant: N#CCCNc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(N)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=Nc1ccc(C(=O)Cn2c(-c3nonc3NCCC#N)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 0.05 ml N,N-diisopropylethylamine in 1 mL of N,N-dimethylformamide is slowly added to a solution of 116 mg (0.3 mmol) 3-(4-{1-[2-(4-amino-phenyl)-2-oxo-ethyl]-1H-benzoimidazol-2-yl}-furazan-3-ylamino)-propionitrile and 459 mg (0.3 mmol) phosphorus oxychloride in 3 mL of N,N-dimethylformamide at −10° C. After the addition, the mixture is allowed to warm to room temperature and stirred for three days. Then, saturated aqueous ammoniumchloride solution is added and the reaction mixture is extracted with dichloromethane. A precipitate is formed in the dichloromethane phase. This precipitate is collected by filtration, washed with water and dichloromethane, and dried under reduced pressure. The residue is solved in acetonitrile and the solution is added to a 2 N solution of sodium hydroxide in water at 0° C. The resulting pH value is above 11. The mixture is stirred at room temperature for 1 h. The formed precipitate is collected by filtration, washed with water and acetonitrile, and dried under reduced pressure to provide 89 mg of the desired product.