Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[C:22](=[O:23])[C:14]3=[CH:15][N:16]4[C:21]([CH2:20][CH2:19][CH2:18][CH2:17]4)=[C:13]3[CH:12]=[N:11]2)[N:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)[C:26]1=[O:57].C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>O>[CH3:24][N:25]1[C:26](=[O:57])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:54][O:55][CH2:56]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([N:10]3[C:22](=[O:23])[C:14]4=[CH:15][N:16]5[C:21]([CH2:20][CH2:19][CH2:18][CH2:17]5)=[C:13]4[CH:12]=[N:11]3)[N:5]=[CH:4][CH:3]=2)=[CH:30]1
Reactant: O=Cc1c(Cl)ccnc1-n1ncc2c3n(cc2c1=O)CCCC3
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2ccnc(-n3ncc4c5n(cc4c3=O)CCCC5)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 50 °C
Yield: 40.8 %

Procedure:
A 50-mL round bottomed flask equipped with a reflux condenser was charged with 4-chloro-2-(4-oxo-7,8,9,10-tetrahydropyridazino[4,5-a]indolizin-3(4H)-yl)nicotinaldehyde 192c (118 mg, 0.36 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl-amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 101l (171 mg, 0.36 mmol), Na2CO3 (78 mg, 0.72 mmol), Pd (dppf)Cl2 (30 mg, 0.036 mmol), DMF (10 mL), and water (1 mL). After bubbling nitrogen through the mixture for 30 minutes, it was heated at 50° C. for 10 hours under N2 protection. It was then cooled to room temperature and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 20:1 dichloromethane/methanol to afford 198a (93 mg, 40%) as a brown solid. MS-ESI: [M+H]+ 634.3.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:13]1[N:14]=[N+:15]([O-:26])[C:16]2[CH:25]=[C:24]3[C:20]([CH2:21][CH2:22][CH2:23]3)=[CH:19][C:17]=2[N:18]=1.CCN(CC)CC>COCCOC>[N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:13]2[N:14]=[N+:15]([O-:26])[C:16]3[CH:25]=[C:24]4[C:20]([CH2:21][CH2:22][CH2:23]4)=[CH:19][C:17]=3[N:18]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Reactant: NCCCCN1CCOCC1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: [O-][n+]1nc(NCCCCN2CCOCC2)nc2cc3c(cc21)CCC3
Yield: 88 %

Procedure:
4-(4-Morpholinyl)butylamine (306) (2.02 g, 12.8 mmol) was added to a stirred solution of chloride 21 (1.89 g, 8.5 mmol) and Et3N (1.8 mL, 12.8 mmol) in DME (80 mL) and the solution stirred at reflux temperature for 16 h. The solvent was evaporated and the residue was partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 62 (2.57 g, 88%) as pale yellow solid: mp (MeOH/EtOAc) 151-152° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.38 (s, 1H, H-5), 5.78 (br s, 1H, NH), 3.78 (br t, J=4.6 Hz, 4H, 2×CH2O), 3.50 (br dd, J=6.6, 5.9 Hz, 2H, CH2N), 2.95-3.02 (m, 4H, H-6, H-8), 2.45 (br t, J=4.4 Hz, 4H, 2×CH2N), 2.40 (t, J=7.0 Hz, 2H, CH2N), 2.15 (p, J=7.5 Hz, 2H, H-7), 1.67-1.74 (m, 2H, CH2), 1.58-1.64 (m, 2H, CH2); 13C NMR δ 158.8, 154.5, 148.8, 143.2, 129.8, 120.5, 114.7, 66.9 (2), 58.5, 53.7 (2), 41.3, 33.1, 32.3, 27.4, 25.7, 24.0. Anal. Calcd for C18H25N5O2: C, 63.0; H, 7.3; N, 20.4. Found: C, 62.9; H, 7.2; N, 20.5%.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:18][CH3:19])=[C:7]([CH:17]=1)[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].P(Br)(Br)[Br:21]>C(COC)OC.CCOCC>[Br:21][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:18][CH3:19])=[C:7]([CH:17]=1)[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: BrP(Br)Br
Reactant: COc1ccc(CO)cc1CNC(=O)OC(C)(C)C
Solvent: COCCOC
Solvent: CCOCC
Product: COc1ccc(CBr)cc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.65 g of t-butyl N-[5-(hydroxymethyl)-2-methoxybenzyl]carbamate was dissolved in 20 ml of dimethoxyethane, 0.53 ml of phosphorus tribromide was added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ether and washed with water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography, to give 1.76 g of the title compound from the 3:1 hexane-ethyl acetate fraction.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12]>O.C(O)(=O)C>[OH:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[NH:5][C:2]([NH2:3])=[O:1]
Reactant: N#C[O-]
Reactant: Nc1ccccc1O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccccc1O
Reaction time: 8 h
Yield: 47.9 %

Procedure:
A solution of potassium cyanate (3.94 g, 48.6 mmol) in water (30 mL) was added during 15 min. to suspension of 2-aminophenol (2.41 g, 22.1 mmol) in 50% aqueous acetic acid (160 mL). The resulting solution was allowed to stand at room temperature overnight and then extracted with ethyl ether (3 times). The combined organic extracts was concentrated to small volume and poured into cold saturated aqueous sodium hydrogen carbonate. The solid was filtered and washed with water to afford the subtitle compound (1.61 g, 47.9%).
Reaction SMILES: C([O:4][C@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[C:23]2[N:24]=[CH:25][NH:26][C:27](=[S:28])[C:22]=2[CH:21]=[CH:20]1)(=O)C.[Na]>CO>[C@@H:6]1([N:19]2[C:23]3[N:24]=[CH:25][NH:26][C:27](=[S:28])[C:22]=3[CH:21]=[CH:20]2)[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(=S)[nH]cnc32)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na]
Solvent: CO
Product: OC[C@H]1O[C@@H](n2ccc3c(=S)[nH]cnc32)[C@@H](O)[C@@H]1O

Procedure:
A solution of 3.0 g of 7-β-D-arabinofuranosyl-3,7-dihydro-4H-pyrrolo[2,3d]-pyrimidine-4-one, eight ml of acetic anhydride, 150 ml of pyridine, and 50 mg of p-dimethylaminopyridine is stirred at room temperature for 24 hours, evaporated in vacuo, co-evaporated with xylenes, and distributed between ethyl acetate and water. The ethyl acetate layer is washed with saturated NaHCO3 and dried with MgSO4. Removal of the ethyl acetate provides 7-(2,3,5-tri-O-acetyl-β-D-arabinofuranosyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one. This is dissolved in 150 ml of dry pyridine, treated with 8.8 g of phosphorus pentasulfide, and heated under reflux for 5 hours. The pyridine is removed in vacuo and the residue is treated with water. The precipitate is filtered, washed with water, and recrystallized from ethanol to afford 7-(2,3,5-tri-O-acetyl-β-D-arabinofuranosyl)-3,7-dihydro-4H-pyrrolo[2,3-]pyrimidine-4-thione. A solution of 5.0 g of 7-(2,3,5-tri-O-acetyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-4-thione, 200 ml of methanol, and 54 mg of sodium methalate is heated under reflux for 2 hours and treated with IRC-50 ion exchange resin. The filtrate is evaporated in vacuo and the resulting residue is recrystallized from ethanol-water to provide 7-β-D-arabinofuranosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidine-4-thione.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([N:11]=[C:12]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][N:21]=[C:20]4[NH:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=4)=[C:30]([CH3:42])[CH:29]=3)[O:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:42][C:30]1[CH:29]=[C:28]([NH:27][C:20]2[C:19]3[C:24](=[CH:25][CH:26]=[C:17]([NH:16][C:12]4[O:13][CH:14]5[CH2:15][NH:8][CH2:9][CH:10]5[N:11]=4)[CH:18]=3)[N:23]=[CH:22][N:21]=2)[CH:33]=[CH:32][C:31]=1[O:34][C:35]1[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC5=NC6CN(C(=O)OC(C)(C)C)CC6O5)cc34)cc2C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC5=NC6CNCC6O5)cc34)cc2C)cn1

Procedure:
N4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-N6-(4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine is prepared from 2-{4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-3a,4,6,6a-tetrahydropyrrolo[3,4-d]oxazole-5-carboxylic acid tert-butyl ester by standard BOC deprotection methods using TFA in methylene chloride. MS APCI (+) m/z 468 (M+1) detected; 1H NMR (400 mHz, CD3OD) δ 8.42 (s, 1H), 8.21 (bs, 1H), 8.13 (d, 1H), 7.68 (m, 2H), 7.60 (m, 2H), 7.28 (m, 2H), 6.98 (d, 1H), 5.18 (m, 1H), 4.74 (m, 1H), 3.34 (d, 1H), 3.16 (d, 1H), 2.86 (m, 2H), 2.50 (s, 3H), 2.26 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([F:32])=[CH:4][N:3]=1.[CH3:33][O:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[CH3:31][O:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[CH2:21][N:15]([C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[S:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:36]1[CH:37]=[CH:38][C:39]([C:41]([F:44])([F:43])[F:42])=[CH:40][C:35]=1[O:34][CH3:33])=[N:3][CH:4]=[C:5]2[F:32])(=[O:14])=[O:13]
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)ncc(F)c3c2)c(OC)c1
Temperature: 100 °C

Procedure:
A microwave vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate PPP; 0.041 g, 0.083 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (0.027 g, 0.125 mmol), Pd(PPh3)4 (9.59 mg, 8.30 μmol), and potassium carbonate (0.057 g, 0.415 mmol). Dioxane (0.415 mL) and water (0.138 mL) were added, the vial was flushed with argon and sealed, and heated in a microwave reactor at 100° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel chromatography (12 g, gradient elution 0 to 100% EtOAc:Heptane) to afford N-(2,4-dimethoxybenzyl)-4-fluoro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide. The material was dissolved in DCM and TFA (0.1 mL, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature after which time the reaction was concentrated and triturated with diethyl ether. The solids were filtered, washed with diethyl ether, and vacuum dried to afford 4-fluoro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.008 g, 0.017 mmol, 19.94% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=13.00 (s, 1H), 8.74 (d, J=1.6 Hz, 1H), 8.51 (d, J=1.4 Hz, 1H), 7.99 (dd, J=1.7, 8.9 Hz, 1H), 7.79 (dd, J=1.8, 9.0 Hz, 1H), 7.61-7.55 (m, 1H), 7.55-7.46 (m, 2H), 7.31 (d, J=4.6 Hz, 1H), 6.90 (d, J=4.6 Hz, 1H), 3.75 (s, 3H). m/z (ESI) 484.2 (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1Cl)=[O:4].Cl.[CH2:14]([O:16][C:17](=[O:21])[CH2:18][NH:19][CH3:20])[CH3:15].C(N(CC)CC)C>C(#N)C>[CH2:14]([O:16][C:17]([C:18]1[N:19]([CH3:20])[C:10]2[CH:9]=[C:8]([Cl:12])[N:7]=[N:6][C:5]=2[C:3]=1[OH:4])=[O:21])[CH3:15]
Reactant: COC(=O)c1nnc(Cl)cc1Cl
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1c(O)c2nnc(Cl)cc2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
To a stirred solution of 4,6-dichloro-pyridazine-3-carboxylic acid methyl ester (2.9 g, 14 mmol) and sarcosine ethyl ester hydrochloride (2.15 g, 14 mmol) in acetonitrile (75 ml) was added triethylamine (4.9 mL, 35 mmol). The resultant reaction mixture was stirred at room temperature for 2 hours before adding further triethylamine (4.9 mL, 35 mmol) and heating the reaction mixture at 80° C. for 18 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the resultant residue treated with water and extracted with ethyl acetate (×3), the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo to give a solid. The solid was triturated in hot methanol to give the title compound as a yellow solid (1.6 g, 45%). LCMS (method B): RT=2.64 min, M+H+=256.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:12].[Li]CCCC.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28](=[O:30])[CH3:29])=[CH:26][N:27]=2)[N:24]=1>C1COCC1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28]([C:10]3[C:2]([F:1])=[C:3]4[C:7](=[CH:8][C:9]=3[F:11])[N:6]([CH3:12])[N:5]=[CH:4]4)([OH:30])[CH3:29])=[CH:26][N:27]=2)[N:24]=1
Reactant: Cn1ncc2c(F)cc(F)cc21
Reactant: CC(=O)c1cnc2ccc(Cl)nn12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1ncc2c(F)c(C(C)(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Reaction time: 1 h
Yield: 40.8 %

Procedure:
To a solution of 4,6-difluoro-1-methyl-1H-indazole (intermediate P) (600 mg, 3.57 mmol) in anhydrous THF (20 mL) at −78° C. was added n-BuLi (1.6M solution in hexane, 2.56 mL, 4.1 mmol). The solution was stirred at this temperature for 1 h and then a solution of 1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethanone (intermediate M) (698 mg, 3.57 mmol) in anhydrous THF (10 mL) was added dropwise. The resulting solution was stirred at this temperature for 3 h and allowed to warm to it slowly and stirred overnight. The reaction mixture was quenched with water, extracted with EtOAc three times. The organic layers were combined and washed with brine, dried over Na2SO4. The crude was purified by flash chromatography (DCM:MeOH=95:5) to give 530 mg (41%) of the title compound as yellow oil. 1H-NMR (400 MHz, CDCl3) ppm 8.05 (d, 1H), 8.0 (s, 1H), 7.85 (s, 1H), 7.1 (d, 1H), 6.85 (d, 1H), 4.0 (s, 3H), 2.3 (s, 3H). LCMS (method B): [MH]+=363.9, tR=2.15 min.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([I:11])[C:3]=1[OH:12].[C:13]([CH:15]1[CH2:17][CH2:16]1)#[CH:14].O>N1C=CC=CC=1>[CH:15]1([C:13]2[O:12][C:3]3[C:4]([I:11])=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=3[CH:14]=2)[CH2:17][CH2:16]1
Reactant: C#CC1CC1
Reactant: O=[N+]([O-])c1cc(I)c(O)c(I)c1
Solvent: c1ccncc1
Solvent: O
Product: O=[N+]([O-])c1cc(I)c2oc(C3CC3)cc2c1
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
A solution of 2,6-diiodo-4-nitrophenol (10 g, 25.6 mmol), ethynylcyclopropane (1.9 g, 28.8 mmol) and Cu2O (1.9 mg, 13.2 mmol) in 100 mL of dry pyridine was refluxed for 2 h. The reaction mixture was poured into 1 L of water and stirred for 10 min. The resulting mixture was filtered. The cake was purified by column chromatography on silica gel eluting with EtOAc/PE (0-20%) to give the title compound (6.6 g, 78% yield) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.47 (d, J=2.4 Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 6.58 (s, 1H), 2.13-2.07 (m, 1H), 1.14-1.04 (m, 4H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18]CC4C=CC=CC=4)=[CH:14][CH:13]=3)[N:9]=[C:8]2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:3][CH:2]=1>[Pd].CCOC(C)=O>[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=3)[N:9]=[C:8]2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:5][CH:6]=1
Reactant: Fc1ccc(-c2nc(-c3ccc(OCc4ccccc4)cc3)cn2-c2ccncc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1ccc(-c2cn(-c3ccncc3)c(-c3ccc(F)cc3)n2)cc1
Reaction time: 10 h
Yield: 70.4 %

Procedure:
A mixture containing 1-(4-pyridyl)-2-(4-fluorophenyl)-4-(4-benzyloxyphenyl)imidazole (0.13 g, 0.3 mmol) and 10% palladium on activated carbon (100 mg) in EtOAc was stirred under an atmosphere of H2 for 10 h, at which time the reaction mixture was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography, eluting with 1:1 EtOAc/hexanes. The material which was isolated was crystallized from EtOAc/hexanes to afford the title compound (0.07 g, 70%). m.p. 230-231° C.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH:16]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.I[CH3:40].[H-].[Na+]>CN(C=O)C>[F:1][C:2]([F:37])([F:38])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([N:20]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[CH3:40])[CH:16]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CI
Reactant: O=C(NC1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OCc1ccccc1)C1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 500 mg of benzyl carbamate prepared in Example 4, Step B and 0.12 mL of iodomethane in 5 mL of DMF was added 60 mg of 60% sodium hydride in mineral oil. After 2 hours, the reaction was quenched with 2N hydrochloric acid and water and extracted twice with ethyl acetate. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography eluting with 25% ethyl acetate in hexanes to obtain 500 mg of title compound as an oil. NMR (CDCl3): δ1.80-2.0 (m, 3H), 2.0-2.2 (m, 1H), 2.80 and 2.87 (2 br s, 3H), 3.05-3.15 (m, 1H), 3.9-4.0 (m, 1H), 4.36 and 4.40 (2 s, 1H), 4.4-4.55 (m, 1H), 4.55-4.85 (2 br m, 1H), 4.91 and 5.03 (2 br s, 2H), 7.0-7.3 (m, 10H), 7.58 (br s, 2H), 7.72 (s, 1H).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:31][CH2:30][CH:29]([CH2:32][C:33](O)=[O:34])[CH2:28][CH2:27]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:33](=[O:34])[CH2:32][CH:29]5[CH2:30][CH2:31][O:26][CH2:27][CH2:28]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)CC1CCOCC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(CC1CCOCC1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (29.3 mg, 78.5%), MS (ISP) m/z=457.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and 2-(tetrahydro-2H-pyran-4-yl)acetic acid.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=1[CH3:15])[CH2:4][CH3:5])[CH3:2].[OH:16][CH2:17][C:18]([NH:20][CH2:21][C@H:22]([OH:36])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[NH:34])[NH:32]O)=[C:27]([CH3:35])[CH:26]=1)=[O:19]>>[CH2:4]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:14][N:34]=[C:31]([C:28]3[CH:29]=[CH:30][C:25]([O:24][CH2:23][CH:22]([OH:36])[CH2:21][NH:20][C:18](=[O:19])[CH2:17][OH:16])=[CH:26][C:27]=3[CH3:35])[N:32]=2)=[CH:9][C:8]=1[CH3:15])[CH2:1][CH3:2])[CH3:5]
Reactant: Cc1cc(OC[C@@H](O)CNC(=O)CO)ccc1C(=N)NO
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(OCC(O)CNC(=O)CO)cc3C)no2)cc1C
Yield: 5.2 %

Procedure:
The title compound (3 mg) is prepared starting from 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (30 mg, 130 μmol) and (S)-2-hydroxy-N-(2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-3-methyl-phenoxy]-propyl)-acetamide (35 mg, 117 μmol) according to Method A; LC-MS: tR=0.50 min; [M+1]+=489.23.
Reaction SMILES: [C:1]1([C:7]2[N:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:21]([C:23]1[S:27][C:26](=[N:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[N:25]([CH2:35][C:36]2[CH:41]=[CH:40][C:39](I)=[CH:38][CH:37]=2)[N:24]=1)[CH3:22].C(OCC)(=O)C>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[C:12]([N:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[C:39]2[CH:40]=[CH:41][C:36]([CH2:35][N:25]3[N:24]=[C:23]([CH2:21][CH3:22])[S:27][C:26]3=[N:28][C:29](=[O:34])[C:30]([F:31])([F:33])[F:32])=[CH:37][CH:38]=2)=[N:8][N:9]=[N:10]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)n1nnnc1-c1ccccc1
Reactant: CCc1nn(Cc2ccc(I)cc2)c(=NC(=O)C(F)(F)F)s1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1nn(Cc2ccc(-c3ccccc3-c3nnnn3C(C)(C)C)cc2)c(=NC(=O)C(F)(F)F)s1
Temperature: -5 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To a solution of 5-phenyl-1-tert-butyl-1H-tetrazole (1.0 g) in tetrahydrofuran (20 ml) was added dropwise n-butyl lithium (1.6M hexane solution, 3.5 ml) keeping the temperature below -20° C., followed by stirring at -5° C. for one hour. Zinc chloride (1.0M diethyl ether solution, 6.0 ml) was added dropwise to the reaction mixture keeping the temperature below -30° C., followed by stirring at room temperature for 2 hours. To the resulting mixture were added 5-ethyl-3-(4-iodobenzyl)-2-trifluoroacetylimino-1,3,4-thiadiazoline (1.2 g) and tetrakis(triphenyl-phosphine)palladium (100 mg), and they were heated under reflux overnight. Ethyl acetate (100 ml) was added to the reaction mixture, and the resulting mixture was washed with 10% aqueous citric acid solution and dried over anhydrous magnesium sulfate, followed by removal through distillation. The residue so obtained was separated by column chromatography on silica gel, whereby 830 mg of the title compound was obtained in the oily form.
Reaction SMILES: I.[NH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:8]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[C:15](=[O:27])[O:14][N:13]=2)=[N:9][O:10][N:11]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[O:27]=[C:15]1[O:14][N:13]=[C:12]([C:8]2[C:7]([NH:6][CH2:5][CH2:4][CH2:3][NH:2][S:36]([CH3:35])(=[O:38])=[O:37])=[N:11][O:10][N:9]=2)[N:16]1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1
Reactant: NCCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-{4-[(3-aminopropyl)amino]-1,2,5-oxadiazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5(4H)-one hydroiodide (from Example 15, Step F; 25 mg, 50 μmol) in dichloromethane (1 mL) was treated with triethylamine (17 μL, 0.12 mmol) and methanesulfonyl chloride (6 μL, 70 μmol) and stirred at 25° C. for 2 h. The reaction mixture was concentrated to give the intermediate, N-{3-[(4-{5-oxo-4-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1,2,4-oxadiazol-3-yl}-1,2,5-oxadiazol-3-yl)amino]propyl}methanesulfonamide, as a crude residue which was used without further purification. A solution of the crude intermediate in methanol (1 mL) was treated with 2 N NaOH (0.25 mL, 0.5 mmol) and stirred at 25° C. for 30 min. The reaction mixture was treated with acetic acid (50 μL, 0.9 mmol), filtered and purified by preparative LCMS to give the desired product (13 mg, 65%) as a solid. LCMS for C14H18F3N6O4S (M+H)+: m/z=423.1. 1H NMR (400 MHz, DMSO-d6): δ 11.6 (s, 1H), 9.11 (s, 1H), 7.37 (dd, J=8.0, 8.0 Hz, 1H), 7.20 (d, J=7.8 Hz, 1H), 7.07-7.01 (m, 2H), 6.96 (d, J=8.0 Hz, 1H), 6.20 (t, J=5.9 Hz, 1H), 3.27-3.22 (m, 2H), 2.99-2.94 (m, 2H), 2.87 (s, 3H), 1.78-1.71 (m, 2H).