Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].Br[CH2:11][C:12]1[CH:25]=[CH:24][C:23]2[C:14](=[CH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=1.[C:26](#[N:28])[CH3:27]>>[Cl-:1].[CH:13]1[C:14]2[C:23](=[CH:22][C:21]3[C:16]([CH:15]=2)=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:24]=[CH:25][C:12]=1[CH2:11][N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([CH2:27][C:26]2[CH:16]=[CH:15][C:14]3[C:13](=[CH:12][CH:25]=[CH:24][CH:23]=3)[N:28]=2)[CH:4]=1
Reactant: Clc1nc[nH]c1Cl
Reactant: CC#N
Reactant: BrCc1ccc2cc3ccccc3cc2c1
Agent: [K+]
Agent: [OH-]
Product: Clc1c(Cl)[n+](Cc2ccc3cc4ccccc4cc3c2)cn1Cc1ccc2ccccc2n1
Product: [Cl-]

Procedure:
4,5-Dichloroimidazole (0.18 g, 1.33 mmol) and potassium hydroxide (0.08 g, 1.46 mmol) will be dissolved in a minimum volume of acetonitrile and stirred at reflux for 30 min. 2-(Bromomethyl)anthracene (2.71 g, 10.0 mmol) will be added and the mixture will be returned to reflux for 3 h. The mixture will be filtered hot to remove the KBr generated. A solution of 2-(chloromethyl)quinoline will be prepared by combining 2-(chloromethyl)quinolone hydrochloride (2.14 g, 10 mmol) and potassium hydroxide (0.56 g, 10.0 mmol) in acetonitrile and refluxing the mixture for 30 min, and this solution will be added to the filtrate. The combined mixture will be returned to reflux for 6 h. The volatile components will be removed under reduced pressure, and the resulting solid will be washed with water to remove the KCl generated in the neutralization of the quinoline. The remaining solid will be dried and will be the product.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:13][CH2:14][CH:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[OH:16].[BH4-].[Na+]>CO.O.CCOC(C)=O>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCC(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(CNCC(O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1 ml of 4-tert-butylbenzaldehyde (6.15 mmol) and 960 mg of [rac]-2-amino-1-(4-chloro -phenyl)-ethanol (estimated 4.1 mmol) were dissolved in 40 ml methanol at rt, and after stirring for 5 min at rt, were refluxed for 2 h. After cooling down to rt, 310 mg (8.2 mmol) of sodium borohydride were added and after stirring for 15 min at rt, the reaction mixture was then refluxed for 2 h. After cooling down to rt, the residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was stirred with a small quantity of diethylether/heptane, filtered and the solid dried under high vacuo, leading to 723 g of [rac]-(4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-2-hydroxy-ethyl]-amine as a white solid (55%). MS (ISP) 318.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](OCC)=O.[O-]CC.[Na+].[C:14]([C:17]1[CH:22]=[CH:21][C:20]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1)(=O)[CH3:15].O.[NH2:36][NH2:37]>C(OC)(C)(C)C>[F:1][C:2]([F:9])([F:8])[C:3]1[NH:37][N:36]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([C@H:23]3[CH2:28][CH2:27][C@H:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH:15]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: NN
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(C)=O)cc2)CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: CCOC(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A 50 mL flask was charged with 6.6 mL methyl tert-butyl ether and ethyl trifluoroacetate (520 uL, 3.47 mmol). To this solution was then added 533 μL of sodium ethoxide (21% in ethanol) slowly, followed by the product of Example 26A (1.00 g, 3.47 mmol) in 3 mL of methyl tert-butyl ether over 5 minutes. After stirring overnight, the solution was quenched with sat NH4Cl and extracted with ethyl acetate (×2). The ethyl acetate layers were then evaporated to dryness, and the residue taken up in ethanol (5 mL). Two equivalents of hydrazine hydrate (35% in water) were added, and the solution heated to 70° C. overnight. After this time, the solution was cooled to room temperature and the solvent evaporated in vacuo. The residue was taken up in 1:1 methanol/DMSO and purified over RP-HPLC to afford the title product. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.03-1.15 (m, 1 H), 1.19 (t, J=7.12 Hz, 3 H), 1.37-1.60 (m, 2 H), 1.69-1.86 (m, 5 H), 2.15-2.27 (m, 2 H), 4.07 (q, J=7.12 Hz, 2 H), 6.96-7.22 (m, 1 H), 7.26-7.43 (m, 2 H), 7.63-7.80 (m, 2 H), 13.98 (s, 1H): MS (ESI) m/z 381 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[F:32])=[O:23])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([OH:17])=O)[S:14][C:7]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[N:66]1([CH2:72][C:73]([O:75][CH2:76][CH3:77])=[O:74])[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]1>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[F:32])=[O:23])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([N:69]3[CH2:68][CH2:67][N:66]([CH2:72][C:73]([O:75][CH2:76][CH3:77])=[O:74])[CH2:71][CH2:70]3)=[O:17])[S:14][C:7]=12
Reactant: CCOC(=O)CN1CCNCC1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CN1CCN(C(=O)c2cc3nccc(Oc4ccc(NC(=O)Nc5cc(C)ccc5F)c(F)c4)c3s2)CC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (100 mg, 0.22 mmol), HATU (91 mg, 0.24 mmol) and N,N-diisopropylethylamine (62 mg, 0.48 mmol) in anhydrous tetrahydrofuran (10 ml) was heated at 60° C. for 10 minutes, followed by addition of ethyl piperazinoacetate (57 mg, 0.33 mmol). Heating was continued at 60° C. for 30 minutes and the mixture was poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3˜5% methanol in chloroform to give ethyl [4-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)piperazin-1-yl]acetate as white solid. Yield: 73 mg, 54%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].C([Li])CCC.[CH:16](OC)=[O:17]>COC(C)(C)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[CH:16]=[O:17]
Reactant: COC=O
Reactant: COc1ccc(F)c(Cl)c1
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Product: COc1ccc(F)c(Cl)c1C=O
Reaction time: 3 h

Procedure:
To a solution of 3-chloro-4-fluoroanisole (28.5 g, 178 mmol) in t-butyl methyl ether (200 mL, dried over anhydrous MgSO4) at −78° C. was added 2.5 M n-butyl lithium in hexanes (107 mL, 267.5 mmol). After 3 h, methyl formate (18.76 mL) was added drop-wise while keeping the temperature below −60° C. The reaction mixture was quenched with sat. aq. ammonium chloride (250 mL) after 45 minutes and the organic layer was separated. The aq. layer was extracted with ethyl acetate (2×100 mL) and the combined organic layer was washed with water (200 mL) followed by brine, dried (Na2SO4) and concentrated to give a residue which on trituration with hexanes gave solids. The solids were filtered, taken again in hexanes and heated over steam bath. It was cooled, the light yellow desired product filtered and air dried to give the title compound. 1H NMR (400 MHz, CDCl3): δ=10.48 (d, J=0.8 Hz, 1H), 7.31 (dd, J=9.4, 7.8 Hz, 1H), 6.88 (dd, J=7.8, 3.8 Hz, 1H), 3.92 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]=1[N+:12]([O-])=O.[ClH:15].O>C(O)C.[Pd]>[ClH:15].[ClH:15].[NH2:12][C:3]1[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])=[N:5][N:6]([CH3:7])[C:2]=1[NH2:1]
Reactant: Cn1nc(C(C)(C)C)c([N+](=O)[O-])c1N
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cn1nc(C(C)(C)C)c(N)c1N
Reaction time: 3 h

Procedure:
A suspension of 8.5 g (0.035 mol) of 5-amino-1-methyl-4-nitro-3-tert-butylpyrazole and 1.5 g of 5% by weight palladium-on-charcoal containing 50% water in 200 cm3 of ethanol was placed in a hydrogenator. After stirring for 3 hours under a hydrogen pressure of 10 bar, at a temperature of 75° C., the reaction medium was poured into a solution, precooled to 0° C., of 60 cm3 of ethanol and 20 cm3 of 12 N hydrochloric acid. The solution was clarified by filtration on a sinter funnel and then evaporated to dryness under reduced pressure. The brown solid obtained was taken up, at reflux, in 35 cm3 of 5 N hydrochloric ethanol and 11 cm3 of water and then cooled to room temperature. The white crystals obtained were filtered off on a sinter funnel and then dried under vacuum at room temperature. 4.9 g of the expected product were obtained in the form of white crystals, the melting point of which was 260° C. The elemental analysis for C8H10N4.2HCl was:
Reaction SMILES: [CH2:1]([N:5]([CH2:11][CH:12]=O)[C:6](=[O:10])[O:7][CH2:8][CH3:9])[CH:2]=[CH:3][CH3:4].C([O-])(=O)C.[Na+].Cl.[CH3:20][NH:21][OH:22]>O1CCOCC1.O>[CH3:20][N:21]1[O:22][CH:3]([CH3:4])[CH:2]2[CH:12]1[CH2:11][N:5]([C:6]([O:7][CH2:8][CH3:9])=[O:10])[CH2:1]2
Reactant: CC=CCN(CC=O)C(=O)OCC
Reactant: CNO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)N1CC2C(C)ON(C)C2C1

Procedure:
18.4 g (0.1 mol) of ethyl N-(but-2-enyl)-N-(2-oxo-ethyl)-carbamate are dissolved in 100 ml of dioxane, and 9 g of anhydrous sodium acetate and 9 g (0.108 mol) of N-methylhydroxylamine hydrochloride in 10 ml of water are added. The mixture is heated under reflux overnight and cooled and the salts are filtered off with suction and washed with dioxane. The filtrate is concentrated, the residue is taken up in 100 ml of water and K2CO3 is added. The mixture is extracted with CHCl3, the extract is dried over K2CO3 and concentrated and the residue is distilled.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([NH:34][CH3:35])=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([N:34]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:17])=[O:18])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)[CH3:35])=[CH:32][CH:31]=1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Reactant: CNc1ccc(Cl)cc1
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)cc1)c1ccc(Cl)cc1
Yield: 72 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 4-chloro-N-methylaniline, the title compound was isolated as a yellow solid in 72% yield (94% purity by HPLC).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O.[C:22]1([CH2:34][C:35]([NH2:37])=[O:36])[C:32]2=[C:33]3[C:28](=[CH:29][CH:30]=[CH:31]2)[CH2:27][CH2:26][CH2:25][N:24]3[CH:23]=1>>[C:22]1([C:34]2[C:35](=[O:36])[NH:37][C:3](=[O:2])[C:4]=2[C:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15]4[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=4)=[CH:12][CH:13]=3)[NH:8][CH:7]=2)[C:32]2=[C:33]3[C:28](=[CH:29][CH:30]=[CH:31]2)[CH2:27][CH2:26][CH2:25][N:24]3[CH:23]=1
Reactant: COC(=O)C(=O)c1c[nH]c2cc(-c3ccncc3)ccc12
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2cc(-c3ccncc3)ccc12

Procedure:
Beginning with (6-(pyridin-4-yl)indol-3-yl)oxoacetic acid methyl ester and 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[C:9]1(C)[CH:14]=CC(S(O)(=O)=O)=C[CH:10]=1.COC(OC)(C)C>C1(C)C=CC=CC=1>[CH3:10][C:9]1([CH3:14])[N:7]2[C:6](=[O:8])[CH2:5][CH2:4][C@@H:3]2[CH2:2][O:1]1
Reactant: O=C1CC[C@H](CO)N1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: Cc1ccccc1
Product: CC1(C)OC[C@H]2CCC(=O)N21

Procedure:
Prepared according to WO patent: 2013004290A1. To a stirred suspension of (R)-(−)-5-(hydroxymethyl)-2-pyrrolidinone (Sigma Aldrich Chemical Company, St. Louis, Mo., 5.36 g, 46.5 mmol) and p-toluenesulfonic acid (44 mg, 0.233 mmol) in toluene (100 mL), 2,2-dimethoxypropane (17.1 mL, 140 mmol) was added and the reaction was refluxed for 1.5 h. The reaction was equipped with a Dean-Stark apparatus then additional 2,2-dimethoxypropane (17.1 mL, 140 mmol) was added and the reaction was refluxed for 36 h. The solvent was evaporated to afford (R)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one as an orange waxy solid. MS (ESI) 156.1 [M+H]+. The crude material was taken to the next step without further purification.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([CH2:18][CH2:19][N:20]4[CH:25]5[CH2:26][CH2:27][CH:21]4[CH2:22][CH:23]([N:28]4[C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=6[N:30]=[C:29]4[CH3:37])[CH2:24]5)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:11][C:6]=2[O:5][CH2:4]1.C(N(CC)CC)C.[CH3:45][C:46]([CH3:51])([CH3:50])[C:47](Cl)=[O:48]>ClCCl>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([CH2:18][CH2:19][N:20]4[C@H:25]5[CH2:26][CH2:27][C@@H:21]4[CH2:22][CH:23]([N:28]4[C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=6[N:30]=[C:29]4[CH3:37])[CH2:24]5)[CH2:13][CH2:14][N:15]([C:47](=[O:48])[C:46]([CH3:51])([CH3:50])[CH3:45])[CH2:16][CH2:17]3)=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccc3c(c2)OCO3)CCNCC1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccc3c(c2)OCO3)CCN(C(=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
Title compound in example 659. A mixture of 1-(8-{2-[4-(1,3-benzodioxol-5-yl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.2 g, 0.39 mmol), triethylamine (0.11 mL, 0.78 mmol) and trimethylacetyl chloride (0.053 mL, 0.43 mmol) in dichloromethane (4 mL) was stirred at rt for 1 h before the reaction mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated, dried and concentrated to give 1-((1R,5S)-8-{2-[4-(1,3-benzodioxol-5-yl)-1-(2,2-dimethylpropanoyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole as a foam (0.18 g, 82%). 1H NMR (400 MHz, CDCl3) δ 7.81 (m, 1H), 7.29 (m, 3H), 6.83 (m, 2H), 6.75 (m, 1H), 6.21 (m, 1H), 6.00 (s, 2H), 3.95 (m, 2H), 3.84 (m, 2H), 3.38 (m, 2H), 2.98 (m, 2H), 2.86 (s, 3H), 2.56 (m, 2H), 2.31 (m, 4H), 2.07-2.21 (m, 4H), 1.82 (m, 4H), 1.26 (s, 9H). HRMS C34H44N4O3 m/z 557.3492 (M+H)Cal., 557.3495 (M+H)Obs..
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[N:13]=[N:14][C:15]([O:21][CH2:22][CH3:23])=[CH:16][C:17]=1[O:18][CH2:19][CH3:20])=O)C>C1COCC1>[CH2:19]([O:18][C:17]1[CH:16]=[C:15]([O:21][CH2:22][CH3:23])[N:14]=[N:13][C:12]=1[CH2:10][OH:9])[CH3:20]
Reactant: CCOC(=O)c1nnc(OCC)cc1OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1cc(OCC)c(CO)nn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Lithium aluminum hydride (1N solution in THF, 1 mL) is added to a stirred solution of 4,6-diethoxy-pyridazine-3-carboxylic acid ethyl ester (213 mg, 0.8 mmol) in THF (8 mL) cooled to 0° C. The solution is stirred at 0° C. for 3 hours. Excess Na2SO4-10H2O is then added and the mixture is stirred at room temperature for 45 minutes. The solid is filtered and washed with EtOAc. Evaporation of the filtrate in vacuo provides (4,6-diethoxy-pyridazin-3-yl)-methanol as a light yellow oil, which is used without further purification for the next step.
Reaction SMILES: [CH2:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:22]O>C(O)CC.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH2:12]([N+:11]([O-:22])=[CH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: OO
Reactant: CCCCCCCCCCNCCCCCCCCCC
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: CCCO
Solvent: O
Product: CCCCCCCCCC=[N+]([O-])CCCCCCCCCC
Temperature: 40 °C

Procedure:
To a solution of 29.8 grams of didecylamine in 120 ml of n-propanol is added sequentially 1.6 grams of sodium tungstate dihydrate and 14.3 grams of a 50% aqueous hydrogen peroxide solution at 5°-10° C. The reaction mixture is allowed to warm up to 40° C. and is maintained at that temperature for 20 hours. An additional 7.2 grams of 50% aqueous hydrogen peroxide solution is added to the solution at 40° C. After further stirring for another day, the reaction mixture is concentrated under reduced pressure. The residue is partitioned between chloroform and water. The combined organic extracts are washed with water and then dried over anhydrous sodium sulfate. Removal of the chloroform solvent leaves a crude product which is purified by recrystallization from heptane to afford the above-named compound as a white solid melting at 63°-65° C. in a yield of 9.8 grams.
Reaction SMILES: [C:1](Cl)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:10]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:23][C:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([OH:37])[CH:33]=4)[CH:28]=3)=[N:25][N:26]=2)=[CH:18][CH:17]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>N1C=CC=CC=1>[CH2:10]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:23][C:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([O:37][C:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:33]=4)[CH:28]=3)=[N:25][N:26]=2)=[CH:18][CH:17]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCC(=O)Cl
Reactant: CCCCCCc1ccc(-c2nnc(-c3ccc4cc(O)ccc4c3)s2)cc1
Solvent: c1ccncc1
Product: CCCCCCC(=O)Oc1ccc2cc(-c3nnc(-c4ccc(CCCCCC)cc4)s3)ccc2c1
Reaction time: 8 h
Yield: 69.8 %

Procedure:
In a 30 ml-round-bottomed flask, 0.30 g (0.77 mM) of 2-(4-hexylphenyl)-5-(6-hydroxynaphthalene-2-yl)-1,3,4-thiadiazole was dissolved in 5 ml of pyridine. To the solution, 0.20 ml (1.29 mM) of heptanoyl chloride was added dropwise under cooling with an iced water bath and stirring. After the addition, the iced water bath was removed. Then, the mixture was stirred for 7 hours at room temperature and left standing overnight at room temperature. The resultant mixture was poured into 100 ml of iced water to precipitate a crystal. The crystal was recovered by filtration, washed with water and dissolved in toluene under heating, followed by drying with anhydrous sodium sulfate and distilling-off of the solvent. The residue was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (toluene-acetone) to obtain 0.27 g of 2-(4-hexylphenyl)-5-(6-heptanoyloxynaphthalene-2-yl)-1,3,4-thiadiazole (Yield: 69.8%) ##STR39##
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])/[C:8]([OH:10])=[O:9])[N:6]=1.[Cl:21]N1C(=O)CCC1=O>CCCCCC>[NH2:1][C:2]1[S:3][C:4]([Cl:21])=[C:5](/[C:7](=[N:11]/[O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1csc(N)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1nc(N)sc1Cl
Yield: 97.2 %

Procedure:
Six grams of 2-(2-aminothiazol-4-yl)-2(Z)-(tert-butoxycarbonylmethoxyimino)acetic acid and 3.2 g of N-chlorosuccinimide are reacted in the manner of Reference Example 35 and the product obtained is solidified by treating hexane to give 6.5 g of the above-identified compound as a powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[C:16]([C:28]([NH2:30])=[O:29])=[N:17][CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=4)[CH:20]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:31][C:32]([F:39])([F:38])[CH2:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl.N1C=CC=CC=1>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[C:16]([C:28]([NH2:30])=[O:29])=[N:17][CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][S:34]([CH2:33][C:32]([F:39])([F:38])[F:31])(=[O:36])=[O:35])[CH:22]=4)[CH:20]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(Nc3cc(-c4cccc(N)c4)cnc3C(N)=O)cc2)CC1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN1CCN(c2ccc(Nc3cc(-c4cccc(NS(=O)(=O)CC(F)(F)F)c4)cnc3C(N)=O)cc2)CC1
Temperature: 0 °C

Procedure:
A solution of EXAMPLE 65A (18 mg, 0.045 mmol) in dichloromethane (0.4 mL) and pyridine (0.1 mL) was added to a cooled to 0° C. 2,2,2-trifluoroethanesulfonyl chloride (9 mg, 0.05 mmol). The reaction mixture was stirred slowly warming to ambient temperature over 18 hours and concentrated under reduced pressure. The crude material was purified by RP-HPLC (10 mM ammonium acetate/acetonitrile) to afford the title compound. 1H NMR (DMSO-d6) δ ppm 10.27 (s, 1H), 8.21 (d, J=3.0, 1H), 8.14 (d, J=1.9, 1H), 7.68-7.63 (m, 1H), 7.52-7.40 (m, 2H), 7.40-7.33 (m, 2H), 7.30-7.23 (m, 1H), 7.20-7.14 (m, 2H), 7.00-6.94 (m, 2H), 4.54 (q, J=9.8, 2H), 3.13 (m, 4H), 2.45 (m, 4H), 2.24 (s, 3H); MS (ESI) m/z 549 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][C@@H:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][C@H:10]([C:19]([O:21][CH3:22])=[O:20])[C@H:9]1[C:23]([O:25]CC1C=CC=CC=1)=[O:24])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:15]([O:14][C@@H:12]1[CH2:13][NH:8][C@H:9]([C:23]([OH:25])=[O:24])[C@@H:10]([C:19]([O:21][CH3:22])=[O:20])[CH2:11]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: [H][H]
Reactant: COC(=O)[C@H]1C[C@H](OC(C)(C)C)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](OC(C)(C)C)CN[C@@H]1C(=O)O

Procedure:
A solution of 2-benzyl 3-methyl (2S,3S,5S)-1-benzyl-5-tert-butoxypiperidine-2,3-dicarboxylate (80.0 mg, 0.000182 mol) in 5 mL of MeOH was hydrogenated in the presence of 10% Pd/C, under a balloon pressure of hydrogen, overnight. After filter off the catalyst, the filtration was concentrated to dry and used directly in next step (43 mg, 91.1%). MS (ESI): (M+H)+=260.1.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([F:22])[C:20]=1[F:21])[C:15](O)=O.N>>[F:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:18]=[C:19]([F:22])[C:20]=1[F:21]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Fc1cc(-c2nc(-c3cccnc3)no2)cc(F)c1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3,4,5-trifluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.64 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 8.01-8.13 (m, 2H), 8.56 (ddd, J=8.1, 1.8, 1.6 Hz, 1H), 8.75 (dd, J=4.8, 1.6 Hz, 1H), 9.29 (dd, J=2.0, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 278 (M+H)+.