Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].P(O[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(OCC)(OCC)=O.ClC1C=CC(CC2C=C(C=O)SC=2)=CC=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:6]2[S:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)=[CH:22][CH:23]=1
Reactant: CCOP(=O)(OCC)OCc1ccc(Cl)cc1
Reactant: O=Cc1ccc(B(O)O)s1
Agent: O=Cc1cc(Cc2ccc(Cl)cc2)cs1
Product: O=Cc1ccc(Cc2ccc(Cl)cc2)s1
Yield: 48 %

Procedure:
The title compound was synthesized from 5-formylthiophen-2-ylboronic acid and diethyl 4-chlorobenzyl phosphate using the conditions to synthesize 4-(4-chlorobenzyl)thiophene-2-carbaldehyde (Example 1.1.a). Purification by flash chromatography (0-20% heptane/EtOAc) yielded 5-(4-chlorobenzyl)thiophene-2-carbaldehyde (730 mg, 48%). 1H NMR (400 MHz, CDCl3) δ ppm 9.82 (s, 1H), 7.62 (d, 1H), 7.31 (m, 2H), 7.18 (m, 2H), 6.90 (m, 1H), 4.17 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1O)([O-:3])=[O:2].[CH:11]1([O:16][C:17](=[O:30])[C@@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:20][OH:21])[CH2:15][CH2:14][CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH:11]1([O:16][C:17](=[O:30])[C@@H:18]([NH:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:19][CH2:20][O:21][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OC1CCCC1
Reactant: O=[N+]([O-])c1ccccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCOc1ccc([N+](=O)[O-])cc1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a slurry of 4 nitrophenol (0.32 g, 2.3 mmol) in anhydrous DCM (100 ml) at 0° C. was added (S)-2-tert-butoxycarbonylamino-4-hydroxy-butyric acid cyclopentyl ester (1 g, 3.5 mmol) (Scheme 9) in DCM (100 ml), triphenyl phosphine (2.5 g, 9.5 mmol) followed by slow addition of DIAD (1.9 ml, 9.6 mmol). The reaction was allowed to warm to room temperature and stirred for 16 h. The solvent was removed and the crude material purified by column chromatography to furnish the desired product. (EtOAc:heptane, 1:9), (0.45 g, 48%). LCMS purity 97%, m/z 309 [M++H-boc]+.
Reaction SMILES: N[C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N([CH2:25][CH3:26])CC)C>C(Cl)Cl>[CH2:11]([O:10][C:8]([C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@@H:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:9])[C:26]1[CH:25]=[CH:4][CH:3]=[CH:2][CH:7]=1
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 188.1 %

Procedure:
A solution of 252E (180 mg, 0.66 mmol) in CH2Cl2 (5 mL) was treated with benzyloxychloroformate (0.1 mL, 0.73 mmol) and triethylamine (0.12 mL, 0.86 mmol). The reaction was stirred at room temperature for 18 hours, diluted with CH2Cl2 (10 mL) and washed with water (2×10 mL), 0.1 N HCl (2×10 mL), saturated aqueous NaHCO3 (2×10 mL) and brine (1×10 mL). The organic layer was dried (Na2SO4), filtered and concentrated to give 243 mg (yield: 91%) of Compound 254A as an oil.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[N:13][S:14][CH:15]=1.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>C(O)(C)(C)C>[C:17]([NH:21][CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[N:13][S:14][CH:15]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)N
Reactant: c1ccc(-c2csnn2)c(OCC2CO2)c1
Solvent: CC(C)(C)O
Product: CC(C)(C)NCC(O)COc1ccccc1-c1csnn1

Procedure:
To a solution of 1.95 g. of 4-[2(2,3-epoxypropoxy)phenyl]-1,2,3-thiadiazole in 45 ml. of t-butylamine is added 5 ml. of t-butanol, and the reaction mixture is stirred at room temperature for 5 days. It is then evaporated to dryness under vacuo. Crystallization of the residue from methylene chloride-benzene affords the pure 4-[2(3-t-butylamino-2-hydroxypropoxy)phenyl]1,2,3-thiadiazole, m.p. 99°-100° C λmax 244, 290 nm (ε 10,500, 4,600) ir 3355, 1600 cm-1.
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:12][N:13]([CH3:28])[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23](OCC)=[O:24])[N:22]=2)[CH:19]=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH3:12][N:13]([CH3:28])[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23]([NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:24])[N:22]=2)[CH:19]=1
Reactant: CCOC(=O)c1cn2cc(N(C)C)ccc2n1
Reactant: Nc1ccccc1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CN(C)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.46 ml of a 2M solution of trimethylaluminum in toluene is added dropwise to a solution, cooled to 0° C., of 60.8 μl of aniline in 3 ml of toluene, followed, at 20° C., by the addition of 76 mg of ethyl 6-dimethylaminoimidazo[1,2-a]pyridine-2-carboxylate. The reaction mixture is stirred at ambient temperature for 15 minutes. It is cooled to 0° C. and then 20 ml of a saturated ammonium chloride solution are added. The organic phase is dried over magnesium sulfate, filtered through Celite and evaporated to dryness under reduced pressure. The residue is chromatographed on a silica cartridge, elution being carried out with a mixture of dichloromethane and ethyl acetate. The fractions comprising the product are combined and concentrated to dryness under reduced pressure. The residue obtained is crystallized from methanol to give 36 mg of 6-(dimethylamino)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a gray powder.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:5]([F:10])=[N:6][CH:7]=[CH:8][CH:9]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH3:26]>C(Cl)Cl>[NH2:26][CH2:2][CH2:3][C:4]1[C:5]([F:10])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: OCCc1cccnc1F
Reactant: N
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: NCCc1cccnc1F
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.20 g (1.42 mmol) of 3-(2-hydroxyethyl)-2-fluoropyridine in 8 ml of dry CH2Cl2 cooled to -40° C. was added 0.18 ml (0.8 mmol) trifluoromethanesulfonic anhydride under an atmosphere of nitrogen. After stirring for 30 min at -40° C., 30 ml of cold (-78° C.) NH3 (l) was added. The mixture was stirred for 30 min at -40° C., and then concentrated in vacuo to afford 1.03 g of crude salt which was washed twice with 20 ml diethyl ether to yield 0.82 g of 3-(2-aminoethyl)-2-fluoropyridine as a trifluoromethanesulfonic acid salt.
Reaction SMILES: [N:1]1[C:2]2[N:3]([C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:4]=[CH:5][C:6]=1[C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([F:14])[CH:8]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:26](C)=O.[Na+]>ClCCCl>[N:1]1[C:2]2[N:3]([C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:4]=[CH:5][C:6]=1[C:7]1[CH:13]=[CH:12][C:10]([NH:11][CH3:26])=[C:9]([F:14])[CH:8]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1ccc(-c2ccn3c(n2)nc2ccccc23)cc1F
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: CNc1ccc(-c2ccn3c(n2)nc2ccccc23)cc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 21.4 %

Procedure:
To a suspension of 4-(Benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)-2-fluoroaniline (20 mg, 0.072 mmol) in 1 mL DCE was added paraformaldehyde (4.5 mg, 0.14 mmol), followed by NaBH(AcO)3 (51 mg, 0.24 mmol). The reaction was stirred at rt for 6 h and quenched by adding Na2CO3 (5 mL, saturated). The mixture was extracted with EtOAc (2×10 mL) and the combined organic phase was washed with water (2×20 mL) and concentrated under reduced pressure. The residue was subjected to reversed phase HPLC (TFA buffered water/MeCN) to afford 4-(Benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)-2-fluoro-N-methylaniline as orange solid (4.5 mg, 21%). 1H NMR (400 MHz, methanol-d4): δ 9.10 (d, J=7.2 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 8.01 (d, J=11.2 Hz, 2H), 7.75 (d, J=8.4 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.51 (t, J=7.2 Hz, 1H), 7.38 (d, J=7.2 Hz, 1H), 6.94 (t, J=8.8 Hz, 1H), 2.90 (s, 3H); MS (ESI) m/z [M+H]+293.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:23][CH:22]=1)(=[O:20])=[O:19].[ClH:35]>>[ClH:35].[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:23][CH:22]=1)(=[O:19])=[O:20]
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(CCN4CCOCC4)cc3)c(C)o2)cc1
Agent: Cl
Product: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(CCN2CCOCC2)cc1
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of methyl 4-(5-methyl-4-((4-(2-morpholinoethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoate (600 mg, 1.24 mmol, 1.00 equiv) in 6N hydrochloric acid (30 mL) was refluxed for 8 h. The reaction mixture was cooled to room temperature and concentrated under vacuum to give 0.6 g (96%) of 4-(5-methyl-4-((4-(2-morpholinoethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoic acid hydrochloride as a white solid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:31]=[CH:30][N:29]([CH2:32][C:33]([CH3:36])([OH:35])[CH3:34])[N:28]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH:13]=[N:12]2)[C:8]([NH:26][C:27]2[CH:31]=[CH:30][N:29]([CH2:32][C:33]([OH:35])([CH3:36])[CH3:34])[N:28]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2F)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3F)cc2=O)n1
Yield: 69 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(2-fluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 43) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-2-[4-(2-fluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (0.48 g, 69%); ES+-HRMS m/e calcd for C25H30N5O4F [M+H+] 484.2355 found 484.2355. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.10 (m, 1H), 1.25-1.75 (m, 8H), 1.92 (m, 1H), 2.28 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.47 (dd, J=4.1, J=10.7 Hz, 1H), 5.80 (d, J=2.7 Hz, 1H), 6.40 (d, J=2.1 Hz, 1H), 7.28-7.52 (m, 4H), 7.52 (d, J=2.1 Hz, 1H), 8.20 (d, J=2.7 Hz, 1H), 10.82 (s, 1H).
Reaction SMILES: [CH3:1][S:2][CH:3]([O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([CH3:17])=[C:12]([CH3:18])[CH:11]=1)[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>C1COCC1.O>[CH3:1][S:2][CH:3]([O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([CH3:17])=[C:12]([CH3:18])[CH:11]=1)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(Oc1cc(C)c(C)c(C)c1)SC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSC(Oc1cc(C)c(C)c(C)c1)C(=O)O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
The product from Step 2 (2.0 g) in THF (10 ml) and water (3 ml) containing sodium hydroxide (0.4 g) were stirred at 60° C. for 2 hours then cooled to ambient temperature, evaporated under reduced pressure, diluted with water and washed with diethyl ether. The aqueous fraction was acidified with dilute hydrochloric acid and extracted with ethyl acetate (three times). The extracts were combined, washed with brine, dried over magnesium sulphate, then evaporated to give 2-methylthio-2-(3,4,5-trimethylphenoxy)acetic acid, 1.05 g, as a yellow gum. A portion of the gum was fractionated by chromatography (silica; ethyl acetate then methanol) to provided an analytical sample and the remainder used in the next stage without further purification.
Reaction SMILES: [F:1][C:2]1(F)[CH2:12][CH2:11][CH:5]2[C:6]([O:8][C:9](=[O:10])[CH:4]2[CH2:3]1)=[O:7].ClC1C=CC(Cl)=CC=1Cl>[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)C2CC(F)(F)CCC12
Agent: [Pd]
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: O=C1OC(=O)c2cc(F)ccc21
Reaction time: 3.5 h
Yield: 51 %

Procedure:
A mixture of 500 parts of 4,4-difluorohexahydrophthalic anhydride and 100 parts of 5 percent Pd/C catalyst in 3615 parts of 1,2,4-trichlorobenzene was charged to an autoclave reactor. The autoclave atmosphere was purged with nitrogen. The autoclave was then sealed, heated to about 250°-285° C. and maintained thereat for about 3.5 hours, then cooled to about room temperature. Analysis of the reaction product by gas chromatographic techniques, indicated a yield of about 51 percent 4-fluorophthalic anhydride, based on the difluorohexahydrophthalic anhydride reactant.
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([S:18]([C:21]#[N:22])(=[O:20])=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:1]([N:8]1[C:21]([S:18]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])=[N:22][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: N#CS(=O)(=O)Cc1ccccc1
Product: O=S(=O)(Cc1ccccc1)c1nnnn1Cc1ccccc1

Procedure:
Heating a mixture of benzyl azide (Fr. Moulin, loc. cit.) and benzylsulfonyl cyanide as in Example 2 gives the title compound, m.p. 94°-96° C.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5]([C:7]1[CH:23]=[CH:22][C:10]2[N:11]=[C:12]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[S:13][C:9]=2[CH:8]=1)[CH3:6])C.[OH-].[Na+].C(O)(=O)C>C1COCC1.O>[C:18]([O:17][C:15]([NH:14][C:12]1[S:13][C:9]2[CH:8]=[C:7]([CH:5]([CH3:6])[C:4]([OH:24])=[O:3])[CH:23]=[CH:22][C:10]=2[N:11]=1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C(C)c1ccc2nc(NC(=O)OC(C)(C)C)sc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc2nc(NC(=O)OC(C)(C)C)sc2c1
Temperature: 25 °C

Procedure:
A mixture of 5 (239 mg, 1 mmol) in THF (10 ml) and H2O (10 ml) is stirred at room temperature. Sodium hydroxide (68.2 mg, 2.5 mmol) is added to the mixture. The reaction mixture is stirred for 15 h at room temperature. The reaction mixture is acidified to pH 3˜4 with acetic acid. Water is added to the mixture and extracted with dichloromethane. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Yield: quantitative.
Reaction SMILES: [CH3:1][C@:2]1(CN2CCN(C(OC(C)(C)C)=O)CC2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.C(N(CC)CC)C.C1(C2C=CC(C=O)=CC=2)C=CC=CC=1.[B-]C#N.[Na+].C(O)(=O)C>>[CH3:1][CH:2]1[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Agent: O=Cc1ccc(-c2ccccc2)cc1
Agent: [B-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC1Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 146.7 %

Procedure:
A mixture of tert-butyl (R)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-piperazine-1-carboxylate prepared in Example 396 (100 mg, 0.27 mmol) and trifluoroacetic acid (2 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (5 ml) and neutralized with triethylamine (1 ml, 7.17 mmol), and then the solution was concentrated under reduced pressure. The residue was dissolved in methanol (5 ml). To the solution, 4-phenylbenzaldehyde (149 mg, 0.82 mmol), sodium cyanotrihydroborate (51 mg, 0.82 mmol) and acetic acid (48 μl, 0.82 mmol) were added in this order followed by stirring at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added a saturated sodium hydrogencarbonate solution. The precipitates were filtered off and purified by silica gel column chromatography (ethyl acetate) to afford (R)-2-(biphenyl-4-ylmethyl)piperazin-1-ylmethyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (67 mg, yield 57%) as a light yellow powder.
Reaction SMILES: [C:1]([S@:5]([NH:7][C@@:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])([CH:17]([F:19])[F:18])[C:9]([F:16])([F:15])[C:10](OCC)=[O:11])=[O:6])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C1COCC1>[CH3:4][C:1]([S@:5]([NH:7][C@:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])([C:9]([F:15])([F:16])[CH:10]=[O:11])[CH:17]([F:19])[F:18])=[O:6])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(F)(F)[C@](N[S@](=O)C(C)(C)C)(c1ccccc1F)C(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)[S@@](=O)N[C@@](c1ccccc1F)(C(F)F)C(F)(F)C=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-2,2,4,4-tetrafluoro-3-(2-fluorophenyl)-butanoate (3.20 g, 7.97 mmol) in dry THF (35 mL) was added dropwise a solution of DIBAL-H (diisobutylaluminium hydride) in toluene (1.0 M, 16 mL, 16 mmol) at −78° C. under N2. The mixture was stirred at −78° C. for 2 hours. The reaction was quenched carefully with methanol (3 mL) at −78° C. Then water (20 mL) and ethyl acetate (200 mL) were added and the mixture was warmed to 25° C. The mixture was aged for 30 minutes. The resulting mixture was filtered through a Celite pad. The organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated to give crude product (R)-2-methyl-N—((S)-1,1,3,3-tetrafluoro-2-(2-fluorophenyl)-4-oxobutan-2-yl)propane-2-sulfinamide, which was used immediately in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:17])[C@H:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Li+].[OH-].OS([O-])(=O)=O.[K+].ClCCl>CO.O>[CH3:16][S:13]([NH:12][C@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:17])=[O:2])(=[O:15])=[O:14]
Reactant: COC(=O)[C@@H](Cc1ccccc1)NS(C)(=O)=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
A mixture of 2-(R)-methanesulfonylamino-3-phenyl-propionic acid methyl ester (0.90 g) and 0.10 g of LiOH in 10 mL of methanol and 1 mL of water was stirred for 16 h at ambient temperature. KHSO4 was added, the volatiles were pumped off followed by addition of water, extraction with dichloromethane and removal of the solvent. Yield: 0.70 g (83%) of the title compound as a colorless oil. (−)-APCI-MS: 242 ([M-H]−).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1.[Cl:25][C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C>C(OCC)(=O)C>[Cl:25][C:26]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)=[O:28]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1cccc(-c2cccc(OCCCCCCO)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2cccc(OCCCCCCOC(=O)Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 6-(3-(6-hydroxyhexyloxy)phenyl)picolinate (13), (33 mg, 0.10 mmol, 1 eq.) in ethyl acetate (1 mL) was added triphosgene (14 mg, 0.047 mmol, 1.4 eq) dissolved in a minimum amount of ethyl acetate, followed immediately by DIEA (26 μL, 20 mg, 0.15 mmol, 1.5 eq). The mixture was stirred at room temperature for 30 min, the precipitated DIEA hydrochloride was filtered off, and the filtrate evaporated to dryness in vacuo. The oily residue of crude 14 was used directly for the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:13]=[C:12]([N+:14]([O-])=O)[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[F:17]>CCOC(C)=O.[Pd]>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:6]=[C:5]([F:17])[C:4]([C:3]([O:2][CH3:1])=[O:18])=[CH:13][C:12]=1[NH2:14]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C(=O)OC)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)c(C(=O)OC)cc1N
Reaction time: 1 h
Yield: 89.5 %

Procedure:
A mixture of 174A (48.5 g, 0.178 mol) and palladium/carbon (4.6 g) in EtOAc (450 mL) was evacuated under reduced pressure and charged with hydrogen (3×). The reaction mixture was subsequently stirred under a steady stream of nitrogen for 1 h. The reaction mixture was filtered through a pad of Celite, concentrated, and recrystallized form a mixture of MeOH and DCM to provide 36.2 g (90%) of 174B as a bright yellow solid. HPLC retention time=2.68 min. (Condition B), and LC/MS M+1=228. 1H-NMR (500 MHz, CDCl3) δ 3.89 (s, 3H), 3.92 (s, 3H), 7.20 (d, 1H), and 7.61 (d, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[S:14][C:13]([NH2:15])=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:16][C:17](=O)[CH2:18][C:19](OC)=[O:20].O=P(Cl)(Cl)Cl.CCN(C(C)C)C(C)C>CC#N>[Cl:16][C:17]1[N:15]=[C:13]2[S:14][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[N:11][N:12]2[C:19](=[O:20])[CH:18]=1
Reactant: COC(=O)CC(=O)Cl
Reactant: Nc1nnc(-c2cccc([N+](=O)[O-])c2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: O=c1cc(Cl)nc2sc(-c3cccc([N+](=O)[O-])c3)nn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
In a particular instance, the compound of this example is prepared as described or similarly described as follows: To 5-(3-nitrophenyl)-1,3,4-thiadiazol-2-amine (2) (3.0 g, 13.50 mmol) in MeCN (120 ml) is added methyl 3-chloro-3-oxopropanoate (1.735 mL, 16.20 mmol). The mixture is stirred at room temperature for 2 hours. After consumption of the starting material, POCl3 (60 mL, 644 mmol) is added along with DIPEA (2.358 mL, 13.50 mmol) in MeCN (10 mL). The mixture is heated in the microwave at 150° C. for 25 min, cooled, and concentrated in vacuo. The resulting slurry is taken up in chloroform, poured over ice and washed with saturated NaHCO3, water and brine, dried over MgSO4, and concentrated in vacuo to give a dark red oil which is purified via column chromatography on a 100 g snap column with 0-10% EtOAc/DCM gradient elution to give 7-chloro-2-(3-nitrophenyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (1.36 g, 4.41 mmol, 32.6% yield) as an orange solid.