Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(F)cc(O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(F)cc(OCc2ccccc2)c1[N+](=O)[O-]
Yield: 100 %

Procedure:
In DMF (20 ml), 5-fluoro-3-methoxy-2-nitrophenol (4.14 g, 22.1 mmol), benzyl bromide (3.2 ml, 26.5 mmol) and potassium carbonate (4.58 g, 33.2 mmol) were stirred at 70° C. for 5 hours. The reaction mixture was poured in water (200 ml), followed by extraction with ethyl acetate (300 ml). The extract was washed with saturated brine (200 ml), dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (4:1) eluate fractions, the title compound (6.13 g, 100%) was obtained as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[Si:14]([O:21][CH2:22][CH:23]=O)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C([BH3-])#N.C(O)(=O)C>CN(C=O)C>[Si:14]([O:21][CH2:22][CH2:23][NH:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: [BH3-]C#N
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OCCNCc1nc2c(c(=O)[nH]1)COCC2
Temperature: 150 °C
Yield: 10.5 %

Procedure:
To a mixture of 2-(aminomethyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (50 mg, 0.28 mmol) and 2-(tert-butyldimethylsilyloxy)acetaldehyde (53 uL, 0.28 mmol) in DMF (1 mL) was added siliabond cyanoborohydride (300 mg, 0.30 mmol, 1 mmol/g) and acetic acid (0.158 mL, 2.8 mmol). The mixture was heated via microwave at 150° C. for 5 minutes, concentrated in vacuo and the resulting material was purified via HPLC to provide the title compound (10 mg, 11% yield). 1H NMR (400 MHz, CDCl3) δ 4.51 (s, 2 H), 3.87 (t, J=5.5 Hz, 2H), 3.71 (s, 2H), 3.58-3.68 (m, 2H), 2.62 (ddd, J=14.7, 5.3, 5.1 Hz, 4H), 0.82 (s, 9H), 0.00 (s, 6H). Retention time=1.52 min.
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:11]([CH3:13])[CH3:12])[CH:3]=1.C([Mg]Cl)(C)C.[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:31]=1)[C:25](N(OC)C)=[O:26]>C1COCC1>[Br:19][C:20]1[CH:31]=[C:24]([C:25]([C:2]2[C:10]3[CH:9]=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH:11]([CH3:13])[CH3:12])[CH:3]=2)=[O:26])[CH:23]=[N:22][CH:21]=1
Reactant: CON(C)C(=O)c1cncc(Br)c1
Reactant: CC(C)n1cc(I)c2cncnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)n1cc(C(=O)c2cncc(Br)c2)c2cncnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a stirred solution of 5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (Preparation 93, 4.85 g, 16.9 mmol) in THF (90 mL) at 0° C., under nitrogen was added isopropyl magnesium chloride (9.28 mL, 18.6 mmol, 2.0 M in diethyl ether). The mixture was stirred at 0° C. for 1 hour then a solution of 5-bromo-N-methoxy-N-methylnicotinamide (Preparation 227, 4.55 g, 18.6 mmol) in THF (10 mL) was added dropwise at 0° C. The mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organics were concentrated under reduced pressure and purified by silica gel column chromatography eluting with gradient of EtOAc:DCM 95:5 to 50:50 to afford a light brown oil. The crude material was recrystallised using EtOAc:heptane (15:200 mL) to afford the title compound as a white solid in 33% yield, 2.16 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]2[O:15][CH:16]=[N:22][N:23]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)c1ccccc1S(=O)(=O)c1ccc(Br)cc1
Solvent: O
Product: O=S(=O)(c1ccc(Br)cc1)c1ccccc1-c1nnco1
Temperature: 90 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
Methyl 2-[(4-bromophenyl)sulfonyl]benzoate (Example 144 Step 1; 150 mg, 0.46 mmol) and hydrazine hydrate (0.06 mL, 2.32 mmol) were stirred together at room temperature for 1.5 h then at 90° C. for 2 h. The excess hydrazine was removed in vacuo and the residue was dissolved in triethylorthoformate (4.6 mL) with catalytic camphorsulfonic acid and the mixture heated at 90° C. overnight. The cooled reaction mixture was partitioned between EtOAc and water and the organic layer was washed with brine and evaporated in vacuo. The residue was purified by flash column chromatography on silica (eluant 50% EtOAc/isohexane) to yield 2-{2-[(4-bromophenyl)sulfonyl]phenyl}-1,3,4-oxadiazole (60 mg, 35%). δH (400 MHz, d6 DMSO): 9.42 (1H, s), 8.35-8.33 (1H, m), 7.97-7.91 (2H, m), 7.86-7.84 (3H, m), 7.80-7.78 (2H, m).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[NH:3]1.C1(C)C=CC=CC=1.[S:16]1[CH2:18][CH2:17]1>>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[N:3]1[CH2:18][CH2:17][SH:16]
Reactant: CC1CCCC(C)N1
Reactant: C1CS1
Solvent: Cc1ccccc1
Product: CC1CCCC(C)N1CCS

Procedure:
In a 500 ml three-necked flask 113.2 g(1 mol) of 2,6-dimethylpiperidine in 250 mol toluene was heated at 90° C. Then 60.12 g (1 mol) thiirane is added to the resulting reaction mixture dropwise and the reaction mixture is heated for 5 hours under reflux. The reaction mixture is concentrated in vacuum with a rotary evaporator and is fractionally distilled using a Vigreux column. The yield amounts to 60.55 g of the named compound(35%).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[C@@H:30]3[CH2:31][C@@H:27]([CH:28]=[CH:29]3)[C@@H:26]2[C:32]([NH2:34])=[O:33])[C:21]([Cl:35])=[CH:20][N:19]=1>>[Cl:35][C:21]1[C:22]([NH:24][C@@H:25]2[C@@H:30]3[CH2:31][C@@H:27]([CH:28]=[CH:29]3)[C@@H:26]2[C:32]([NH2:34])=[O:33])=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)ccc2C1

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide in an analogous manner to example 712. Product was isolated as a tan solid (0.034 g, 35%). Mp 117-120° C.; LCMS (m/e) 482 (M); 1H-NMR (DMSO, 400 MHz) δ 9.11 (s, 1H), 7.94 (s, 1H), 7.72 (s, 1H), 7.70 (d, 1H, J=7.83 Hz), 7.39-41 (d, 1H, J=8.59 Hz), 7.26 (s, 1H), 7.14 (s, 1H), 6.99-7.01 (d, 1H, J=8.59 Hz), 6.38-6.34 (m, 1H), 6.30-5.97 (m, 1H), 4.15 (t, 1H, J=7.33 Hz), 3.59 (s, 2H), 3.10-12 (q, 2H, J=7.33 Hz), 2.91 (s, 1H), 2.88 (s, 1H), 2.77 (s, 3H), 2.40 (m, 2H), 2.10-12 (d, 1H, J=8.59 Hz), 1.39-42 (d, 1H, J=9.10 Hz), 1.13-17 (t, 3H, J=6.57 Hz), 1.01-04 (t, 3H, J=6.82 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[N:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([CH2:16][NH2:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)[C@@H:5]2[CH2:18][CH2:19][CH2:20][CH2:21][C@H:4]2[O:3]1.CCN(C(C)C)C(C)C.[Cl:32][C:33]1[C:38]([N+:39]([O-:41])=[O:40])=[C:37](Cl)[N:36]=[CH:35][N:34]=1>>[Cl:32][C:33]1[N:34]=[CH:35][N:36]=[C:37]([NH:17][CH2:16][C:14]2[CH:13]=[CH:12][C:10]3[N:11]=[C:7]([N:6]4[C@@H:5]5[CH2:18][CH2:19][CH2:20][CH2:21][C@H:4]5[O:3][C:2]4([CH3:22])[CH3:1])[S:8][C:9]=3[CH:15]=2)[C:38]=1[N+:39]([O-:41])=[O:40]
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(CN)cc2s1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(CNc3ncnc(Cl)c3[N+](=O)[O-])cc2s1
Reaction time: 4 h
Yield: 46 %

Procedure:
To a stirred mixture of (2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methanamine (236 mg, 0.7 mmol) from Step 4 of this Example and DIEA (388 μL, 2.2 mmol) at 0° C. under argon was added 4,6-dichloro-5-nitropyrimidine (159 mg, 0.8 mmol) in one portion. The mixture was stirred for 4 h and then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluting with a gradient of 100% hexanes to 50% EtOAc in hexanes) to afford 6-chloro-N-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-5-nitropyrimidin-4-amine (153 mg, 43%) as an oil. 1H NMR (300 MHz, CDCl3) δ 8.45 (s, 1H), 7.81 (br s, 1H), 7.57-7.63 (m, 2H), 7.22-7.31 (m, 1H), 4.85 (d, J=5.7 Hz, 2H), 3.11 (m, 1H), 2.82 (m, 1H), 2.11-2.16 (m, 1H), 1.90 (m, 1H), 1.80 (s, 3H), 1.51-1.69 (m, 5H), 1.19-1.49 (m, 4H). LCMS (ESI) m/z 475 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:38])[NH:27][CH2:28][C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[CH:32][NH:33]3)=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23])=[O:16])[CH2:5][NH:6]C(OC(C)(C)C)=O.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[CH3:1][O:2][C:3](=[O:39])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:38])[NH:27][CH2:28][C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[CH:32][NH:33]3)=[CH:20][C:21]=1[C:22]([F:24])([F:25])[F:23])=[O:16])[CH2:5][NH2:6]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ccc23)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ccc23)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-3-tert-Butoxycarbonylamino-2-({5-[(1H-indol-4-ylmethyl)-carbamoyl]-3-trifluoromethyl-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.278 g, 0.49 mmol) in DCM (5 mL) was added TFA (3.0 mL). The mixture was stirred at room temperature 1 h and evaporated. Isolate 0.32 g of crude product which was used without further purification.
Reaction SMILES: C(O[CH:5]1[N:9]([CH3:10])[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[O:13])=[N:7][C:6]1=[O:22])(=O)C.Cl.[CH2:24]([SH:26])[CH3:25]>CCOCC.C(#N)C>[Cl:21][C:17]1[CH:16]=[C:15]([NH:14][C:12]([NH:11][C:8]2[N:9]([CH3:10])[CH:5]([S:26][CH2:24][CH3:25])[C:6](=[O:22])[N:7]=2)=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: CCS
Reactant: CC(=O)OC1C(=O)N=C(NC(=O)Nc2cccc(Cl)c2)N1C
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: CCSC1C(=O)N=C(NC(=O)Nc2cccc(Cl)c2)N1C
Yield: 73.2 %

Procedure:
A solution of 3.00 g (9.20 mmol) of N-(5-acetyloxy-4,5-dihydro-1-methyl-4-oxo-1H-imidazol-2-yl)-N'-(3-chlorophenyl)urea, the compound of Example 1a, in 75 ml of anhydrous ether was treated with anhydrous HCl until no more precipitation occurred. The solid was filtered, washed with anhydrous ether and suspended in a mixture of 1.8 ml (25 mmol) of ethyl mercaptan and 30 ml of acetonitrile. After heating under reflux for 1 hr, the reaction mixture was evaporated in vacuo. The crystalline residue was dissolved in THF/water and extracted with ether. The combined ether layers were washed with water to pH 5-6, dried (MgSO4) and evaporated in vacuo. Crystallization of the residue from methanol/water afforded 2.20 g (73%) of the title compound. Recrystallization from ether/hexane and finally ethanol/water gave an analytical sample mp 102°-104° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][N:15]=[C:14]([N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]=3[CH:32]=2)O1.[OH:34]O>O1CCCC1>[OH:34][C:9]1[CH:10]=[CH:11][C:12]2[O:16][N:15]=[C:14]([N:17]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C:13]=2[CH:32]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1noc2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: OO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1noc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of di-tert-butyl [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-benzoxazol-3-yl]imidodicarbonate (0.81 g, 1.8 mmol) in tetrahydrofuran (15 mL) was added 30% w/v aqueous hydrogen peroxide (0.75 mL, 7.0 mmol). The mixture was stirred at ambient temperature for 18 h and concentrated in vacuo. The residue was taken up in ethyl acetate (20 mL), washed with water (2×15 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford di-tert-butyl (5-hydroxy-1,2-benzoxazol-3-yl)imidodicarbonate as a colorless solid in quantitative yield (0.65 g): 1H NMR (300 MHz, CDCl3) δ7.46-7.43 (m, 1H), 7.12-7.09 (m, 1H), 6.86-6.85 (m, 1H), 1.39-1.36 (m, 9H), 1.26-1.21 (m. 9H); MS (ES+) m/z 350.9 (M+1).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:8][CH:7]=1)([OH:3])=O.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43](=[N:45]O)[NH2:44])[CH:38]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][C:27]=1[CH2:26][O:25][CH:13]1[CH:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:1]3[O:3][N:45]=[C:43]([C:39]4[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=4)[N:44]=3)=[CH:7][CH:8]=2)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCC(=O)O)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: NC(=NO)c1cccnc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3nc(-c4cccnc4)no3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
(nn) In an analogous manner to that described in Example 38, by condensing tert-butyl (3RS,4RS)-4-(4-carboxymethoxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 86(mm)] with 3-pyridinamidoxime in the presence of HBTU and subsequent cyclization there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(3-pyridin-3-yl-[1,2,4]oxadiazol-5ylmethoxy)-phenyl]-piperidine-1-carboxylate as a yellowish solid; MS: 593 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:14])[CH2:3][O:4][C:5]1[C:6]([CH3:13])=[CH:7][C:8]([CH:11]=O)=[N:9][CH:10]=1.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>>[F:1][CH:2]([F:14])[CH2:3][O:4][C:5]1[C:6]([CH3:13])=[CH:7][C:8](/[CH:11]=[N:21]/[S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])=[N:9][CH:10]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: Cc1cc(C=O)ncc1OCC(F)F
Product: Cc1cc(/C=N/[S@](=O)C(C)(C)C)ncc1OCC(F)F
Yield: 11 %

Procedure:
The title compound is prepared in 11% yield (147 mg, colorless oil) from 5-(2,2-difluoroethoxy)-4-methylpicolinaldehyde (860 mg, 4.27 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (777 mg, 6.41 mmol) in a similar manner to Step-6 of Amine-49.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([OH:14])=[O:13])[CH:3]=1.[CH3:15][N:16]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.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>[C:15]([C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([OH:14])=[O:13])[CH:3]=1)#[N:16]
Reactant: CN1CCCC1=O
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(C(=O)O)nc(C(F)(F)F)c1
Temperature: 160 °C
Reaction time: 0.08 h

Procedure:
4-Bromo-6-(trifluoromethyl)pyridine-2-carboxylic acid (0.150 g, 0.556 mmol, Anichem) and zinc cyanide (0.39 g, 3.3 mmol) were mixed in N-methylpyrrolidinone (2 mL) and the mixture was degassed by bubbling a stream of nitrogen through the mixture for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.096 g, 0.083 mmol) was added, the degassing was continued for 5 minutes, then the reaction was sealed and heated in the microwave to a temperature of 160° C. for 15 minutes. The mixture was filtered and purified by preparative HPLC (eluting with a gradient from 18.8 to 40.9% MeCN/H2O containing 0.1% TFA over 1-6 min at 60 mL/min thru C18 SunFire 30×100 mm, 5 um particle size) using UV detection. The product eluted at 5.25 minutes.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[S:16](Cl)(=[O:18])=[O:17])([O-:3])=[O:2].[CH3:20][NH:21][CH3:22].C(O)(=O)C>O>[CH3:20][N:21]([CH3:22])[S:16]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:4]=1[N+:1]([O-:3])=[O:2])[NH:11][C:10](=[O:14])[C:9](=[O:15])[NH:8]2)(=[O:18])=[O:17]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(S(=O)(=O)Cl)cc2[nH]c1=O
Reactant: CNC
Solvent: O
Solvent: CC(=O)O
Product: CN(C)S(=O)(=O)c1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 81 %

Procedure:
A mixture of 4.58 g (0.015 mole) of 1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxalinesulfonyl chloride and 30 ml of 25% ethanolic dimethylamine is stirred at a temperature between 5° C. and 10° C. for 3 hours, and then allowed to stand for 16 hours. To the reaction mixture 5 ml of acetic acid and 60 ml of water are added, the separated crystals are filtered, washed with water and acetone, dried, dissolved in a slight amount of hot dimethyl sulfoxide and precipitated from this solution with water. Thus 3.80 g (81%) of N,N-dimethyl-1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxaline sulfonamide are obtained, m.p.: 318-332° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[C:9]([NH:17][NH2:18])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:17][N:18]=2)[N:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: Clc1ccc(Cl)nn1
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: Clc1ccc2nnc(-c3ccccc3)n2n1
Yield: 55.3 %

Procedure:
3,6-Dichloropyridazine (20 g, 134 mmol) was suspended in xylene (200 ml) with benzoylhydrazine (20.1 g, 1.1 mol eq) and triethylamine hydrochloride (20.3 g, 1.1 mol eq) and the reaction mixture was heated under reflux for 2 hours. The solvent was removed under high vacuum and the residue was purified by chromatography on silica gel using 1% methanol in dichloromethane as eluent to give the required product (17.1 g mp=199° C.). 1H NMR (250 MHz, CDCl3) δ7.16 (1 H, d, J=9.7 Hz), 7.53-7.61 (3 H, m), 8.16 (1 H, d, J=9.7 Hz), 8.44-8.50 (2 H, m); MS (ES+) m/e 231 [MH]+.
Reaction SMILES: [S:1](=[O:38])(=[O:37])([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([C@H:15]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([Cl:35])[C:28]=3[CH3:36])[C@@H:16]([O:18][Si](C(C)(C)C)(C)C)[CH3:17])=[N:13][N:14]=2)=[CH:6][CH:5]=1)[NH2:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[S:1](=[O:38])(=[O:37])([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][C:12]([C@H:15]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([Cl:35])[C:28]=3[CH3:36])[C@@H:16]([OH:18])[CH3:17])=[N:13][N:14]=2)=[CH:8][CH:9]=1)[NH2:2]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(OS(N)(=O)=O)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(OS(N)(=O)=O)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a pre-cooled (0° C.) solution of 4-(5-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-cyano-2-methylphenylamino)propyl)-1,3,4-oxadiazol-2-yl)phenyl sulfamate (190 mg, 0.422 mmol) in THF (20 mL) was added TBAF (0.63 mL, 0.63 mmol, 1 M solution in THF) dropwise. The mixture was allowed to warm to room temperature and stirred for two hours, whereupon, concentration under reduced pressure furnished a yellow oil (195 mg). The resulting residue was taken up in EtOAc (60 mL) and washed with H2O (20 mL). The biphasic mixture was separated and the aqueous layer extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel [Dichloromethane-Methanol (7:1) as eluent] to provide the title compound as a white solid (0.032 g, 16%). The resulting solid was diluted with CH2Cl2 (30 mL) and hexanes (70 mL) was added. Upon concentration of the suspension a white solid was provided (1.02 g, 35%). 1H NMR (400 MHz, Acetone d6, δ in ppm) 8.2 (d, J=8.8 Hz, 2H), 7.99 (d, J=9 Hz, 2H), 7.47 (d, J=9 Hz, 1H), 6.86 (d, J=9 Hz, 1H), 5.64 (d, J=8 Hz, 1H), 5.18-5.15 (m, 1H), 4.81 (br s, 1H), 4.63 (br s, 1H), 2.40 (s, 3H), 1.40 (d, J=7 Hz, 3H).
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([OH:13])[C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1.[CH3:15][OH:16].[ClH:17]>C(Cl)Cl.O1CCOCC1>[ClH:17].[F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([OH:13])[C:11](=[NH:12])[O:16][CH3:15])[CH:7]=[CH:8][CH:9]=1
Reactant: N#CC(O)c1cccc(OC(F)F)c1
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=N)C(O)c1cccc(OC(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 131A (1.83 g, 9.2 mmol) in anhydrous CH2Cl2 (30 mL) at 0° C. was added MeOH (2.24 mL) and 4.0 N HCl in dioxane (9.2 mL). The mixture was stirred at 0° C. for 30 min and then at rt for 4.0 h. Solvent was removed to give methyl 2-(3-(difluoromethoxy)-phenyl)-2-hydroxyacetimidate HCl salt. To this salt in CH2Cl2 (10 mL) was added H2O (10 mL). The mixture was stirred at rt for 30 min, then extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried and concentrated. The crude prouduct was purified by silica gel chromatography to give 131B (700 mg, 33% yield) as a viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.70 (s, 3H) 5.22 (s, 1H) 6.82 (t, J=74.04 Hz, 1H) 7.09 (dd, J=7.91, 2.20 Hz, 1H) 7.23 (s, 1H) 7.28-7.34 (m, 1H) 7.38 (t, J=7.91 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[Br:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:21][C:22]1[CH:26]=[CH:25][N:24]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[N:23]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: Brc1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3-n3ccc(Br)n3)nc2c1
Temperature: 50 °C
Yield: 76.4 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.19 g of 3-bromopyrazole, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at 50° C. for 1.5 hours. Then, the reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.31 g of 2-[3-(3-bromopyrazole-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 59”).