Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](O)([C:17]1[C:25]([OH:26])=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=1)[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:17]1[C:25]([OH:26])=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=1)[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.1 %

Procedure:
To a solution of 4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one (34.9 g, 80.4 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (18.7 g, 161 mmol) and triethylsilane (18.3 g, 161 mmol). The brown solution was stirred at ambient temperature for 3 h and concentrated in vacuo to dryness. The residue was diluted with dichloromethane (200 mL), washed with saturated ammonium chloride solution (50.0 mL), brine (3×50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was crystallized from ether to give the title compound (16.5 g, 49%) as a brown solid: 1H NMR (300 MHz, CDCl3) δ 7.29-7.21 (m, 2H), 7.14 (dd, 1H), 6.58 (s, 1H), 6.10 (s, 1H), 5.85 (dd, 2H), 5.01 (s, 1H), 3.75-3.55 (m, 2H), 1.69-1.56 (m, 2H), 1.35-1.21 (m, 4H), 0.86 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 177.9, 150.9, 147.6, 145.4, 141.6, 130.3 127.1 126.8, 120.8, 113.3 108.0, 106.7, 101.5, 101.2, 59.9, 48.6, 40.7, 28.9, 26.9, 22.3 13.9; MS (ES+) m/z 418.3 (M+1), 420.3 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C:9]2O[C:13](=O)[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)(O)O.[NH2:26][NH:27][C:28]([NH2:30])=[NH:29]>N1C=CC=CC=1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C:9]2[N:26]3[N:27]=[C:28]([NH2:30])[N:29]=[C:13]3[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N=C(N)NN
Reactant: O=c1oc(Cc2ccc([N+](=O)[O-])cc2)nc2ccccc12
Agent: O=C(O)O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Nc1nc2c3ccccc3nc(Cc3ccc([N+](=O)[O-])cc3)n2n1
Yield: 41.7 %

Procedure:
A solution of 2-(4-nitrobenzyl)-4H-3,1-benzoxazin-4-one (5.7 g, 20.2 mmol) and aminoguanidine hydrogencarbonate (2.7 g, 20.2 mmol) in pyridine (25 mL) was heated under microwave condition at 180° C. for 30 minutes. After cooling, the red solution was taken up in ethyl acetate, washed with brine and dried over Na2SO4. The solvent was removed in vacuum and the residue was chromatographed on silica gel eluting with DCM/CH3OH 95/5 to furnish the title compound (2.7 g, 42% yield)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc(C=O)c1
Temperature: 80 °C
Yield: 23 %

Procedure:
3-hydroxy benzaldehyde/ethyl 2-bromoacetate (1.1 eq) and K2CO3 (2 eq) were taken in DMF and heated at 80° C. for 16 h when TLC indicated completion of reaction. The reaction mixture was cooled to rt and poured into water. Extraction was done with DCM. The combined organic extracts was dried, concentrated and purified by column chromatography using silica gel (100-200 mesh) to afford the pure product (23%) as a colorless oil. NMR: δ 1.298 (t, J=7.2 Hz, 3H), 4.27 (q, J=7.2 Hz, 2H), 4.683 (s, 1H), 7.20-7.27 (m, 1H), 7.361 (s, 1H), 7.42-7.52 (m, 2H), 9.96 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:38]([N:39]([CH3:45])[CH:40]3[CH2:44][CH2:43][S:42][CH2:41]3)=[CH:37][C:15]3[N:16]([CH3:36])[C:17]([NH:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:21]=4[Cl:35])=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:5][CH2:4]1.C1C=C(Cl)C=C(C(OO)=[O:56])C=1.C(Cl)Cl.C(O)(=O)C>C([O-])(O)=O.[Na+]>[F:47][C:2]([F:1])([F:46])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:38]([N:39]([CH3:45])[CH:40]3[CH2:44][CH2:43][S:42](=[O:56])[CH2:41]3)=[CH:37][C:15]3[N:16]([CH3:36])[C:17]([NH:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:31])[CH3:32])[C:21]=4[Cl:35])=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(c1cc2c(cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1)nc(Nc1c(Cl)ccc(CNC(=O)C(C)(C)C)c1Cl)n2C)C1CCSC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(c1cc2c(cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1)nc(Nc1c(Cl)ccc(CNC(=O)C(C)(C)C)c1Cl)n2C)C1CCS(=O)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-6-[N-methyl-N-(tetrahydro-thiophen-3-yl)-amino]-1-methyl-1H-benzimidazole-5-carboxylic acid amide (compound 117, 70 mg, 0.098 mmol), mCPBA (23 mg, ˜0.10 mmol), DCM (5 mL) and glacial acetic acid (0.5 mL) is stirred for 2.5 h at rt. The mixture is diluted with sat aq NaHCO3, extracted with EtOAc, the combined organic phases are dried with Na2SO4, filtered and concentrated.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14](O)=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.C(Cl)(Cl)[Cl:23].S(Cl)(Cl)=O>CN(C)C=O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([Cl:23])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: ClC(Cl)Cl
Reactant: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C(=O)Cl)c1ccc2c(=O)c3ccccc3ccc2c1
Reaction time: 1 h

Procedure:
1.0 G. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid is dissolved in 25 ml. of chloroform, and 1 ml. of thionyl chloride and 0.1 ml. of dimethylformamide are added thereto. The mixture is left for 1 hour then evaporated under high vacuum to afford 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionyl chloride. In similar manner, substituting the acids prepared in Preparations 3 and 5-9 for the 2-5-oxo-5H-dibenzo[a,d]cyclohepten-2yl)propionic acid used above, the corresponding acid chlorides are prepared.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:24]1[N:25]=[C:26]([CH3:29])[S:27][CH:28]=1)[C:20]([O:22][CH3:23])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:24]2[N:25]=[C:26]([CH3:29])[S:27][CH:28]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)C(N)c1csc(C)n1
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1csc(C)n1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(2-methylthiazol-4-yl)acetate (prepared from N-Boc-2-amino-2-(2-methylthiazol-4-yl)acetic acid [CAS 105381-90-6] using General Procedure H above), the title compound was prepared as a solid. The product was purified by tituration using Et2O/hexanes.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C:4](O)=[O:5].[Br:9][C:10]1[CH:24]=[C:23](/[CH:25]=[CH:26]/[CH:27]([C:32]2[CH:37]=[C:36]([Cl:38])[C:35]([Cl:39])=[C:34]([Cl:40])[CH:33]=2)[C:28]([F:31])([F:30])[F:29])[CH:22]=[CH:21][C:11]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:13].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:9][C:10]1[CH:24]=[C:23](/[CH:25]=[CH:26]/[CH:27]([C:32]2[CH:33]=[C:34]([Cl:40])[C:35]([Cl:39])=[C:36]([Cl:38])[CH:37]=2)[C:28]([F:31])([F:29])[F:30])[CH:22]=[CH:21][C:11]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:4](=[O:5])[CH2:3][C:2]([F:8])([F:7])[F:1])[CH2:17][CH2:16]1)=[O:13]
Reactant: O=C(O)CC(F)(F)F
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCN(C(=O)CC(F)(F)F)CC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 3,3,3-trifluoropropanoic acid (0.02 g, 0.16 mmol) in CH2Cl2 (10.0 mL), (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol), PYBOP (0.09 g, 0.17 mmol), and DIPEA (0.06 g, 0.48 mmol) were added at ambient temperature. The reaction mixture was stirred at ambient temperature for 5 h. The reaction mixture was diluted with CH2Cl2. The combined CH2Cl2 layer was washed with 3N HCl and saturated NaHCO3 solution, the separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; eluting with 2% MeOH in CH2Cl2) to afford the title compound as a off white gummy material (0.035 g, 29.%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC(C)([O-])C.[Na+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([C:26]3[N:31]=[CH:30][C:29]([CH2:32][N:33]4[CH2:38][CH2:37][CH2:36][O:35][C:34]4=[O:39])=[CH:28][CH:27]=3)[S:25][C:18]=12.O>CS(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[CH:23]=[C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][N:33]5[CH2:38][CH2:37][CH2:36][O:35][C:34]5=[O:39])=[CH:28][CH:27]=4)[S:25][C:18]=23)=[C:4]([F:9])[CH:3]=1
Reactant: O=C1OCCCN1Cc1ccc(-c2cc3nccc(Cl)c3s2)nc1
Reactant: Nc1ccc(O)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCOC5=O)cn4)sc23)c(F)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 117.4 %

Procedure:
To a solution of 4-amino-2-fluorophenol (70.7 mg, 0.556 mmol) in DMSO (5 mL) was added sodium tert-butoxide (53.4 mg, 0.556 mmol) and the reaction mixture was stirred for 30 min. Chloride 199 (100 mg, 0.278 mmol) was added and the reaction mixture was heated at 100° C. overnight. The mixture was then cooled to RT and poured into water (20 mL) and the precipitated product was collected by filtration and purified by Biotage (MeOH/EtOAc 0-50%, SNAP 25 g cartridge) to give title compound 200 (147 mg, 33% yield) as a beige solid. MS: 451 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([CH3:9])[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: C1CCNC1
Solvent: CC(C)O
Product: Cc1cc(N2CCCC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
0.815 g (5 mmol) of 2,4-dichloro-6-methylpyrimidine dissolved in in 5 ml isopropanol were treated under ice-cooling dropwise with 0.71 g (10 mmol) pyrrolidine. The mixture was stirred for 1 h at RT the concentrated in vacuo. The residue was purified on a silica gel chromatography column with CH2Cl2/AcOEt (4/1) as eluent to give 0.72 g (73%) of the desired 2-chloro-4-methyl-6-pyrrolidin-1-yl-pyrimidine as an off-white solid. EI mass spectrum, m/e: 197 (M calculated for C9H12N3Cl: 197).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@H:5](O)[CH2:4][C@H:3]1[C:8]([NH2:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:42]([OH:45])(=[S:44])[CH3:43]>CN(C)C=O.ClCCl>[CH3:1][N:2]1[CH2:6][C@@H:5]([S:44][C:42](=[O:45])[CH3:43])[CH2:4][C@H:3]1[C:8]([NH2:10])=[O:9]
Reactant: CN1C[C@H](O)C[C@H]1C(N)=O
Reactant: CC(O)=S
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)S[C@H]1C[C@@H](C(N)=O)N(C)C1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
(2S,4R)-1-Methyl-2-aminocarbonyl-4-hydroxypyrrolidine (540 mg) was dissolved in dry dimethylformamide (10 ml), and triphenylphosphine (1.78 g) was added thereto. To the resultant mixture, diethyl azodicarboxylate (1.07 ml) was added under nitrogen steam while ice-cooling, and the mixture was stirred for 35 minutes. Thioacetic acid (0.76 ml) was added to the mixture under ice-cooling, and stirring was continued for 30 minutes under ice-cooling and at room temperature for 4 hours. The reaction mixture was diluted with dichloromethane, washed with aqueous sodium bicarbonate solution and dried over magnesium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography to give (2S,4S)-1-methyl-2-aminocarbonyl-4-acetylthiopyrrolidine.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].O>CS(C)=O>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][N:1]=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CCCCBr
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CCCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
Add sodium azide (12.5 g, 193 mmol) to a rapidly stirred solution of methyl 5-bromovalerate (25.08 g, 129 mmol) in DMSO (200 mL, anhydrous). Stir at room temperature overnight under N2. Add water (400 mL) and stir for 30 minutes. Extract with Et2O (×3) and wash combined Et2O layers with brine (×3). Dry organic layer over MgSO4 and concentrate to give the title compound (20.3 g, 100%).
Reaction SMILES: Cl.C[O:3][C:4](=O)[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[NH2:6].[NH3:16]>CO>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C@@H:5]([C:4]([NH2:16])=[O:3])[NH2:6])=[CH:9][CH:10]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)cc1
Reactant: N
Agent: Cl
Solvent: CO
Product: NC(=O)[C@@H](N)Cc1ccc(Cl)cc1
Reaction time: 96 h

Procedure:
0.1 mole (25 grams) of 4-chlorophenylalanine methyl ester hydrochloride were dissolved in 250 ml of methanol. Then ammonia was led in at 0° C. several times, each time up to saturation. The reaction was finished after 4 days. The solvent was drawn off and the white residue dried. The product was employed in this form in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]([F:27])[F:26])[CH:22]=[C:21]([C:28]#[N:29])[CH:20]=2)[C:12]=1[F:30])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]([F:26])[F:27])[CH:22]=[C:21]([C:28]#[N:29])[CH:20]=2)[C:12]=1[F:30])=[O:8]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)cc(C(F)F)c2)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)cc(C(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
To a solution of 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(difluoromethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (81 mg, 0.138 mmol) dissolved in DCM (5 ml) was added TFA (2.00 ml) and the reaction mixture was stirred at RT for 2 hours. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(difluoromethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (56 mg, 0.123 mmol, 89% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.77 (s, 1H), 7.65 (s, 1H), 7.23-7.50 (m, 4H), 6.81 (t, 1H), 4.64 (s, 2H). LC-MS (ES+) m/z 454.97, [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[F:41])=[C:6]([C:8]2[C:16]3[C:11](=[C:12]([O:30][CH3:31])[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)[CH:15]=3)[N:10]([CH3:32])[CH:9]=2)[CH:7]=1.C(N(C(C)C)C(C)C)C.[CH2:51]([S:53](Cl)(=[O:55])=[O:54])[CH3:52].[OH-].[Na+]>ClCCl>[F:41][C:35]1[CH:36]=[C:37]([F:40])[CH:38]=[CH:39][C:34]=1[O:33][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:53]([CH2:51][CH3:52])(=[O:55])=[O:54])=[CH:7][C:6]=1[C:8]1[C:16]2[C:11](=[C:12]([O:30][CH3:31])[N:13]=[C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19][CH2:18]3)[CH:15]=2)[N:10]([CH3:32])[CH:9]=1
Reactant: COc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)cc2c(-c3cc(N)ccc3Oc3ccc(F)cc3F)cn(C)c12
Reactant: CCS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c3c(OC)nc(C4CCN(C(=O)OC(C)(C)C)CC4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of Example 183B (205 mg, 0.363 mmol) in 10 mL dichloromethane was added N-ethyl-N-isopropylpropan-2-amine (254 μL, 1.452 mmol) and ethanesulfonyl chloride (120 μL, 1.271 mmol). The mixture was stirred at ambient temperature overnight. The mixture was concentrated. The viscous oil residue was taken into dioxane (10 mL) and treated with sodium hydroxide (5446 μL, 5.45 mmol, 1N aqueous solution). The mixture was stirred at ambient temperature for 80 minutes and then quenched with saturated ammonium hydroxide solution, and partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phases were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel with a gradient of 0-60% ethyl acetate in heptanes to give the title compound (110 mg, 0.167 mmol, 46.1% yield).
Reaction SMILES: CN(C=O)C.[C:6]([Cl:11])(=O)[C:7](Cl)=O.[I:12][C:13]1[CH:22]=CC2[C:15](=[CH:16][NH:17][C:18](=O)[N:19]=2)[CH:14]=1>ClCCCl>[I:12][C:13]1[CH:22]=[C:7]2[C:16](=[CH:15][CH:14]=1)[N:17]=[CH:18][N:19]=[C:6]2[Cl:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=c1nc2ccc(I)cc2c[nH]1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Clc1ncnc2ccc(I)cc12
Temperature: 25 °C

Procedure:
To a stirred solution of DMF (6.3 mL) in DCE (20 mL) cooled to 0° C. was added dropwise a solution of oxalyl chloride (60 mL of a 2M solution in DCE). After addition was complete, the cooling bath was removed and 6-iodo-3H-quinazolinone (10 g, 36.8 mmol) was added as a solid. The resulting mixture was heated to reflux under nitrogen for 3 hours. Upon cooling to room temperature, the reaction was quenched cautiously with H20. CH2Cl2 was added and the bilayer transferred to a separatory funnel. The aqueous layer was extracted with CH2Cl2 (2×50 mL) and the combined organic layers dried (Na2SO4). The solvent was removed in vacuo to provide a yellow solid which was triturated with diethyl ether to remove any remaining impurities. The resulting yellow solid obtained by filtration was shown to be pure by NMR. 1HNMR (CDCl3, 400 MHz): δ: 9.05 (s, 1H), 8.65 (d, 1H), 8.21 (dd, 1H), 7.78 (d, 1H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16](O)(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH3:26][C:27]1([CH3:35])[O:34][C:32](=[O:33])[CH2:31][C:29](=[O:30])[O:28]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:26][C:27]1([CH3:35])[O:34][C:32](=[O:33])[CH:31]([C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:29](=[O:30])[O:28]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
N,N′-Dicyclohexylcarbodiimide (11 mmol) was added to a stirred solution of octanoic acid (10 mmol) and 4-dimethylaminopyridine (12 mmol) in dry dichloromethane (40 ml). The mixture was stirred at room temperature for 1 hour and Meldrum's acid (10 mmol) was added. The stirring was continued at room temperature overnight. The solvent was removed in vacuum and the residue redissolved in ethyl acetate and filtered. The filtrate was washed with 2 M HCl solution and dried over MgSO4. The solvent was rotary evaporated to obtain the title product as an oil in 95% yield and was used without purification in the next step.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:9]([F:10])[CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1)=[N+]=[N-].[H][H]>C(O)C.[Pt]=O>[NH2:1][CH2:4][C@@H:5]1[C@H:9]([F:10])[CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1
Reactant: [N-]=[N+]=NC[C@H]1CN(Cc2ccccc2)C[C@H]1F
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: NC[C@H]1CN(Cc2ccccc2)C[C@H]1F
Yield: 99.9 %

Procedure:
(3R,4S)-3-Azidomethyl-1-benzyl-4-fluoropyrrolidine (215 mg) was dissolved in ethanol (3 mL). To this solution, platinum oxide (IV) (30.0 mg) was added and the mixture was stirred at room temperature for 5 hours in a stream of hydrogen (provided from a balloon). Subsequently, the catalyst was removed from the reaction mixture by filtration through a Celite pad. The removed catalyst and the Celite pad were washed with ethanol. The filtrate and the washing solution were combined and the combined organic layer was concentrated under reduced pressure to obtain 191 mg of (3S,4S)-3-aminomethyl-1-benzyl-4-fluoropyrrolidine as a brown oil.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[CH3:12].Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1COCC1.CCOCC>[CH2:17]([O:16][C:14](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[CH3:12])[CH3:18]
Reactant: Cc1cc(F)ccc1Br
Reactant: CCOC(=O)Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(F)cc1C
Temperature: -78 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
Magnesium (0.644 g, 26.5 mmol) was added wit THF (4 mL) and a small amount of iodine. After the mixture was stirred, the mixture was added dropwise with a solution of 1-bromo-4-fluoro-2-methylbenzene (5.00 g, 26.5 mmol) in THF (50 mL). The mixture was stirred at room temperature for 30 minutes, and then cooled at −78° C. and added dropwise with a solution of ethyl chloroformate (3.80 mL, 39.8mmol) in THF (40 mL). The mixture was warmed slowly up to room temperature and stirring was continued at room temperature for 2 hours. The reaction mixture was diluted with ether and washed with water, saturated aqueous sodium bicarbonate solution, and then with saturated brine, and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated, and the resulting oily substance was purified by silica gel column chromatography (hexane/ether) to obtain the title compound (3.65 g, yield: 76%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([NH:16][C:17]([NH:19][C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[N:23][NH:24]4)=[O:18])[CH2:7][C:8]([CH2:14][CH3:15])([CH2:12][CH3:13])[O:9]2)=[CH:4][CH:3]=1.[H-].[Na+].S(OC)(O[CH3:35])(=O)=O>CN(C)C=O>[CH2:12]([C:8]1([CH2:14][CH3:15])[CH2:7][CH:6]([NH:16][C:17]([NH:19][C:20]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:21]=2[CH:22]=[N:23][N:24]3[CH3:35])=[O:18])[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)[O:9]1)[CH3:13]
Reactant: COS(=O)(=O)OC
Reactant: CCC1(CC)CC(NC(=O)Nc2cccc3[nH]ncc23)c2ccc(F)cc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1(CC)CC(NC(=O)Nc2cccc3c2cnn3C)c2ccc(F)cc2O1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of Example 77D (212 mg, 0.554 mmol) in N,N-dimethylformamide (2.2 mL) was treated with 60% NaH (28 mg, 0.7 mmol), and the mixture was stirred at rt for 45 min. Dimethyl sulfate (0.06 mL, 0.634 mmol) was then added, and the reaction was allowed to stir for 1 h. Concentration in vacuo, followed by silica gel chromatography (98:2 dichloromethane-methanol, eluent) afforded the title compound as a tan foamy solid, 109 mg (50%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.72 (s, 1H), 8.03 (s, 1H), 7.70 (d, J=7.1 Hz, 1H), 7.25-7.36 (m, 2H), 7.17 (m, 1H), 6.70-6.77 (m, 2H), 6.63 (dd, J=10.5, 2.7 Hz, 1H), 4.94 (m, 1H), 4.00 (s, 3H), 2.19 (m, 1H), 1.58-1.77 (m, 5H), 0.84-0.94 (m, 6H). MS (ESI) m/z 397 (M+H).