Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([NH:17]OC)([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:20])[C:3]=1[C:21]1[NH:26][C:25]2[CH:27]=[CH:28][C:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][C:24]=2[S:23](=[O:40])(=[O:39])[N:22]=1>CC#N.O.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[NH2:17][C@@:5]1([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:21]2[NH:26][C:25]3[CH:27]=[CH:28][C:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][C:24]=3[S:23](=[O:40])(=[O:39])[N:22]=2)[C:4]1=[O:20]
Reactant: CON[C@]1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Agent: [Mo]
Agent: [C-]#[O+]
Solvent: CC#N
Solvent: O
Product: CC(C)CC[C@@]1(N)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 77.5 %

Procedure:
To a solution of Example 83A (905 mg, 1.6 mmol) in CH3CN (72 mL) and H2O (5 mL) was added molybdenum hexacarbonyl (293 mg, 1.1 mmol) and the solution was refluxed for 2 hours, cooled to room temperature, solvent removed in vacuo and the crude residue purified by column chromatography on silica gel (2% methanol/chloroform) to give the title compound as a colorless solid (670 mg, 78%): 1H NMR (d6-DMSO) δ 14.34 (s, 1H), 9.64 (s, 1H), 8.59 (br s, 2H), 8.13, 8.11 (d, 1H), 7.93 (s, 1H), 7.69-7.45 (m, 4H), 7.27, 7.24 (d, 1H), 2.08-1.95 (m, 1H), 1.92-1.80 (m, 1H), 1.30-0.99 (m, 4H), 0.54-0.46 (m, 1H), 1.50 (s, 9H), 1.45-1.23 (m, 1H), 1.18-0.96 (m, 1H), 0.92-0.62 (m, 7H); MS (ESI) m/z 541 (M+H+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][C:7]=1[S:15](=[O:18])(=[O:17])[NH2:16].[C:19]1([S:25]([N:28]2[CH:32]=[CH:31][CH:30]=[CH:29]2)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:19]1([S:25]([N:28]2[CH:29]=[CH:30][C:31]([C:10]([C:9]3[CH:13]=[CH:14][C:6]([Cl:5])=[C:7]([S:15]([NH2:16])(=[O:18])=[O:17])[CH:8]=3)=[O:11])=[CH:32]2)(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=S(=O)(c1ccccc1)n1cccc1
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(C(=O)c2ccn(S(=O)(=O)c3ccccc3)c2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.9 %

Procedure:
To a suspension of aluminum chloride (1.89 g, 14 mmol) in methylene chloride (10 mL) is added 4-chloro-3-sulfamoyl-benzoyl chloride (2 g, 7.9 mmol). The reaction mixture is stirred at room temperature for 10 minutes then a solution of 1-benzenesulfonyl-1H-pyrrole (1.13 g, 5.45 mmol) in methylene chloride (3.3 mL) is added. After stirring at room temperature overnight, the reaction is quenched with 6 N HCl and extracted with ethyl acetate three times. The combined organic layers are washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (ethyl acetate/hexane: 2:8) provides 0.6 g (26%) of the title compound as a yellow solid. 1H NMR (DMSO): δ 8.30 (s, 1H), 8.15 (m, 2H), 8.05 (m, 2H), 7.80 (m, 4H), 7.70 (m, 2H), 7.40 (m, 1H), 6.70 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.[NH2:18][C:19](=[N:25]O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]1[O:11][N:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=1
Reactant: O=C(O)Cc1ccccc1F
Reactant: CCOC(=O)C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc(Cc2ccccc2F)n1
Yield: 13.1 %

Procedure:
This compound was prepared according to general method 2 with 2-(2-fluorophenyl)acetic acid (1.19 g; 7.57 mmol) and oxalyl chloride (0.704 mL; 8.33 mmol) in dichloromethane (5 mL) with a few drops of DMF; and ethyl 2-amino-2-(hydroxyimino)acetate (1.0 g; 7.57 mmol) and N,N diisopropylethylamine (2.11 mL; 12.11 mmol) in dichloromethane (10 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.249 g (14%) of ethyl 5-(2-fluorobenzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[C:6](\[CH3:9])/[CH:7]=O)[C@H:3]1[C:10]([O:12][CH3:13])=[O:11].Cl.[CH2:16]([O:18][NH2:19])[CH3:17].N1C=CC=CC=1>C(OCC)(=O)C>[CH2:16]([O:18][N:19]=[CH:7]/[C:6](/[CH3:9])=[CH:5]/[C@@H:4]1[C@@H:3]([C:10]([O:12][CH3:13])=[O:11])[C:2]1([CH3:14])[CH3:1])[CH3:17]
Reactant: COC(=O)[C@@H]1[C@@H](/C=C(\C)C=O)C1(C)C
Reactant: CCON
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCON=C/C(C)=C/[C@@H]1[C@@H](C(=O)OC)C1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.3 %

Procedure:
Under nitrogen atmosphere, a mixture of 0.94 g of methyl (1R)-trans-2,2-dimethyl-3-[(E)-2-methyl-3-oxo-1-propenyl]cyclopropanecarboxylate, 0.47 g of O-ethylhydroxylamine hydrochloride and 2 ml of pyridine was stirred at room temperature for 4 hours. Then, ethyl acetate was added to the reaction mixture, and the mixture was washed with 1 mol/L hydrochloric acid and saturated brine respectively. The organic layer was dried over anhydrous magnesium sulfate, then, filtrated, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.92 g of methyl (1R)-trans-3-[(E)-3-ethoxyimino-2-methyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylate:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:16])=[C:12]([F:15])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:17].[NH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:16][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][C:12]=1[F:15])[N:5]([CH2:4][CH2:3][CH2:2][N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:20][CH2:19]1)[C:6](=[O:17])[CH2:7][CH2:8]2
Reactant: CC(C)(C)C(=O)OCC1CCNCC1
Reactant: O=C1CCc2cc(F)c(F)cc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)OCC1CCN(CCCN2C(=O)CCc3cc(F)c(F)cc32)CC1
Temperature: 80 °C
Reaction time: 72 h
Yield: 31 %

Procedure:
A 4 ml vial was charged with 1-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (52 mg, 0.20 mmol), 2,2-dimethylpropionic acid piperidin-4-ylmethyl ester (45 mg, 0.21 mmol) (40 mg, 0.20 mmol), and Cs2CO3 (200 mg, 0.60 mmol) in dry DMF (1 ml). The reaction was shaken at 80° C. for 3 days and the reaction was poured into water and extracted with EtOAc. The combined organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The oily residue was purified by ion-exchange column chromatography to yield the title product as an oil (26 mg, 62 μmol, 31%). 1H NMR (CDCl3) d 7.07 (dd, J=1.8, 3.1 Hz, 1H), 6.98-6.91 (m, 1H), 3.94-3.87 (m, 4H), 2.94-2.86 (m, 2H), 2.82 (br t, J=6.8 Hz, 2H), 2.02 (dd, J=5.2, 7.6 Hz, 2H), 2.35 (t, J=6.8 Hz, 2H), 1.94 (dt, J=2.0, 11.6 Hz, 2H), 1.74-1.58 (m, 3H), 1.42-1.28 (m, 2H), 1.91 (s, 9H); 13C NMR (CDCl3) d178.7, 169.7, 149.3 (dd, J=13, 230 Hz), 145.6 (dd, J=243, 13 Hz), 136.7 (br), 122.7 (br), 116.6 (d, J=18 Hz), 105.3 (d, J=22 Hz), 68.8, 55.8, 53.7, 42.3, 39.1, 35.7, 31.1, 29.1, 25.2, 24.9; HPLC-MS (ammonium acetate) [M+H]+=423.20.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]3[N:27]=[CH:26][N:25]([CH2:28][CH2:29][OH:30])[N:24]=3)[C@H:17]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[S:39](Cl)([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40].C(N(CC)CC)C>ClCCl>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[O:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]3[N:27]=[CH:26][N:25]([CH2:28][CH2:29][O:30][S:39]([C:42]4[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=4)(=[O:41])=[O:40])[N:24]=3)[C@H:17]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:37])[F:38])[CH:8]=1
Reactant: C[C@@H](O[C@H]1OCCN(Cc2ncn(CCO)n2)[C@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCn2cnc(CN3CCO[C@H](O[C@H](C)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The alcohol from step (a), above, (1.81 g, 3.22 mM) was dissolved in dichloromethane (20 ml), tosyl chloride (1.84 g, 9.66 mM) and triethylamine (1.34 ml, 9.66 mM) were added and the reaction stirred at room temperature for 18 hrs. The solvent was removed and the residue redissolved in ethyl acetate and washed with water and brine, dried (MgSO4) and evaporated. The product was purified on silica eluting with methanol-clichloromethane mixtures (1.87 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:15]([F:18])([F:17])[F:16])=[O:12])=[CH:8][C:7]=2[CH:29]=1.N1C=CC=CC=1.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl.C(OCC)(=O)C>[C:36]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=3)[C:15]([F:16])([F:17])[F:18])=[O:12])=[CH:8][C:7]=2[CH:29]=1)(=[O:38])[CH3:37]
Reactant: NCc1ccc2oc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)cc2c1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCc1ccc2oc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)cc2c1
Temperature: 0 °C

Procedure:
A solution of 5-(aminomethyl)-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1-benzofuran-2-carboxamide (50 mg, 0.12 mmol) in dichloromethane (1 ml) was admixed with pyridine (0.01 ml) and cooled to 0° C. Then acetyl chloride (9 μl, 0.12 mmol) was added dropwise and the mixture was warmed up to room temperature overnight. The mixture was diluted with ethyl acetate and washed with hydrochloric acid (1 M). The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was chromatographed on a preparative HPLC with water/acetonitrile as the eluent (gradient=43 min from 10% acetonitrile in water to 100% acetonitrile).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:36]([NH:39][C@@H:40]1[CH2:44][NH:43][C@H:42]([CH2:45][OH:46])[CH2:41]1)(=[O:38])[CH3:37].CS(C)=O.CC#N>C(O)(C(F)(F)F)=O>[C:36]([NH:39][C@@H:40]1[CH2:44][N:43]([C:21]2[N:20]=[CH:19][C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]3[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=[C:3]([C:2]([F:34])([F:1])[F:35])[CH:4]=3)([CH3:33])[CH3:32])=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH:22]=2)[C@H:42]([CH2:45][OH:46])[CH2:41]1)(=[O:38])[CH3:37]
Reactant: CC(=O)N[C@@H]1CN[C@H](CO)C1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Solvent: CC#N
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N[C@H]1C[C@@H](CO)N(c2cc(-c3ccccc3Cl)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)C1
Temperature: 130 °C
Yield: 59.8 %

Procedure:
A mixture of 30 mg (0.056 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 200 mg (1.27 mmol) (2S,4S)-4-acetylamino-2-hydroxymethyl-pyrrolidine and 0.2 ml dimethyl sulfoxide was heated at 130° C. for 24 h. After cooling to room temperature, 22 mg (59%) of the title compound were isolated as a white solid by automated, preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min). (2S,4S)-4-Acetylamino-2-hydroxymethyl-pyrrolidine can be obtained by the method described by Terry Rosen, Daniel T. W. Chu, Isabella M. Lico, Isabella M. Lico, Prabhavathi B. Fernandes, Kennan Marsh, Linus Shen, Valerie G. Cepa, André G. Pernet, J. Med. Chem. 1988, 31, 1598.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>C(#N)C>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:3][CH:4]=1
Reactant: OCc1ccc(O)cc1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(COc1ccc(CO)cc1)c1ccccc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 82.2 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged 20 mL of acetonitrile. To the stirred solvent was added 4-Hydroxy-benzylalcohol (6.74 g, 25.1 mmol) and K2CO3 (10.4 g, 75.3 mmol). Then it was stirred for 5 min. 2-bromo-1-phenylethanone (5 g, 25.1 mmol) was added. Then RM heated 80° C. for 2 h. After completion of the reaction (reaction monitored by TLC), the RM was concentrated in vacuum to remove the acetonitrile. To the residue was then added 10 mL of water and extracted with ethyl acetate (15 mL×2). The organic layer was washed with saturated brine solution (15 mL), dried over anhydrous Na2SO4 and evaporated to dryness gave the titled compound (5 g, yield: 82.2%); 1H NMR (300 MHz, CDCl3): δ 7.92-7.94 (d, 2H), 7.53-7.58 (t, 1H), 7.41-7.46 (t, 2H), 7.21-7.24 (d, 2H), 6.85-6.86 (d, 2H), 5.22 (s, 2H), 4.55 (s, 2H).
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:30])[NH:28][OH:29])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.C(Cl)[Cl:32]>>[ClH:32].[NH2:8][CH:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:30])[NH:28][OH:29])=[CH:23][CH:22]=2)=[CH:18][CH:19]=1)[C:10]([OH:12])=[O:11]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(C(=O)NO)cc2)cc1)C(=O)O
Product: Cl
Product: NC(Cc1ccc(Oc2ccc(C(=O)NO)cc2)cc1)C(=O)O
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
The hydroxamate 8 (0.2 g) was dissolved in CH2Cl2 and cooled to 0-5° C. Hydrogen chloride gas was bubbled through this solution for 20 min. The bubbling was discontinued and the reaction mixture was stirred at room temperature for 1 h. The excess HCl was degassed and the CH2Cl2 was removed. The residual solid was triturated with EtOAc (2×25 mL), decanted, and dried to yield the desired compound 9 as a white amorphous solid (0.17 g, quantitative yield). 1H NMR (360 MHz, DMSO-d6): 11.15 (s, 1H), 8.96 (br, 1H), 7.77 (d, J=9.0 Hz, 2H), 7.32 (d, J=7.9 Hz, 2H), 7.04 (d, J=9.0 Hz, 2H), 6.99 (d, J=8.6 Hz, 2H), 4.16 (m, 1H), 3.09-3.14 (m, 2H). LCMS (m/e): Obsd. 317.0, Calcd. 316.31.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:10]1[CH:11]=[C:12]([NH:25][C:26]([NH:28][C@@H:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@H:32]([O:39][C:40]3[CH:41]=[CH:42][C:43]4[N:44]([C:46]([N:49]5[CH2:54][CH2:53][CH2:52][CH2:51][C@@H:50]5[CH3:55])=[N:47][N:48]=4)[CH:45]=3)[CH2:31][CH2:30]2)=[O:27])[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][OH:24])[CH:16]=2)[N:14]=1)([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C.O>C(Cl)Cl>[C:6]([C:10]1[CH:11]=[C:12]([NH:25][C:26]([NH:28][C@@H:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@H:32]([O:39][C:40]3[CH:41]=[CH:42][C:43]4[N:44]([C:46]([N:49]5[CH2:54][CH2:53][CH2:52][CH2:51][C@@H:50]5[CH3:55])=[N:47][N:48]=4)[CH:45]=3)[CH2:31][CH2:30]2)=[O:27])[N:13]([C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[O:21][CH2:22][CH2:23][O:24][S:2]([CH3:1])(=[O:4])=[O:3])[N:14]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.8 %

Procedure:
Methanesulfonyl chloride (81 μL, 1.05 mmol) was added to a stirred solution of Intermediate 95e (545 mg, 803 mmol) and DIPEA (420 μL, 2.41 mmol) in DCM (20 mL), under argon and the reaction mixture was stirred at RT for 1.5 h. A further 25 μL, 0.32 mmol of methanesulfonyl chloride was added and the reaction mixture continued to stir at RT for 2 h. Water (20 mL) was added and the two layers were shaken thoroughly before being separated. The aqueous layer was extracted with DCM (2×20 mL) and the combined organics were passed through a phase separator and concentrated in vacuo to afford the title compound as an orange glass (690 mg, >100%). LCMS (Method 3): Rt 3.89 min, m/z 757 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)=[CH:4][C:3]=1[C:17](=[O:20])[CH2:18][CH3:19].[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[Li].C1N=CN([C:32](N2C=NC=C2)=[O:33])C=1>C1COCC1>[Cl:16][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:32](=[O:33])[O:20][C:17]([CH2:18][CH3:19])([C:22]4[S:21][CH:25]=[CH:24][CH:23]=4)[C:3]=3[CH:4]=2)[CH:14]=[CH:13][C:12]=1[F:15]
Reactant: CCC(=O)c1cc(Nc2ccc(F)c(Cl)c2)ccc1N
Reactant: [Li]c1cccs1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCC1(c2cccs2)OC(=O)Nc2ccc(Nc3ccc(F)c(Cl)c3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.8 %

Procedure:
To a stirred solution of 1-{2-amino-5-[(3-chloro-4-fluorophenyl)amino]-phenyl}propan-1-one (2.40 g, 8.20 mmol) in THF (80 mL) was added 1.0M thienyllithium (32 mL, 32 mmol) slowly at 0° C. over 20 minutes. The reaction was stirred overnight at room temperature, quenched with ammonium chloride solution (sat.), and extracted with ethyl acetate several times. The organic layer washed with brine and dried over magnesium sulfate. The concentrated crude material was dissolved in THF (40 mL). CDI (2.66 g, 16.40 mmol) was added and the reaction was stirred overnight at room temperature. The reaction solution was partitioned between ammonium chloride solution (sat.) and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. Flash silica gel column separation with 30% ethyl acetate/hexane followed by trituration with methylene chloride/ether gave 6-[(3-chloro-4-fluorophenyl)amino]-4-ethyl-4-thien-2-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid (0.19 g, 5%). 1H NMR (DMSO-d6): δ 10.22 (s, 1H), 8.20 (s, 1H), 7.53 (dd, J=5.0, 1.3 Hz, 1H), 7.24 (t, J=9.0 Hz, 1H), 7.07 (dd, J=8.5, 2.3 Hz, 1H), 7.0 (m, 3H), 6.92 (dd, J=3.6, 1.3 Hz, 1H), 6.88 (m, 2H), 2.43 (m, 2H), 0.96 (t, J=7.1 Hz, 3H); MS (ESI) m/z 403/405 ([M+H]+); MS (ESI) m/z 401/403 ([M−H]−); HRMS: calcd for C20H16ClFN2O2S, 402.0605; found (ESI+), 403.06762; Anal. calcd for C20H16ClFN2O2S: C, 59.63; H, 4.00; N, 6.95. Found: C, 59.79; H, 4.35; N, 6.55.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.O=[C:18]([CH2:25][CH2:26][CH3:27])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH2:25][CH2:26][CH3:27])[NH:11][C:12]2=[N:13][NH:14][CH:15]=[C:16]12
Reactant: O=Cc1cc(F)ccc1F
Reactant: CCCC(=O)CC(=O)OCC
Reactant: Nc1cc[nH]n1
Product: CCCC1=C(C(=O)OCC)C(c2cc(F)ccc2F)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2,5-difluorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [OH-:1].[K+].[F:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C:14]1[C:23]2[N:22]=[CH:21][CH:20]=[N:19][C:18]=2[C:17]([C:24]#N)=[CH:16][CH:15]=1.[OH2:26]>C(O)CO.CCOCC.O>[F:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C:14]1[C:23]2[N:22]=[CH:21][CH:20]=[N:19][C:18]=2[C:17]([C:24]([OH:26])=[O:1])=[CH:16][CH:15]=1
Reactant: [OH-]
Reactant: O
Reactant: COc1cc(OC)c(F)c(-c2ccc(C#N)c3nccnc23)c1
Agent: [K+]
Solvent: CCOCC
Solvent: OCCO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)O)c3nccnc23)c1
Temperature: 150 °C
Reaction time: 5 h

Procedure:
A solution of KOH (2.95 g, 52.7 mmol, 10 equiv) in H2O (20 mL) was added to 8-(2-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carbonitrile (Step 94.2) (1.63 g mg, 5.3 mmol) in ethylene glycol (20 mL). The reaction mixture was stirred at 150° C. for 5 h, allowed to cool to rt, diluted with Et2O/H2O, and extracted with Et2O. The aqueous phase was acidified to pH 3 by addition of HCl. The resulting yellow solid was collected by vacuum filtration to provide 1.71 g of the title compound: ESI-MS: 329.1 [M+H]+; tR=4.18 min (System 1).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[CH2:24]([O:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]=1[C:37](O)=[O:38])[CH3:25].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C1CCN2C(=NCCC2)CC1.Cl>CN(C)C=O.O>[CH2:24]([O:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]=1[C:37]([NH:22][CH:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[C:9]([C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=1)=[O:23])=[O:38])[CH3:25]
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1
Reactant: CCOc1ccc2ccccc2c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCOc1ccc2ccccc2c1C(=O)NC(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 1-(4-fluorophenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (600 mg, 1.73 mmol) and 2-ethyloxy-1-naphthalenecarboxylic acid (411 mg, 1.90 mmol) in N,N-dimethylformamide (10 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (496 mg, 2.59 mmol), 1-hydroxy-1H-benzotriazole (396 mg, 2.59 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.28 ml, 1.90 mmol) and the mixture was stirred overnight. To the reaction solution were added 1N aqueous hydrochloric acid solution (10 ml) and water (100 ml) and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization from ethyl acetate-hexane gave 2-(ethyloxy)-N-(2-(4-fluorophenyl)-2-oxo-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide (670 mg, 76%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:17])=[C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:10]=1[CH3:11])=[O:5])[CH3:2].[O:18]1CCCC1>C(O)(=O)C.O.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:17]=[O:18])=[C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(C)c(CCC(=O)O)c1C
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1[nH]c(C=O)c(CCC(=O)O)c1C
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a mixture of 7 g 4-(2-carboxyethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester in 35 mL each of tetrahydrofuran (THF), acetic acid (AcOH) and water at −10° C. was added 70 g of ceric ammonium nitrate in portion over 20 minutes, the reaction temperature being maintained at about 5° C. The resulting mixture was them cooled to 0° C., stirred for another 2 hr and then diluted with 250 mL of brine. The mixture was then extracted with 2×300 mL 10% MeOH in dichloromethane (DCM). The organic extracts were combined and dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated. The residue was purified on silica gel column with hexanes(hex)/ethyl acetate (EtOAc)/AcOH (6:4:0.05) followed by crystallization in EtOAc to give 1.5 g of 4-(2-carboxyethyl)-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester as a white solid.