Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.FC1C=CC(SC2CCNCC=2)=CC=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1.[H-].[Al+3].[H-].[H-]>CCOCC>[ClH:16].[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([S:23][C:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH:25]=2)=[CH:21][CH:22]=1
Reactant: Clc1ccc(Sc2ccncc2)cc1
Agent: Cl
Agent: Fc1ccc(SC2=CCNCC2)cc1
Agent: [Al+3]
Solvent: CCOCC
Product: Clc1ccc(SC2=CCNCC2)cc1

Procedure:
The product is prepared according to the procedure for the synthesis of 4-[(4-fluorophenyl)thio]-1,2,3,6-tetrahydropyridine hydrochloride by reducing 26.3 g of 4-[(4-chlorophenyl)thio]pyridine with aluminum hydride. The hydrochloride salt is generated in ether from the crude oil to afford a light tan powder, m.p. 174°-175° C.
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:7])[CH:4]=[CH:5][CH:6]=1.[N+:8]1([O-])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Pd]>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:6]1[CH:5]=[CH:4][C:3](=[O:7])[NH:2][N:1]=1
Reactant: [O-][n+]1ccccc1
Reactant: O=c1cccn[nH]1
Agent: [Pd]
Product: O=c1ccc(-c2ccccn2)n[nH]1

Procedure:
Haginiwa et al. [Yakugaku Zasshi 98 (1), 67-71 (1978); Chem. Abstrs. 88, 170,096v (1978)] reacted 3(2H)-pyridazinone with pyridine 1-oxide and platinized Pd-C catalyst to produce 6-(2-pyridinyl)-3(2H)-pyridazinone.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:21])[C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[F:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N+:17]([C:15]1[CH:16]=[C:11]([C:10]2[O:21][C:2]3[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=3[N:9]=2)[C:12]([F:20])=[CH:13][CH:14]=1)([O-:19])=[O:18]
Reactant: O=C(Nc1cc(Cl)ccc1O)c1cc([N+](=O)[O-])ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(Cl)ccc3o2)c1

Procedure:
Prepared by the method of Example 15b), from N-(2-hydroxy-5-chlorophenyl)-2-fluoro-5-nitrobenzamide (800 mg, 2.6 mmol) and p-toluenesulfonic acid monohydrate (1.17 g, 6.16 mmol) the subtitle compound was obtained (403 mg, 53%). MS m/z 291.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15].Cl[Sn]Cl.[OH-].[Na+]>CCO.Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15]
Reactant: CN(C)CCOc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(C)CCOc1cc(N)ccc1Cl
Temperature: 25 °C
Yield: 94.7 %

Procedure:
To 4-chloro-3-(2-dimethylaminoethoxy)nitrobenzene (1.5 g 0.006 mol) in EtOH (25 ml) at 60° C., was added SnCl2 (4.2 g) in concentrated hydrochloric acid (7.6 ml) dropwise. The mixture was then heated under reflux for 30 mins and after cooling to room temperature, diluted with water (50 ml), and basified by addition of 40% aq. sodium hydroxide. The mixture was extracted into CH2Cl2 and the combined organic layers, dried (Na2SO4) and concentrated in vacuo to give the title compound as a brown oil (1.22 g, 93%).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3Cl)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:31][C:32]1[C:37]([CH:38]([CH3:40])[CH3:39])=[CH:36][C:35](B(O)O)=[C:34]([O:44][CH3:45])[CH:33]=1.[OH-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCCC>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[C:35]3[CH:36]=[C:37]([CH:38]([CH3:40])[CH3:39])[C:32]([F:31])=[CH:33][C:34]=3[O:44][CH3:45])[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1c(F)cccc1Cl
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: CCCCCC
Product: COc1cc(F)c(C(C)C)cc1-c1cccc(F)c1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-chloro-6-fluorobenzyl)-4-methyl-1,3-oxazolidin-2-one (327 mg, 0.72 mmol) in 1,4-dioxane (4 mL) was added (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (228 mg, 1.08 mmol), Palladium(II) acetate (33 mg, 20 mol %), potassium hydroxide (588 μL, 3M, 2.5 eq.) and tri-tert-butylphosphine (44 mg, 0.22 mmol, 30 mol % as a 10% w/w hexane solution). The resulting reaction mixture was purged with nitrogen and sealed in a microwave vessel. The vessel was subject to microwave irradiation at 135° C. for 50 min. LC-MS indicated the starting material/product ratio was about 55:45. The reaction mixture was re-submitted to reaction conditions (μw at 135° C. for 50 min). The LC-MS trace indicated that no progress was made from the 2nd irradiation. More palladium(II) acetate (33 mg, 20 mol %) and tri-tert-butylphosphine (44 mg, 0.22 mmol, 30 mol % as a 10% w/w hexane solution) were added into reaction mixture. The mixture was resubmitted to reaction conditions (μw at 135° C., 1 hr). Again, the LC-MS indicated no significant progress. The reaction mixture was quenched with H2O. The volatiles were removed under reduced pressure. The resulting mixture was extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo to a yellow oil. The oil was dissolved in DMSO and purified twice by a reversed phase prep-HPLC (column: Kromasil, 100-5C18, 100×21.1 mm) eluted by 10% to 90% H2O (0.1% TFA, v/v)/MeCN (0.1% TFA, v/v). The resulting glassy material was then purified on a prep-TLC plate by 100% dichloromethane to afford the titled compound. LC-MS: 588.21 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 1:1 mixture of rotamers δ 7.83 (s, 1 H), 7.67 (s, 1 H) 7.65 (s, 1 H), 7.32-7.41 (m, 1H), 7.09-7.16 (m, 1H), 6.96-7.06 (m, 1H), 6.64-6.70 (m, 1H), 5.47 (d, J=8.0 Hz, 0.5 H), 5.19 (d, J=7.8 Hz, 0.5 H), 4.96 (d, J=14.9 Hz, 0.5 H), 4.80 (d, J=15.1 Hz, 0.5 H), 4.31 (d, J=15.1 Hz, 0.5 H), 3.91 (d, J=15.1 Hz, 0.5 H), 3.78 (s, 1.5 H), 3.75 (s, 1.5 H), 3.62-3.69 (m, 1 H), 3.15-3.26 (m, 1 H), 1.14-1.25 (m, 6 H), 0.54 (d, J=6.6 Hz, 1.5 H), 0.33 (d, J=6.4 Hz, 1.5 H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:37](Cl)(=[O:40])[CH:38]=[CH2:39]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:27])[NH:10][CH:11]1[CH2:12][CH2:13][N:14]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:37](=[O:40])[CH:38]=[CH2:39])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:15][CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)N2CCC(NC(=O)OCc3ccccc3)CC2)cc1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCC(NC(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 0.7 %

Procedure:
[1-(4-Amino-benzenesulfonyl)-piperidin-4-yl]-carbamic acid benzyl ester (1.29 g, 3.3 mmol) was dissolved in DCM (20 ml). To this was added diisopropylethylamine (1.64 ml, 9.9 mmol) in one portion followed by the drop wise addition of acryloyl chloride (0.3 ml, 3.6 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. The THF was removed under vacuum and the resulting crude material was purified by Prep HPLC to give the title compound (10.4 mg, 1% yield) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[N:7]=2)[CH:3]=1.[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:34]=[CH:33][C:29]([C:30]([O-])=[O:31])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[O:20]1[CH2:21][CH2:22][N:23]([C:26]2[CH:27]=[CH:28][C:29]([C:30]([NH:1][C:2]3[CH:10]=[CH:9][C:8]4[C:4](=[CH:5][N:6]([C:11]5[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=5)[N:7]=4)[CH:3]=3)=[O:31])=[CH:33][CH:34]=2)[CH2:24][CH2:25]1
Reactant: Nc1ccc2nn(-c3ccc([N+](=O)[O-])cc3)cc2c1
Reactant: O=C([O-])c1ccc(N2CCOCC2)cc1
Product: O=C(Nc1ccc2nn(-c3ccc([N+](=O)[O-])cc3)cc2c1)c1ccc(N2CCOCC2)cc1

Procedure:
Compound 540 was prepared according to the procedure described in Scheme IV from 5-amino-2-(4-nitrophenyl)indazole and 4-morpholinobenzoate. [M+H]+ calcd for C24H21N5O4: 444.16; found: 444.27.
Reaction SMILES: FC1C=C(OC)C=CC=1C#N.COC1C=CC(C#N)=C([N+]([O-])=O)C=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([O:35][N:36]=C(C)C)[CH:28]=1>>[NH2:32][C:31]1[C:30]2[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][C:29]=2[O:35][N:36]=1
Reactant: COc1ccc(C#N)c(ON=C(C)C)c1
Agent: COc1ccc(C#N)c(F)c1
Agent: COc1ccc(C#N)c([N+](=O)[O-])c1
Product: COc1ccc2c(N)noc2c1

Procedure:
Alternatively, 2-Fluoro-4-methoxy-benzonitrile can be substituted for 4-methoxy-2-nitrobenzonitrile. 3-Amino-6-methoxy-1,2-benzisoxazole is prepared following substantially the procedure of Example 25a starting from 4-methoxy-2-[[(1-methylethylidene)amino]oxy]-benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CN(C)C=O.[BH4-].[Na+].Br[CH2:22][CH2:23][O:24][CH2:25]C>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:25][O:24][CH2:23][CH3:22])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CCOCCBr
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCSc1ccc(N)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
6 G. of 1-amino-2-nitro-4-thiocyanatobenzene in 20 ml. of dimethylformamide is treated under nitrogen with 1.17 g. of sodium borohydride in 10 ml. of dimethylformamide at not greater than 30° C. The mixture is stirred at 15° to 20° C for 1 hour, then treated with 5 g. of 2-bromoethyl ethylether at 20°-25° C. The mixture is heated to 100° C for 2 hours, then cooled and diluted with water. The product is extracted with chloroform and after drying of the chloroform solution with sodium sulfate, 1-amino-2-nitro-4-(2-ethoxyethylthio) benzene is obtained by evaporation of the solution.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH2:12][CH3:13])[C:10]([CH3:15])([CH3:14])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:24][OH:25]>>[F:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:24][O:25][C:2]1[CH:3]=[C:4]2[N:11]([CH2:12][CH3:13])[C:10]([CH3:15])([CH3:14])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CCN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1cccc(F)c1F
Product: CCN1c2cc(OCc3cccc(F)c3F)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1-ethyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (2,3-difluorophenyl)methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH3:13])[C:6]3[CH2:20][CH2:21][NH:22][CH2:23][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:31][C:32](=[O:34])[CH3:33]>C(#N)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH3:13])[C:6]3[CH2:20][CH2:21][N:22]([CH2:31][C:32](=[O:34])[CH3:33])[CH2:23][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(=O)CCl
Reactant: CC(=Cn1c2c(c3cc(C)ccc31)CNCC2)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)CN1CCc2c(c3cc(C)ccc3n2C=C(C)c2ccncc2)C1
Temperature: 70 °C
Yield: 32 %

Procedure:
8-Methyl-5-(2-pyridin-4-yl-propenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (50 mg, 0.165 mmol) was dissolved in 1 mL acetonitrile. Potassium carbonate (70 mg, 0.50 mmol) and chloroacetone (30 mg, 0.33 mmol) were added to the reaction mixture under nitrogen and the contents heated to 70° C. for 2 h. The reaction was monitored by TLC and LCMS. Acetonitrile was evaporated under vacuum and the reaction mixture diluted with water (10 mL). The desired compound was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to obtain crude compound which was purified by column chromatography (Eluent: 3% MeOH in DCM) to obtain 19 mg of 1-[8-methyl-5-(2-pyridin-4-yl-propenyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl]-propan-2-one. 1H NMR (CD3OD, oxalate salt) δ (ppm): 8.60 (d, 2H), 7.78 (d, 2H), 7.40 (s, 1H), 7.30 (s, 1H), 7.15 (m, 2H), 4.59 (s, 2H), 4.50 (s, 2H), 3.70 (m, 2H), 3.20 (m, 2H), 3.44 (s, 3H), 3.30 (s, 3H), 2.06 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[OH:15])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]#[N:26]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:12])=[O:13])=[CH:7][C:6]=1[O:15][CH2:24][C:25]#[N:26])[CH3:2]
Reactant: N#CCCl
Reactant: CCOC(=O)c1ccc(S(C)(=O)=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(S(C)(=O)=O)cc1OCC#N
Temperature: 75 °C

Procedure:
A stirring solution of 11 (6.0 g) in DMF (200 mL) was treated with K2CO3 (6 g) and chloroacetonitrile (6 mL) and heated at 75° C. overnight. The mixture was cooled and partitioned between 1:1 EtOAc/hexanes and H2O. The organic layer was washed with 1 M NaOH, washed with brine, dried (MgSO4), filtered, and evaporated. The residue was triturated with Et2O/hexanes. The resulting solid was collected by filtration giving 6.6 g of 2-cyanomethoxy-4-methanesulfonyl-benzoic acid ethyl ester 12.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.COCCNC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.[F:49][P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[C:15]([F:49])[CH:16]=2)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1C(=O)Nc1ccncc1
Reactant: F[P-](F)(F)(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNCCOC
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccc(C(=O)O)c(F)c2)cc1C(=O)Nc1ccncc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
60 mg (0.18 mmol) of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid and 23.13 μl (0.22 mmol) of N-(methoxyethyl)methylamine are dissolved in 2 mL DMF. 102.36 mg HATU ((2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate) and 59.19 μL N-methylmorpholine are added to the solution. The mixture is stirred for 3 h at room temperature. The DMF is evaporated and the product is purified by chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13](=[O:14])[NH:12][C:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)=[N:10]1.[F:27][C:28]([F:37])([F:36])[C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:13](=[O:14])[NH:12][C:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[C:29]([C:28]([F:27])([F:36])[F:37])[CH:30]=3)=[O:21])=[C:17]([O:25][CH3:26])[CH:16]=2)=[N:10]1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)[nH]2)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)[nH]2)ccc1C(=O)Nc1cccc(C(F)(F)F)c1
Yield: 56.2 %

Procedure:
To a solution of methyl 4-(1-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-methoxybenzoate (Intermediate-46, 0.070 g, 0.17 mmol) in dry toluene was added 3-(trifluoromethyl)aniline (0.043 g, 0.17 mmol) followed by addition of trimethyl aluminum (2M solution in toluene) (0.5 mL). The reaction mixture was refluxed for 1 hr under inert atmosphere. The reaction mixture was brought to RT and quenched with water. Few drops of dilute HCl were added and the reaction mixture was extracted with DCM and concentrated. The obtained product was purified with column chromatography to afford 0.050 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.95 (s, 3H), 7.46 (d, J=6.9 Hz, 1H), 7.54-7.65 (m, 4H), 7.72-7.76 (m, 3H), 7.94 (d, J=8.4 Hz, 1H), 8.24 (s, 1H), 10.51 (s, 1H), 12.85 (s, 1H); MS (m/z): 523.04 (M+).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])([O-:5])=[O:4].[CH2:13]([O:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19]Br)[CH3:14]>CN(C)C=O>[CH2:13]([O:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N+:3]([O-:5])=[O:4])[CH3:14]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccccc1[N+](=O)[O-]
Reaction time: 0.33 h
Yield: 70.8 %

Procedure:
Sodium hydride (16.5 9, content: 62.4%) was suspended in N,N-dimethylformamide (500 ml). 0-nitrophenol (60 g) dissolved in N,N-dimethylformamide (100 ml) was added dropwise into the mixture with stirring in ice-bath over about 20 mins. The mixture was stirred for 1 hr. at a room temperature. 4-bromobutanoic acid ethyl ester (84.2 g) dissolved in N,N-dimethylformamide (200 ml) was added to the mixture. The solution was stirred for 15 hrs at about 70° C. N,N-dimethylformamide was evaporated in vacuo. Ethyl acetate (800 ml) was added to the residue. The mixture was washed with a water and a saturated brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (n-hexane: ethyl acetate =5:1→3:1) to give the title compound (77.3 g) having the following physical data:
Reaction SMILES: C([O:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:23]([NH:25][N:26]1[C:30](=[O:31])[CH2:29][NH:28][C:27]1=[O:32])=[O:24])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])C1C=CC=CC=1>CO.[Pd]>[OH:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:23]([NH:25][N:26]1[C:30](=[O:31])[CH2:29][NH:28][C:27]1=[O:32])=[O:24])[CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:11]
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)CNC1=O)[C@H](CCCc1ccccc1)C(=O)NOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CNC1=O)[C@H](CCCc1ccccc1)C(=O)NO
Yield: 17.7 %

Procedure:
A solution of 0.290 g of 2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenylbutyl]-4-methyl-N-(2,5-dioxo-1-imidazolidinyl)valeramide in 10 ml of methanol was hydrogenated for 2 hours in the presence of 0.087 g of 5% palladium-on-carbon. The catalyst was removed by filtration and evaporation of the solvent gave a residue which was purified by flash column chromatography on silica gel using dichloromethane/methanol (95:5) for the elution to give 0.042 g of 2(R)-[1(S)-(hydroxycarbamoyl)-4-phenylbutyl]-4-methyl-N-(2,5-dioxo-1-imidazolidinyl)valeramide in the form of a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:3]=1.[Li]CCCC.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:30][CH2:31][C:32]2([CH2:39][O:40][S:41]([C:44]3[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C1COCC1>[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:30][CH2:31][C:32]2([CH2:39][O:40][S:41]([C:44]3[CH:45]=[CH:46][C:47]([CH3:50])=[CH:48][CH:49]=3)(=[O:43])=[O:42])[CH2:33][CH2:34][C:35]([OH:38])([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:3]=3)[CH2:36][CH2:37]2)(=[O:28])=[O:29])=[CH:23][CH:22]=1
Reactant: Brc1cccc(Oc2ccccc2)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2(COS(=O)(=O)c3ccc(C)cc3)CCC(=O)CC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCC2(COS(=O)(=O)c3ccc(C)cc3)CCC(O)(c3cccc(Oc4ccccc4)c3)CC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
To a solution of 1-bromo-3-phenoxybenzene (0.320 g, 1.29 mmol) in anhydrous THF (10 mL) at −78° C. was added n-BuLi (0.804 mL of a 1.6 M solution in hexanes; 1.286 mmol). The reaction was stirred at −78° C. for 0.5 h and a solution of (4-oxocyclohexane-1,1-diyl)bis(methylene) bis(4-methylbenzenesulfonate) (0.5 g, 1.07 mmol) in THF (5 mL) was then added dropwise. The reaction mixture was slowly warmed to rt and stirred overnight. The reaction was quenched with sat′d aq NH4Cl and diluted with water. The mixture was extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated in vacuo. The crude oil was purified by flash chromatography on SiO2 (0 to 50% EtOAc:hexanes) to afford the title compound (0.39 g, 57% yield) as a white foam. 1H NMR (500 MHz, CDCl3) δ 7.78 (t, J=8.6 Hz, 4H), 7.41-7.33 (m, 6H), 7.29 (dd, J=11.4, 5.0 Hz, 1H), 7.16-7.10 (m, 1H), 7.08-6.99 (m, 4H), 6.89-6.84 (m, 1H), 4.01 (s, 2H), 3.81 (s, 2H), 2.49 (s, 3H), 2.45 (s, 3H), 1.75-1.47 (m, 8H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([F:31])=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:76][CH:77]1[CH2:82][CH2:81][N:80]([C:83]([O:85][C:86]([CH3:89])([CH3:88])[CH3:87])=[O:84])[CH2:79][CH2:78]1>CN(C)C=O>[C:86]([O:85][C:83]([N:80]1[CH2:81][CH2:82][CH:77]([NH:76][C:26](=[O:27])[C:25]2[CH:29]=[C:30]([F:31])[C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:14])([F:13])[CH2:12][N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:7]=4[N:20]=3)=[CH:23][C:24]=2[F:32])[CH2:78][CH2:79]1)=[O:84])([CH3:89])([CH3:87])[CH3:88]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)O)cc3F)ncc21
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc3F)ncc21
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
To a mixture of 0.1055 g (0.233 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-benzoic acid (I-232) and 4 mL of dimethylformamide was added 0.0515 g (0.382 mmole) of 1-hydroxybenzotriazole, 0.1361 g (0.359 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1778 g (1.378 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0742 g (0.370 mmole) of 4-amino-1-Boc-piperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-90:10) gave 0.1183 g of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-239) as a white solid.