Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[F:11][C:12]([F:39])([F:38])[C:13]1[CH:14]=[C:15]([NH:19][C:20]2[N:37]=[CH:36][CH:35]=[CH:34][C:21]=2[C:22](OC2C=CC([N+]([O-])=O)=CC=2)=[O:23])[CH:16]=[CH:17][CH:18]=1>C1(C)C=CC=CC=1>[C:3]([CH:5]([C:22](=[O:23])[C:21]1[C:20]([NH:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:39])([F:11])[F:38])[CH:14]=2)=[N:37][CH:36]=[CH:35][CH:34]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CCOC(=O)CC#N
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1cccnc1Nc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)C(=O)c1cccnc1Nc1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a stirred mixture of NaH (524 mg, 21.8 mmol) in toluene (20 mL) was added dropwise ethyl cyanoacetate (3.7 g, 32.7 mmol, 3.5 mL). The slurry was stirred for 1 h and then 4-nitrophenyl 2-{[3-(trifluoromethyl)phenyl]amino}nicotinate (4.4 g, 10.9 mmol) was added. The reaction mixture was stirred for 1 h and then quenched with water (20 mL). CH2Cl2 (30 mL) was added and the layers were partitioned. The organic layer was washed with brine (2×) and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by silica gel flash chromatography (5:1 to 2:1 Hex:EtOAc) to afford 3 Ethyl 2-cyano-3-oxo-3-(2-{[3-(trifluoromethyl)phenyl]amino}-3-pyridinyl)propanoate. (6 g, 87%): LCMS RT: 2.83 min, MH+: 378.0.
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10]([CH3:19])([CH3:18])[C:9]2=[O:20])=CC=1.Br.C([O-])([O-])=[O:25].[Na+].[Na+]>C(O)(=O)C>[OH:25][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([CH3:19])([CH3:18])[C:9](=[O:20])[NH:8]2)=[CH:12][C:13]=1[CH3:17]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CN2C(=O)C(C)(C)c3cc(C)ccc32)cc1
Agent: Br
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc2c(cc1O)NC(=O)C2(C)C
Temperature: 0 °C
Yield: 74 %

Procedure:
6-Methoxy-1-(4-methoxy-benzyl-3,3,5-trimethyl-1,3-dihydro-indol-2-one (640 mg, 1.97 mmol) was mixed with acetic acid (0.7 mL)and 48% hydrobromic acid (7 mL) and heated to reflux 12 hours. The solution was cooled to 0° C. and aqueous Na2CO3 was added to adjust to pH=7 then extracted with EtOAc, washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane: EtOAc/4:1 to 1:1) to give 280 mg of 6-Hydroxy-3,3,5-trimethyl-1,3-dihydro-indol-2-one (74%). 1H NMR (300 MHz, DMSO-d6, ppm): δ: 1.15 (s, 6 H), 2.026.34 (s,1 H), 6.89 (s, 1 H), 9.21 (s,1 H), 10.01(s, 1 H).
Reaction SMILES: C([Li])CCC.[S:6]1[CH2:11][CH2:10][CH2:9][S:8][CH:7]1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1.[CH3:24][C:25]([CH3:41])([CH3:40])[CH2:26][C:27]1[N:28]=[C:29]([CH:38]=[O:39])[N:30]([S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[CH:31]=1>O1CCCC1>[CH3:24][C:25]([CH3:41])([CH3:40])[CH2:26][C:27]1[N:28]=[C:29]([CH:38]([OH:39])[C:7]2([C:12]3[CH:13]=[CH:14][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[CH:16][CH:17]=3)[S:8][CH2:9][CH2:10][CH2:11][S:6]2)[N:30]([S:32]([N:35]([CH3:36])[CH3:37])(=[O:33])=[O:34])[CH:31]=1
Reactant: c1ccc(-c2ccc(C3SCCCS3)cc2)nc1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(O)C1(c2ccc(-c3ccccn3)cc2)SCCCS1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
n-Butyllithium (2.5 M in hexane) (0.14 mL, 0.17 mol) was added to a −78° C. solution of 2-[4-(1,3-dithian-2-yl)phenyl]pyridine (50 mg, 0.18 mmol) in tetrahydrofuran (3 mL). After stirring at 0° C. for 10 min, the reaction mixture was re-cooled to −78° C. and a solution of 4-(2,2-dimethylpropyl)-2-formyl-N,N-dimethyl-1H-imidazole-1-sulfonamide (intermediate 13) (100 mg, 0.37 mmol) in tetrahydrofuran (1 mL) was added. After stirring at −78° C. for 5 min then at ambient temperature for a further 10 min, the reaction mixture was quenched with water and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Preparative plate chromatography eluting with 50% ethyl acetate/hexane afforded 4-(2,2-dimethylpropyl)-2-{hydroxy[2-(4-pyridin-2-ylphenyl)-1,3-dithian-2-yl]methyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4]O.[C:7]([O-:13])([O-])([O:9][CH2:10][CH3:11])[CH3:8]>P(=O)(O)(O)O>[CH3:1][C:2]([CH3:6])([CH:3]=[CH2:4])[CH2:8][C:7]([O:9][CH2:10][CH3:11])=[O:13]
Reactant: CCOC(C)([O-])[O-]
Reactant: CC(C)=CCO
Agent: O=P(O)(O)O
Product: C=CC(C)(C)CC(=O)OCC
Yield: 78.9 %

Procedure:
A mixture of 4.3 g of 3-methyl-2-buten-1-ol, 16.2 g of ethyl orthoacetate and 3 drops of phosphoric acid was reacted as described in Example V A to give 6.15 g (79% yield) of ethyl 3,3-dimethyl-4-pentenoate, b.p. 87°-88°/58 mm.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][OH:22])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][O:22][S:24]([CH3:23])(=[O:26])=[O:25])[N:20]=2)=[CH:12]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
The compound obtained in Example 5 (820 mg, 2.6 mmol) was dissolved in dichloromethane (50 ml). Methanesulfonyl chloride (0.24 ml, 3.1 mmol) and triethylamine (0.81 ml, 3.1 mmol) were added, which was then stirred for 30 min at 0° C. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and purified by column chromatography to give the title compound (600 mg, Yield 60%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>CN(C)C=O>[CH2:9]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[N:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc(O)cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
140 g of 3-hydroxy-6-methylpyridine was dissolved in 1.4 L of dimethylformamide, and with cooling with ice, 178 ml of benzyl chloride was added to it and stirred overnight at room temperature. The reaction liquid was poured into water with ice, extracted with ethyl acetate, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=40/1 to 2/1) to obtain 246.7 g of the entitled compound as an orange oil.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[N:31]=[CH:30][C:14]2[NH:15][C@@H:16]([CH3:29])[CH2:17][N:18]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:13]=2[CH:12]=1.[C:32](Cl)(=[O:34])[CH3:33]>ClCCl>[Br:10][C:11]1[N:31]=[CH:30][C:14]2[N:15]([C:32](=[O:34])[CH3:33])[C@@H:16]([CH3:29])[CH2:17][N:18]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=3)(=[O:21])=[O:20])[C:13]=2[CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)N2C[C@H](C)Nc3cnc(Br)cc32)cc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1c2cnc(Br)cc2N(S(=O)(=O)c2ccc(C)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
N,N-Diisopropylethylamine (0.018 mL, 0.102 mmol) was added to a solution of (S)-7-bromo-3-methyl-1-tosyl-1,2,3,4-tetrahydropyrido[3,4-b]pyrazine (0.013 g, 0.034 mmol) and acetyl chloride (3.6 μL, 0.051 mmol) in dichloromethane (2.0 mL), and the mixture stirred at room temperature for 2 h. The reaction mixture was partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a yellow oil. This material was purified via column chromatography on silica gel (Biotage 10 g column, gradient elution with 50-100% ethyl acetate-hexane) to afford (S)-1-(7-bromo-3-methyl-1-tosyl-2,3-dihydropyrido[3,4-b]pyrazin-4(1H)-yl)ethanone (0.010 g, 69%) as an off-white solid. MS (ESI, pos. ion) m/z 424, 426.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=2[O:16]C)[CH:11]=[O:12])=[CH:4][C:3]=1[S:18]([CH3:21])(=[O:20])=[O:19].B(Br)(Br)Br.CO>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=2[OH:16])[CH:11]=[O:12])=[CH:4][C:3]=1[S:18]([CH3:21])(=[O:19])=[O:20]
Reactant: COc1ccc(C=O)cc1-c1ccc(F)c(S(C)(=O)=O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)c1cc(-c2cc(C=O)ccc2O)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
To a cooled solution (0° C.) of 3-(4-fluoro-3-(methylsulfonyl)phenyl)-4-methoxybenzaldehyde (27) (400 mg, 1.3 mmol, 1 eq.) in DCM (20 mL) was added BBr3 (0.4 mL). The reaction mixture was stirred room temperature for 3 h. After cooling to 0° C., methanol was added and the mixture was concentrated under vacuum. The residue was diluted with DCM and washed with water. The DCM was dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (eluent: PE:EA=1:1) to give 340 mg (89%) of 3-(4-fluoro-3-(methylsulfonyl)phenyl)-4-hydroxybenzaldehyde (28).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[C:12](/[C:17]#[N:18])\[C:13]([O:15][CH3:16])=[O:14].[N+:19]([CH3:22])([O-:21])=[O:20].N1CCCCC1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH:12]([C:17]#[N:18])[C:13]([O:15][CH3:16])=[O:14])[CH2:22][N+:19]([O-:21])=[O:20]
Reactant: COC(=O)/C(C#N)=C1\C(=O)Nc2ccc(Cl)cc21
Reactant: C[N+](=O)[O-]
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: COC(=O)C(C#N)C1(C[N+](=O)[O-])C(=O)Nc2ccc(Cl)cc21
Reaction time: 3 h
Yield: 73.8 %

Procedure:
A suspension of methyl (2Z)-(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)(cyano)acetate, intermediate 1 (10.000 g; 38.1 mmol) in dry nitromethane (61 ml; 1.14 mol) was treated with piperidine (189 μl; 1.90 mmol). After stirring for 3 hours, the mixture was diluted with ethyl acetate and filtered through silica. Evaporation of the solvent gave methyl [5-chloro-3-(nitromethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl](cyano)acetate as an oil (9.1 g, 73.8%). This was a mixture of diastereomers which was sufficiently pure for subsequent reaction (HPLC purity 97%). MS (ESI+): 324.2; MS (ESI−): 322.2
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[O:4][N:3]=1.C(O[CH:19](N(C)C)[N:20]([CH3:22])[CH3:21])(C)(C)C>>[CH3:19][N:20]([CH3:22])[CH:21]=[C:9]1[CH2:10][CH2:11][CH2:12][CH:7]([C:5]2[O:4][N:3]=[C:2]([CH3:1])[N:6]=2)[C:8]1=[O:13]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1noc(C2CCCCC2=O)n1
Product: Cc1noc(C2CCCC(=CN(C)C)C2=O)n1

Procedure:
2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-cyclohexanone (90 mg, 0.5 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (123 mg) as a red oil which was used directly in the next step. MS ISP (m/e): 236.1 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:15][C:16]1[C:21]([F:22])=[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:19]=[CH:18][C:17]=1B(O)O.O>COCCOC.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>[F:15][C:16]1[C:21]([F:22])=[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:19]=[CH:18][C:17]=1[C:5]1[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: CCCCCCCCOc1ccc(B(O)O)c(F)c1F
Reactant: Brc1cnc(I)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)c(F)c1F
Yield: 55.5 %

Procedure:
--To a degassed mixture of 5-bromo-2-iodopyrimidine 2 (4.0 g, 14.0 mmol), tetrakis(triphenylphosphine)palladium (323 mg, 0.28 mmol), DME (30 ml), and aqueous 2M sodium carbonate (50 ml) was added 2,3-difluoro-4-octyloxyphenylboronic acid 3 (4.42 g, 15.4 mmol) dropwise in DME (10 ml) under an atmosphere of nitrogen. The mixture was heated under reflux overnight; water was added to the mixture and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (twice) and the combined organic solutions were washed with brine and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography (5% to 10% ethyl acetate-light petroleum; the crude material was preloaded onto silica in dichloromethane) to give the phenylpyrimidine 4 (3.1 g, 55%) (from methanol), m.p. 74.6° C.; νmax /cm-1 (KBr) 2920, 2850, 1625, 1475, 1420, 1310 and 1090; δ 0.91(1H, t, Me), 1.2-1.55(10H, m), 1.85 (2H, quint. OCH2CH2), 4.11 (2H, t, OCH2), 6.82 (1H, ddd, 5'-H), 7.83 (1H, ddd, 6'-H) and 8.86 (2H, s, 4- and 6-H); m/z 288 (M+ -C8H16), 286 (M+ -C8H16), 178 and 155.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:5][N:4]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>>[CH3:13][S:14]([O:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=1)(=[O:16])=[O:15]
Reactant: COc1ccc(CCCO)cn1
Reactant: CS(=O)(=O)Cl
Product: COc1ccc(CCCOS(C)(=O)=O)cn1

Procedure:
In substantially the same manner as in Reference Example 85, 3-(2-methoxy-5-pyridyl)propanol was reacted with methanesulfonyl chloride to give 3-(2-methoxy-5-pyridyl)propyl methanesulfonate. The yield was quantative. Oily substance.
Reaction SMILES: [CH3:1][CH:2]1[N:15]2[C:6]([CH2:7][O:8][C:9]3[C:14]2=[CH:13][C:12]([N+:16]([O-])=O)=[C:11]([CH3:19])[CH:10]=3)=[N:5][NH:4][C:3]1=[O:20].[Cl-].[NH4+]>CO.C1COCC1.[Zn]>[NH2:16][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[CH3:19])[O:8][CH2:7][C:6]1[N:15]2[CH:2]([CH3:1])[C:3](=[O:20])[NH:4][N:5]=1
Reactant: Cc1cc2c(cc1[N+](=O)[O-])N1C(=NNC(=O)C1C)CO2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2c(cc1N)N1C(=NNC(=O)C1C)CO2
Temperature: 70 °C
Yield: 77.4 %

Procedure:
To a solution of 4,7-dimethyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.085 g, 0.31 mmol) and ammonium chloride (0.164 g, 3.1 mmol) in MeOH (10 mL) and THF (10 mL) was added zinc powder (0.200 g, 3.1 mmol) and the resulting mixture was heated at 70° C. for 4 h. The reaction mixture was cooled to ambient temperature, filtered and the filtrate was washed with MeOH (15 mL). The filtrate was concentrated in vacuo and the residue was dissolved in water (20 mL). The aqueous solution was extracted with EtOAc (3×15 mL) and the combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give 6-amino-4,7-dimethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.060 g, 0.24 mmol, 79%) as a solid, which was used directly in the next step. TLC (eluting with 25% EtOAc in petroleum ether) Rf=0.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:29])[NH:22][C:23]([CH3:28])=[CH:24][C:25]=2[CH2:26]O)=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:50]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:29])[NH:22][C:23]([CH3:28])=[CH:24][C:25]=2[CH2:26][Br:50])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(CO)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(CBr)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
To a stirred solution of 6-bromo-1-cyclopentyl-N-((4-(hydroxymethyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (0.6 g, 1.3 mmol) in DCM (5 mL), triphenylphosphine (0.54 g, 2.06 mmol) was added at 0° C. followed by carbon tetrabromide (0.684 g, 2.262 mmol) at the same temperature. Reaction mixture was stirred at room temperature for 2 h. On completion, the reaction mixture was purified by column over silica gel to afford intermediate 6-bromo-N-((4-(bromomethyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-cyclopentyl-1H-indazole-4-carboxamide (0.4 g, 58.8%). To a solution of this intermediate in DMF, respective amine (5 equiv.) was added and reaction stirred for overnight at room temperature. On completion, reaction mixture was poured into water and extracted with 15% MeOH/DCM. The combined organic layers were dried over sodium sulfate and concentrated to obtain crude material which was purified by prep HPLC affording 6-bromo-1-cyclopentyl-N-((4-((dimethylamino)methyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (19.2% yield). LCMS: 486.05 (M+1)+; HPLC: 99.59% (@ 254 nm) (Rt; 5.723); 1H NMR (DMSO-d6, 400 MHz) δ 11.65 (s, 1H), 8.83 (s, 1H), 8.36 (s, 1H), 8.20 (s, 1H), 7.62 (s, 1H), 6.07 (s, 1H), 5.23-5.18 (m, 1H), 4.41 (d, 2H, J=4 Hz), 3.37 (m, 2H), 2.16 (s, 6H), 2.15-2.05 (m, 5H), 1.99-1.91 (m, 2H), 1.86 (m, 2H), 1.69 (m, 2H).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7](=[O:17])[CH2:8][N:9]2[CH2:16][CH2:15][CH2:14][C@H:10]2[C:11](O)=[O:12])=[CH:3][CH:2]=1.C(N1CCOCC1)C.ClCCl.[CH2:35]([NH:42][C:43](=[O:50])[C@H:44]([CH2:46][CH2:47][S:48][CH3:49])[NH2:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(#N)C>[C:1]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:2]=[CH:3][C:4]([C:7](=[O:17])[CH2:8][N:9]2[CH2:16][CH2:15][CH2:14][C@H:10]2[C:11]([N:42]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:43](=[O:50])[C@H:44]([CH2:46][CH2:47][S:48][CH3:49])[NH2:45])=[O:12])=[CH:5][CH:6]=1
Reactant: CSCC[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(CN1CCC[C@H]1C(=O)O)c1ccc(-c2ccccc2)cc1
Agent: CCN1CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CSCC[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)c1ccc(-c2ccccc2)cc1
Yield: 38.9 %

Procedure:
A solution of N-[2-(biphenyl-4-yl)-2-oxoethyl] L-proline (54 mg, 0.17 mmol, 1.0 eq), N-ethylmorpholine (133 uL, 1.04 mmol, 6 eq) in acetonitrile (0.5 mL) was cooled to 0° C. and treated with a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (180 uL, 0.27 mmol, 1.6 eq) followed by the L-methionine benzylamide (71.36 mg, 0.30 mmol, 1.7 eq). Purification by HPLC provided 35 mg (38%) of L-methionine, N-[1-(2-(biphenyl-4-yl)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C:5]([CH3:40])([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[C:18](=[O:32])[NH:17]2)=[CH:9][CH:8]=1)[CH3:2].[H-].[Na+].I[CH3:45]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:41])[C:5]([CH3:40])([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:45])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CI
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2)cc1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A slurry of 2-Methyl-3-(4-{2-[2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid ethyl ester (0.544 g, 0.953 mmol) and sodium hydride (0.042 g, 1.05 mmol, 60% dispersion on mineral oil) in DMF (10 mL) is stirred for 1 h, then cooled to 0° C. Iodomethane (0.60 mL, 9.53 mmol, d=2.28) is added, then the reaction mixture is stirred 18 h at ambient temperature and diluted with ethyl acetate. The organic layer is washed, dried, concentrated, and purified by flash chromatography to provide the title compound. 1H NMR (400 MHz, CDCl3): δ 7.56 (d, 2H, J=8.0 Hz), 7.37 (d, 2H, J=8.0 Hz), 7.26-7.19 (m, 2H), 7.15 (d, 2H, J=8.9 Hz), 6.97 (t, 1H, J=8.0 Hz), 6.82 (d, 2H, J=8.0 Hz), 6.74 (d, 2H, J=8.9 Hz), 4.46, 4.38 (ABq, 2H, J=15.1 Hz), 4.20 (q, 2H, J=7.1 Hz), 3.97 (t, 2H, J=7.1 Hz), 3.67-3.59 (m, 1H), 3.78 (t, 1H, J=8.9 Hz), 3.26, 3.10 (ABq, 2H, J=14.2 Hz), 2.99 (t, 1H, J=8.9 Hz), 2.85 (s, 3H), 2.28-2.21 (m, 1H), 1.93-1.84 (m, 1H), 1.39 (s, 3H), 1.21 (t, 3H, J=7.1 Hz). MS [EI+]. 585 (M+H)+. Rf=0.35 in 50% acetone in hexanes.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[Cl:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:11]([Cl:18])[C:10]=1[OH:19]>>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:19][C:10]1[C:11]([Cl:18])=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:9]=1[Cl:8]
Reactant: BrCCCCCBr
Reactant: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Product: O=[N+]([O-])c1cc(Cl)c(OCCCCCBr)c(Cl)c1

Procedure:
In a manner similar to Preparation 40 react 1,5-dibromopentane with 2,6-dichloro-4-nitrophenol to obtain the title compound.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:15][C:16]1[C:17](=O)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1>CO>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([C:22]3[C:16](=[O:15])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COc1cccccc1=O
Solvent: CO
Product: O=c1cccccc1N1CCN(Cc2ccccc2)CC1
Yield: 81.9 %

Procedure:
A mixture of 1-(phenylmethyl)-piperazine (3.2 g) and 2-methoxy-2,4,6-cycloheptatrien-1-one (1.6 g) in methanol (6 ml) was refluxed for 10 hr and evaporated. The residue was dissolved in a mixture of chloroform and water. The organic phase was separated, dried and evaporated. The residue was chromatographed on silica gel (200 g) using methanol-chloroform (5:95). The eluates were evaporated to give the title compound (2.7 g): mp 78°-80° C.; ir(CHCl3) 2400, 1705, 1620, 1350 and 1570 cm-1 ; uv max(MeOH) 343 (ε=9440) and 250 nm (ε=14975); nmr(CDCl3) δ2.9 (s, 3H), 3.5 (m, 8H), 6.27 (s, 2H), 7.0 (m, 5H) and 14.5 (broad, 2H); and Anal. Calcd for C18H20N2O2 : C, 77.11% H, 7.19% N, 9.99% and Found: C, 77.08% H, 7.17% N, 9.74%.
Reaction SMILES: BrBr.S1C=CC(C=O)=C1C=O.Br[C:13]1[C:14]([CH:21]=[O:22])=[C:15]([CH:19]=[O:20])[S:16][C:17]=1[Br:18].C(Cl)Cl>C(O)(=O)C>[Br:18][C:17]1[S:16][C:15]([CH:19]=[O:20])=[C:14]([CH:21]=[O:22])[CH:13]=1
Reactant: O=Cc1sc(Br)c(Br)c1C=O
Agent: BrBr
Agent: O=Cc1ccsc1C=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=Cc1cc(Br)sc1C=O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Bromine (1.2 mL, 7.5 mmol) was added drop wise to a solution of 2,3-thiophenedicarboxaldehyde (1.0 g, 7.1 mmol) in 20 mL of glacial acetic acid. The reaction mixture was stirred overnight at 70° C. and then excess bromine was quenched with a saturated solution of Na2S2O3. The organic layer was extracted with CH2Cl2, dried over Na2SO4 and volatiles were removed in vacuo to obtain a mixture of 1 and 4,5-dibromo-2,3-thiophenedicarboxaldehyde 2 as a brown solid (30:65 by 1H NMR spectroscopy). Spectroscopically pure compound was isolated by column chromatography using silica gel as stationary phase and a 4:1 mixture of CH2Cl2:hexanes. 1H NMR (500 MHz, CDCl3): δ 10.37 (s, 1H), 10.26 (s, 1H), 7.59 (s, 1H). 1H NMR data for 4,5-dibromo-2,3-thiophenedicarboxaldehyde (500 MHz, CDCl3): δ 9.81 (s, 1H), 7.36 (s, 1H).