Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][C:10]=1[C:25](OCC)=[O:26]>C1(C)C=CC=CC=1>[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:11][C:10]=1[C:25]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1)=[O:26]
Reactant: Cc1csc(N)n1
Reactant: CCOC(=O)C1=C(O)c2ccccc2N(c2ccccc2)C1
Solvent: Cc1ccccc1
Product: Cc1csc(NC(=O)C2=C(O)c3ccccc3N(c3ccccc3)C2)n1
Yield: 67.3 %

Procedure:
A solution of 14.5 g of 2-amino-4-methylthiazole and 25.0 g of 1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxylic acid, ethyl ester in 250 ml of toluene was refluxed for 24 hours in a soxhlet apparatus containing 20 g of 4Å molecular sieves. Evaporation of the volatiles afforded a residue which was purified by means of high pressure liquid chromatography (silica gel: 2% diethyl ether-dichloromethane as the eluent) followed by recrystallization from diethyl ether to yield 20.7 g (67%) of 1,2-dihydro-4-hydroxy-N-(4-methyl-2-thiazolyl)-1-phenyl-3-quinolinecarboxamide, m.p. 228°-230° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH:9]1([CH2:12]Br)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:9]1([CH2:12][S:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: BrCC1CC1
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(SCC2CC2)cc1

Procedure:
4-Bromothiophenol (106.12 g, 561 mmol), cyclopropylmethyl bromide (83.3 g, 617 mmol) and potassium carbonate (85.2 g, 617 mmol) were stirred in DMF (400 mL) overnight. The mixture was diluted with water (1.5 L) and the product extracted into hexanes (2×1 L). The combined organic extracts were dried (MgSO4) and concentrated to give 4-bromophenyl cyclopropylmethyl sulphide as an oil (130.7 g, quantitative). The aforementioned sulphide (10 g, 41 mmol) was dissolved in THF (400 mL) and cooled to −78° C. n-Butyllithium (51 mL of a 1.6 M solution in hexanes) was added dropwise. On completion of addition, the mixture was stirred for a further 15 min before dropwise addition of DMF. The reaction mixture was stirred for 18 h, allowing to warm to room temperature. The reaction was quenched by addition of satd. NH4Cl(aq) followed by water. The product was extracted into diethyl ether (×2) and the combined organic layers were dried (MgSO4) and concentrated. Purification by chromatography on silica eluting with 5 to 10% ethyl acetate in hexane gave the title compound (5.50 g, 70% yield). 1H NMR δ (360 MHz, CDCl3) δ 9.92 (1H, s), 7.76 (2H, d, J=8.4 Hz), 7.38 (2H, d, J=8.2 Hz), 2.97 (2H, d, J=7.0 Hz), 1.14-1.08 (1H, m), 0.67-0.62 (2H, m) 0.35-0.30 (2H, m).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[C:9](=[O:35])[NH:10][C:11](=[O:34])[N:12]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH:22]4[C@:20]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=5)([CH2:21]4)[CH2:19]3)[CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:36].O1CCOCC1>>[ClH:36].[ClH:36].[F:1][C:2]1[C:7]([C:8]2[C:9](=[O:35])[NH:10][C:11](=[O:34])[N:12]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][C@H:22]4[C@:20]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=5)([CH2:21]4)[CH2:19]3)[CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=c1[nH]c(=O)n(CCCCN2CC3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1-c1cccnc1F
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n(CCCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1-c1cccnc1F
Yield: 89 %

Procedure:
5-(2-fluoro-3-pyridinyl)-1-(4-{(1S)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2,4(1H,3H)-pyrimidinedione was treated with 4N HCl in dioxane (2 eq). After evaporation of the solvent and trituration with diethyl ether, 41 mg of the title compound were obtained as a white powder. (89% yield)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH2:18][NH:19][C:20]4[CH:21]=[CH:22][N:23]=[C:24]5[C:29]=4[N:28]=[CH:27][C:26]([C:30]4([OH:43])[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)=[CH:25]5)=[N:16][N:17]=3)[N:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.CC1C=C(C2C=CC3N(C(CN)=NN=3)N=2)SN=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH2:18][NH:19][C:20]4[CH:21]=[CH:22][N:23]=[C:24]5[C:29]=4[N:28]=[CH:27][C:26]([C:30]4([OH:43])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[CH:25]5)=[N:16][N:17]=3)[N:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cnc3c(NCc4nnc5ccc(-c6cc(F)cc(F)c6)nn45)ccnc3c2)CC1
Agent: Cc1cc(-c2ccc3nnc(CN)n3n2)sn1
Product: OC1(c2cnc3c(NCc4nnc5ccc(-c6cc(F)cc(F)c6)nn45)ccnc3c2)CCNCC1

Procedure:
Deprotection of tert-butyl 4-(8-((6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-yl)-4-hydroxypiperidine-1-carboxylate using the method described for (6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine M/Z=489.2 [M+H], calc 488.19 for C25H22F2N8O.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][OH:20].Cl>ClCCl.C(N(CC)CC)C>[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: OCc1ccccc1SCCCCCl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=Cc1ccccc1SCCCCCl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To a 5 liter 4-neck round-bottom flask fitted with mechanical stirrer, thermowell and addition funnel, under a nitrogen atmosphere, was added 78.4 ml of oxalyl chloride and 925 ml of dichloromethane. The reaction was cooled to -78° C. with a dry ice/acetone bath. Then 125.3 ml of distilled dimethylsulfoxide was added dropwise, maintaining the reaction temperature below -65° C. After the addition was complete, 138.4 g of 2-[(4-chlorobutyl)thio]benzyl alcohol was added in 300 ml of dichloromethane. After addition was complete, the mixture was stirred for 30 min., then 417.3 ml of triethylamine was added. The bath was allowed to warm gradually to room temperature and stirred overnight at this temperature. The reaction mixture was poured into a 12 liter flask containing a stirring mixture of 3100 g of crushed ice and 4730 ml of 1N HCl. After stirring for 30 min., the mixture was extracted with dichloromethane (3×300 ml) the organic solution was dried over magnesium sulfate, filtered and concentrated to a brown oil. The product was further purified by column chromatography on silica gel, eluting with 10% ethyl acetate in hexane to give 117.7 g of the pure product as an oil. 1H-NMR (CDCl3) δ 1.8-2.0(m,4H); 3.0(t,2H); 3.6(t,2H); 7.2-7.6(m,3H); 7.8(m,1H); 10.4(s,1H).
Reaction SMILES: C(ON=O)CC(C)C.I[CH2:10][I:11].NC1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][N:19]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][C:29]=3[C:30]([F:33])([F:32])[F:31])[C:20]2=[O:23])=[CH:15][C:14]=1[F:34].C(OCC)(=O)C>C1COCC1.CCCCCC.[Cu]I>[F:34][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:10]=1[I:11])[C:20](=[O:23])[N:19]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:29]=1[C:30]([F:31])([F:33])[F:32])[CH2:18][CH2:17]2
Reactant: Nc1cc2c(cc1F)CCN(c1cnccc1C(F)(F)F)C2=O
Reactant: ICI
Agent: [Cu]I
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2cc(I)c(F)cc2CCN1c1cnccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 1 h
Yield: 3.2 %

Procedure:
Isoamylnitrite (0.4 mL, 3.2198 mmol), diiodomethane (0.4 mL, 5.36 mmol) and CuI (203.9 mg, 1.07 mmol) were added to a stirred solution of 7-amino-6-fluoro-2-(4-(trifluoromethyl)pyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-79b: 350 mg, 1.07 mmol) in dry THF (10 mL). The resulting mixture was stirred for 1 hour at 70° C. The reaction was monitored by TLC (40% ethyl acetate in hexane). The reaction mixture was concentrated to yield the crude product. Purification by column chromatography on silica gel (30% ethyl acetate in hexane), followed by preparative HPLC afforded 15 mg of the product (10% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH2:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)(=[O:34])=[O:33]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH2:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:41][CH:38]2[CH2:39][CH2:40][N:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:36][CH2:37]2)[N:3]=1
Reactant: CCOc1ccc(F)cc1C(=O)c1cnc(S(=O)CC)nc1N
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The compound was prepared from (4-amino-2-ethylsulfinyl-pyrimidin-5-yl)-(2-ethoxy-5-fluoro-phenyl)-methanone (Example 201) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) in an analogous manner as described in Example 172. HR-MS (ES, m/z) calculated for C19H25N5O4SF [(M+H)+] 438.1606, observed 438.1610.
Reaction SMILES: Br[C:2]([CH3:13])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:14](#[N:18])[CH2:15][C:16]#[N:17].CC(C)([O-])C.[K+].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:16]([CH:15]([C:2]([CH3:13])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:14]#[N:18])#[N:17]
Reactant: N#CCC#N
Reactant: CCOC(=O)C(C)(Br)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C(=O)OCC)C(C#N)C#N

Procedure:
19.156 g (75.686 mmol) of diethyl 2-bromo-2-methylmalonate were initially charged in THF (120 ml), and 5 g (75.686 mmol) of malononitrile and then 8.493 g (75.686 mmol) of potassium tert-butoxide were added. The mixture was then heated to reflux overnight. Ethyl acetate and sat. ammonium chloride solution were then added to the reaction, and the phases were separated. The aqueous phase was extracted two more times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness. This gave a crude product which was purified by chromatography on silica gel (cyclohexane/ethyl acetate 9:1).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[N:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[S:12][C:10]3=2)[N:5]=[CH:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[N:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[S:12][C:10]3=2)[N:5]=[CH:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2ccc3nc(S(C)(=O)=O)sc3c2c1O
Product: CCOC(=O)c1cnc2ccc3nc(S(C)(=O)=O)sc3c2c1Cl

Procedure:
A mixture of 3.52 g of ethyl 9-hydroxy-2-methylsulfonylthiazolo[5,4-f]quinoline-8-carboxylate and 30 ml of phosphorus oxychloride was refluxed for 6 hours.
Reaction SMILES: [O:1]=[C:2]([C:8]1[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12)/[CH:3]=[CH:4]/[C:5]([OH:7])=[O:6]>[Zn].C(O)(=O)C>[O:1]=[C:2]([C:8]1[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=C(O)/C=C/C(=O)c1c(-c2ccccc2)nn2ccccc12
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C(O)CCC(=O)c1c(-c2ccccc2)nn2ccccc12
Temperature: 100 °C
Yield: 45.4 %

Procedure:
A mixture of 4-oxo-4-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)crotonic acid (3.61 g), zinc powder (5.0 g) and acetic acid (50 ml) was heated at 100° C. for 1.5 hours. The zinc powder was filtered off and washed with acetic acid. The filtrate and washings were combined and evaporated in vacuo. To the residue a saturated aqueous solution of sodium hydrogen carbonate (50 ml) was added and extracted with ethyl acetate (50 ml×2). The combined extracts were washed with a saturated aqueous solution of sodium chloride (50 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol to give crystals of 4-oxo-4-(2-phenylpyrazolo[1,5-a]pyridine-3-yl)butyric acid (1.65 g).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2.[OH-].[Na+]>OS(O)(=O)=O>[Br:8][C:13]1[CH:12]=[CH:11][C:10]([CH3:9])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2
Reactant: Cc1cccc2cccnc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(Br)c2cccnc12
Temperature: 5 °C
Reaction time: 18 h
Yield: 97.9 %

Procedure:
NBS (13.7 g, 76.9 mmol, 1.1 equiv) was added portionwise to a cold (5° C.) solution of 8-methyl-quinoline (10 g, 69.9 mmol) in concentrated H2SO4 (150 mL). The reaction mixture was stirred for 18 h at 5° C., diluted in ice (300 mL) and basified by addition of an aqueous solution of NaOH (10% wt). The resulting white solid was collected by vacuum filtration, rinsed with water, and dissolved in DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated to afford 15.2 g of the title compound as a beige solid: ESI-MS: 221.9/223.9 [M+H]+; tR=3.59 min (System 1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=2)[O:9][N:8]=1.B1([C:25]2[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=2)OCCCO1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH:17]=2)[O:9][N:8]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: Brc1cncc(-c2nc(-c3ccccn3)no2)c1
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: COCCOC
Product: c1ccc(-c2noc(-c3cncc(-c4cccnc4)c3)n2)nc1
Yield: 34.8 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-pyrid-3-yl)-1,2,4-oxadiazole (60.6 mg, 0.2 mmole), pyridine-3-boronic acid 1,3-propanediol cyclic ester (48.9 mg, 0.3 mmol) and Pd(PPh3)4 (34.65 mg, 0.03 mmole) in a solution of 2M sodium carbonate (2 mL) and ethylene glycol dimethyl ether (2 mL) was heated overnight at 105° C. Standard work up afforded 21 mg (35%) 3-(2-pyridyl)-5-[5-(3-pyridyl)-pyrid-3-yl]-1,2,4-oxadiazole.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[C:10]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([NH:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:19][CH2:20]2)[C:10]1=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(N=C2CCN(c3ccncc3)CC2)C1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCN(NC2CCN(c3ccncc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
(3S)-3-(tert-Butoxycarbonylamino)-1-[1-(4-pyridyl)-4-piperidinylideneamino]-2-pyrrolidone (3.57 g) was dissolved in methanol (40 ml), combined with acetic acid (2.05 g) with cooling on ice, followed by sodium cyanoborohydride (807 mg) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was combined with an aqueous solution of sodium hydroxide, extracted with dichloromethane, dried, concentrated, and purified by a column chromatography (dichloromethane: 10% aqueous ammonia-containing methanol=20:1) to obtain the title compound (2.56 g) as a colorless amorphous material.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(=NC1CCCCC1)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH2:26][C:27]3([CH2:33][C:34]([CH3:39])([CH3:38])[C:35]=2C=O)[S:32][CH2:31][CH2:30][CH2:29][S:28]3)=[CH:21][C:20]=1[CH3:40].[CH2:41]1C[O:44][CH2:43][CH2:42]1>CCOCC>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH2:26][C:27]3([CH2:33][C:34]([CH3:38])([CH3:39])[C:35]=2/[CH:41]=[CH:42]/[CH:43]=[O:44])[S:28][CH2:29][CH2:30][CH2:31][S:32]3)=[CH:21][C:20]=1[CH3:40]
Reactant: Cc1cc(C2=C(C=O)C(C)(C)CC3(C2)SCCCS3)ccc1F
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: CC=NC1CCCCC1
Agent: [Li+]
Solvent: CCOCC
Product: Cc1cc(C2=C(/C=C/C=O)C(C)(C)CC3(C2)SCCCS3)ccc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a -20° C. solution of LDA (19.0 mmol) in 60 mL anhydrous THF was added ethylidenecyclohexylamine (Org. Syn. 50, 66) (2.38 gm, 19.0 mmol). The solution was stirred for 30 min, cooled to -78° C. and a solution of 8 (3.50 g, 10.0 mmol) in 60 mL was added. The mixture was stirred for 3 h, diluted with ether and quenched with H2O. The organic layer was washed with H2O and brine and dried (MgSO4). Removal of the volatiles in vacuo and purification of the residue by HPLC. using 10:1 hexanes:EtOAc provided 1.6 g of the orange color gum.
Reaction SMILES: Cl.C(O[C:5](=N)[CH2:6][CH2:7][CH3:8])C.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([NH2:20])[CH:14]=1)([O-:12])=[O:11]>C(O)C>[CH2:6]([C:5]1[NH:20][C:15]2[CH:14]=[C:13]([N+:10]([O-:12])=[O:11])[CH:18]=[CH:17][C:16]=2[N:19]=1)[CH2:7][CH3:8]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: CCCC(=N)OCC
Agent: Cl
Solvent: CCO
Product: CCCc1nc2ccc([N+](=O)[O-])cc2[nH]1
Yield: 51.7 %

Procedure:
A mixture of ethyl-butyroimidate hydrochloride (7.6 g, 50 mmol) and 4-nitro-1,2-phenylenediamine (7.6 g, 50 mmol) in ethanol (100 mL) was refluxed for 18 hours. The ethanol was evaporated under vacuum. The sticky solid was suspended in H2O (100 mL). Separation of the yellow solid gave the title compound (5.3 g, 52% yield). 1H-NMR (DMSO-d6 ; 200 MHz) δ 12.9 (s, 1H), 8.4 (s, 1H), 8.0-8.05 (d, 1H), 7.6-7.64 (d, 1H), 2.8-2.85 (t, 2H), 1.7-1.85 (m, 2H), 0.9-1.0 ppm (t, 3H),
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1.[Cl-].[NH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:14]([F:17])([F:16])[F:15])=[CH2:2])=[CH:9][CH:8]=1
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C(c1ccc(Br)cc1)C(F)(F)F
Reaction time: 1 h
Yield: 69.7 %

Procedure:
n-BuLi (9.5 mL, 2.5 M solution with toluene, 24 mmol) was added to a stirring mixture of methyltriphenylphosphonium bromide (8.5 g, 24 mmol) and THF (100 mL) at room temperature under a nitrogen atmosphere. After 1 h, 1-(4-bromophenyl)-2,2,2-trifluoroethanone (3.0 mL, 20 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. After an additional 1 h, saturated aqueous ammonium chloride (50 mL) was added. The mixture was partitioned between diethyl ether (100 mL) and saturated aqueous ammonium chloride (50 mL). The layers were separated, the organic material was washed sequentially with saturated aqueous ammonium chloride (50 mL) and brine (50 mL), dried (MgSO4), and purified via column chromatography (35 g of silica, 1% EtOAc in hexanes) to provide 1-bromo-4-(1-(trifluoromethyl)ethenyl)benzene (3.5 g) as an orange oil.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH2:23][CH2:24][CH3:25])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:26]([C:28]1[CH:33]=[C:32]([CH2:34][CH3:35])[N:31]2[N:36]=[C:37]([CH:39]=O)[N:38]=[C:30]2[N:29]=1)[CH3:27].CC1C=C(C)N2N=C(C=O)N=C2N=1>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH2:23][CH2:24][CH3:25])[CH:17]=3)[O:11][C:10](=[O:12])[C:9]([CH2:39][C:37]3[N:38]=[C:30]4[N:29]=[C:28]([CH2:26][CH3:27])[CH:33]=[C:32]([CH2:34][CH3:35])[N:31]4[N:36]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cc(CC)n2nc(C=O)nc2n1
Reactant: CCCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1O
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: CCCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(CC)cc(CC)n4n3)C(=O)O2)ccc1O

Procedure:
The title compound was prepared analogously to Example A(131), where 6-cyclopentyl-6-[2-(4-hydroxy-3-propylphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione was substituted in place of 6-cyclopentyl-6-[2-(3-fluoro-4-{methyl[methyl(dimethylene)-sulfanyl]amino}phenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione and 5,7-diethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in place of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. 1H NMR (CDCl3): δ 1.00 (t, J=7.54 Hz, 3H), 1.40–1.80 (brm, 16H), 2.00–2.18(m, 5H), 2.59 (m, 2H), 2.73 (m, 4H), 2.95 (m, 2H), 4.00 (s, 2H), 6.67 (d, J=5.78 Hz, 1H), 6.95 (m, 2H), 7.21 (s, 1H). Anal. Calcd. For C32H40O4N4: C, 70.56; H, 7.40; N, 10.29. Found: C, 70.23; H, 7.69; N, 10.31.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[N:6][NH:5][C:4](=[O:15])[CH:3]=1.[OH-].[NH4+].[H][H]>[Pd].C(O)C>[CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][NH:5][C:4](=[O:15])[CH:3]=1
Reactant: [H][H]
Reactant: Cc1cc(=O)[nH]nc1-c1ccc(Br)cc1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(=O)[nH]nc1-c1ccccc1
Temperature: 50 °C

Procedure:
A 10.0 g. portion of 5-methyl-6-p-bromophenyl-3(2H)-pyridazinone and 1.0 g. of 10% palladium on carbon catalyst in 150 ml. of ethanol and 50 ml. of ammonium hydroxide is shaken under 40 lb. of hydrogen pressure for 4 hours in a Parr bottle, heated to 50° C. with an outside jacket. The reaction mixture is suction filtered and the filtrate concentrated to a white solid which is washed with water and air dried to afford 5-methyl-6-phenyl-3(2H)-pyridazinone as white crystals.
Reaction SMILES: [C:1]1(=[O:26])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.[CH2:27]([NH2:29])[CH3:28]>>[CH2:27]([NH:29][C:8](=[O:9])[CH2:7][CH:6]([N:5]1[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]2[C:1]1=[O:26])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[CH3:28]
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC
Reactant: CCN
Product: CCNC(=O)CC(c1ccc(OC)c(OC)c1)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 77 %

Procedure:
The procedure of Example 46 was followed utilizing 3-phthalimido-3-(3,4-dimethoxyphenyl)propionic acid and ethylamine (1.0 equiv). After the reaction mixture was concentrated, the residue was diluted with 20 mL of water and 1 mL of ether. The mixture was stirred for 1 hour to afford a slurry. The slurry was filtered and the solid dried in vacuo to afford 0.66 g (77%) of 3-phthalimido-3-(3,4-dimethoxyphenyl)propionic ethylamide compound as a white powder: mp 131.0°-132.5° C.; 1H NMR (DMSO-6, 250 MHz) δ8.08 (t, 1H, J=5 Hz), 7.78-7.95 (m, 4H), 7.03 (s, 1H), 6.85-7.00 (m, 2H), 5.69 (t, 1H, J=8 Hz), 3.74 (s, 3H), 3.72 (s, 3H), 3.18 (d, 2H, J=8 Hz), 2.98 (m, 2H), 0.88 (t, 3H, J=7 Hz); 13C (DMSO-d6) δ168.8, 167.7, 148.5, 148.2, 134.5, 131.6, 131.2, 123.1, 119.4, 111.6, 111.1, 55.5, 50.5, 37.3, 33.2, 14.5; Anal. Calcd. for C21 H22N2O5. Theoretical: C, 65.96; H, 5.80; N, 7.33. Found: C, 65.85; H, 5.84; N, 7.24.