Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C(C2C=NC=NC=2)=CC(C(NC2C=CC(OC(Cl)(F)F)=CC=2)=O)=CN=1.CC(N(C([O-])=O)C1CN(C(F)(F)F)CC1)(C)C.CCN(C(C)C)C(C)C.[Cl:54][C:55]([F:96])([F:95])[O:56][C:57]1[CH:62]=[CH:61][C:60]([NH:63][C:64]([C:66]2[CH:67]=[C:68]([C:89]3[CH:90]=[N:91][CH:92]=[N:93][CH:94]=3)[C:69]([N:72]3[CH2:76][CH2:75][C@:74]([NH:81]C(=O)OC(C)(C)C)([C:77]([F:80])([F:79])[F:78])[CH2:73]3)=[N:70][CH:71]=2)=[O:65])=[CH:59][CH:58]=1.C(O)(C(F)(F)F)=O>CC(O)C.CCOC(C)=O.C(Cl)Cl>[NH2:81][C@:74]1([C:77]([F:80])([F:79])[F:78])[CH2:75][CH2:76][N:72]([C:69]2[C:68]([C:89]3[CH:94]=[N:93][CH:92]=[N:91][CH:90]=3)=[CH:67][C:66]([C:64]([NH:63][C:60]3[CH:61]=[CH:62][C:57]([O:56][C:55]([Cl:54])([F:95])[F:96])=[CH:58][CH:59]=3)=[O:65])=[CH:71][N:70]=2)[CH2:73]1
Reactant: CC(C)(C)OC(=O)N[C@]1(C(F)(F)F)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2cncnc2)C1
Agent: CC(C)(C)N(C(=O)[O-])C1CCN(C(F)(F)F)C1
Agent: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2cncnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N[C@]1(C(F)(F)F)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2cncnc2)C1
Temperature: 140 °C
Reaction time: 12 h

Procedure:
A stirred mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(pyrimidin-5-yl)nicotinamide (Stage 247.1, 150 mg, 0.365 mmol) in iPrOH (0.5 mL) was treated with tert-butyl[3-(trifluoromethylpyrrolidine-3-yl)]carbamate (179 mg, 0.547 mmol) and DIPEA (0.159 mL, 0.912 mmol) were added at RT. The resulting mixture was stirred at 140° C. for 12 h. The solution was diluted in EtOAc (50 mL), washed with a 2 N citric acid solution (20 mL), aq. sat. solution of NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4, filtered and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, 40 g, DCM/MeOH 95:5). Obtained (R)-tert-butyl (1-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-3-(pyrimidin-5-yl)pyridin-2-yl)-3-(trifluoromethyl)pyrrolidin-3-yl)carbamate (137 mg, 0.196 mmol) was suspended in DCM (1 mL) and TFA (0.453 mL, 5.88 mmol) was added at RT. The resulting light yellow solution was stirred for 1.5 h at RT. The RM was diluted with EtOAc (50 mL), then washed with an aq. sat. solution of NaHCO3 and twice with water (2×20 mL). The aqueous phase was extracted with EtOAc (40 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel, 12 g, DCM/MeOH 95:5). The obtained residue re-suspended in MeOH (2 mL) was stirred at RT for 15 min. The crystals were filtered and washed with MeOH (2 mL) to afford the title product as a white solid. HPLC (Condition 10) tR=5.92 min, UPLC-MS (Condition 3) tR=1.05 min, m/z=529.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.76-1.85 (m, 1H) 2.02 (s, 1H) 2.24-2.35 (m, 2H) 3.13-3.27 (m, 2H) 3.37-3.52 (m, 2H) 7.35 (d, J=8.60 Hz, 2H) 7.86 (m, J=9.00 Hz, 2H) 8.14 (d, J=2.35 Hz, 1H) 8.81 (d, J=2.35 Hz, 1H) 8.92 (s, 2H) 9.22 (s, 1H) 10.23 (s, 1H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9].[CH3:12][NH2:13]>C(O)C.O>[CH3:12][NH:13][C:3](=[O:2])[CH2:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CN
Reactant: CCCCC(=O)CC(=O)OC
Solvent: O
Solvent: CCO
Product: CCCCC(=O)CC(=O)NC
Temperature: 90 °C

Procedure:
0.378 mol (60.2 ml) 3-oxo-heptanoic acid methylester, 400 ml 33% methylamine solution in ethanol and 40 ml water were stirred for 48 hours at 80° C. in a round-bottomed flask with a reflux condenser. After cooling off, the solvents were distilled off on a rotavap, the raw products were taken up in 200 ml water and 40 ml ethanol and set to about pH 3 with 40 ml 32% HCl. The reaction mixture was heated to 90° C. for 24 hours and then again concentrated to dryness in the rotavap. The raw product heated with 150 ml to reflux, filtrated hot and the filtrate was left to cool off. The product was filtrated off and dried in a vacuum drying cabinet at 50° C. 5.9 g of the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:13][C:12]3[CH2:11][CH2:10][NH:9][C:8](=[O:14])[C:7]=3[C:6]=2[CH:15]=1.Br[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:23]([F:26])([F:25])[F:24].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:13][C:12]3[CH2:11][CH2:10][N:9]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:22]=4[C:23]([F:26])([F:25])[F:24])[C:8](=[O:14])[C:7]=3[C:6]=2[CH:15]=1
Reactant: O=C1NCCc2sc3ccc(F)cc3c21
Reactant: FC(F)(F)c1ccncc1Br
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2c(sc3ccc(F)cc23)CCN1c1cnccc1C(F)(F)F
Yield: 9.1 %

Procedure:
Using analogous conditions and workup as described for the preparation of Example 1A above, 8-fluoro-3,4-dihydro-2H-benzo[4,5]thieno[3,2-c]pyridin-1-one (I-50g: 100 mg, 0.452 mmol) was reacted with 3-bromo-4-trifluoromethylpyridine (102.26 mg, 0.452 mmol), 1,4-dioxane (3 mL), copper iodide (8.58 mg, 0.0452 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (19.25 mg, 0.135 mmol) and potassium phosphate (286.56 mg, 1.35 mmol) in a vial at 115° C. overnight under nitrogen atmosphere to afford the crude product. Purification by preparative HPLC afforded 15 mg of the product (9.09% yield).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:6]2[N:16]=[C:17]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[N:26](C(OC(C)(C)C)=O)[CH:27]=[CH:28][C:21]=34)[CH:18]=[N:19][C:5]=2[NH:4][CH2:3]1>Cl>[NH:26]1[C:22]2=[N:23][CH:24]=[CH:25][C:20]([C:17]3[N:16]=[C:6]4[N:7]([CH2:8][CH2:9][CH:10]5[CH2:15][CH2:14][O:13][CH2:12][CH2:11]5)[C:2](=[O:1])[CH2:3][NH:4][C:5]4=[N:19][CH:18]=3)=[C:21]2[CH:28]=[CH:27]1
Reactant: CC(C)(C)OC(=O)n1ccc2c(-c3cnc4c(n3)N(CCC3CCOCC3)C(=O)CN4)ccnc21
Agent: Cl
Product: O=C1CNc2ncc(-c3ccnc4[nH]ccc34)nc2N1CCC1CCOCC1
Yield: 63 %

Procedure:
7-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-1-[2-(tetrahydro-pyran-4-yl)-ethyl]-3,4-dihy dro-1H-pyrazino[2,3-b]pyrazin-2-one. A mixture of 1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (See Example 15.C) (1 equiv), 4-bomo-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (1 equiv), tris(dibezylideneacetone) palladium (0.13 equiv), tri-o-tolylphosphine (0.25 equiv) and triethylamine (2.8 equiv) in anhydrous dioxane was purged, degassed for 2 min and stirred at 95° C. under nitrogen for 3-4 h. Upon completion of the reaction as indicated by TLC, the volatiles were removed under reduced pressure and the residue was purified by column chromatography to give the desired product in 35% yield. MS (ESI) m/z 479.7 [M+1]+. Tert-Butyl 4-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was stirred in methanolic hydrochloride solution at room temperature. Upon completion of the reaction as indicated by TLC, the solvent was removed under reduced pressure and the residue was purified on silica gel to give the title compound in 63% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 11.72 (s, 1H), 8.38 (s, 1H), 8.25 (d, J=4.8 Hz, 1H), 7.79 (s, 1H), 7.53-7.51 (m, 2H), 6.97 (q, J=1.6 Hz, 1H), 4.23 (s, 2H), 4.14 (t, J=7.6 Hz, 2H), 3.81 (dd, J1=2.4 Hz, J2=11.2 Hz, 2H), 3.25 (d, J=10.8 Hz, 2H), 1.67 (d, J=13.2 Hz, 2H), 1.61 (m, 3H), 1.22 (m, 2H); MS(ESI): m/z 379.2 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:32][C:33]#[N:34]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)([CH2:32][C:33]#[N:34])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: N#CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC#N)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Ethyl 2,2-bis(4-chlorophenyl)acetate (5.50 g, 17.8 mmol) was dissolved in 100 mL of dry tetrahydrofuran and cooled to −78° C. Lithium bis(trimethylsilyl)amide (1.0 M in hexane, 18.0 mL, 18.0 mmol) was added dropwise via syringe under nitrogen. The reaction was brought to 0° C., stirred for 1 hour, and then cooled to −78° C. A solution of bromoacetonitrile (1.24 mL, 17.8 mmol) dissolved in tetrahydrofuran was added, and the reaction was stirred for 2 hours while warming to room temperature. The reaction was quenched with saturated NH4Cl solution and extracted with diethyl ether. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated. Chromatography on silica gel (Analogix Intelliflash 280; 10% ethyl acetate/hexane) yielded the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 7.38-7.32 (m, 4H), 7.22-7.17 (m, 4H), 4.25 (q, J=7.2, 2H), 3.32 (s, 2H), 1.23 (t, J=7.2, 3H); MS (DCI+) m/z 365 (M+NH4)+.
Reaction SMILES: [Li]CCCC.[CH2:6]([N:13]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:27][C:28]([CH3:33])([CH3:32])[C:29](Cl)=[O:30]>C1COCC1>[CH2:20]([N:13]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C@@H:14]([C:29](=[O:30])[C:28]([CH3:33])([CH3:32])[CH3:27])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)CN(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C(=O)C(C)(C)C)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.6 %

Procedure:
In a round bottomed flask, at −78° C., under argon atmosphere, a solution of DIPA (0.29 mL, 2.12 mmol) in dry THF (10 ml) was treated with n-BuLi (2.5 M in n-hexane, 0.776 mL, 1.94 mmol). After 30 min a solution of ethyl 2-(dibenzylamino)-acetate [prepared as described in Example 47, step 1] (0.5 g, 1.77 mmol) in dry THF (10 mL) was added dropwise via cannula. After 15 min, trimethylacetyl chloride (0.53 mL, 3.53 mmol) was added dropwise at −78° C. and the mixture stirred for 10 min at rt. The reaction was then quenched with H2O, and Et2O was subsequently added. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product as an oil. Purification by column chromatography using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (98:2) gave the title compound (0.492 g, 76%) as a colorless oil. MS (ESI) m/z: 368 [M−H]+; (ESI) m/z: 366 [M−H]−. 1H NMR (DMSO-d6) δ 0.93 (s, 9H), 1.16-1.25 (m, 3H), 3.79 (d, J=13.97 Hz, 2H), 3.98 (d, J=13.96 Hz, 2H), 4.07-4.25 (m, 2H), 4.60 (s, 1H), 7.20-7.41 (m, 10H).
Reaction SMILES: [F:1][C:2](=[C:6]1[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)[CH:3]([F:5])[F:4].[H][H]>C(O)C.[Pd]>[F:1][CH:2]([CH:6]1[CH2:7][CH2:8][C:9]2([O:10][CH2:11][CH2:12][O:13]2)[CH2:14][CH2:15]1)[CH:3]([F:5])[F:4]
Reactant: FC(=C1CCC2(CC1)OCCO2)C(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: FC(F)C(F)C1CCC2(CC1)OCCO2

Procedure:
At atmospheric pressure, 22 g of 8-(1,2,2-trifluoroethylidene)-1,4-dioxaspiro[4.5]decane in 250 ml of ethanol in the presence of palladium on carbon as catalyst were hydrogenated until 2.2 liter of hydrogen had been taken up. The catalyst was subsequently filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel (petroleum ether/ethyl acetate, 7:1), to give the title product as a colourless oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=[O:15])[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.[CH2:24](O)[CH3:25]>>[CH2:24]([O:15][C:14]([C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=1)=[O:16])[CH3:25]
Reactant: O=C(O)c1cnoc1-c1cccc(C(F)(F)F)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cnoc1-c1cccc(C(F)(F)F)c1
Yield: 80 %

Procedure:
A portion of the 5-(3'-trifluoromethylphenyl)-4-isoxazolecarboxylic acid (2.5 g.; 0.01 mol.) in 25 ml. of ethanol and 2 ml. of sulfuric acid were heated at reflux for 4 hours. The reaction mixture was cooled, concentrated to one-half its initial volume, then diluted with 175 ml. of methylene chloride. The organic solution was washed with water, sodium bicarbonate, again with water, dried over magnesium sulfate, filtered and concentrated to give an oil. The oil was distilled through a Vigreux column to yield ethyl-5-(3'-trifluoromethylphenyl)-4-isoxazolecarboxylate (2.2 g.; 80% yield) as a colorless oil (b.p.=88°-90° C. at 0.15 torr.) having the following analysis:
Reaction SMILES: [C:1]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:9][CH2:8][CH2:7]1)(=O)[CH2:2][CH2:3][CH3:4].[CH:18]([NH2:20])=[O:19]>C(O)=O>[CH:18]([NH:20][CH:1]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:9][CH2:8][CH2:7]1)[CH2:2][CH2:3][CH3:4])=[O:19]
Reactant: NC=O
Reactant: CCCC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Solvent: O=CO
Product: CCCC(NC=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reaction time: 5 h

Procedure:
The ketone produced as described above (37.0 g) and 98% formic acid (9 ml) were added to formamide (23.5 ml) at 170° C. and the temperature kept at 175°-180° C. for five hours. A further portion of formic acid (4.5 ml) was added and the mixture was maintained at 175°-180° C. for a further fifteen hours. The mixture was extracted with ether which on evaporation gave a thick oil which was crystallised from petroleum ether (b.p. 60°-80°) to give N-formyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine havng a melting point of 103°-105° C. (Formula I R1 =propyl; R2 =H; R3 =H; R4 =CHO; R5 =4-Cl and R6 =3-Cl).
Reaction SMILES: C([Li])CCC.IC1C=CC=CC=1.C(NC(C)C)(C)C.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.[CH:27](N1CCCCC1)=[O:28]>C1COCC1>[Cl:20][C:21]1[N:22]=[CH:23][CH:24]=[CH:25][C:26]=1[CH:27]=[O:28]
Reactant: O=CN1CCCCC1
Reactant: Clc1ccccn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: Ic1ccccc1
Product: O=Cc1cccnc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
THF (200 mL) in a dry flask under N2 is chilled by placing the flask in a dry-ice/acetone bath at −78° C. Butyllithium (125 mL, 200 mmol) is added drop-wise, followed by the drop-wise addition of iodobenzene (11.19 mL, 100 mmol) in THF (10 mL). The solution is allowed to stir for 30 min at −78° C. Diisopropylamine (0.70 mL, 5 mmol) in THF (3 mL) and 2-chloropyridine (9.46 mL, 100 mmol) in THF (30 mL) are added successively in a drop-wise manner, and the solution is stirred for 1 h at −40° C. Formyl piperidine (11.1 mL, 100 mmol) in THF (25 mL) is added drop-wise, and the solution is stirred for 1 h at −40° C. The reaction is quenched with 40 mL 6N HCl, diluted with 250 mL ether, and a small amount of sodium thiosulfate solution is added to remove the iodine color. The solution is neutralized with saturated NaHCO3, filtered, and extracted with ether (3×150 mL). The combined organic layer is dried over Na2SO4, filtered, and concentrated in vacuo. The crude material is chromatographed over 600 g slurry-packed silica, eluting with 20% EtOAc/hexane. The fractions with the desired compound are collected and concentrated to afford 2-chloronicotinaldehyde (C90) as a pale orange solid (54% yield). MS (EI) for C6H4ClNO, m/z: 141 (M)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: Oc1ccc(I)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccc(-c2ccc(F)cc2)cc1
Temperature: 100 °C
Reaction time: 36 h

Procedure:
A mixture of p-Iodophenol linked to the Wang's resin from Step A (1 eq), 4-fluorobenzene boronic acid (6 eq), K2CO3 (12 eq) and Pd(OAc)2 (0.5 eq) were suspended in a mixture of dioxane/water (6/1) and the mixture was heated at 100° C. and stirring for 36 hours. The resin was washed with DMF/H2O and MeOH/THF/HCl diluted and MeOH/CH2Cl2. After it was dried, was suspended in dichloromethane, and TFA 95% was added. The mixture was stirred at room temperature for 30 min then filtered and washed with MeOH and dichloromethane. The solvents were concentrated to dryness to give the title product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[OH-:14].[Na+]>O>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:14])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
A mixture of water and 2,4-dinitrochlorobenzene is heated to boil. An aqueous sodium hydroxide solution is added dropwise thereto and the mixture is stirred under heating to boil for 1 h to form 2,4-dinitrophenol. Then sodium polysulfide is added dropwise thereto over a period of 3 to 4 h while maintaining a boiling state to promote vulcanization for 24 h under exiling water.
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:23])[CH2:6][S:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10])([CH3:3])[CH3:2].[OH:24]O>C(O)(=O)C>[CH:1]([NH:4][C:5](=[O:23])[CH2:6][S:7]([CH2:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][CH:16]=1)=[O:10])=[O:24])([CH3:3])[CH3:2]
Reactant: OO
Reactant: CC(C)NC(=O)CSCC(=O)c1ccc(-c2ccccc2)cc1
Solvent: CC(=O)O
Product: CC(C)NC(=O)CS(=O)CC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
A suspension of 2.0 gm (6.1 millimols) of [2-(4-biphenylyl)-2-oxo-ethylthio]-acetic acid isopropylamide in 20 ml of glacial acetic acid was admixed with 1.3 ml of 30% hydrogen peroxide, and the mixture was stirred at room temperature for 2 hours. The reaction product was precipitated with water and recrystallized from ethyl acetate after drying. Yield: 71.4% of theory; m.p. 138°-1/3°C.
Reaction SMILES: CNCCNC.[Cl:7][C:8]1[C:12]([NH:13][C:14](=[O:24])[CH2:15][CH2:16][S:17][CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:11][NH:10][N:9]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>[Cu]I.C(#N)C>[Cl:7][C:8]1[C:12]([NH:13][C:14](=[O:24])[CH2:15][CH2:16][S:17][CH2:18][CH2:19][C:20]([F:21])([F:22])[F:23])=[CH:11][N:10]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[N:9]=1
Reactant: O=C(CCSCCC(F)(F)F)Nc1c[nH]nc1Cl
Reactant: Brc1cccnc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: O=C(CCSCCC(F)(F)F)Nc1cn(-c2cccnc2)nc1Cl
Temperature: 80 °C
Yield: 53.3 %

Procedure:
A 100 mL, 3-neck round bottom flask was charged with copper(I) iodide (0.343 g, 1.80 mmol), acetonitrile (50 mL), N,N′-dimethylethane-1,2-diamine (0.318 g, 3.61 mmol), N-(3-chloro-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide (2.72 g, 9.02 mmol), potassium carbonate (2.49 g, 18.0) and 3-bromopyridine (1.71 g, 10.8 mmol). The mixture was purged with nitrogen three times and heated to 80° C. for 4 hours, at which point thin layer chromatography analysis [Eluent: ethyl acetate] indicated that only a trace of starting material remained. The mixture was filtered through a Celite® pad and the pad was rinsed with acetonitrile (20 mL). The filtrates were concentrated to dryness and the residue was purified by flash column chromatography using 0-100% ethyl acetate/hexanes as eluent. The fractions containing pure product were concentrated to dryness and further dried under vacuum to afford a white solid (1.82 g, 53%): mp 99-102° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.05 (d, J=2.7 Hz, 1H), 8.86 (s, 1H), 8.54 (dd, J=4.5, 1.4 Hz, 1H), 8.21 (ddd, J=8.4, 2.7, 1.4 Hz, 1H), 7.54 (dd, J=8.4, 4.7 Hz, 1H), 2.86 (t, J=7.3 Hz, 2H), 2.74 (td, J=6.5, 5.6, 4.2 Hz, 4H), 2.59 (ddd, J=11.7, 9.7, 7.4 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 169.32, 147.49, 139.44, 135.47, 133.40, 126.60 (q, J=296 Hz), 125.49, 124.23, 122.30, 120.00, 35.18, 33.42 (q, J=27.2 Hz), 26.77, 23.05 (q, J=3.3 Hz); EIMS m/z 378 ([M]+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:12]2([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=3)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH2:36](Br)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]>C(O)C>[CH2:53]([O:21][C:20](=[O:22])[CH2:19][CH2:18][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C:12]1([C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1)[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=1)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH3:36]
Reactant: CC(C)(C)c1cc(C2(c3ccc(O)c(C(C)(C)C)c3)CCCCC2CCC(=O)O)ccc1O
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCC1CCCCC1(c1ccc(O)c(C(C)(C)C)c1)c1ccc(O)c(C(C)(C)C)c1

Procedure:
45.2 g (0.1 mol) of 2,2-bis-(3'-tert.butyl-4'-hydroxyphenyl)-cyclohexanepropionic acid are dissolved in ethanol and neutralizaed with an ethanolic solution of 5.7 g (0.1 mol) of potassium hydroxide. The solution is concentrated nearly to dryness, taken up in 250 ml of toluene and mixed with 33.3 g (0.1 mol) of octadecyl bromide. The batch is refluxed for 3 hours, filtered off from the precipitated KBr and concentrated to about 100 ml. The product precipitated after some time is recrystallized from toluene/heptane. Yield 50 g, which corresponds to 71 % of the theory. Melting point 155° C.
Reaction SMILES: [N:1]1([CH:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Br:15][C:16]1[CH:17]=[C:18]([Cl:25])[C:19]([CH2:23]Br)=[C:20]([Cl:22])[CH:21]=1>CN(C=O)C.C(OCC)C>[Br:15][C:16]1[CH:17]=[C:18]([Cl:25])[C:19]([CH2:23][N:9]2[CH2:10][CH2:11][CH:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:8]2=[O:12])=[C:20]([Cl:22])[CH:21]=1
Reactant: O=C1NCCC1N1CCCCC1
Reactant: Clc1cc(Br)cc(Cl)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1C(N2CCCCC2)CCN1Cc1c(Cl)cc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
Treat a solution of 3-piperidin-1-yl-pyrrolidin-2-one (0.33 g, 1.96 mmol) in DMF (6 mL) with 60% sodium hydride (0.12 g, 3.00 mmol) and stir at room temperature for 15 minutes under N2. Cool the reaction to 0° C., treat with 5-bromo-2-(bromomethyl)-1,3-dichlorobenzene (0.70 g, 2.19 mmol), stir for 15 minutes at 0° C., warm to room temperature, and stir for 3 hours under N2. Quench the reaction with water and dilute with diethyl ether. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with a 0 to 5% methanol in CH2Cl2 gradient to afford 0.718 g (90%) of the titled product. Rf=0.29 (9/1 CH2Cl2/methanol). ES MS (m/z): 407 (M+).