Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:5][CH:4]([C:6](=O)[CH2:7][C:8]#[N:9])[CH2:3]1.O.[NH2:13][NH2:14]>CCO>[F:1][C:2]1([F:11])[CH2:5][CH:4]([C:6]2[NH:14][N:13]=[C:8]([NH2:9])[CH:7]=2)[CH2:3]1
Reactant: NN
Reactant: N#CCC(=O)C1CC(F)(F)C1
Solvent: CCO
Solvent: O
Product: Nc1cc(C2CC(F)(F)C2)[nH]n1
Temperature: 75 °C
Reaction time: 8 h
Yield: 25.4 %

Procedure:
To a solution of 3-(3,3-difluorocyclobutyl)-3-oxopropanenitrile (12.5 g, 78.6 mmol) in EtOH (250 mL) was added hydrazine hydrate (5.9 g, 117.9 mmol) and the resulting mixture was stirred at 75° C. overnight. After concentrating the reaction mixture in vacuo, the residue was redissolved in EtOAc (500 mL) and washed with satd. aq. NaHCO3. The aqueous layer was extracted with EtOAc and the combined extracts washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (10:1) to afford 3.46 g (39%) of 5-(3,3-difluoro-cyclobutyl)-1H-pyrazol-3-ylamine as a light yellow solid: 1H NMR (400 MHz, DMSO-do): δ 11.20 (br s, 1H), 5.23 (s, 1H), 4.65 (br s, 2H), 3.16-3.13 (m, 1H), 2.88-2.84 (m, 2H), 2.64-2.57 (m, 2H); MS (ESI+) m/z: 174 [M+1]+.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[N+]([O-])([O-])=O.S([O-])([O-])(=O)=O.[N+]([O-])(O)=O.CC(OC(C)=O)=O.[CH3:25][N:26]([N+:39]([O-:41])=[O:40])[CH2:27][N:28]([N+:36]([O-:38])=[O:37])[CH2:29][N:30]([N+:33]([O-:35])=[O:34])[CH2:31]O.CN1CCC(=C2C3C(=CC=CC=3)C=CC3C2=CC=CC=3)CC1>O.CC(O)=O>[C:1]([O:4][CH2:31][N:30]([N+:33]([O-:35])=[O:34])[CH2:29][N:28]([N+:36]([O-:38])=[O:37])[CH2:27][N:26]([N+:39]([O-:41])=[O:40])[CH3:25])(=[O:3])[CH3:2]
Reactant: CN(CN(CN(CO)[N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-]
Reactant: CC(=O)[O-]
Agent: CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: O=S(=O)([O-])[O-]
Agent: O=[N+]([O-])[O-]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: CC(=O)OCN(CN(CN(C)[N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
"Acetate or nitrate of 6-alkyl-2,4,6-trinitro-2,4,6-triazahexanol. Jiri Denkstein and Vladimir Kaderabek. Czech. 98,248, Jan. 15, 1961, Appl. Nov. 13, 1959. The described method is the nitrolysis of N-alkylhexamethylene-tetraminium nitrate, sulfate, or acetate with a mixt. of HNO3 with Ac2O, or anhydride of HNO3. Thus, a mixt. of 30 g N-methylhexamethylenetetraminium nitrate (I) and 49 ml. AcOH added during 15-30 min with stirring at 15°-20° to the mixt. of 52 ml. 98-9% HNO3, and 48 ml. Ac2O under stirring, the temp. increased to 75° and kept 15 min. gave after cooling to 20°-5° 22.2 g cryst. 6-methyl-2,4,6-trinitro-2,4,6-triazahexanol (II). The reactin mixt. dild. with water gave addnl. 5.3 g II. The total yield was 27.5 g of a product, m. 151°-3° , i.e., 68% of theory calcd. on I."
Reaction SMILES: CC(C)([O-])C.[K+].CS(C)=O.[F:11][C:12]([F:18])([CH:15]([F:17])[F:16])[CH2:13][OH:14].[Br:19][C:20]1[CH:25]=[C:24](F)[CH:23]=[C:22]([F:27])[CH:21]=1>O>[Br:19][C:20]1[CH:25]=[C:24]([O:14][CH2:13][C:12]([F:18])([F:11])[CH:15]([F:17])[F:16])[CH:23]=[C:22]([F:27])[CH:21]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: OCC(F)(F)C(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Fc1cc(Br)cc(OCC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.2 %

Procedure:
To a 50 mL flask flushed with nitrogen, equipped with a stir bar was added potassium tertbutoxide (1.1 g, 10 mmol, 95%). DMSO was added (10 mL) followed by addition of a solution of 2,2,3,3-tetrafluoropropan-1-ol (0.95 mL, 11 mmol) via syringe. After 5 min, 1-bromo-3,5-difluorobenzene (1.1 mL, 9.5 mmol) was added and the reaction mixture stirred at room temperature for 18 h. Water was added (100 mL), and the aqueous phase extracted with ether (2×100 mL). The organic portion was then washed successively with water (2×100 mL) and saturated NaCl solution (2×100 mL), dried over Na2SO4, decanted and concentrated under reduced pressure yielding a crude yellow liquid which was purified by distillation under reduced pressure at 140° C. yielding the 1-Bromo-3-fluoro-5-(2,2,3,3-tetrafluoropropoxy)benzene as a colorless oil (1.6 g, 54% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([NH2:21])=[O:20])=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:30].[Na+].O.OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[NH2:21][C:19](=[O:20])[CH2:18][O:17][C:16]1[CH:15]=[CH:14][C:13]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][C:2]=2[Cl:1])[NH:8][CH:7]=[C:6]3[C:11]([OH:30])=[O:12])=[CH:23][CH:22]=1
Reactant: NC(=O)COc1ccc(-c2cc3c(C=O)c[nH]c3cc2Cl)cc1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CC#N
Product: NC(=O)COc1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 21.3 %

Procedure:
To a mixture of 2-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenoxy]acetamide (100 mg, 0.30 mmol) in acetonitrile (5 mL) and tert-butanol (5 mL) was added 2-methyl-2-butene (4 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (540 mg, 6.00 mmol) and sodium phosphate monobasic hydrate (850 mg, 6.00 mmol) in water (5 mL) dropwise via additional funnel. The ice bath was removed and the reaction was stirred at room temperature for 48 h. The solvent was removed in vacuo to give a residue, which was purified by prep-HPLC (Prep-HPLC: Column: Kromasil Eternity-5-C18 150*30 mm*5 μm Mobile phase: from 24% MeCN in water (0.225% FA) to 34% MeCN in water (0.225% FA); Wavelength: 220 nm Flow rate: 30 mL/min) to give 5-[4-(2-amino-2-oxoethoxy)phenyl]-6-chloro-1H-indole-3-carboxylic acid (22 mg, 20% yield) as a white solid. MS (ES+) 344.8 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 8.01-7.99 (m, 2H), 7.57 (s, 1H), 7.43-7.39 (m, 2H), 7.07-7.05 (m, 2H), 4.56 (s, 2H).
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][C:12]1(C([O-])=O)[C@@H:16]([CH:17]=[CH:18][C:19]([OH:26])([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:15][C@H:14](C([O-])=O)[C:13]1=[O:30])([O:3]CC)=[O:2].[OH-].[Na+].Cl>O.CO.[Cl-].[Na+]>[OH:26][C:19]([CH3:25])([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:18]=[CH:17][C@H:16]1[CH2:15][CH2:14][C:13](=[O:30])[C@H:12]1[CH2:11][CH:10]=[CH:9][CH2:8][CH2:7][CH2:6][C:1]([OH:3])=[O:2]
Reactant: CCCCCC(C)(O)C=C[C@H]1C[C@H](C(=O)[O-])C(=O)C1(CC=CCCCC(=O)OCC)C(=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCC(C)(O)C=C[C@H]1CCC(=O)[C@H]1CC=CCCCC(=O)O

Procedure:
The cyclopentanonetriester of formula 6, diethyl cis, trans-3-(6-carboethoxy-2-hexenyl)-4-(3-hydroxy-3-methyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate (11.2 g), described in Example 45, is heated to reflux for 1 hr. in a solution of sodium hydroxide (13.4 g) in 80 ml of water and 110 ml of methanol. The mixture is cooled, adjusted to pH 5 with 2N HCl, diluted with saturated sodium chloride solution and extracted with ether. The ether extract is dried (Na2SO4) and concentrated. Chromatography on silica gel yields the title compound νmaxCHCl3 3580, 1740, 1720 cm-1, nmr (CDCl3) δ 0.88 (t, J = 5, 3H), 1.28 (s, 3H), 5.3 - 5.75 (m, 4H), 6.3 (2×s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[OH:28]O>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([S:20]([CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:14]2[C:2]([Cl:1])=[CH:3][C:4]3[NH:9][C:8](=[O:10])[O:7][C:6]([CH3:12])([CH3:11])[C:5]=3[CH:13]=2)=[O:28])=[CH:26][CH:25]=1
Reactant: OO
Reactant: CC1(C)OC(=O)Nc2cc(Cl)c(OCCCCSc3ccc(Cl)cc3)cc21
Product: CC1(C)OC(=O)Nc2cc(Cl)c(OCCCCS(=O)c3ccc(Cl)cc3)cc21

Procedure:
Prepared analogously to Example 2 from 7-chloro-6-[4-(4-chloro-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH2:16][C:17]3[CH:27]=[CH:26][C:20]4[N:21]=[C:22]([S:24][CH3:25])[S:23][C:19]=4[CH:18]=3)[CH:14]=[N:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:38])C=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH2:16][C:17]3[CH:27]=[CH:26][C:20]4[N:21]=[C:22]([S:24]([CH3:25])=[O:38])[S:23][C:19]=4[CH:18]=3)[CH:14]=[N:15][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Cn3cnc4cc(OCc5ccccc5)ccc43)cc2s1
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cc(OCc5ccccc5)ccc43)cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A mixture of 6-((5-(benzyloxy)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (1.6 g, 3.8 mmol) from the previous step and meta-chloroperbenzoic acid (0.82 g, 4.75 mmol) in DCM (38 mL) was stirred at 0° C. for 2 h. The mixture was diluted with DCM and washed sequentially with aq Na2S2O3, saturated aq NaHCO3, and water. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 6-((5-(benzyloxy)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (1.58 g, 96%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.02 (d, J=8.4 Hz, 1H), 7.96 (s, 1H), 7.76 (s, 1H), 7.44-7.47 (m, 2H), 7.31-7.40 (m, 5H), 7.12 (d, J=8.7 Hz, 1H), 6.97 (m, 1H), 5.49 (s, 2H), 5.11 (s, 2H), 3.08 (s, 3H); LCMS (ESI) m/z 434 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7](=[O:10])[CH2:8]C)[CH3:3].C(C(C)=O)C1C=CC=CC=1>>[CH3:3][C:2](=[CH:4][CH2:5][CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7](=[O:10])[CH3:8])[CH3:1]
Reactant: CCC(=O)C(CC=C(C)C)c1ccccc1
Agent: CC(=O)Cc1ccccc1
Product: CC(=O)C(CC=C(C)C)c1ccccc1

Procedure:
If in paragraph (E) ethyl benzyl ketone is replaced by methyl benzyl ketone, then there is obtained 2-methyl-5-phenyl-hept-2-en-6-one of boiling point 97° C./2 mmHg; nD20 =1.5135.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:36][C:37]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)([CH3:40])[CH:38]=O.N1CCCCC1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:36][C:37]([CH3:40])([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH3:38])[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C=O)N1CCOCC1
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)N1CCOCC1
Temperature: 100 °C
Reaction time: 22 h
Yield: 55.6 %

Procedure:
To a sealed tube was added 3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (762.6 mg, 1.62 mmol), 2-methyl-2-morpholino-propanal (508.54 mg, 3.23 mmol), piperidine (0.08 mL, 0.81 mmol) and ethanol (6 mL). The tube was sealed and heated at 100° C. After 22 hrs, the reaction was cooled and evaporated. The residue was purified by Isolera (column size 100 g, 3%-7% MeOH/EtOAc) to obtain 550 mg (56% yield) of the title compound. MS (pos. ion) m/z: 611 (M+1).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7](F)=[N:8][CH:9]=1.[OH:11][CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15]>O1CCCC1.CN1CCCN(C)C1=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[N:8][CH:9]=1
Reactant: Fc1ccc(Br)cn1
Reactant: COC(=O)C(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(C)(C)COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
Sodium hydride (60% disp. in oil, 908.0 mg, 22.72 mmol) was added portionwise at room temperature to a solution of 5-bromo-2-fluoropyridine A-5 (1.16 mL, 11.36 mmol) and methyl 3-hydroxy-2,2-dimethylpropanoate (1.88 mL, 14.77 mmol) in anhydrous tetrahydrofuran (32.9 mL) and anhydrous 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (5.0 mL) under an atmosphere of argon and in the presence of 4 Å molecular sieves. After 2 h of stirring at room temperature, the reaction mixture was heated at 50° C. for 10 h and then at 70° C. for 3 h. The suspension was cooled to room temperature, filtered over a thin celite pad, and the pad was rinsed with diethyl ether (150 mL). The filtrate was concentrated to a volume of ca. 5 mL, then diluted with diethyl ether (150 mL), quenched with water (90 mL) and decanted. The aqueous layer was extracted with diethyl ether (2×100 mL); the combined extracts were successively washed with water (3×70 mL), brine (70 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (100:0 to 80:20 hexanes:ethyl acetate gradient) to give methyl 3-(5-bromopyridin-2-yloxy)-2,2-dimethylpropanoate A-6 (1.796 g, Yield=55%). MS (ESI), [M+1]+ 288, 290.
Reaction SMILES: C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:27][S:28]([OH:31])(=[O:30])=[O:29].O[C@H:33]1[CH2:37][N:36]([S:38]([C:41]2[CH:50]=[CH:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=2)(=[O:40])=[O:39])[C@H:35]([CH2:51][N:52]2[C:60](=[O:61])[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:53]2=[O:62])[CH2:34]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.C1COCC1.CCOC(C)=O.O>[O:61]=[C:60]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:53](=[O:62])[N:52]1[CH2:51][C@H:35]1[N:36]([S:38]([C:41]2[CH:50]=[CH:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=2)(=[O:40])=[O:39])[CH2:37][C@H:33]([O:29][S:28]([CH3:27])(=[O:31])=[O:30])[CH2:34]1
Reactant: CS(=O)(=O)O
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccc2ccccc2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
3.0 ml (21.7 mmol, 1.2 eq) triethylamine and 6.05 g (22.6 mmol, 1.2 eq) triphenylphosphine were added to a solution of 1.42 ml (21.7 mmol, 1.25 eq) methanesulfonic acid in 60 ml toluene, successively followed by a solution of 7.9 g (18.1 mmol) (2S,4R)-2-[4-hydroxy-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-ylmethyl]-isoindole-1,3-dione in 80 ml toluene/THF (5/3) and 5.06 ml (23.6 mmol, 1.3 eq) DIAD. The suspension was heated to 80° C. for 6 h and stirred at room temperature overnight. After diluting the mixture with EtOAc and water, the phases were separated, and the inorganic one was extracted with EtOAc and CH2Cl2, the combined organic phases were washed with 1M KHSO4 and brine, dried over Na2SO4 and evaporated. Column chromatography with a gradient of CH2Cl2: EtOAc 4:1 to 1:1 yielded 8.3 g (90%) of (3R,5S)-methanesulfonic acid 5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1-(naphthalene-2-sulfonyl)-pyrrolidin-3-yl ester as white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:21])[C:6]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2ccc(Oc3ccc([N+](=O)[O-])cc3)cc21
Agent: [Pd]
Solvent: CCO
Product: CC1(C)OCc2ccc(Oc3ccc(N)cc3)cc21
Reaction time: 4 h
Yield: 32 %

Procedure:
1,1-Dimethyl-6-(4-nitrophenoxy)-1,3-dihydro-2-benzofuran (Intermediate 69, 280 mg, 0.98 mmol) was dissolved in ethanol (5 ml), 5% w/w Pd/C was added and the reaction mixture was stirred for 4 hours under hydrogen atmosphere (2 bar). The catalyst was filtered off and the solvent evaporated to dryness to afford a pale yellow solid, which was purified by re-slurry in Et2O, to afford the title compound (80 mg) as off-white solid.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=O.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.[C:32]1([NH:38][NH2:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C=O.C(Cl)Cl.O>[C:32]1([N:38]2[C:12](=[O:14])[C:3]3=[CH:4][NH:5][C:6]4[CH:7]=[CH:8][CH:9]=[N:10][C:11]=4[C:2]3=[N:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1cnc2cccnc2c1O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c2c[nH]c3cccnc3c-2nn1-c1ccccc1
Reaction time: 0.58 h

Procedure:
To a slurry of 1.5 g of ethyl 4-hydroxy-1,5-naphthyridine-3-carboxylate (prepared according to J. Inorg. Nucl. Chem., (1966) 28, 2439) in 17 ml of dimethylformamide is added 0.907 g of oxalyl chloride in 2 ml of methylene chloride while maintaining the reaction temperature between -25° and -30°. The mixture is stirred at -25° for 35 minutes. A solution of 0.995 g of diisopropylethylamine and 0.833 g of phenylhydrazine in 4 ml of methylene chloride is added to the mixture in 8 minutes at -30° to -25°. The mixture is then stirred for 30 minutes at -25°, 20 minutes at 0° and 40 minutes at 23°. The resultant dark purple solution is poured into 60 ml of water. Dark precipitate is collected, washed with water and crystallized from methanol to yield 2-phenyl-pyrazolo[4,3-c] [1,5]naphthyridin-3(5H)-one, m.p. 314°-316°.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:30][C:29]([C:31](=[O:34])[CH2:32][CH3:33])=[N:28][N:27]=2)=[CH:22][CH:21]=1>C1COCC1>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:30][C:29]([C:31]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)([OH:34])[CH2:32][CH3:33])=[N:28][N:27]=2)=[CH:24][CH:25]=1
Reactant: Ic1ccncc1
Reactant: CCC(=O)c1nnc(-c2ccc(F)cc2)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(O)(c1ccncc1)c1nnc(-c2ccc(F)cc2)s1
Reaction time: 0.5 h
Yield: 16.5 %

Procedure:
To a solution of 4-iodo pyridine (0.142 g, 0.635 mmol) in THF (12 mL) at −78° C. was added n-BuLi in hexane (1.6 M, 0.582 mL, 0.8474 mmol) and the mixture stirred for 30 min. A solution of 1-(5-(4-fluorophenyl)-1,3,4-thiadiazole-2-yl)propan-1-one (0.1 g, 0.4237 mmol) in THF (8 mL) was added to above solution at −78° C. and the mixture stirred for 1 hour at −78° C. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and diluted with water (25 mL). The reaction mixture was extracted with ethyl acetate (200 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain crude product. The crude compound was purified by preparative TLC (using 5% methanol and dichloromethane) to afford 1-(5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)-1-(pyridin-4-yl)propan-1-ol as white solid (22 mg, 17% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.55 (d, 2H), 8.0-7.96 (m, 2H), 7.56 (d, 2H), 7.35 (t, 2H), 7.06 (s, 1H), 2.40-2.30 (m, 2H), 0.80 (t, 3H); LC-MS m/z calculated for [M+H]+ 316.08, found 316.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1>[Pd].CO>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1
Reactant: Cc1ccnc(C#Cc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccnc(CCc2ccccc2)c1
Temperature: 25 °C

Procedure:
A mixture of 4-methyl-2-phenylethynyl-pyridine (18.2 g) and 10% palladium on carbon (2.0 g) in methanol (300 mL) is stirred under hydrogen atmosphere (50 psi) at ambient temperature until the triple bond is completely reduced (20 h). The mixture is filtrered and the solvent is removed under reduced pressure.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[CH2:20][C:21]#[N:22].C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(#N)C>[CH3:1][S:2]([C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:20][C:21]#[N:22])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: N#CCCl
Reactant: CS(=O)(=O)c1ccc(Oc2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(Oc2ccc(OCC#N)cc2)cc1
Yield: 92.3 %

Procedure:
To a solution of 5.29 g (0.0200 mole) of 4-(4-(methylsulfonyl)phenoxy)phenol and 1.51 g (0.0200 mole) of 2-chloroacetonitrile in 100 ml of acetonitrile was added 3.0 g (0.0220 mole) of K2CO3. The mixture was heated at reflux for 3.5 hrs and cooled. The mixture was poured into aqueous NaOH and the product extracted from the mixture with CH2Cl2. The organic layer was extracted with aqueous NaOH, water and dried (Na2SO4). Removal of solvent in vacuo afforded 5.6 g (92.4% yield) of product. Recrystallization from ethanol followed by washing with aqueous NaOH and water afforded purified (4-(4-(methylsulfonyl)phenoxy)phenoxy)acetonitrile, mp 114°-115.5° C.
Reaction SMILES: [CH:1]([S:3]([CH3:6])(=[O:5])=[O:4])=[CH2:2].Cl.[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][NH2:18])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>CO>[CH3:6][S:3]([CH2:1][CH2:2][N:15]([CH2:16][CH2:17][NH2:18])[C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])(=[O:5])=[O:4]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: C=CS(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CCN)CCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.1 %

Procedure:
Methyl vinyl sulfone (0.42 mL, 4.8 mmol) was added dropwise to a cooled solution of N-tert-butyloxycarbonyl-1,2-ethylenediamine hydrochloride (1.00 g, 5.1 mmol) and triethylamine (1.4 mL, 10.7 mmol) in methanol (20 mL). The reaction was stirred at room temperature for 18 h and concentrated. Purification of the crude residue by chromatography over silica gel using 0-5% methanol in methylene chloride gave 2-(N-tert-butyloxycarbonyl-2-aminoethylamino)ethyl methyl sulfone (1.05 g, 77%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][N:5]([C:16]1[N:21]=[CH:20][N:19]=[C:18]([N:22]([CH:40]2[CH2:45][C:44]([CH3:47])([CH3:46])[NH:43][C:42]([CH3:49])([CH3:48])[CH2:41]2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]2)[N:17]=1)[CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1.OO.[OH2:52].O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)(C)C>[CH3:1][CH2:2][CH2:3][CH2:4][N:5]([C:16]1[N:21]=[CH:20][N:19]=[C:18]([N:22]([CH:40]2[CH2:45][C:44]([CH3:47])([CH3:46])[NH:43][C:42]([CH3:48])([CH3:49])[CH2:41]2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][CH:30]2[CH2:31][C:32]([CH3:39])([CH3:38])[NH:33][C:34]([CH3:37])([CH3:36])[CH2:35]2)[N:17]=1)[CH:6]1[CH2:11][C:10]([CH3:12])([CH3:13])[NH:9][C:8]([CH3:14])([CH3:15])[CH2:7]1.[NH:5]=[O:52]
Reactant: O
Agent: CCCCN(c1ncnc(N(CCCCCCNC2CC(C)(C)NC(C)(C)C2)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: OO
Solvent: CC(C)(C)O
Product: N=O

Procedure:
100 g Chimassorb 2020® (commercial product of Ciba Specialty Chemicals Inc.) in t-butanol is reacted with 120 g 50% hydrogen peroxide in the presence of 3 g sodium carbonate decahydrate to afford the Chimassorb 2020-nitroxyl after approximately 7-9 hrs. of reaction at 75° C. The batch is treated with sodium sulfite solution to destroy unreacted peroxides and then the aqueous layer is split off. The batch pH is brought to 7 with a trace of glacial acetic acid. Additional 140 g t-butanol is added, followed by 100 g butyraldehyde and 0.2 g Cu(I)Cl. Hydrogen peroxide (120 g) is dosed in while maintaining the reaction temperature at 35° C. The batch is on hold at 35° C. until the reaction is complete. A combination of sodium sulfite and sodium hydroxide solution is added. t-Butanol/water is stripped off under partial vacuum (15-20 mm Hg.) and the t-butanol is replaced by hexane. After 30 min. of stirring at 60° C., the aqueous layer is split. The batch pH is adjusted to 7 with a small quantity of acid. An EDTA wash is performed and the product is isolated with hot water stripping and dried in an oven at 80° C. to constant weight. Yield: 117 g; yellow powder.