Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15](F)=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C([O-])(O)=O.[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([NH:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Reactant: NCCCN1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Brc1cccc(Nc2ncnc3cc(NCCCN4CCOCC4)ccc23)c1
Temperature: 110 °C
Yield: 77.7 %

Procedure:
To a solution of 4-[(3-bromophenyl)amino]-7-fluoroquinazoline (0.60 g, 1.89 mmol) in Dimethylsulfoxide (DMSO) (10 mL) was added 4-(3-aminopropyl)morpholine (7.54 mmol, 1.10 mL). The reaction mixture was heated at 110° C. for 26 hours and then diluted with water, basified by the addition of saturated NaHCO3 and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Column chromatography on Grade III alumina with gradient elution from EtOAc to EtOAc/MeOH (98:2) followed by recrystallization from EtOAc/hexane gave 4-[(3-bromophenyl)amino]-7-[(3-morpholinopropyl)amino]-quinazoline (0.65 g, 78%) as cream crystals, mp 162-162.5° C.
Reaction SMILES: C([O:8][C:9](=[O:42])[C@@H:10]([NH:24][CH2:25][P:26]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[C:15]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][C:12]([CH2:11][C@H:10]([NH:24][CH2:25][P:26]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:27])[C:9]([OH:42])=[O:8])=[CH:17][CH:16]=1
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(Oc1ccccc1)Oc1ccccc1

Procedure:
(S)-3-(Biphenyl-4-yl)-2-[(diphenylphosphonomethyl)-amino]-propionic acid benzyl ester (0.8 g, 1.38 mmol) is dissolved in ethyl acetate (25 mL) and treated with hydrogen (50 lbs) in a Parr apparatus in the presence of 10% palladium on carbon (0.8 g). After uptake of 1 mole, the catalyst is filtered off and the solvent is evaporated in vacuo. The solid residue is recrystallized at 0° from ethyl acetate/hexane. After being dried under high vacuum at 50°, (S)-3-(biphenyl-4-yl)-2-[(diphenylphosphonomethyl)-amino]-propionic acid is obtained as a white solid, m.p. 118°-119°; [α]405 =+9.49 (c 1.01, CHCl3)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])/[CH:4]=[CH:5]\[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[F:17])([CH3:8])[CH3:7]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[F:17])([CH3:8])[CH3:7]
Reactant: COC(=O)/C=C\C(C)(C)c1cccc(OC)c1F
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCC(C)(C)c1cccc(OC)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
23.30 g (84.33 mmol) of E/Z-4-(2-fluoro-3-methoxyphenyl)-4-methylpent-2-enoic acid methyl ester is mixed in 310 ml of ethanol with 1.2 g of palladium on carbon, and it is stirred under hydrogen atmosphere overnight at room temperature. The catalyst is removed by filtration through a glass-fiber filter, and the residue that remains after concentration by evaporation is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 19.58 g (83.4%) of the desired compound is isolated.
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]2[O:6][C:7]3[CH:27]=[CH:26][CH:25]=[CH:24][C:8]=3[C:9]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:13][CH2:12]3)=[N:10][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:32][N:33](C=O)C>>[C:32]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:14]1[CH2:13][CH2:12][N:11]([C:9]2[C:8]3[CH:24]=[CH:25][CH:26]=[CH:27][C:7]=3[O:6][C:5]3[CH:28]=[CH:29][CH:2]=[CH:3][C:4]=3[N:10]=2)[CH2:16][CH2:15]1)#[N:33]
Reactant: Clc1ccc2c(c1)N=C(N1CCN(Cc3ccccc3)CC1)c1ccccc1O2
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: N#Cc1ccccc1CN1CCN(C2=Nc3ccccc3Oc3ccccc32)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 11-(1-piperazinyl)dibenz[b,f][1,4]oxazepine (2.79 g, 10.0 mmol) (prepared from 10,11-dihydrodebenz[b,f][1,4]oxazepine-11-one, Aldrich and piperazine, as in example 1) in DMF (25 mL) was added sodium hydride (0.56 g, 60% in oil, 14 mmol) at 0° C. under argon. The mixture was stirred at 0° C. for 10 minutes at room temperature for 20 minutes, and then treated with β-bromo-ο-tolunitrile (2.35 g, 12.0 mmol, Aldrich). The resulting mixture was stirred at room temperature overnight and quenched with saturated ammonium chloride solution (25 mL). The mixture was separated and extracted with ethyl acetate (3×50 mL). The combined organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to dryness and the residue was subjected to column chromatography using ethyl acetate:hexane (1:2) as the eluent. The title compound was obtained as a white solid (2.34 g, 59%), m.p. 136°-138° C.; MS 395 (M+ +1).
Reaction SMILES: [N:1]1([C:6]2[CH:18]=[CH:17][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>ClCCl.[OH-].[Na+]>[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:9]2[CH:17]=[CH:18][C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:7][CH:8]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: NCCCCCOc1ccc(-n2ccnc2)cc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCCCOc1ccc(-n2ccnc2)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 2.9 g of 5-[4-(1H-imidazol-1-yl)phenoxy]pentaneamine (Example 27) in 150 ml of dichloromethane and 100 ml 1N NaOH are combined and stirred vigorously as 2.8 g of 4-bromobenzoyl chloride is added. The reaction mixture is stirred at room temperature for 20 hours, the dichloromethane layer separated and dried over Na2SO4. The dichloromethane solution is diluted with 200 ml of hexane, and the solution concentrated to turbidity. Cooling the mixture at room temperature gives the desired product as white crystals, m.p. 150°-151° C.; yield, 1.4 g.
Reaction SMILES: COC([C:5]1([C:18]2[C:27]3[C:22](=[CH:23][C:24]([F:29])=[C:25]([F:28])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=O.[Li+].[Cl-].O.[Na+].[Cl-]>CS(C)=O>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][CH:5]([C:18]2[C:27]3[C:22](=[CH:23][C:24]([F:29])=[C:25]([F:28])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C1(c2ncnc3cc(F)c(F)cc23)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)c(F)cc23)CC1
Temperature: 150 °C
Reaction time: 7.5 h
Yield: 39.1 %

Procedure:
A mixture of 4-(6,7-Difluoro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (451 mg, 1.11 mmol), as prepared in the previous step, LiCl (89 mg, 2.12 mmol), water (60 μL, 3.3 mmol), and DMSO (430 μL) was stirred at 150° C. for 7.5 hrs with a reflux condenser. The reaction was then allowed to cool to rt, shaken with 1M NaCl (5 mL), and extracted with DCM (1×3 mL) and 9:1 DCM/MeOH (1×3 mL). The organic layers were combined, dried (Na2SO4), and concentrated. The residue was purified by silica flash chromatography (3:1 hex/EtOAc→2:1 eluent) to provide the title compound (151.8 mg, 39%). 1H-NMR (300 MHz, CDCl3) δ 9.22 (s, 1H), 7.90 (dd, 1H), 7.81 (dd, 1H), 4.33 (br m, 2H), 3.50 (tt, 1H), 2.96 (br t, 2H), 2.11-1.82 (m, 4H), 1.49 (s, 9H). LC/MS (ESI): calcd mass 349.2, found 368.3 (MH.H2O)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:10][CH2:11][CH2:12][Cl:13])=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: Sc1ccc(Br)cc1
Product: ClCCCSc1ccc(Br)cc1

Procedure:
Prepared by Procedure R and Scheme Z using 4-bromobenzenethiol and 1-bromo-3-chloropropane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([CH:8]2[CH2:13][C:12](=O)[CH2:11][C:10](=[O:15])[CH2:9]2)[CH:7]=1.C([O-])(=O)C.[NH4+:21]>C(O)C>[NH2:21][CH:12]1[CH2:13][CH:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:16])[CH2:9][C:10](=[O:15])[CH2:11]1
Reactant: O=C1CC(=O)CC(c2cc(Cl)ccc2F)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC1CC(=O)CC(c2cc(Cl)ccc2F)C1
Yield: 72.2 %

Procedure:
A solution of 5-(5-chloro-2-fluorophenyl)cyclohexane-1,3-dione (2 g) and ammonium acetate (1.9 g) in ethanol (15 ml) was refluxed for 15 hours. The reaction solution was concentrated under reduced pressure, and to the residue were added water (30 ml) and ethyl acetate (150 ml). The mixture was shaken, and the separated upper layer was washed with water and concentrated under reduced pressure. The residue was washed with ethyl acetate and dried to give 1-amino-5-(5-chloro-2-fluorophenyl)cyclohexan-3-one (1.45 g) as yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:22][CH2:21][C:16]2(OCC[O:17]2)[CH2:15][CH:14]=1)([O-:3])=[O:2].Cl>CC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:22][CH2:21][C:16](=[O:17])[CH2:15][CH:14]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Reaction time: 14 h
Yield: 99.7 %

Procedure:
A solution of compound 78 (4.7 g, 15.650 mmol) in acetone (50 mL) was treated with 10% aq. HCl (50 mL) at room temperature and stirred for over night (14 h). Acetone was evaporated and crude was basified using 10% aq. NH4OH solution (100 mL). The precipitate was filtered off, washed with 10% NH4OH solution (2×10 mL) and water (2×10 mL). The product was dried under vacuum to obtain compound 79 (4.0 g, quantitative) as a solid. For spectral data, please see Example 23.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Mg].[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][C@H:17]([CH3:26])[C:18](N1CCOCC1)=[O:19].[Cl-].[NH4+]>O1CCCC1.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:18](=[O:19])[C@H:17]([O:16][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)[CH3:26])=[CH:3][CH:4]=1
Reactant: C[C@@H](OC1CCCCO1)C(=O)N1CCOCC1
Reactant: Clc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](OC1CCCCO1)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 235.1 %

Procedure:
To a solution of 1-bromo-4-chlorobenzene (20 g) in tetrahydrofuran (260 ml) was added magnesium (turnings, 7.47 g). The mixture was vigorously stirred at room temperature. When the temperature of the mixture reached 40° C., the reaction vessel was cooled in a water bath. A solution of 1-bromo-4-chlorobenzene (38.9 g) in tetrahydrofuran (90 ml), was added dropwise to the mixture at 34°-40° C., followed by stirring for an hour at 30° C. To the mixture was added dropwise a solution of 4-[(2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (60 g) in tetrahydrofuran (60 ml) over the period of 15 minutes at 0° C. The mixture was stirred for 3 hours at room temperature. To the reaction mixture were added a saturated aqueous ammonium chloride solution (120 ml) and water (100 ml). The mixture was extracted with ethyl acetate (500 ml). The organic layer was washed with water, dried over magnesium sulfate and distilled under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 900 g, eluent: hexane/ethyl acetate=30:1→10:1) to give (2R)-4'-chloro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (66 g) as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9](F)[CH:8]=2)=[CH:4][CH:3]=1.Br.[CH:17]1([CH2:20][S:21]C(=N)N)[CH2:19][CH2:18]1>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([S:21][CH2:20][CH:17]3[CH2:19][CH2:18]3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: N=C(N)SCC1CC1
Reactant: N#Cc1ccc(-c2ccc(Cl)s2)cc1F
Agent: Br
Product: N#Cc1ccc(-c2ccc(Cl)s2)cc1SCC1CC1
Yield: 89.9 %

Procedure:
0.9 g (4.0 mmol) of 4-(5-chlorothiophen-2-yl)-2-fluorobenzonitrile and 0.9 g (4.3 mmol) of S-cyclopropylmethylisothiourea hydrobromide were allowed to react in the same manner as described above in Example 8 (4), and purification of the crude product by silica gel icolumn chromatography afforded 1.1 g of 4-(5-chlorothiophen-2-yl)-2-cyclopropylmethylthiobenzonitrile (yield 91%) as yellow feathery crystals (m.p. 123-124° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:7][CH:8]=[CH:9][C:2]=12.[Br:10]Br>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Br:10][C:9]1[C:2]2[C:3](=[N:4][CH:5]=[CH:6][N:1]=2)[NH:7][CH:8]=1
Reactant: c1cnc2[nH]ccc2n1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c[nH]c2nccnc12
Reaction time: 1.5 h

Procedure:
7-Bromo-5H-pyrrolo[2,3-b]pyrazine (4) is prepared by dissolving 5H-pyrrolo[2,3-b]pyrazine (3) in chloroform and slowly adding Br2 in carbon tetrachloride at 0° C. After stirring for 1-2 hours, the reaction may be quenched in aqueous hydrochloric acid. Isolation by conventional means (e.g. extraction and silica gel chromatography) provides compound 4.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][N:8]=2)[N:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:21]#[N:22].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][SH:31].[F-].[Cs+].O>CS(C)=O>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][S:31][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][N:8]=2)[N:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:21]#[N:22]
Reactant: Fc1ccccc1CS
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(C#N)c2Cl)nc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(C#N)c2SCc2ccccc2F)nc1
Reaction time: 48 h
Yield: 82.5 %

Procedure:
5-Chloro-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile (0.512 g, 1.46 mmol) and (2-fluoro-phenyl)-methanethiol (0.415 g, 2.92 mmol) were dissolved in dry DMSO (5 ml) and cesium fluoride (0.154 g, 2.92 mmol) was added to the clear solution. The resulting mixture was stirred at 20° for a period of 48 hours. Analytical HPLC indicated the reaction completion. The reaction mixture was poured into water (50 ml) and the resulting mixture was extracted with ethyl acetate (20 ml). The organic extract was dried over magnesium sulfate and concentrated with a rotary evaporator. The desired product (0.55 g, 83%) was isolated by chromatography on silica gel eluting with a gradient (from 20-40%) of ethyl acetate in hexane. MS: 457, r.t.: 27, 1H-NMR (CDCl3, 400 MHZ) δ 9.05 (d, 1H, H—Ar), 8.44-8.41 (q, 1H, H—Ar), 8.05 (d, 1H, H—Ar), 7.34-7.27 (m, 2H, H—Ar), 7.13-7.02 (m, 2H, H—Ar), 4.61 (s, 2H, CH2 of the benzyl group), 3.16 (s, 3H, CH3 of the CH3SO2 group) ppm.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:18](=[N:19][OH:20])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]2=[N:7][C:8]=1[C:9]([NH2:11])=[O:10])#[N:2].[C:21](Cl)(=[O:23])[CH3:22].O>N1C=CC=CC=1>[C:1]([C:3]1[N:4]=[C:5]2[C:18](=[N:19][O:20][C:21](=[O:23])[CH3:22])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]2=[N:7][C:8]=1[C:9]([NH2:11])=[O:10])#[N:2]
Reactant: CC(=O)Cl
Reactant: N#Cc1nc2c(nc1C(N)=O)-c1ccccc1C2=NO
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)ON=C1c2ccccc2-c2nc(C(N)=O)c(C#N)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.7 %

Procedure:
To a solution of 33 (1.0 g, 3.77 mmol) in dry pyridine (30 ml) cooled at 0° C., acetyl chloride (0.8 ml, 11.3 mmol) was added dropwise and the mixture was stirred 16 h at room temperature. Water (40 ml) was added and the precipitate was collected by filtration. The crude was purified by flash chromatography (CH2Cl2/acetone/MeOH 8:2:0.5) and triturated with Et2O/CH2Cl2/MeOH, affording 35 (251 mg, 21%) as yellow solid as single isomer. 1H NMR (300 MHz, DMSO d6): δ 8.12 (d, 1H), 7.91 (m, 2H), 7.77 (ddd, 1H), 7.43 (bs, 2H), 2.27 (s, 3H). ESI+MS: calcd for C15H9N5O3: 307.27; found: 308.1 (MH+).
Reaction SMILES: Br[C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][N:3]=1.[C:14]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(CC)CC)C>C1COCC1>[CH2:23]([O:22][C:14]([CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][N:3]=1)=[O:21])[CH3:24]
Reactant: Brc1nsc2nc3ccccc3n12
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)OCC)c1nsc2nc3ccccc3n12
Yield: 53.8 %

Procedure:
A mixture of 3-bromo-1,2,4-thiadiazolo[4,5-a]benzimidazole (0.2 g, 0.78 mmole), diethyl malonate (0.15 g, 0.94 mmol) and triethylamine (0.13 mL, 0.94 mmole) in 8 mL of THF was refluxed under a nitrogen atmosphere for 36 h. The resulting mixture was extracted with ethyl acetate, washed with water and 10% aqueous sodium sulfate. The organic layer was dried over magnesium sulfate to give the crude product, which was purified by flash chromatography (35% ethyl acetate:65%. hexane) to afford 0.14 g (54%) of the title compound as a yellow oil:
Reaction SMILES: [NH2:1][C:2](=[NH:15])[CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O=[C:17]1[CH2:22][CH2:21][O:20][CH2:19][CH:18]1[C:23](OC)=[O:24].C(=O)([O-])[O-].[K+].[K+]>CO>[O:24]=[C:23]1[NH:1][C:2]([CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:15][C:17]2[CH2:22][CH2:21][O:20][CH2:19][C:18]1=2
Reactant: N=C(N)CNC(=O)OCc1ccccc1
Reactant: COC(=O)C1COCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(NCc1nc2c(c(=O)[nH]1)COCC2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.5 %

Procedure:
To benzyl 2-amino-2-iminoethylcarbamate (1.77 g, 8.54 mmol) in methanol (67.5 mL) was added methyl 4-oxotetrahydro-2H-pyran-3-carboxylate (1.35 g, 8.54 mmol) and potassium carbonate (3.54 g, 25.6 mmol). The reaction mixture was stirred 15 h at room temperature. The solution was filtered and concentrated under vacuum. Purification was accomplished on a 100 g Isco column with 0% to 10% methanol in dichloromethane over 20 column volumes to give title compound (1.63 g, 59% yield). Exact mass calculated for C16H17N3O4 315.3. found 316.2 (ESI, M+H); 1H NMR (400 MHz, MeOD) 8 ppm 7.17-7.46 (m, 5H) 5.11 (s, 2H) 4.47 (br. s., 2H) 4.22 (s, 2H) 3.92 (t, J=5.31 Hz, 2H) 2.65 (br. s., 2H).
Reaction SMILES: [C:1]([N:4]([CH2:13][CH:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[C:1]([N:4]([CH2:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(Cc1ccc(Cl)cc1)CC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N(Cc1ccc(Cl)cc1)CC1CCNCC1

Procedure:
To a solution of 4-(N-acetyl-N-(4-chlorobenzyl)aminomethyl)-1-t-butoxycarbonylpiperidine (280 mg, 0.73 mmol) in dichloromethane (20 mL) stirring at room temperature, was added trifluoroacetic acid (5 mL). After 16 h the solvent was evaporated under vacuum, then toluene was added and evaporated (5 mL twice), followed by diethyl ether (10 mL twice) to obtain 4-(N-acetyl-N-(4-chlorobenzyl)aminomethyl)piperidine trifluoroacetic acid salt (298 mg, quantitative yield) as a tan solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[NH:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22]>C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([O:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][O:25][C:8](=[O:9])[C:7]1[CH:11]=[C:12]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:13]([OH:14])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1)[C:8](=[O:9])[C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]([OH:14])=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: OCCNCCO
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(C(=O)OCCN(CCOC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O

Procedure:
One mole of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in benzene was reactedwith two moles of diethanolamine in benzene to produce N,N-bis(3',5'-di-t-butyl-4'-hydroxybenzoyloxyethyl) 3,5-di-t-butyl-4-hydroxybenzamide; melting point 200°-202° C. When tested by the procedure of Example 2, the sample containing this compound lasted 1,300 hours, about 2.4 times as long as the control.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:12])=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][OH:11].[NH2:13][NH2:14]>O>[OH:11][CH2:10][CH2:9][NH:8][C:7]1[CH:6]=[C:5]([Cl:12])[N:4]=[N:3][C:2]=1[NH:13][NH2:14]
Reactant: NN
Reactant: OCCNc1cc(Cl)nnc1Cl
Solvent: O
Product: NNc1nnc(Cl)cc1NCCO
Reaction time: 20 h

Procedure:
To 40 g of 3,6-dichloro-4-(2-hydroxyethylamino)pyridazine is added slowly with stirring 430 g of 97% hydrazine. The mixture is stirred for 20 hours and cooled. Water is added, and the precipitate, 4-(2-hydroxyethylamino)-6-chloro-3-hydrazino pyridazine (m.p. 168° to 172°C.), is collected by filtration
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][CH2:25][C:26]2=O)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:32]([O:35][CH2:36][CH3:37])(=[O:34])[CH3:33].O>C(COC)OC>[Si:3]([O:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][CH:25]=[C:26]2[CH2:33][C:32]([O:35][CH2:36][CH3:37])=[O:34])([C:16]([CH3:19])([CH3:17])[CH3:18])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC2=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)CC1=CCCc2c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cccc21
Reaction time: 0.5 h

Procedure:
To a solution of diethyiphosphoric acid ethyl ester (19 g) in dimethoxyethane (200 ml) was added NaH (3.4 g, 60%) in oil) at 0° C. under N2. After being stirred for 30 minutes, 5-t-butyidiphenylsilyloxy-1-oxo-1,2,3,4-tetrahydronaphthalene (20 g) was added to the mixture. After being stirred for 12 hours at 80° C., the solution was poured hnto a mixture of ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was dissolved into a mixture of toluene (100 ml and 1,8-diazabicyclo[5.4.0]-7-undecene (17 ml) and the mixture was stirred for 3 days at 100° C. The solution was washed with 1N-HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 5-t-butyldiphenylsilyloxy-1-ethoxycarbonylmethyl-3,4-dihydronaphthalene (20.3 g).