Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[O:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][C:15]([OH:17])=O)=[CH:13][C:8]=2[O:7][CH2:6]1.[OH-].[Na+].Cl.[CH3:21][NH:22][O:23][CH3:24].O1C2C=CC(CC(Cl)=O)=CC=2OC1>C1(C)C=CC=CC=1.O.CN(C)C=O>[O:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][C:15]([N:22]([O:23][CH3:24])[CH3:21])=[O:17])=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)Cc1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CON(C)C(=O)Cc1ccc2c(c1)OCO2
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 95.2 %

Procedure:
Thionyl chloride (39.6 g) and a drop of dimethylformamide were added to a solution of benzo(1,3)dioxol-5-yl-acetic acid (30.0 g) in toluene (200 ml) and then the mixture was stirred for 2.5 hours at 60° C., after distilling out the solvent, to yield unpurified benzo(1,3)dioxol-5-yl-acetyl chloride. A solution of sodium hydroxide (20.0 g) in water (150 ml) was added to a solution of N,O-dimethylhydroxylamine hydrochloride (19.5 g) in toluene (200 ml) at 0° C., and further the unpurified benzo(1,3)dioxol-5-yl-acetyl chloride was added thereto, and then the mixture was stirred for 3 hours. The reaction mixture was extracted with toluene and dried over anhydrous magnesium sulfate, and from which the solvent was evaporated to yield unpurified 2-benzo(1,3)dioxol-5-yl-N-methoxy-N-methylacetoamide (35.4 g).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:26]1([CH2:31]O)[CH2:30][CH2:29][CH2:28][CH2:27]1.OCC1CCN(CC2(C(OC)=O)CCCC2)CC1>>[CH:26]1([CH2:31][O:1][C:2]2[C:7]3[C:8]([O:11][CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[N:9][O:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: OCC1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O)c23)CC1
Agent: COC(=O)C1(CN2CCC(CO)CC2)CCCC1
Product: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(OCC4CCCC4)c23)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 4 of EXAMPLE 9 using tert-butyl 4-{[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidine-1-carboxylate (EXAMPLE 17, Step 2) and cyclopentylmethanol instead of 4-[(4-methoxybenzyl)oxy]-1,2-benzisoxazol-3-ol and methyl 1-{[4-(hydroxymethyl)piperidin-1-yl]methyl}cyclopentanecarboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10]C)=O)=[N:4][CH:5]=[CH:6][N:7]=1.[NH3:12]>CO>[NH2:1][C:2]1[C:3]([C:8]([NH2:12])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: N
Reactant: COC(=O)c1nccnc1N
Solvent: CO
Product: NC(=O)c1nccnc1N
Temperature: 112.5 °C
Yield: 97.7 %

Procedure:
A suspension of methyl 3-aminopyrazine-2-carboxylate (5 g, 32.6 mmol) and 150 mL of dry methanol saturated with anhydrous ammonia were heated in an autoclave at 110-115° C. for 24 h. Concentration and filtration afforded 3-aminopyrazine-2-carboxamide (4.4 g, 97.7% yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:22])[CH3:21])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(OCC)(=O)C.CCCCCC>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:19][C:14]2[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]3[O:10][C:9]([CH3:22])([CH3:21])[CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:12]=3[C:13]=2[CH3:20])=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(F)cc1)C(C)(C)O2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(F)cc1)C(c1ccc(F)cc1)C(C)(C)O2
Yield: 75 %

Procedure:
By using 3-(4-fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 75%. Melting point: 140-142° C. (Ethyl acetate-hexane)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Na]>C(O)(=O)C.ClCCl>[CH2:15]([N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(Cc2ccccc2)C1
Reaction time: 0.25 h

Procedure:
In a flask, dichloromethane (2 mL) and acetic acid (2 drops) was added to (S)-tert-butyl piperidin-3-ylcarbamate (100 mg, 0.5 mmol) and benzaldehyde (1 mmol). The reaction was stirred for 15 minutes. Sodium triacetoxyborohydride (422 mg, 2 mmol) was added in one portion. The reaction was stirred overnight. Saturated sodium bicarbarbonate (5 mL) was added. The reaction was stirred for an additional 5 minutes and was extracted with dichloromethane (3×10 mL). The extracts were combined, dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: [CH3:1][N:2]([C:7]12[CH2:16][CH:12]([CH2:13][CH2:14][CH2:15]1)[CH:11]1[CH2:17][CH:8]2[CH2:9][CH2:10]1)[C:3](=[O:6])[CH2:4]Cl.[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K]>>[CH3:1][N:2]([C:7]12[CH2:16][CH:12]([CH2:13][CH2:14][CH2:15]1)[CH:11]1[CH2:17][CH:8]2[CH2:9][CH2:10]1)[C:3](=[O:6])[CH2:4][N:22]1[C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]2[C:18]1=[O:28]
Reactant: CN(C(=O)CCl)C12CCCC(C1)C1CCC2C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Product: CN(C(=O)CN1C(=O)c2ccccc2C1=O)C12CCCC(C1)C1CCC2C1
Yield: 83 %

Procedure:
Under the same reaction conditions as described in section (A) of Example 7, N-methyl-N-(1-tricyclo[4.3.1.12,5 ]undecyl)-2-chloroacetamide was reacted with potassium phthalimide to obtain N-methyl-N-(1-tricyclo[4.3.1.12,5 ]undecyl)-2-phthalimidoacetamide in a yield of 83%.
Reaction SMILES: [Na+].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([O-:6])=O.S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([O:38][CH3:39])=[C:29](C(N2C=CN=C2)=O)[CH:30]=1.[Cl-].[Mg+2].[Cl-].Cl>C(#N)C>[CH2:9]([O:8][C:2](=[O:7])[CH2:3][C:4]([C:27]1[CH:26]=[C:25]([Cl:24])[CH:30]=[CH:29][C:28]=1[O:38][CH3:39])=[O:6])[CH3:10]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: COc1ccc(Cl)cc1C(=O)n1ccnc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cc(Cl)ccc1OC
Temperature: 10 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a stirred mixture of ethyl malonate sodium salt (3.8 g, 24.7 mmol) and magnesium sulfate (3.2 g, 26.3 mmol) in acetonitrile (60 ml) was added triethylamine (4.7 ml, 33.5 mmol) under an argon atmosphere. After stirring for 2 hours, the solution containing (5-chloro-2-methoxy-phenyl)-imidazol-1-yl-methanone was added. After stirring at 80° C. for 2 hours, magnesium chloride (2.5 g, 26.3 mmol) was added and the mixture was stirred for 16 hours. After cooling to 10° C., concentrated hydrochloric acid (5 ml) was added and the mixture was stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×60 ml). The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:4 followed by 1:3) to provide 3-(5-chloro-2-methoxy-phenyl)-3-oxopropionic acid ethyl ester (2.3 g, 76% yield) as an oil. 1H NMR (CDCl3) δ 1.23 (t, 3H, J=8.7 Hz CH3), 3.89 (s, 3H, CH3), 3.94 (s, 2H, CH2), 4.17 (q, 2H, CH2), 6.91 (d, 1H, J=8.6 Hz, Ar), 7.45 (dd, 1H, J=8.8 Hz, J=2.6 Hz, Ar), 7.85 (d, 1H, J=2.6 Hz, Ar).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([SH:12])[CH:6]=[CH:5]2.I[C:14]1[CH:15]=[C:16]([C:20]2([O:26][CH3:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12][C:18]1[CH:17]=[C:16]([C:20]3([O:26][CH3:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:15]=[CH:14][CH:19]=1)[CH:6]=[CH:5]2
Reactant: COC1(c2cccc(I)c2)CCOCC1
Reactant: Sc1ccc2cc(Br)ccc2c1
Product: COC1(c2cccc(Sc3ccc4cc(Br)ccc4c3)c2)CCOCC1
Yield: 30 %

Procedure:
Using a similar procedure to that described in Example 12, 6-bromo-2-naphthalenethiol was reacted with 4-(3-iodophenyl)-4-methoxytetrahydropyran to give 4-[3-(6-bromonaphth-2-ylthio)phenyl]-4-methoxytetrahydropyran in 30% yield, as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:13]=2[NH2:20])=[C:6]([CH3:21])[CH:5]=1.[CH3:23][C:24]1[O:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1.C(OCC)(=O)C.O>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:13]=2[NH:20][S:29]([C:27]2[O:28][C:24]([CH3:23])=[CH:25][CH:26]=2)(=[O:31])=[O:30])=[C:6]([CH3:21])[CH:5]=1
Reactant: COC(=O)c1ccc(COc2cc(C)c(C)cc2N)c(C)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)o1
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(COc2cc(C)c(C)cc2NS(=O)(=O)c2ccc(C)o2)c(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4-(2-amino-4,5-dimethylphenoxymethyl)-3-methylbenzoic acid methyl ester prepared in Reference Example 2 (632 mg) in pyridine (4 ml) was cooled to 0° C., then 5-methylfuran-2-sulfonyl chloride (490 mg) was added dropwise thereto. After the solution was stirred for 1 hour at room temperature, the reaction mixture was diluted by ethyl acetate, and poured into water. The organic layer was washed, dried, concentrated under reduced pressure. The residue was washed by mixed solvent of diisopropylether and hexane to give the title compound (875 mg) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH:32]([NH2:34])[CH3:33]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:13])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:34][CH:32]([C:28]1[S:27][CH:31]=[CH:30][CH:29]=1)[CH3:33]
Reactant: CC(N)c1cccs1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: CC(Nc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1cccs1
Yield: 66.5 %

Procedure:
Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.47 mmol) with (±)-1-thiophen-2-yl-ethylamine (prepared as described in J. Amer. Chem. Soc. 1942, 64, 477-479) (200 mg, 1.57 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1 and 4:1) to give (±)-7-chloro-6-[(1-thiophen-2-yl-ethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (126 mg, 67%).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].Cl[C:7]1[S:8][C:9]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=1>C(#N)C>[CH2:1]([NH:5][C:7]1[S:8][C:9]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[C:10]([C:12]([F:14])([F:13])[F:15])[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OCc1ccccc1)c1sc(Cl)nc1C(F)(F)F
Reactant: CCCCN
Solvent: CC#N
Product: CCCCNc1nc(C(F)(F)F)c(C(=O)OCc2ccccc2)s1
Yield: 36.3 %

Procedure:
By the procedure of Example 39, a stirred mixture of 20 ml acetonitrile, 3.65 g (49.8 mmol) of n-butylamine, and 8 g (24.9 mmol) of benzyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate (prepared as described in U.S. Pat. No. 4,199,506), was heated at reflux for 24 hours. The product was separated and then recrystallized from hexane to yield 3.24 g of a yellow solid product (m.p.=77°-79° C.) identified in Table I.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[C@@H:14]([OH:15])[CH:13]=[CH:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)Cl.N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>>[C:4]([Si:1]([O:8][CH2:9][C@@H:10]1[CH2:11][CH:12]=[CH:13][C@@H:14]1[O:15][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CC=C[C@@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CC=C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 18 h
Yield: 108.3 %

Procedure:
In an oven-dried 2 L two-neck flask, cooled under nitrogen, to a solution of (1S,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopent-2-en-1-ol (11) (98.07 g, 0.3864 mol) in methylene chloride (500 mL, 8 mol) was added 1H-imidazole (31.57 g, 0.4637 mol). To the resulting yellow solution was added a solution of tert-butyldimethylsilyl chloride (58.2 g, 0.386 mol) in methylene chloride (300 mL, 5 mol) via addition funnel over ˜30 min. The mixture was stirred mechanically for 18 hours. The reaction was quenched via addition of water (500 mL) and the layers were separated. The organic layer was washed with water (2×500 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford tert-butyl[((1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclopent-3-en-1-yl)methoxy]dimethylsilane (143.3 g) as a crude residue that was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:14])[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1>>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13]([N:15]2[CH2:16][CH2:17][N:18]([CH2:27][C:26]3[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[CH2:19][CH2:20]2)=[O:14])[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2]
Reactant: COc1ccc(CCl)cc1
Reactant: CCc1cc(NC(=O)N2CCNCC2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(Cc3ccc(OC)cc3)CC2)c(OC)nc1C
Yield: 42 %

Procedure:
1-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonylpiperazine and 4-methoxybenzylchloride were reacted by the same way with the example 72 to obtain the titled compound.
Reaction SMILES: Cl[C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:21][S-:22].[Na+]>CO.CN(C)C=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:3]2[C:2]([S:22][CH3:21])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=2)=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: COc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(-c2ncc(C(F)(F)F)cc2SC)ccc1Cl
Temperature: 80 °C
Reaction time: 7 h

Procedure:
3.0 g (9.3 mmol) of 3-chloro-2-(4-chloro-3-methoxyphenyl)-5-trifluoromethylpyridine and 0.7 g (10 mmol) of sodium thiomethoxide in a mixture of 50 ml of methanol and 20 ml of dimethylformamide were stirred at 80° C. for 7 h and then at 23° C. for 72 h. The mixture was then poured into 500 ml of ice-water, which was then extracted three times with 150 ml of tert-butyl methyl ether each time. The combined organic phases were washed twice with 100 ml of water each time, dried over sodium sulfate and concentrated.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[C:26]([OH:28])=[O:27])[C:19]([C:29]#[C:30][CH2:31][CH2:32][CH2:33][CH2:34]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:18][CH:17]=1)[OH:15])([CH3:3])[CH3:2].[N-:46]=[N+:47]=[N-:48].[Na+].[Cl-].[Na+]>C(O)(=O)C>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[N:13]=[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[C:26]([OH:28])=[O:27])[C:19]([C:29]#[C:30][CH2:31][CH2:32][CH2:33][CH2:34][N:46]=[N+:47]=[N-:48])=[CH:18][CH:17]=1)[OH:15])([CH3:11])[CH3:12]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCCCC#Cc2ccc(C(O)=Nc3c(C(C)C)cccc3C(C)C)c3c(C(=O)O)cccc23)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1cccc(C(C)C)c1N=C(O)c1ccc(C#CCCCCN=[N+]=[N-])c2cccc(C(=O)O)c12

Procedure:
A solution of 0.50 g (0.82 mmol) N-(2,6-diisopropylphenyl)-4-(6-tosyloxy-1-hexinyl)naphthaline-1,8-dicarboxylic acid imide and 0.36 g (5.5 mmol) sodium azide were stirred for 17 hours at room temperature under nitrogen atmosphere. 250 ml acetic acid and saturated sodium chloride solution were added to the reaction mixture. After mixing, the organic phase was removed and washed once with saturated sodium chloride solution and two times with water. The organic phase was dried with MgSO4 and the solvent was evaporated in a rotary evaporator at a temperature of the water-bath of 25° C. The obtained oil (0.40 g) was purified on silica gel ((60 Å, 60-200 μm) free flow agent:methylene chloride. 0.10 g (25% of the theoretical yield) of a orange-yellow solid material were obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:17]=[CH:18][C:4]1=2)[CH3:2].[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH:28]=[CH2:29].[Cl-].[Li+].C(N(CC)CC)C>CN(C=O)C>[CH2:32]([O:31][C:27](=[O:30])/[CH:28]=[CH:29]/[C:16]1[CH:17]=[CH:18][C:4]2[N:3]([CH2:1][CH3:2])[C:9](=[O:10])[C:8]([CH3:11])([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[CH:15]=1)[CH3:33]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: C=CC(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc2c(c1)N(C)C(=O)C(C)(C)C(=O)N2CC
Temperature: 180 °C
Yield: 103.1 %

Procedure:
Trifluoromethane sulfonic acid 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl ester(0.40 g), ethyl acrylate(0.13 g), dichlorobis(triphenylphosphine) Palladium (II) (35 mg),lithium chloride(64 mg), and triethylamine(0.19 ml) were added to DMF(4 ml). The mixture was heated at 180° C. (microwave reactor) for 20 minutes. The reaction liquid was cooled to room temperature, and subjected to celite filtration. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate=70:30→30:70). The purified product was condensed under reduced pressure to give the title compound(0.36 g) as a pale yellow solid.
Reaction SMILES: [CH2:1]([Zn]CC)C.ClCI.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH2:17])[N:11]=1.[Cl-].[NH4+]>ClCCl>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:1][CH2:17]2)[N:11]=1
Reactant: C=C(O[Si](C)(C)C(C)(C)C)c1cccc(Br)n1
Reactant: CC[Zn]CC
Agent: ClCI
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1(c2cccc(Br)n2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60.9 %

Procedure:
To a solution of diethylzinc (1M in hexane, 2.0 mL, 2.0 mmol) in dichloromethane (3.7 mL) at −4° C. was added chloroiodomethane (714 mg, 4.0 mmol) dissolved in dichloromethane (1 mL) dropwise. The reaction mixture was stirred at 0° C. for 15 minutes. A solution 2-bromo-6-(1-((tert-butyldimethylsilyl)oxy)vinyl)pyridine (200 mg, 0.6 mmol) in dichloromethane (3.0 mL) was added. The reaction mixture was stirred at 0° C. for 2 h. A cold saturated aqueous solution of ammonium chloride was added and the mixture was extracted with dichloromethane. The organics were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified via flash chromatography (100% heptanes) to afford 2-bromo-6-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridine (120 mg, 58%). 1H NMR (400 MHz, CDCl3) δ 0.11 (s, 6H), 0.95 (s, 9H), 1.22-1.28 (m, 2H), 1.39-1.45 (m, 2H), 7.23 (dd, 1H), 7.47 (t, 1H), 7.60 (dd, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1[S:11][CH2:12][CH2:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])=O)C.[BH4-].[Li+].CO>C1COCC1>[OH:3][CH2:4][C:6]1[N:7]=[CH:8][S:9][C:10]=1[S:11][CH2:12][CH2:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: CCOC(=O)c1ncsc1SCCS(=O)(=O)c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: O=S(=O)(CCSc1scnc1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a solution of 4-ethoxycarbonyl-5-[2-(phenylsulfonyl)ethylthio]thiazole (702 mg, 2 mmol) in 20 ml of THF was added lithium borohydride (2M, 1 ml) and methanol (0.16 ml, 4 mmol) at -30° C. The reaction mixture was allowed slowly warm up to room temperature and stirred overnight. The solvent was removed under reduced pressure and the crude residue was subjected to chromatography by using dichloromethane and methanol as the eluent to give the title compound (400 mg, 650%). 1H NMR (CDCl3) δ2.55 (s, 1H), 3.00 (t, 2H, J=6), 3.40 (t, 2H, J=6), 4.71 (s, 2H), 7.6 (t, 2H, J=7), 7.68 (t, 1H, J=7), 7.82 (d, 2H, J=7), and 8.80 (s, 1H).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:11])[C:4](=[O:10])[CH2:5][CH2:6][C:7](=[O:9])[CH3:8].[CH2:12](O)[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:1][O:2][N:3]([CH3:11])[C:4](=[O:10])[CH2:5][CH2:6][C:7]1([CH3:8])[O:14][CH2:13][CH2:12][O:9]1
Reactant: CON(C)C(=O)CCC(C)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CON(C)C(=O)CCC1(C)OCCO1

Procedure:
To a solution of 4-1 (38 g, 0.239 mol) in 500 mL benzene was added ethylene glycol (17.3 mL, 0.310 mol) and p-toluenesulfonic acid (1 g). The mixture was heated at reflux for 2 h with azeotropic removal of water. After cooling, the solution was washed with 200 mL sat. NaHCO3, brine, and dried over Na2SO4. Evaporative removal of the solvent gave 4-2 as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH:10]([C:13]1[N:17]=[C:16]([CH2:18][NH2:19])[O:15][N:14]=1)([CH3:12])[CH3:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)C.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:19][CH2:18][C:16]2[O:15][N:14]=[C:13]([CH:10]([CH3:12])[CH3:11])[N:17]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1noc(CN)n1
Reactant: O=Cc1cccc(Br)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)c1noc(CNCc2cccc(Br)n2)n1
Temperature: 25 °C

Procedure:
6-Bromopyridine-2-carbaldehyde (1.18 g, 6.34 mmol) and 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)methanamine (0.90 g, 6.34 mmol) were combined and dissolved in dichloroethane (26.0 ml), reacted for 45 minutes, at which time sodium triacetoxyborohydride (1.88 g, 8.88 mmol) was added and the reaction was maintained at room temperature overnight. The reaction was diluted with ethyl acetate followed by the addition of saturated sodium bicarbonate and saturated sodium carbonate to make sure the pH was basic. The organic layer was separated and washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude reaction mixture was purified by silica gel chromatography to yield the title compound.