Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:9][C:8](=[O:10])[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[NH:4]1.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].C(=O)([O-])O.[Na+]>ClCCCl>[CH2:11]([N:7]1[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[NH:4][CH:3]([CH:2]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH2:1])[CH2:9][C:8]1=[O:10])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NCC1CC(=O)N(Cc2ccccc2)c2ccccc2N1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: NC(C(=O)OCc1ccccc1)C1CC(=O)N(Cc2ccccc2)c2ccccc2N1
Reaction time: 0.17 h

Procedure:
A solution of 4-(aminomethyl)-1-benzyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (0.99 g, 3.5 mmol) in 1,2-dichloroethane (15 mL) was cooled to 0° C., to which was added dropwise benzyl chloroformate (0.51 mL, 3.6 mmol). The mixture was stirred for 10 minutes at the same temperature, and for 25 minutes at room temperature. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was separated, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride, which was dried over magnesium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure to give a crude product of l-benzyl-4-(benzyloxycarbonyl aminomethyl)-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one. This crude product was dissolved in 1,2-dichloroethane (10 mL), to which was added phthalimidoacetyl chloride (0.79 g, 3.5 mmol). The mixture was stirred for 20 minutes at room temperature. To this solution was added 4-dimethylaminopyridine (DMAP) (43 mg, 0.35 mmol). The mixture was stirred for 25 minutes at room temperature, to which was further added DMAP (0.17 g, 1.4 mmol), and the mixture was stirred for 14 hours. To the reaction mixture was added water. The aqueous layer was separated. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, which was dried over magnesium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure. The concentrate was recrystallized from chloroform-petroleum ether to afford the end product (1.42 g, 67%). m.p.219°-221° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([Mg]Br)[CH:29]=[CH:30][CH:31]=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH3:24])[CH:31]=2)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1=O
Reactant: COc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1(O)c1cccc(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
6-Methoxy-1-oxo-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (100 mg, 0.325 mmol) obtained in Example 1 was dissolved in THF and 1.5 equivalents of 3-methoxyphenylmagnesium bromide were added thereto, followed by stirring for 1 hr at 0° C. Then, the reaction mixture washed with saturated saline and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 122 mg of the titled compound (yield: 90.4%).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.[CH:20]([C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=1[C:30]([F:33])([F:32])[F:31])=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.O>[O:15]=[C:13]1[N:12]=[C:11]([NH:16][CH2:17][C:18]#[CH:19])/[C:10](=[CH:9]/[CH:6]2[CH2:7][CH2:8][N:3]([CH2:20][C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=3[C:30]([F:31])([F:32])[F:33])[CH2:4][CH2:5]2)/[S:14]1
Reactant: N#Cc1ccc(C=O)c(C(F)(F)F)c1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C#N)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56 %

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (823 mg) in DMF (12.8 mL) were added 4-formyl-3-(trifluoromethyl)benzonitrile (610 mg) and triethylamine (1.42 mL). The reaction mixture was stirred at room temperature for 1.5 hr, and sodium triacetoxyborohydride (1.62 g) was added. The mixture was further stirred at room temperature for 1 hr, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (618 mg).
Reaction SMILES: Br[CH2:2][C@H:3]1[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])[O:4]1.[Na+].[I-].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])(O)=O.[Na+].[Na]>O.C1COCC1.CS(C)=O>[O:24]1[CH2:25][CH2:26][N:21]([CH2:2][CH:3]2[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])[O:4]2)[CH2:22][CH2:23]1
Reactant: COc1ccc(F)cc1CC[C@H]1CC[C@H](CBr)O1
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(F)cc1CCC1CCC(CN2CCOCC2)O1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
To a flask under Ar was added trans-2-(bromomethyl)-5-(2′-methoxy-5′-fluorophenethyl)tetrahydrofuran (43 mg, 0.136 mmol), NaI (30 mg), morpholine (65 mg, 0.75 mmol), NaHCO3 (130 mg) and dry DMSO (2.5 mL) and dry THF (4 mL). The mixture thus obtained was heated to reflux under Ar(g) for 12 h. After it was cooled to room temperature, the reaction mixture was poured to a separatory funnel containing sodium bicarcarbonate aqueous solution (sat. NaHCO3:H2O=1:1, 30 mL). The organic function was extracted with ethyl acetate (3×30 mL) and the combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. The solvent then was removed in vacuo and crude product thus obtained was purified by flash column chromatography (2% MeOH in CH2Cl2, 0.1% TEA, Rf=0.21) to give the product (29 mg, 66%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:16](N)=[NH:17].C(OC(O)C)C>C(OCC)C>[Cl:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4]([OH:5])=[N:17][CH:16]=[N:1]2)=[CH:7][CH:8]=1
Reactant: N=CN
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: CCOC(C)O
Solvent: CC(=O)O
Solvent: CCOCC
Product: Oc1ncnc2cc(Cl)ccc12
Temperature: 25 °C
Yield: 130.2 %

Procedure:
2-Amino-4-chloro-benzoic acid (1.00 g, 11.7 mmol, 1.0 eq.), formamidine acetate (3.64 mL, 35.0 mmol, 3 eq.), and ethoxyethanol (20 mL) were refluxed under nitrogen overnight. Cooled to rt. Added 25 mL of diethyl ether. Solids precipitated. Filtered off solids. Pumped under high vacuum to give 2.75 g of white solids as product. LCMS detects (M+H)+=181.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:22][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23]
Reactant: CN(C)CCO
Reactant: Oc1cccc(Br)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCOc1cccc(Br)c1
Temperature: 25 °C
Yield: 63 %

Procedure:
Diisopropyl diazene-1,2-dicarboxylate (1.1 eq.) was added dropwise to a 0° C. solution of 3-bromophenol (1.155 g, 6.68 mmol, 1.0 eq.), 2-(dimethylamino)ethanol (1.1 eq.) and triphenylphosphine (1.1 eq.) in THF (20 mL). The mixture was allowed to warm to room temperature over 16 hours, and then the volatiles were removed under reduced pressure. The resulting residue was partitioned between EtOAc (20 mL) and 1N HCl (20 mL), and the aqueous layer was collected and washed with EtOAc. The aqueous layer was neutralized with saturated NaHCO3 (50 mL), extracted with EtOAc, and dried (MgSO4). Purification via silica chromatography (eluting with 4% MeOH/DCM) afforded 2-(3-bromophenoxy)-N,N-dimethylethanamine (1.032 g, 63%) as an oil.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[N:15]=[C:14]([Cl:16])[CH:13]=[C:12]([CH3:17])[N:11]=1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>O1CCCC1>[Cl:9][C:10]1[N:15]=[C:14]([Cl:16])[CH:13]=[C:12]([CH2:17][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=2)[N:11]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: Clc1ccc(CBr)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1ccc(CCc2cc(Cl)nc(Cl)n2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
Lithium diisopropylamide (11 mL, 2 M solution in heptane/tetrahydrofuran/ethylbenzene) was added dropwise over 5 min to a solution of 2,4-dichloro-6-methylpyrimidine (3.0 g) in tetrahydrofuran (20 mL) at −78° C. under nitrogen. The reaction was stirred at −78° C. for 30 minutes. 4-Chlorobenzylbromide (4.4 g) was dissolved in tetrahydrofuran (5 mL) and added dropwise over 5 minutes. The reaction was stirred at −78° C. for 30 min, allowed to warm to rt and stirred at rt for 16 h. Solvent was removed under vacuum. The residue was purified by column chromatography (5% ethyl acetate in hexanes) to afford 2,4-dichloro-6-[2-(4-chlorophenyl)ethyl]pyrimidine, (2.8 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3([C:21]([F:24])([F:23])[F:22])[N:20]=[N:19]3)=[CH:14][CH:13]=2)([OH:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]#[C:26][Si](C)(C)C)[CH:8]=2)[N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH2:1][C:2]1[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3([C:21]([F:24])([F:23])[F:22])[N:20]=[N:19]3)=[CH:14][CH:13]=2)([OH:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]#[CH:26])[CH:8]=2)[N:3]=1
Reactant: C[Si](C)(C)C#Cc1ccc2c(c1)C(O)(c1ccc(C3(C(F)(F)F)N=N3)cc1)C(N)=N2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc2c(c1)C(O)(c1ccc(C3(C(F)(F)F)N=N3)cc1)C(N)=N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.4 %

Procedure:
2-amino-3-{4-[3-(trifluoromethyl)diazirin-3-yl]phenyl}-5-[2-(trimethylsilyl)ethynyl]indol-3-ol (30.5 mg, 0.07 mmol, 1 eq.) was dissolved in THF (5 mL), and 1 M TBAF in THF (0.078 mL, 0.08 mmol, 1.1 eq.) was added. The reaction was stirred at room temperature for 10 minutes. Solvents were then evaporated, and the residue was purified by silica column (DCM/MeOH, 39:1→19:1→9:1→4:1), resulting in 21.8 mg (86%) of the title compound as a yellow solid. 1H NMR (500 MHz, CD3OD) δ 7.45 (d, J=8.5, 2H, Ar—H), 7.33 (dd, J=1.5, 8.0, 1H, Ar—H), 7.23 (d, J=8.2, 2H, Ar—H), 7.10-6.94 (m, 2H, Ar—H). 13C NMR (126 MHz, CD3OD) δ 180.61 (CNH2), 156.96 (C—Ar), 144.65 (C—Ar), 140.97 (C—Ar), 135.30 (C—Ar), 129.59 (C—Ar), 127.92 (d, J=0.90, C—Ar), 127.76 (C—Ar), 127.02 (C—Ar), 123.73 (q, J=273.90, CF3), 117.13 (C—Ar), 116.69 (C—Ar), 84.96 (CCH), 84.23 (Ar—COH), 77.31 (CCH), 29.56 (q, J=40.35, CN2). Exact Mass, 356.09. 354.7202 [M−H]−, 356.7268 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:38])([CH3:37])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH2:17][CH:18]2[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH:9]=1.[I:39]N1C(=O)CCC1=O>CC#N>[CH3:34][Si:33]([CH3:36])([CH3:35])[CH2:32][CH2:31][O:30][CH2:29][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:37])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:39])=[C:12]2[N:11]=[C:10]([CH2:17][CH:18]2[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH:9]=1
Reactant: CCOC(=O)C1CCC(Cc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CCOC(=O)C1CCC(Cc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 100 mL round-bottom flask was charged ethyl 4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)cyclohexanecarboxylate (Int-4i, 2.64 g, 4.69 mmol) and N-iodosuccinimide (1.16 g, 5.16 mmol). To this mixture was added MeCN (40 mL). The resulting solution was stirred at room temperature overnight. After 18 hours, the reaction was reduced in vacuo and the residue was purified via silica gel chromatography to yield the title compound. Yield=2.94 g.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.I[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[O:28][CH:29]=[CH:30][N:31]=3)=[CH:23][CH:22]=2)=[CH:16][CH:15]=1>ClCCl>[O:28]1[CH:29]=[CH:30][N:31]=[C:27]1[C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][NH:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:19][CH:18]=2)=[CH:26][CH:25]=1
Reactant: NCCN1CCOCC1
Reactant: ICCOc1ccc(Cc2ccc(-c3ncco3)cc2)cc1
Solvent: ClCCl
Product: c1coc(-c2ccc(Cc3ccc(OCCNCCN4CCOCC4)cc3)cc2)n1
Yield: 86.2 %

Procedure:
A solution of 2-(4-morpholinyl)ethanamine (1 g, 7.4 mmol) in dichloromethane was stirred as a solution of 2-[4-[[4-(2-iodoethoxy)phenyl]methyl]phenyl]oxazole (0.3 g, 0.74 mmol) in dichloromethane was added dropwise and the reaction was heated at reflux for 17 hours. The reaction was concentrated. The residue was dissolved in ethyl acetate and washed with water. The combined organic layers were dried and concentrated. Purification by chromatography on silica gel using a gradient of methanol in dichloromethane gave 0.26 g of N-[2-[4-[[4-(2-oxazolyl)phenyl]methyl]phenoxy]ethyl]-4-morpholineethanamine; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, 2H), 7.68 (s, 1H), 7.27 (d, 2H), 7.21 (s, 1H), 7.13 (d, 2H), 6.82 (d, 2H), 4.08 (t, 2H), 3.96 (s, 2H), 3.67 (m, 4H), 3.03 (t, 2H), 2.78 (t, 2H), 2.51 (t, 2H), 2.43 (m, 4H) ppm.
Reaction SMILES: Cl.[S:2]1[CH:6]=[C:5]([CH2:7][CH2:8][NH2:9])[C:4]2[CH:10]=[CH:11][CH:12]=[CH:13][C:3]1=2.[CH2:14]=O>CO>[CH2:14]1[C:6]2[S:2][C:3]3[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=3[C:5]=2[CH2:7][CH2:8][NH:9]1
Reactant: C=O
Reactant: NCCc1csc2ccccc12
Agent: Cl
Solvent: CO
Product: c1ccc2c3c(sc2c1)CNCC3
Yield: 36.1 %

Procedure:
A mixture of 2-(benzo[b]thien-3-yl)ethylamine hydrochloride (0.5 g, 2.34 mmol) and paraformaldehyde (0.125 g, 4.16 mmol) in methanol (15 mL) was refluxed for 24 h. The reaction mixture was concentrated under reduce pressure and the residue was neutralized with saturated NaHCO3 (50 mL), and extracted with ethyl acetate (2×50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to furnish 1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridine (160 mg, 35%); 1H NMR (200 MHz, CDCl3): δ 2.81 (m, 2H), 3.25 (m, 2H), 4.15 (s,2H), 7.30 (m, 2H), 7.69 (d, J=4.0 Hz, 1H), 7.79 ((d, J=4.0 Hz, 1H).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.CCCCCC.CC1(C)CCCC(C)(C)N1.[Li].[N:33]1([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:38][CH2:37][C:36]2([C:43]3[S:44][CH:45]=[CH:46][C:42]=3[CH2:41][CH2:40][O:39]2)[CH2:35][CH2:34]1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:64])(=O)=O)=CC=1.[Cl-].[NH4+]>O1CCCC1.O>[F:64][C:45]1[S:44][C:43]2[C:36]3([O:39][CH2:40][CH2:41][C:42]=2[CH:46]=1)[CH2:35][CH2:34][N:33]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:38][CH2:37]3
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)OCCc1ccsc12
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)OCCc1cc(F)sc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
2,2,6,6-Tetramethylpiperidine (18.7 mL, 110.5 mmol) is added over tetrahydrofuran (200 mL), and solution is cooled under nitrogen at −78° C. 2.5 M solution of butyl lithium in hexane (37.2 mL, 93 mmol) is added and mixture is stirred for 30 min at −78° C. Over the fresh lithium 2,2,6,6-tetramethylpiperidine solution is added a solution of tert-butyl spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-carboxylate (20 g, 58.2 mmol) in tetrahydrofuran (90 mL) keeping temperature below −70° C. After 20 min. a solution of N-fluorobenzenesulfonimide (30.26 g, 93.07 mmol) in tetrahydrofuran (200 mL) previously cooled under nitrogen at −20° C. is added via cannula. After 1 hr. stirring, water (20 mL) and aqueous solution of ammonium chloride (50 mL) are added. Then, organic layer is separated and the aqueous is washed twice with methyl t-butyl ether (2×25 mL). Organics are combined and solvent is evaporated under reduced pressure. Crude material is purified by normal phase HPLC using hexane/methyl t-butyl ether as solvents to give tert-butyl 2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-carboxylate in 50% yield. MS (m/z): 328 (M+1).
Reaction SMILES: [Cl-].[Li+].Br[C:4]1[N:5]=[C:6]([CH3:25])[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][C:13]=2[Cl:24])[C:8]=1[CH:9]=[O:10].[CH:26]([Sn](CCCC)(CCCC)CCCC)=[CH2:27].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:24][C:13]1[CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:16]=[CH:17][C:12]=1[CH2:11][N:7]1[C:8]([CH:9]=[O:10])=[C:4]([CH:26]=[CH2:27])[N:5]=[C:6]1[CH3:25]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCCCCOc1ccc(Cn2c(C)nc(Br)c2C=O)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1nc(C)n(Cc2ccc(OCCCCC)cc2Cl)c1C=O
Yield: 87.7 %

Procedure:
Lithium chloride (180 mg) was suspended in 1,4-dioxane (10 ml), and 4-bromo-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole-5-carbaldehyde (707 mg), vinyltributyltin (617 mg) and tetrakis(triphenylphosphine)palladium(0) (102 mg) were added. The mixture was refluxed under heating for 12 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was applied to silica gel column chromatography and eluted with hexane/ethyl acetate=5/1. The objective fraction was concentrated under reduced pressure to give 1-(2-chloro-4-(1-pentyloxy)benzyl)-4-ethenyl-2-methyl-1H-imidazole-5-carbaldehyde(538 mg) as a pale-yellow gum.
Reaction SMILES: C([NH:9][C:10](=[S:35])[NH:11][CH2:12][C:13]1[C:14]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=2)=[N:15][C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:17][C:18]=1[CH3:19])(=O)C1C=CC=CC=1.[OH-].[Na+]>CO.O>[CH3:19][C:18]1[N:17]=[C:16]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:15]=[C:14]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=2)[C:13]=1[CH2:12][NH:11][C:10]([NH2:9])=[S:35]
Reactant: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CNC(=S)NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CNC(N)=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
A mixture of 5-(3-benzoylthioureidomethyl)-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine (1.0 g) and sodium hydroxide (0.089 g) in methanol (20 ml) and water (10 ml) was stirred for 1 hour at a room temperature. After evaporating the solvent, water (20 ml) was added thereto and stirred for 30 minutes. The resulting precipitates were collected by filtration, washed with water and dried over phosphorous pentoxide to give 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-thioureidomethylpyrimidine (0.75 g).
Reaction SMILES: C(CCP(CCC(O)=O)CCC(O)=O)(O)=O.[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH2:36][CH2:37][C:38]([NH:40][C@@H:41]([CH2:47]S)[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:39])[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(S)(C)(C)C>CN(C=O)C>[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH2:36][CH2:37][C:38]([NH:40][C@@H:41]([CH3:47])[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:39])[C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)[C@H](CS)NC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: O=C(O)CCP(CCC(=O)O)CCC(=O)O
Solvent: CC(C)(C)S
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C)NC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.1 %

Procedure:
A 0.4 M aqueous tris(2-carboxyethyl)phosphine (TCEP) solution (0.428 ml, 0.171 mmol) was added to a solution of (S)-benzyl 2-((tert-butoxycarbonyl)amino)-5-(((R)-1-ethoxy-3-mercapto-1-oxopropan-2-yl)amino)-5-oxopentanoate (Compound 3a) (20.0 mg, 0.0427 mmol) in DMF (0.8 ml), and the mixture was stirred at room temperature for 15 minutes. tBuSH (0.0144 ml, 0.128 mmol) and a 1 M aqueous 2,2′-azobis-2-(2-imidazolin-2-yl)propane (VA-044) solution (0.0427 ml, 0.0427 mmol) were then added and the mixture was stirred at 50° C. for 2.5 hours. The reaction solution was then diluted by adding water, and subsequent purification by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=70/30→20/80) afforded (S)-benzyl 2-((tert-butoxycarbonyl)amino)-5-(((S)-1-ethoxy-1-oxopropan-2-yl)amino)-5-oxopentanoate (Compound 3b) (18.1 mg, 97%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][CH3:13])[CH:6]=[C:7]([I:10])[C:8]=1[OH:9].Cl.[NH2:16][OH:17].[OH-].[Na+].C(O)C>O>[OH2:9].[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:11](=[N:16][OH:17])[CH2:12][CH3:13])[CH:6]=[C:7]([I:10])[C:8]=1[OH:9]
Reactant: NO
Reactant: CCC(=O)c1cc(I)c(O)c(CN)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(=NO)c1cc(I)c(O)c(CN)c1
Temperature: 25 °C
Yield: 180.5 %

Procedure:
A mixture of 2.0 g of 3'-aminomethyl-4'-hydroxy-5'-iodopropiophenone and 1.2 g of hydroxylamine hydrochloride is added to 10 ml of 4N sodium hydroxide solution and 3.5 ml of ethanol, and then the mixture is refluxed with heating for 45 minutes. After cooling to room temperature, 15 ml of water is added to the reaction mixture. After filtration of the mixture, the filtrate is stirred under ice cooling and adjusted to pH 7.5 with concentrated hydrochloric acid. The white fine powder precipitated is collected by filtration, washed with cold water and dried to give 2.0 g of 3'-aminomethyl -4'-hydroxy-5'-iodopropiophenone oxime monohydrate, melting at 167°-168° C. with decomposition.