Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH2:22])=[NH:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:23]([O:25][C:26](=[O:37])[C:27](=[CH:33]OCC)[C:28](OCC)=[O:29])[CH3:24].CC[O-].[Na+].[Na]>C(O)C>[CH2:23]([O:25][C:26]([C:27]1[C:28]([OH:29])=[N:21][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:11]3[CH:12]=[CH:13][C:8]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:9][CH:10]=3)=[CH:19][CH:18]=2)=[N:22][CH:33]=1)=[O:37])[CH3:24]
Reactant: CCCCCCc1ccc(-c2ccc(C(=N)N)cc2)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCCc1ccc(-c2ccc(-c3ncc(C(=O)OCC)c(O)n3)cc2)cc1

Procedure:
A mixture of 6.0 g. of 4'-n-hexyl-4-biphenyl-amidine hydrochloride and 4.9 g. of ethoxymethylene-malonic acid diethyl ester is stirred in a sodium ethylate solution, from 0.867 g. of sodium and 80 ml. of ethanol, for 40 minutes at room temperature and 40 minutes under reflux. After this, the yellow reaction mixture is evaporated in vacuo and the residue is suspended in 95 ml. of water and acidified with 15 ml. of glacial acetic acid. Filtering, washing with water and drying yields crude 2-(4'-n-hexyl-4-biphenylyl)-4-hydroxy-pyrimidine-5-carboxylic acid ethyl ester which can be sublimed at 185° in high vacuum for purification, m.p. 218.0°.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[CH3:12][N:13]=[C:14]=[S:15]>CN(C=O)C>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH:7][C:14]([NH:13][CH3:12])=[S:15])=[O:5]
Reactant: NNC(=O)c1ccccc1N
Reactant: CN=C=S
Solvent: CN(C)C=O
Product: CNC(=S)NNC(=O)c1ccccc1N

Procedure:
To a solution of 2-aminobenzoic hydrazide (1.5 g) in DMF was added 0.7 g of methyl isothiocyanate and the mixture was stand for a day. The solvent was removed and chloroform was added to the residue to give 2.1 of 1-(2-aminobenzoyl) 4-methylthiosemicarbazide as a precipitate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[Br:20])=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].Br[CH2:36][C:37]([NH2:39])=[O:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH2:36][C:37]([NH2:39])=[O:38])[C:14](=[O:19])[CH:13]=[C:12]3[Br:20])=[CH:6][CH:7]=1
Reactant: O=c1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)Cn1c(=O)cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 25-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromo-1,2-dihydroquinolin-2-one (300 mg, 0.65 mmol, 1.00 equip), N,N-dimethylformamide (10 mg, 0.14 mmol, 0.21 equip) and sodium hydride (52.3 mg, 1.31 mmol, 2.00 equip, 60%). To the resulting mixture was then added 2-bromoacetamide (108 mg, 0.78 mmol, 1.20 equip). The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of water (200 mL). The resulting solution was extracted with ethyl acetate (3×100 mL) and the organic layers combined and dried over sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with DCM: MeOH (20:1) to yield 2-[6-[bis(4-chlorophenyl)methyl]-4-bromo-2-oxo-1,2-dihydroquinolin-1-yl]acetamide as a white solid. LCMS (ES, m/z) 517 [M+H]+
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:23]=[CH:22][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=2)[C:13]#[N:14])=[C:7]([C:24]([F:27])([F:26])[F:25])[CH:6]=1.Cl[C:29]1[CH:30]=[C:31]2[N:38]([CH3:39])[CH2:37][CH2:36][N:32]2[C:33](=[O:35])[N:34]=1>C1COCC1>[CH3:39][N:38]1[C:31]2[N:32]([C:33](=[O:35])[N:34]=[C:29]([O:3][CH2:4][C:5]3[CH:23]=[CH:22][C:8]([O:9][C:10]4[CH:11]=[C:12]([CH:15]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:17]=4)[C:13]#[N:14])=[C:7]([C:24]([F:25])([F:26])[F:27])[CH:6]=3)[CH:30]=2)[CH2:36][CH2:37]1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(Oc2ccc(CO)cc2C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3cc(C#N)cc(C(F)(F)F)c3)c(C(F)(F)F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (9.37 mg, 0.234 mmol), 3-(4-(hydroxymethyl)-2-(trifluoromethyl)phenoxy)-5-(trifluoromethyl)benzonitrile (56.4 mg, 0.156 mmol) in THF (8 mL) and 7-chloro-1-methyl-2,3-dihydroi-midazo[1,2-c]pyrimidin-5(1H)-one (29 mg, 0.156 mmol).
Reaction SMILES: [CH2:1]([N:3]([C:17]1[CH:26]=[CH:25][C:24]2[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=2[CH:18]=1)[C:4](=[O:16])[NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].[CH2:33](I)[CH3:34]>CN(C=O)C>[CH2:33]([N:5]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1)[C:4]([N:3]([CH2:1][CH3:2])[C:17]1[CH:26]=[CH:25][C:24]2[C:23]([CH3:27])([CH3:28])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=2[CH:18]=1)=[O:16])[CH3:34]
Reactant: CCI
Reactant: CCN(C(=O)Nc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)N(CC)c1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccc(C(=O)O)cc1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
A solution of methyl 4-[3-ethyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoate (0.25 g, 0.6 mmole) in 15 mL DMF was treated portionwise with 22 mg of sodium hydride (0.92 mmole). After 5 minutes, ethyl iodide (0.062 mL) was added and the reaction mixture was heated to 150° C. for three days. The solvent was removed in vacuo and the residue was diluted in 25 mL ethyl acetate. The organic phase was washed with two 10 mL portions of water and one 10 mL portion of HCl 1N. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The product was purified by flash chromatography (SiO2, 10% methanol/methylene chloride) giving 90 mg of 4-[1,3-diethyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoic acid as a pale brown solid. M.P. 169-172° C.
Reaction SMILES: [CH3:1][C:2]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])=[N:8][N:7]=1)([CH3:5])[CH:3]=O.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][C:2]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=2)[CH2:14][CH2:15][CH3:16])=[N:8][N:7]=1)([CH3:3])[CH2:5][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: C1COCCN1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)C=O)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)CN2CCOCC2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-2-oxo-ethyl)-[1,3,4]thiadiazol-2-yl]-amide (41 mg), morpholine (25 mg), acetic acid (0.02 ml) in methylene chloride (1 ml) was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (42 mg) was added. The mixture was stirred at room temperature for at least two days. The mixture was quenched with diluted NaOH and extracted with methylene chloride. The organic layer was separated, concentrated to dryness and the residue was purified by silica gel column chromatography using 35% to 65% ethyl acetate in hexane as eluent to give the title compound. The title compound was prepared as the corresponding HCl salt by adding HCl/doxane, followed by concentration to give a solid. LC_MS retention time 1.7 min M+1=497.0, M−1=495.0.
Reaction SMILES: [O:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:13][C:14]([CH3:20])([CH2:18][CH3:19])[C:15](Cl)=[O:16]>>[CH3:13][C:14]([CH3:20])([CH2:18][CH3:19])[C:15]([N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9][N:10]([C:15](=[O:16])[C:14]([CH3:20])([CH3:13])[CH2:18][CH3:19])[CH2:11][CH2:12][O:1][CH2:2][CH2:3]1)=[O:16]
Reactant: C1COCCNCCOCCN1
Reactant: CCC(C)(C)C(=O)Cl
Product: CCC(C)(C)C(=O)N1CCOCCN(C(=O)C(C)(C)CC)CCOCC1

Procedure:
Analogously to Example 2 from 1,7-dioxa-4,10-diazacyclododecane and 2,2-dimethylbutyryl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH2:12][C@H:13]([NH:17][C@@H:18]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:19]([F:22])([F:21])[F:20])[C:14]([OH:16])=O)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[NH2:30][C:31]1([C:37]#[N:38])[CH2:36][CH2:35][S:34][CH2:33][CH2:32]1.C(NC(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[C:37]([C:31]1([NH:30][C:14](=[O:16])[C@@H:13]([NH:17][C@@H:18]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:19]([F:20])([F:21])[F:22])[CH2:12][S:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:10])=[O:11])[CH2:36][CH2:35][S:34][CH2:33][CH2:32]1)#[N:38]
Reactant: O=C(O)[C@H](CS(=O)(=O)Cc1ccc(F)cc1)N[C@@H](c1ccc(F)cc1)C(F)(F)F
Reactant: N#CC1(N)CCSCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: N#CC1(NC(=O)[C@H](CS(=O)(=O)Cc2ccc(F)cc2)N[C@@H](c2ccc(F)cc2)C(F)(F)F)CCSCC1
Reaction time: 1 h
Yield: 16 %

Procedure:
3-(4-Fluorophenylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)-ethylamino]propionic acid (146 mg) and 4-aminotetrahydrothiopyran-4-carbonitrile (104 mg) were weighed into a 4 mL vial fitted with a stir bar and cap and DMF (2 mL) was added to give a dark amber solution. Diisopropylamine (0.23 mL) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (271 mg) were added and the vial was flushed the vial with nitrogen and sealed with the cap. After 1 h, the reaction mixture was diluted with a 9:1 mixture of CH2Cl2:EtOAc (40 mL)) and washed with 1.0M aqueous KHSO4, water, a 1:1 H2O: saturated aqueous NaHCO3, and brine and dried over anhydrous MgSO4. After concentration, the residue was purified by flash chromatography on 20 cm3 silica gel using 9:1 CHCl3: EtOAc eluent to give the N-(4-cyanotetrahydrothiopyran-4-yl)-3-(4-fluorophenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide (30 mg) as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH:7]=[CH:6]2.[Br:22]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>C(#N)C>[Br:22][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9](=[O:13])[N:8]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH:7]=1
Reactant: COc1ccc(-n2ccc3cc(OC)ccc3c2=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(-n2cc(Br)c3cc(OC)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)isoquinolin-1(2H)-one (0.50 g, 1.78 mmol) was placed in a dry 250 mL single-necked round-bottomed flask fitted with a stirring bar and septa. Acetonitrile (10 mL) was added via a syringe under argon atmosphere at room temperature. N-Bromosuccinimide or NBS (0.33 g, 1.87 mmol) was added portionwise under argon atmosphere at room temperature. The reaction mixture was allowed to stir at room temperature for 2 hours. 20 mL of saturated sodium bicarbonate solution was then added. The mixture was extracted with ethyl acetate (3×10 mL). Organic layers were separated, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel, hexanes/EtOAc=2/3 v/v) to give a white solid product, 0.55 g, 85.9% yield. MS: 360.4 [M+H]+. 1H NMR (DMSO-d6, 300 MHz): δ 8.14 (d, 1H, J=8.7 Hz), 7.39-7.34 (m, 3H), 7.19 (d, 1H, J=2.4 Hz), 7.13-7.03 (m, 3H), 6.62 (dd, 1H, J=7.5 Hz), 3.89 (s, 3H), 3.81 (s, 3H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[C:18](=[O:24])[CH2:17][C@@:16]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH:13]=[CH2:14])[CH2:3]1.[C:26](O)(=[S:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1>CC(C)=O>[OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[C:18](=[O:24])[CH2:17][C@@:16]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH2:13][CH2:14][S:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=2)[CH2:3]1
Reactant: OC(=S)c1cccnc1
Reactant: C=CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCSCc4cccnc4)[C@@]3(C)CC(=O)[C@@H]12
Yield: 67.2 %

Procedure:
Treatment of 3α-hydroxy-21-methylene-5α-pregnane-11,20-dione (240 mg) in acetone (15 ml) with thionicotinic acid (150 mg) for 4 hrs. in similar manner to that described in Example 27 gave title compound (220 mg) as a white foam [αD ] + 55.6° (c 1.01).
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[CH3:18][C:19]1[N:24]=[CH:23][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=1>>[CH3:18][C:19]1[N:24]=[CH:23][C:22]([C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)=[CH:21][CH:20]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Product: Cc1ccc(-c2cccc3c4c([nH]c23)C2CCN(CC2)C4)cn1

Procedure:
The product of Example 1B (123 mg, 0.42 mmol) and 6-methylpyridine-3-boronic acid pinacol ester (111 mg, 0.51 mmol; Synthonix) were processed as described in Example 4 to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.01-2.17 (m, 4 H), 2.60 (s, 3 H), 3.03-3.14 (m, 3 H), 3.20-3.29 (m, 2 H), 4.27 (s, 2 H), 7.03-7.06 (m, 1 H), 7.10 (t, J=7.6 Hz, 1 H), 7.34 (dd, J=7.6, 1.2 Hz, 1 H), 7.42 (d, J=8.2 Hz, 1 H), 7.96 (dd, J=7.9, 2.4 Hz, 1 H), 8.63 (d, J=2.1 Hz, 1 H); MS (APCI) m/z 304 (M+H)+.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(O[CH:14](OCC)[N:15]([CH3:17])[CH3:16])C>>[CH3:14][N:15]([CH:17]=[C:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10])[CH3:16]
Reactant: CCOC(OCC)N(C)C
Reactant: O=C1CCc2ccccc21
Product: CN(C)C=C1Cc2ccccc2C1=O

Procedure:
The 2-(dimethylaminomethylene)-indan-1-one starting material was prepared from 1-indanone (3.17 g, 24 mmol) and N,N-dimethylformamide diethyl acetal (21 ml, 120 mmol) to give the desired product as golden yellow crystals (2.61 g) m.p. 156-161°. MS (ES+) 188 (MH+, 100%).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:11]([O:13][C:14](=[O:26])[CH2:15][C:16]1[S:20][N:19]=[C:18]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[N:17]=1)[CH3:12].C([O:31][C:32](=[O:35])[CH2:33]Br)(C)(C)C.[NH4+].[Cl-]>C1COCC1>[CH2:11]([O:13][C:14](=[O:26])[CH:15]([C:16]1[S:20][N:19]=[C:18]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[N:17]=1)[CH2:33][C:32]([OH:35])=[O:31])[CH3:12]
Reactant: CCOC(=O)Cc1nc(-n2ccnc2)ns1
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(=O)O)c1nc(-n2ccnc2)ns1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
LiHMDS (4.62 mL of a 1.0M solution in THF, 4.62 mmol) was added dropwise to a −78° C. solution of (3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-acetic acid ethyl ester (1.00 g, 4.20 mmol) and THF (42 mL) under a nitrogen atmosphere. The reaction mixture stirred for 30 minutes prior to warming to −40° C. and addition of t-butylbromoacetate (620 μL, 4.20 mmol). The reaction stirred for 15 minutes at −40° C. before slowly warming to r.t. and stirring for an additional 6h. Sat. NH4Cl (100 mL) was added, organic layer was separated, aqueous extracted with EtOAc, the organic layers dried over Na2SO4, filtered and concentrated to a yellow solid. The yellow solid was dissolved in TFA/DCM (1:1, 10 mL) and stirred at room temperature for 45 min. The solvent was evaporated to afford 583 mg (47%) of 2-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-succinic acid 1-ethyl ester as a white solid. The product was used directly in the subsequent step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[N:5][CH:6]=[CH:7][CH:8]=1.[OH:17][C:18]1[C:19]([CH:26]=[O:27])=[CH:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:25][O:24][C:21]1[CH:20]=[C:19]([CH:26]=[O:27])[C:18]([O:17][CH2:2][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[N:5][CH:6]=[CH:7][CH:8]=2)=[CH:23][N:22]=1
Reactant: COc1ccccc1-c1ncccc1CCl
Reactant: COc1cc(C=O)c(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C=O)c(OCc2cccnc2-c2ccccc2OC)cn1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-(chloromethyl)-2-(2-methoxyphenyl)pyridine (306 mg, 1.31 mmol, 1.00 equiv) in CH3CN (20 mL). 5-Hydroxy-2-methoxypyridine-4-carbaldehyde (200 mg, 1.31 mmol, 1.00 equiv), potassium carbonate (364 mg, 2.63 mmol, 2.00 equiv), and KI (44 mg, 0.27 mmol, 0.20 equiv) were added to the reaction mixture. The resulting solution was stirred for 5 h at 60° C., and then it was concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.1% HCOOH and MeCN (10.0% MeCN up to 40.0% in 10 min, up to 95.0% in 2 min, down to 10.0% in 2 min); Detector, Waters 2545 UvDector 254 & 220 nm. This resulted in 65 mg (9%) of 2-methoxy-5-[[2-(2-methoxyphenyl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde bis(trifluoroacetic acid) as a yellow solid. The compound exhibited a melting point of 105-107° C. 1HNMR (300 MHz, CDCl3) δ 10.32 (s, 1H), 8.69 (s, 1H), 7.93 (m, 2H), 7.36 (m, 3H), 6.99 (m, 3H), 5.35 (s, 2H), 3.86 (m, 6H); MS (ESI) m/z 351 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[C:6]([F:10])=[CH:5][C:3]=1[NH2:4].[CH3:11][S:12](Cl)(=[O:14])=[O:13].N1C=CC=CC=1.Cl>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:8]=[C:7]([I:9])[C:6]([F:10])=[CH:5][C:3]=1[NH:4][S:12]([CH3:11])(=[O:14])=[O:13]
Reactant: Nc1cc(F)c(I)cc1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(F)c(I)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.7 %

Procedure:
To a solution of 2,5-difluoro-4-iodoaniline (5.3 g, 19.4 mmol, Can. J. Chem., 2000(78), 1081-1088) in DCM(50 ml) was added methanesulfonyl chloride (1.65 ml, 21.3 mmol) and pyridine (4.7 ml, 58.2 mmol) at 0° C. The mixture was stirred for 24 hours at room temperature. The mixture was partitionedbetween EtOAc and 2 M HCl aqueous solution. The organic layer was separated and washed with 2 M aqueous HCl solution and brine, dried over sodium sulfate and concentrated in vacuo. The crude puroduct was purified by silica gel column chromatography eluting with gradually from hexane/EtOAc (4:1) to hexane/EtOAc (3:1) to give the title compound (5.6 g, 87%) as purple solids.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[C:31]([Br:39])=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:40])(=[O:15])=[O:14])=[CH:9][C:8]=1[OH:41])([CH3:4])([CH3:3])[CH3:2].[C:43](O)(=[O:50])[C:44]1[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=1.[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>>[C:1]([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[C:31]([Br:39])=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:40])(=[O:15])=[O:14])=[CH:9][C:8]=1[O:41][C:43]([C:44]1[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=1)=[O:50])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Reactant: O=C(O)c1ccncc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Product: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(OC(=O)c2ccncc2)c1
Yield: 86.3 %

Procedure:
The title compound was prepared according to the procedure in Example 25, step 1, using 4-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2, 6-dimethyl-phenoxysulfonyl]-2-hydroxy-benzoic acid tert-butyl ester (0.500 g, 0.691 mmol), isonicotinic acid (0.0851 g, 0.691 mmol), 2-chloro-1-methylpyridinium iodide (0.212g, 0.829 mmol) and triethylamine (0.327 mL, 2.35 mmol). Purification on Biotage KP-Sil eluting with 25% EtOAc/hexane gave 0.461 g (86%) of the title compound. 1H NMR (DMSO-d6) δ 1.35 (s, 9 H), 1.54 (s, 3 H), 2.17 (s, 6 H), 2.36 (s, 3 H), 7.19 (s, 2 H0, 7.45-7.47 (m, 2 H), 7.61-7.66 (m, 1 H), 8.04 (dd, 2 H), 8.13-8.25 (m, 4 H), 8.92 (dd, 2 H). mass spectrum (+ESI) m/z 772/774 (M+H).
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15]([C@@H:17]1[O:19][CH2:18]1)[Cl:16].[Cl-].[Na+]>C(O)C>[OH:19][CH:17]([CH2:15][Cl:16])[CH2:18][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: ClC[C@H]1CO1
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1nccn1CC(O)CCl

Procedure:
To 1.15 gram of 2-nitroimidazole in 20 mL of absolute ethanol was added 100 mg of potassium carbonate and 1.0 gram (R)-epichlorohydrin. The reaction mixture was refluxed overnight. The cooled reaction mixture is added to 150 mL of saturated aqueous sodium chloride containing 5% sodium bicarbonate. The reaction mixture was extracted with ethyl acetate (3×10 mL ) and the organic extract was dried over anhydrous sodium sulfate, filtered and concentrated to give 1.87 gram of the R enantiomer of 1-(2-hydroxy-3-chloropropyl)-2-nitroimidazole. A similar reaction procedure starting with (S)-epichlorohydrin gives 1.45 gram of the S enantiomer.
Reaction SMILES: C(O[C:9]([NH:11][C@H:12]([C:20]([C@@H:22]1[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[N:24]([NH2:30])[C:23]1=[O:31])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[C:14]1([CH2:13][CH2:12][C:9]([NH:11][C@H:12]([C:20]([C@@H:22]2[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[N:24]([NH2:30])[C:23]2=[O:31])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)O[C@H]1[C@@H](C(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1N
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1[C@@H](C(=O)[C@H](Cc2ccccc2)NC(=O)CCc2ccccc2)C(=O)N1N

Procedure:
(3S,4S)-3-(N-benzyloxycarbonyl-L-phenylalanyl)-amino-4-acetoxy-azetidin-2-one (1.70 g, 4 mmol) obtained in example 7, was hydrogenated with 3.5 g of 10% palladium on activated carbon in 200 ml of ethyl acetate at 50 psi hydrogen pressure at room temperature for 2 hrs. After removal of catalyst by filtration, the deprotected (3S,4S)-3-(L-phenylalanyl)-amino-4-acetoxy-azetidin-2-one in ethyl acetate was obtained.