Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>O1CCCC1.[Zn].[Cu]Cl>[CH2:18]([O:17][C:15](=[O:16])[CH:14]=[C:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)[CH3:19]
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: CCOC(=O)CBr
Agent: Cl[Cu]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCc2cc(OC)ccc21

Procedure:
To a solution of 5-methoxyindanone (150 g, 0.91 mol) in anhydrous tetrahydrofuran (4.5 L), was added zinc (30 mesh, 103.64 g, 1.59 mol) and copper(I) chloride (4.53 g, 0.045 mol). The suspension was stirred under Ar atmosphere and refluxed for 15 minutes; approximately a 25% portion of ethyl bromoacetate (133 mL, 1.18 mol) was added to the refluxing mixture in a slow dropwise fashion. After allowing to cool and stirring overnight at rt, TLC showed the presence of desired product, indicating the formation of reactive zinc species. The remainder of ethyl bromoacetate was added dropwise; an exotherm was observed (internal temperature increased to 35° C.). After 4 hours, TLC showed complete reaction. After the solids settled to the bottom of the flask, the liquid was siphoned off leaving a small amount behind to cover the solids. The flask was re-charged with 5-methoxyindanone (157.6 g, 1.86 mol total), anhydrous tetrahydrofuran (4.5 L), and zinc (80.92 g, 2.73 mol total). Ethyl bromoacetate (140 mL, 2.36 mol total) was added dropwise. An exotherm was observed (internal temperature increased to 35° C.). When the stirred mixture cooled to rt, TLC showed the reaction to be complete. The solids were allowed to settle and the liquid was siphoned off. The combined reaction solutions were concentrated in vacuo to a volume of ˜2 L. The liquid was then poured into sufficient 1N aqueous hydrochloric acid (cooled in ice water) to bring the pH to 1. The product was extracted with ethyl acetate (2×1 L, 1×500 mL). The combined extracts were washed with water, brine (1 L each), dried over sodium sulfate, filtered, and concentrated in vacuo to afford a dark red oil which solidified gradually (438.3 g; theoretical yield=432 g). 1H NMR (CDCl3): 7.5 (d, 1H), 6.8 (m, 2H), 6.2 (t, 1 H), 4.2 (q, 2H), 3.8 (s, 3H), 3.3 (m, 2H), 3.0 (t, 2H), 1.3 (t, 3H). MS (CI) m/z 233 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1.[OH-].[Na+].[CH2:28](O)C>>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([S:17][CH:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:25])=[CH:5][CH:6]=2)[CH2:11][CH:12]([CH3:28])[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:19][CH:20]=1
Reactant: CCCCCCC(Sc1ccc(Br)cc1)c1ccc(C(=O)OC)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(C)CC(Sc1ccc(Br)cc1)c1ccc(C(=O)O)cc1

Procedure:
To a solution of 4-(1-hydroxy-3-methyl-heptyl)-benzoic acid methyl ester (1760 mg, 7.04 mmol) in toluene (70 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 2664 mg, 10.56 mmol) at 0° C., followed by the additions of tributylphosphine (2.63 mL, 8.38 mmol) and 4-bromo-benzenethiol (1597 mg, 8.45 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 4-[1-(4-bromo-phenylsulfanyl)-heptyl]-benzoic acid methyl ester. 1700 mg of the ester product is taken into ethanol (5 mL), treated with sodium hydroxide (5N aqueous, 2 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (2 mL), and extracted with ethyl acetate. The organic layers are dried and concentrated giving 4-[1-(4-bromo-phenylsulfanyl)-3-methyl-heptyl]-benzoic acid (1700 mg).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:17]=1)[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:59][O:60][C:61](=[O:68])[CH2:62][CH2:63][NH:64][CH:65]([CH3:67])[CH3:66]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:59][O:60][C:61](=[O:68])[CH2:62][CH2:63][N:64]([CH:65]([CH3:67])[CH3:66])[C:12](=[O:14])[C:11]1[CH:15]=[C:16]([O:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:17]=[C:9]([CH3:8])[CH:10]=1
Reactant: Cc1cc(OCCNc2ccncc2)cc(C(=O)O)c1
Reactant: COC(=O)CCNC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCN(C(=O)c1cc(C)cc(OCCNc2ccncc2)c1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
To a stirred solution of 3-methyl-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoic acid trifluoroacetate (0.025 g) and TBTU (0.021 g) in DMF (1 ml) was added DIPEA (0.022 ml) followed by 3-isopropylamino-propionic acid methyl ester (0.01 g) after 3 min. The reaction was stirred at room temperature for 18 h, and then concentrated under reduced pressure. The residue was subjected to preparative hplc to give the title compound (0.031 g) as a colourless oil, by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:19]#[N:20])[CH:12]=[CH:11][C:10]1=2.[BH3-]C#N.[Na+].CC(O)=O.[O:29]=[C:30]1[C:34]2[CH:35]=[CH:36][C:37]([CH2:39][CH:40]=O)=[CH:38][C:33]=2[CH2:32][O:31]1.C([O-])([O-])=O.[Na+].[Na+]>CO>[O:1]=[C:2]1[CH2:7][N:6]([CH2:40][CH2:39][C:37]2[CH:36]=[CH:35][C:34]3[C:30](=[O:29])[O:31][CH2:32][C:33]=3[CH:38]=2)[CH2:5][CH2:4][N:3]1[CH2:8][CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:19]#[N:20])[CH:12]=[CH:11][C:10]1=2
Reactant: O=CCc1ccc2c(c1)COC2=O
Reactant: N#Cc1ccc2c(c1)CCCC2CN1CCNCC1=O
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc2c(c1)CCCC2CN1CCN(CCc2ccc3c(c2)COC3=O)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-[(2-Oxopiperazin-1-yl)methyl]-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (40 mg, 0.15 mmol), NaBH3CN (19 mg, 0.30 mmol) and HOAc (18 mg, 0.298 mmol) in 20 mL MeOH was added (1-Oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (52 mg, 0.30 mmol) and the mixture was stirred at RT overnight. Then saturated Na2CO3 (50 mL) was added and stirred for 30 min and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by prep-TLC to give the desired product. 1H-NMR (400 MHz, MeOD) δ ppm 7.78 (d, J=7.8 Hz, 1H), 7.39˜7.51 (m, 4H), 7.31 (d, J=7.8 Hz, 1H), 5.34 (s, 2H), 3.74˜3.80 (m, 1H), 3.32˜3.43 (m, 3H), 3.25˜3.28 (m, 1H), 3.21 (s, 2H), 2.97˜3.01 (m, 2H), 2.74˜2.84 (m, 6H), 1.89˜1.96 (m, 1H), 1.71˜1.79 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[NH2:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([CH2:33][N:34]([CH3:36])[CH3:35])=[CH:29][NH:30]2)=[CH:26][CH:25]=1>>[CH3:36][N:34]([CH2:33][C:28]1[C:27]2[C:31](=[CH:32][C:24]([NH:23][C:20]([C:17]3[CH:18]=[CH:19][C:14]([C:3]4[CH:4]=[C:5]([C:8]5[O:9][C:10]([CH3:13])=[N:11][N:12]=5)[CH:6]=[CH:7][C:2]=4[CH3:1])=[CH:15][CH:16]=3)=[O:21])=[CH:25][CH:26]=2)[NH:30][CH:29]=1)[CH3:35]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: CN(C)Cc1c[nH]c2cc(N)ccc12
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Nc4ccc5c(CN(C)C)c[nH]c5c4)cc3)c2)o1

Procedure:
N-[3-(Dimethylaminomethyl)indol-6-yl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 6amino-3(dimethylaminomethyl)indole using method I. LCMS; retention time 3.16 min, [M-H·]463.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C@@H:10]([OH:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:18][CH:19]=2)[C@@H:10]([OH:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1COCCCCl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(O)cc2)[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2O)cc1

Procedure:
reacting the product of step b) with 1-(3-chloro-propoxymethyl)-2-methoxy-benzene and potassium carbonate to yield (3R,4R)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butylester;
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[CH2:7]([N:14]([CH2:16][CH2:17]Cl)[CH3:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])(O)=O.[Na+]>CCO>[CH2:7]([N:14]([CH2:16][CH2:17][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH3:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(CCCl)Cc1ccccc1
Reactant: c1c[nH]cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN(CCn1ccnc1)Cc1ccccc1
Yield: 34.6 %

Procedure:
A solution of imidazole (2.32 g, 34.1 mmol), the title compound of Step 10 (5.0 g, 22.7 mmol) and NaHCO3 (6.58 g, 78.3 mmol) in anhydrous EtOH (40 mL) was refluxed overnight in a modification of the procedure of Bach et al, [J. Am. Chem. Soc., 79, 2221-2225 (1957)]. After filtration, the filtrate was concentrated to a yellow oil. The oil was dissolved into a 1.0M KOH solution (10 mL) and was extracted with EtOAc (3×5 mL). The organic layer was washed with a 5% NaHCO3, solution (5 mL), H2O (5 mL), and brine (5 mL) and then was dried over MgSO4. The filtrate was concentrated and purified by medium pressure column chromatography on silica gel [eluting with NH4OH-EtOH-CHCI3 (1:4: 94)] to give the title compound as an oil (1.69 g, 30% yield). The proton spectral data were consistent with the proposed structure.
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.I[CH:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[C:38]([C:41]1[CH:48]=[C:47]([CH3:49])[C:44]([C:45]#[N:46])=[C:43](I)[C:42]=1[O:51][CH3:52])(=[O:40])[CH3:39]>CN(C)C(=O)C.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:38]([C:41]1[C:42]([O:51][CH3:52])=[C:43]([CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)[C:44]([C:45]#[N:46])=[C:47]([CH3:49])[CH:48]=1)(=[O:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: COc1c(C(C)=O)cc(C)c(C#N)c1I
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: BrCCBr
Product: COc1c(C(C)=O)cc(C)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Zinc (1.70 g, 26.0 mmol) and celite (oven dried, 500 mg) were ground together in a flask until the solids appeared homogenous, the flask was heated with a heat gun while under high-vac for 5 minutes and then back-filled with nitrogen. The solids were suspended in N,N-dimethylacetamide (4.2 mL) and 1,2-dibromoethane (0.13 mL, 1.5 mmol) was added. The reaction mixture was heated at 70° C. for 30 min and then cooled to room temperature. Chlorotrimethylsilane (0.16 mL, 1.3 mmol) was added dropwise and stirring was continued for 2 hrs at room temperature. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (2.70 g, 9.52 mmol) in N,N-dimethylacetamide (4.35 mL) was then added slowly and the resulting mixture was heated at 50° C. for 2 hrs. The zinc-iodo reagent was allowed to cool to room temperature and was taken up in a syringe and filtered through a PTFE filter (adapted with a needle) directly into a suspension of tris(dibenzylideneacetone)dipalladium(0) (0.111 g, 0.121 mmol) and tri-(2-furyl)phosphine (0.056 g, 0.24 mmol) and 4-acetyl-2-iodo-3-methoxy-6-methylbenzonitrile (2.0 g, 6.3 mmol) in N,N-dimethylacetamide (19.6 mL) pre-degassed by bubbling N2. The reaction mixture was degassed with nitrogen again and heated to 70° C. After heating for 30 minutes the reaction was complete by LC/MS. This was allowed to cool, taken up in ethyl acetate and washed with water, brine, dried over magnesium sulfate and concentrated to give the crude product as an oil. The product was purified by FCC on silica gel eluting hexane; ethyl acetate gradient to give tert-butyl 3-(3-acetyl-6-cyano-2-methoxy-5-methylphenyl)azetidine-1-carboxylate as a clear oil. (1.8 g, 82%). LCMS calculated for C15H17N2O4 (M+H)+: m/z=289.1; found: 289.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]3[CH2:12][CH2:13][CH2:14][CH2:15][C:9]=3[C:8]=2[CH:16]=1)([O-])=O>[Ni].C(O)C>[CH:16]1[C:8]2[C:9]3[CH2:15][CH2:14][CH2:13][CH2:12][C:10]=3[O:11][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccc2oc3c(c2c1)CCCC3
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc2oc3c(c2c1)CCCC3
Yield: 81.2 %

Procedure:
Following method A, potassium t-butoxide (37 g, 320 mmol) was added in portions to a cooled (2° C.) solution of cyclohexanone oxime (35 g, 300 mmol) in DMF (350 mL). The cooled reaction mixture was stirred for 20 minutes and then 1-chloro-4-nitrobenzene (50 g, 320 mmol) was added in portions. The reaction mixture was stirred at ˜10° C. for 30 minutes and then allowed to warm to room temperature and stirred for an additional 4 hours. The reaction mixture was concentrated under reduced pressure to remove the DMF and then treated with water (300 mL). The precipitate was collected by filtration and washed with water. Recrystallization of the crude material from isopropanol and column chromatography provided cyclohexanone O-(4-nitro-phenyl)-oxime (48 g). Cyclohexanone O-(4-nitro-phenyl)-oxime (48 g, 205 mmol) was dissolved in warm isopropanol (350 mL) and 12 N hydrochloric acid (94 mL) was added. The reaction mixture was heated to reflux for 3.5 hours and then cooled in an ice bath. The solid was collected by filtration, washed with water and cold isopropanol, and dried in an oven to give 8-nitro-1,2,3,4-tetrahydro-dibenzofuran (33 g, 150 mmol). A mixture of 8-nitro-1,2,3,4-tetrahydro-dibenzofuran (11 g, 50 mmol) and Raney nickel (˜11 g wet weight) in ethanol (200 mL) was hydrogenated at 50 PSI on a Parr shaker overnight. The mixture was filtered through Celite® and the filtrate was concentrated. The crude solid was recrystallized from hexane to give 6,7,8,9-tetrahydro-dibenzofuran-2-YLAMINE (7.6 g). Mp 71-72° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].S(=O)(=O)(O)O.[N+:15]([O-])([O-:17])=[O:16].[K+]>>[C:5]([C:4]1[CH:3]=[C:2]([F:1])[CH:9]=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16])#[N:6]
Reactant: O=[N+]([O-])[O-]
Reactant: N#Cc1cccc(F)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: N#Cc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 86.5 %

Procedure:
m-Fluorobenzonitrile (96.8 g., 0.8 mole) is added in two and one-half hours to a mixture of concentrated sulfuric acid (600 ml.) and potassium nitrate (80.9 g., 0.8 mole) at 3°-6° C., then allowed to warm to 25° C. The mixture is poured over cracked ice (3000 ml.), extracted with chloroform (5×250 ml.), dried and the solvent removed. The residue is extracted with pentane and dried to give 3-cyano-4-nitrofluorobenzene (115 g., 86.5%) m.p. 102°-104° C.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:15])=[N+:2]=[N-:3].CC(C)([O-])C.[K+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCCC1>[N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:5]1=[O:15])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC1CCc2ccccc2NC1=O
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C(N=[N+]=[N-])CCc2ccccc21
Reaction time: 1 h

Procedure:
3-azido-2,3,4,5-tetrahydro-1H[1]benzazepin-2-one (see example 1, 5.0 kg) was added portionwise under nitrogen to potassium tert-butoxide (3.03 kg) in dry tetrahydrofuran (50 liters) at such a rate that the temperature is is maintained below 5°, and the reaction mixture was stirred for 1 hour after the addition is completed. A solution of ethyl bromoacetate (4.38 kg) in tetrahydrofuran (5 liters) was then added slowly so as to maintain the temperature below 5°. The reaction mixture was then stored at room temperature overnight. Filteraid (1.5 kg of Hiflo) was added, and the reaction mixture was filtered. The filter cake was washed with tetrahydrofuran and the combined tetrahydrofuran solution was evaporated to dryness to give 3-azido-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one which is used without further purification in the next step.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[H-].[Na+].[Br:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10](OC)=[O:11].Cl>C1COCC1.O>[Br:6][C:7]1[CH:8]=[C:9]([C:10](=[O:11])[CH2:2][C:1]#[N:3])[CH:14]=[CH:15][CH:16]=1
Reactant: CC#N
Reactant: COC(=O)c1cccc(Br)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CCC(=O)c1cccc(Br)c1
Temperature: 75 °C
Yield: 92.1 %

Procedure:
Acetonitrile (21.86 mL, 419 mmol) was added to a stirred suspension of 60% NaH (7.25 g, 181 mmol) in THF (150 mL). Then, methyl 3-bromobenzoate (30 g, 140 mmol) was added and the mixture was heated at 75° C. for 4 h. After cooling to room temperature, water followed by 1N HCl (200 mL) was added and the mixture was extracted with ethyl acetate (500 mL), washed with sat .NaHCO3 solution (200 mL), dried (Na2SO4), filtered and concentrated to afford 3-(3-bromophenyl)-3-oxopropanenitrile (29 g, 129 mmol, 93% yield) as light yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.09 (t, J=1.7 Hz, 1H), 7.90-7.86 (m, 1H), 7.83 (ddd, J=8.0, 2.0, 1.1 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 4.08 (s, 2H).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:31])[CH:12]([NH:13][C:14](=[O:30])[CH2:15][CH:16]([NH:22]C(OC(C)(C)C)=O)[C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C@H:4]2[S:3]1>C(O)=O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:31])[CH:12]([NH:13][C:14](=[O:30])[CH2:15][CH:16]([NH2:22])[C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)CC(NC(=O)OC(C)(C)C)c3cccs3)[C@H]2S1
Solvent: O=CO
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)CC(N)c3cccs3)[C@H]2S1
Reaction time: 1 h
Yield: 73.9 %

Procedure:
A solution of 2-methyl-7-[3-(tert.-butoxycarbonylamino)-3-(2-thienyl)propionamido]-3-cephem-4-carboxylic acid (310 mg) in formic acid (1.5 ml) was stirred for 4 hours at room temperature. After the reaction was completed, the solvent was distilled off from the reaction mixture, and the residue was pulverized by treating with ethyl acetate. Thus obtained yellow powder was suspended in a mixture of acetonitrile (10 ml) and water (3 ml), and the suspension was stirred for 1 hour. The precipitate was collected by filtration, and dried to give 2-methyl-7-[3-amino-3-(2-thienyl)propionamido]-3-cephem-4-carboxylic acid (180 mg), mp 218° to 221° C. (dec.).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[CH:10][S:9][C:8]=12.C([Li])CCC.CCCCCC.[CH2:23]([Sn:27](Cl)([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26].C(OCC)(=O)C>C1COCC1>[CH3:1][O:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]2[C:11]([Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:10][S:9][C:8]=12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COCc1ncn2ccsc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1csc2c(COC)ncn12
Reaction time: 1 h
Yield: 35.6 %

Procedure:
A solution of 925 mg of 7-methoxymethylimidazo[5,1-b]thiazole in anhydrous THF was cooled to −70° C. under the atmosphere of argon and 3.54 ml of a 1.6 N n-butyl lithium/n-hexane solution was slowly added, and the mixture was stirred for 1 hour. To the reaction mixture was slowly added a solution of 1.88 g of tri-n-butylstannyl chloride in 2 ml of anhydrous THF, and the mixture was stirred for further 1.5 hours. After the addition of 100 ml of ethyl acetate, the solvent was removed by distillation to concentrate the mixture to a total volume of about 1 ml. Purification by silica gel chromatography gave 896 mg of 7-methoxymethyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole from a low polar fraction eluted with dichloromethane:ethyl acetate=4:1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([N:15]3[CH2:19][C:18]([O:20][CH3:21])=[CH:17][C:16]3=[O:22])[C:7]=2[CH:23]=1)#[N:2].C(O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CS(O)(=O)=O>C(OCC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([N:15]3[CH2:19][C:18]([O:20][CH2:21][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:17][C:16]3=[O:22])[C:7]=2[CH:23]=1)#[N:2]
Reactant: COC1=CC(=O)N([C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2O)C1
Reactant: OCc1ccccc1
Agent: CS(=O)(=O)O
Solvent: CCOCC
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CC(OCc3ccccc3)=CC2=O)[C@@H]1O
Temperature: 80 °C

Procedure:
A mixture of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-3-hydroxy-4-(4-methoxy-2-oxo-3-pyrrolin-1-yl)-2H-1-benzopyran (0.7 g), benzyl alcohol (0.92 ml) and methanesulfonic acid (0.01 g) was heated at 80° C. for 3 hours under reduced pressure (40 mbars). After cooling the residue was stirred with diethylether, and the insoluble product filtered off and washed twice with diethylether, to give 6-cyano-3,4-dihydro-2,2-dimethyl-trans-3-hydroxy-4-(4-benzyloxy-2-oxo-3-pyrrolin-1-yl)-2H-1-benzopyran, m.p. 248° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([N-]C(C)C)(C)C.[Li+].CN(C)[CH:23]=[O:24].[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:12])[C:11]=1[CH:23]=[O:24])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(F)cc(F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)c(C=O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
To a solution of methyl 3,5-difluorobenzoate (1 gm, 5.8 mmol) in dry tetrahydrofuran (20 mL), lithium diisopropylamide (0.621 gm, 5.8 mmol, 15% solution in tetrahydrofuran and heptane) was added at −78° C. The resulting reaction mixture was stirred for about 1 hour. Dimethylformamide (0.51 g, 6.9 mmol) was added drop wise to the reaction mixture and stirring was continued for about 3 hours at −78° C. The reaction was warm up to room temperature. Saturated aqueous ammonium chloride solution (20 mL) was added to quench the reaction mass. The aqueous phase was extracted with ethyl acetate (3×50 mL) and the combined organic layer dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography over silica gel (100-200) using ethyl acetate/hexane gradient elution to afford methyl 3,5-difluoro-4-formylbenzoate (0.5 gm, 31.25%).