Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:13]=[CH:12][C:11]2[O:10][CH2:9][O:8][C:7]=2[CH:6]=1)[CH3:2].C([Li])(CC)C.[C:22](=[O:24])=[O:23].S(=O)(=O)(O)O>O1CCCC1.O>[CH2:15]([N:3]([CH2:1][CH3:2])[C:4](=[O:14])[C:5]1[C:6](=[C:7]2[O:8][CH2:9][O:10][C:11]2=[CH:12][CH:13]=1)[C:22]([OH:24])=[O:23])[CH3:16]
Reactant: CCN(CC)C(=O)c1ccc2c(c1)OCO2
Reactant: O=C=O
Agent: O=S(=O)(O)O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=O)c1ccc2c(c1C(=O)O)OCO2
Temperature: 0 °C

Procedure:
A solution of N,N-diethylpiperonylamide 10.0 g, 45.0 mmol) in tetrahydrofuran is added dropwise at -65° C. to -55° C. to a mixture of sec-Butyllithium (500 mL, 50.0 mmol, 1M in cyclohexane) in tetrahydrofuran under a nitrogen atmosphere. The reaction mixture is poured over tetrahydrofuran saturated with dry ice, allowed to warm to 0° C., treated slowly with water and acidified to pH 3 with concentrated sulfuric acid. The tetrahydrofuran is removed in vacuo and the aqueous residue is extracted with ethyl acetate. The organic extract is dried (MgSO4) and concentrated in vacuo to a yellow-orange gum, NMR and mass spectrographic analysis show it to be a mixture of starting material and the title product. The above aqueous layer is acidified further to pH 2, extracted with ethyl acetate, and the organic extract is dried (MgSO4) and concentrated in vacuo to yield the title product as a yellow foam, 4.00 g (33.6%) identified by NMR spectral analysis.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[C:31]([OH:33])=[O:32])=[C:4]([F:36])[CH:3]=1.Cl.[F:38][C:39]1([F:45])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:38][C:39]1([F:45])[CH2:44][CH2:43][N:42]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[C:13]([O:16][CH2:17][C:18]5[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=5)[CH:14]=[CH:15][C:10]=4[N:9]=[C:8]3[C@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]3[C:31]([OH:33])=[O:32])=[C:4]([F:36])[CH:3]=2)[CH2:41][CH2:40]1
Reactant: Cc1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(Br)cc4F)c3c2)nc1
Reactant: FC1(F)CCNCC1
Agent: Cl
Product: Cc1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(N5CCC(F)(F)CC5)cc4F)c3c2)nc1

Procedure:
The title compound was prepared in a manner analogous to that in Example 152 substituting racemic cis-2-{1-(4-bromo-2-fluorobenzyl)-6-[(5-methylpyridin-2-yl)methoxy]-1H-benzimidazol-2-yl}cyclohexanecarboxylic acid and 4,4-difluoropiperidine hydrochloride. MS (ESI): mass calcd. for C33H35F3N4O3, 592.27; m/z found, 593.3 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.34 (s, 1H), 7.65 (d, J=8.3, 1H), 7.55 (d, J=8.6, 1H), 7.46 (d, J=8.0, 1H), 7.03-6.98 (m, 2H), 6.85-6.76 (m, 2H), 6.67 (dd, J=8.6, 2.3, 1H), 5.47 (d, J=16.7, 1H), 5.41 (d, J=16.7, 1H), 5.12 (s, 2H), 3.64-3.53 (m, 1H), 3.41-3.35 (m, 4H), 2.91-2.81 (m, 1H), 2.35 (s, 4H), 2.34-2.29 (m, 1H), 2.11-1.95 (m, 5H), 1.86-1.72 (m, 4H), 1.56-1.49 (m, 1H), 1.49-1.41 (m, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:7][CH:6]=1)=[O:4].[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>C(#N)C>[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:30][CH2:31][N:32]([CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH2:11][NH:12][S:13]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)(=[O:15])=[O:14])=[CH:7][CH:6]=3)=[O:4])[CH2:33][CH2:34]2)=[CH:25][CH:24]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: Cc1ccc(S(=O)(=O)NCc2ccc(C(=O)CBr)cc2)cc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)NCc2ccc(C(=O)CN3CCN(c4ccncc4)CC3)cc2)cc1
Reaction time: 18 h

Procedure:
A solution of N-([4-bromoacetylphenyl]methyl)-4-methylphenylsulphonamide (470 mg) in acetonitrile (10 ml) was added to a stirred solution of 1-(4-pyridyl)piperazine (400 mg) in acetonitrile (10 ml) and the mixture stirred for 18 hours. The solvent was evaporated in vacuo and the residue purified by flash chromatography on silica, eluting with 10% v/v methanol/dichloromethane. On evaporation of the eluant fraction to a small volume crystallisation occurred. These crystals, on filtration and washing with dichloromethane gave the title compound, 130 mg, as a solid: m.p. 215°-219° C. dec.; NMR(d6DMSO) δ 8.14(3H,m), 7.91(2H,d), 7.69(2H,d), 7.38(4H,d), 6.82(2H,d), 4.03(2H,d), 3.89(2H,s), 3.32(4H,t), 2.62(4H,t), 2.39(3H,s); m/e 465(M+H)+ ; calculated for C25H28N4O3S: C, 64.6; N, 6.1; N, 12.1. found C, 64.7; H, 6.2; N, 12.0%.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([N+:14]([O-])=O)=[C:11]([NH2:13])[CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>CN(C)C=O.C(O)C.[Pd]>[N:1]1([CH2:6][C:7]2[CH:12]=[C:11]([NH2:13])[C:10]([NH2:14])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1cc(Cn2ccnc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1ccc(Cn2ccnc2)cc1N
Yield: 120.3 %

Procedure:
Potassium carbonate (1.18 g, 8.54 mmol) was added to a stirred solution of 4-(bromomethyl)-2-fluoro-1-nitrobenzene (2.0 g, 8.55 mmol) and imidazole (584 mg, 8.58 mmol) in acetonitrile (40 mL), the mixture stirred at room temperature for 3.5 h, the solvent removed under reduced pressure, and the residue partitioned between water and EA. The aqueous layer was extracted three times with EA, then the combined EA layers were extracted three times with 1M hydrochloric acid. The pH of the combined aqueous layers was adjusted to 8 with 5M aqueous sodium hydroxide, and the resulting milky solution was extracted three times with EA. The EA layers were combined, washed with brine, and dried over magnesium sulfate. Filtration and concentration gave 1-(3-fluoro-4-nitrobenzyl)-1H-imidazole (914 mg), which contained about 15% of a bis-alkylated imidazole byproduct. 1-(3-Fluoro-4-nitrobenzyl)-1H-imidazole (914 mg) was treated with an ethanolic ammonia solution (2M NH3, 55 mL) in a sealed tube heated to 80° C. for 2 days. After cooling, the solvent was removed to give 5-[(1H-imidazol-1-yl)methyl]-2-nitrobenzeneamine (1.0 g) as an orange solid. 5-[(1H-Imidazol-1-yl)methyl]-2-nitrobenzeneamine (1.0 g, 4.77 mmol) was dissolved in a 10% solution of dimethylformamide in ethanol (44 mL), and 10% palladium on carbon (130 mg, 0.12 mmol) was added. The solution was degassed and stirred under a hydrogen atmosphere using a balloon for 1 day. Following degassing, the solution was diluted with MeOH and filtered through diatomaceous earth, giving 4-[(1H-imidazol-1-yl)methyl]benzene-1,2-diamine (1.08 g) as a brown oil.
Reaction SMILES: [OH:1][CH:2]([CH2:18][OH:19])[CH2:3][C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.Cl[C:21]([C:34]1C=CC=CC=1)([C:28]1C=CC=CC=1)[C:22]1C=CC=CC=1>N1C=CC=CC=1>[C:21]([O:19][CH2:18][CH:2]([OH:1])[CH2:3][C:4]1([OH:17])[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:8][CH2:9]1)([CH3:34])([CH3:28])[CH3:22]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CC(O)CO)CC1
Solvent: c1ccncc1
Product: CC(C)(C)OCC(O)CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
9.11 g of tert-butyl 4-(2,3-dihydroxypropyl)-4-hydroxy-1-piperidinecarboxylate was dissolved in 40 ml pyridine, 10.0 g of chlorotriphenylmethane was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was partitioned into ethyl acetate and water, washed with 2 N hydrochloric acid, water, saturated aqueous sodium bicarbonate and brine, and dried over magnesium sulfate. After filtration, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 10.3 g of tert-butyl 4-[3-(tert-butoxy)-2-hydroxypropyl]-4-hydroxy-1-piperidinecarboxylate.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[NH2:9].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Cl:8][C:6]1[N:5]=[N:4][C:3]([NH2:9])=[C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1nnc(Cl)cc1Br
Product: Nc1nnc(Cl)cc1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 1, intermediate b, from 4-bromo-6-chloropyridazin-3-amine (CAS RN 446273-59-2) and phenylboronic acid (CAS RN 98-80-6). Light yellow solid (38%). MS (ESI+): m/z=206.048 ([M+H]+).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:12][C:13](=[O:24])[CH2:14][C:15]1([OH:23])[CH:20]2[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]2)[CH2:16]1)(C)(C)C>ClCCl>[CH3:8][O:12][C:13](=[O:24])[CH2:14][C:15]1([OH:23])[CH:20]2[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)CC1(O)CN2CCC1CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CC1(O)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.6 %

Procedure:
Trifluoroacetic acid (40 mL) was added dropwise over 15 minutes to a solution of 2-(3-hydroxy-1-azabicyclo[2.2.2]oct-3-yl)acetic acid t-butyl ester (15.7 g) in anhydrous dichloromethane (40 mL) at 0° C. The mixture was stirred for 24 hours at room temperature, then the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (90 mL) and cooled in an ice bath. Concentrated sulfuric acid (9 mL) was added dropwise over 10 minutes, then the reaction mixture was stirred at room temperature. After 3 hours, the solution was poured into 100 mL of ice water, basified to pH 10 with saturated aqueous sodium carbonate solution, and extracted with chloroform (4×100 mL). The extracts were dried (MgSO4), filtered, and evaporated in vacuo to give a solid. Recrystallization from ethyl acetate provided 6.3 g of the tan crystalline subtitle compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[S:13][C:14]([Br:17])=[CH:15][CH:16]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[H-].[Na+].[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25]Cl>C1COCC1>[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25][N:8]([C:5]1[O:4][N:3]=[C:2]([CH3:1])[C:6]=1[CH3:7])[S:9]([C:12]1[S:13][C:14]([Br:17])=[CH:15][CH:16]=1)(=[O:10])=[O:11]
Reactant: Cc1noc(NS(=O)(=O)c2ccc(Br)s2)c1C
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccc(Br)s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
N-(3,4-dimethyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide (680 mg, 2 mmol) in dry THF (2 ml) was added to sodium hydride (121 mg of a 60% oil dispersion, 3 mmol) in dry THF (1 ml). The resulting suspension was cooled to 0° C. and methoxyethoxymethyl chloride (334 mg, 2.68 mmol) was added dropwise via syringe. The solution was warmed to room temperature, and stirring continued overnight. Evaporation of solvent left an oil that was extracted into ethyl acetate, washed with brine, dried over magnesium sulfate and evaporated. Flash chromatography of the residue on silica gel using 10-15% ethylacetate/hexanes yielded 480 mg (56%) of a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[N:14][OH:15])[CH2:6][CH2:5]2
Reactant: NO
Reactant: O=C1CCc2cc(F)ccc2C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCc2cc(F)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A solution of 6-fluoro-3,4-dihydronaphthalen-2(1H)-one (W. Adcock, P. D. Bettess, S. Q. A. Rizvi, Aust. J. Chem. 1970, 23, 1921-1937; 1.50 g, 9.13 mmol) in ethanol (10 mL) was treated with hydroxylamine hydrochloride (775 mg, 11.14 mmol), sodium acetate (2.01 g, 14.79 mmol) and water (6 mL) and the mixture was stirred at room temperature for 30 min, during which time a dense precipitate formed. The mixture was diluted with water and extracted with ether. The organic phases were dried and concentrated to provide a yellowish solid (1.58 g, 97%) used without further purification.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([Cl:23])[CH:3]=1.FC(F)(F)C(O)=O.C1C(=O)N([Br:38])C(=O)C1.[OH-].[Na+]>OS(O)(=O)=O>[Br:38][C:3]1[C:4]([Cl:23])=[C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])[S:6][C:2]=1[Br:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3Cl)c(C)nc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)c1cc(C)nn2c(-c3sc(Br)c(Br)c3Cl)c(C)nc12
Yield: 93.7 %

Procedure:
To a solution of 3-(5-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (5.92 g, 14.34 mmol) and trifluoroacetic acid (40 mL) and 98% H2SO4 (10 ml) is added NBS (3.83 g, 21.15 mmol). After 10 minutes the solution is poured into ice, and made basic with 5M NaOH. The slurry is extracted with EtOAc (3×100 mL), the combined organic layers washed with water (2×400 mL), brine (400 mL), dried over MgSO4, filtered and concentrated to furnish the title compound (6.61 g, 13.44 mmol, 94%). 1H NMR (CDCl3) δ 0.87 (t, J=7.5 Hz, 6H), 1.72-1.92 (m, 4H), 2.47 (s, 3H), 2.52 (s, 3H), 3.25-3.34 (m, 1H), 6.72 (s, 1H). LC/MS (m/z): calcd. for C17H18Br2ClN3S (M+H)+: 489.9; found: 490.0.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][NH:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][N:31]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1C[C@@H](O)[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ccnc23)C1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f24) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1I.[Li]CCCC.[B:16](OC)([O:19]C)[O:17]C>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[B:16]([OH:19])[OH:17]
Reactant: COB(OC)OC
Reactant: Cc1cc(I)c(F)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(B(O)O)c(F)cc1F
Reaction time: 0.17 h
Yield: 88 %

Procedure:
To 94A (2.8 g, 11 mmol) in THF (50 mL) was added n-BuLi (1.6M in hexane, 8.9 mL) at −78° C. After 10 min stirring, trimethyl borate (2.5 mL) was introduced. The mixture was stirred from −78° C. to rt overnight. The reaction was quenched by 1N HCl and extracted with EtOAc. The organic layer was separated and washed with saturated Na2S2O3, brine and dried over MgSO4. Evaporation of solvent gave product 94B (1.66 g, 88% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.22 (s, 3H) 6.82 (t, J=9.23 Hz, 1H) 7.26 (t, J=7.69 Hz, 1H).
Reaction SMILES: [CH3:1][Si:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([CH2:18]O)[CH:9]=1.C(#N)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:45]>>[Cl:45][CH2:18][C:10]1[CH:9]=[C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:21])([CH3:20])[CH3:1])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: C[Si](C)(C)CCOCOc1cc(CO)cc2ccccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: C[Si](C)(C)CCOCOc1cc(CCl)cc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
23.72 g (77.91 mmol) of [4-(2-trimethylsilyl-ethoxymethoxy)-naphthalen-2-yl]-methanol were dissolved in 350 ml of carbon tetrachloride and the solution was cooled to 0° C. Thereupon, 350 ml of acetonitrile and 26.54 g (1.012 mmol) of triphenylphosphine were added. The light yellow solution was stirred at 0° C. for 30 minutes, warmed to room temperature and stirred for a further 2 hours. A further 10.14 g (38.7 mmol) of triphenylphosphine were added and the reaction mixture was stirred at room temperature for 90 minutes. Subsequently, the mixture was partitioned between methylene chloride and water, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. The crude product was chromatographed on silica gel using a 3:7 mixture of methylene chloride and hexane as the eluent. There were obtained 15.81 g (63% of theory) of 2-chloromethyl-4-(β-trimethylsilylethoxymethoxy)-naphthalene as a light yellow oil; MS: 322, 324 (M)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:15][C@H:14]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]2[F:21])[CH:5]=[N:4][C:3]=1[C:22]([OH:24])=O.[Cl-:25]>O1CCCC1>[C:11]([O:10][C@@H:9]1[C@@H:14]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[O:15][C@@H:7]([N:6]2[C:2]([N:1]=[CH:5][N:6]([CH3:7])[CH3:2])=[C:3]([C:22]([Cl:25])=[O:24])[N:4]=[CH:5]2)[C@@H:8]1[F:21])(=[O:13])[CH3:12]
Reactant: [Cl-]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)O)c2N)[C@H](F)[C@@H]1OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)Cl)c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O
Reaction time: 0.5 h

Procedure:
The compound (18) (62 mg) obtained in item (8) above was dissolved in tetrahydrofuran (3 ml), to which was then added N,N-dimethylchloroforminium chloride (90 mg) under ice-cooling and the resulting mixture was stirred at the same temperature as above for 30 minutes to effect both the chlorination and N,N-dimethylaminomethylenation reactions. Thus, compound (19) was produced.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH2:18][OH:19])[CH2:16][S:17][C@H:12]23)=[O:9])=[CH:4][S:3]1.[CH2:25]=[C:26]1[O:30][C:28](=[O:29])[CH2:27]1>>[NH:1]=[C:2]1[NH:6][C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH2:18][O:19][C:28](=[O:29])[CH2:27][C:26](=[O:30])[CH3:25])[CH2:16][S:17][C@H:12]23)=[O:9])=[CH:4][S:3]1
Reactant: C=C1CC(=O)O1
Reactant: N=c1[nH]c(CC(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CO)CS[C@H]23)cs1
Product: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3csc(=N)[nH]3)[C@H]2SC1

Procedure:
A process as claimed in claim 17, wherein 7β-[2-(2-imino-4-thiazolin-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid or its salt is reacted with diketene to produce 7β-[2-(2-imino-4-thiazolin-4-yl)-acetamido]-3-(3-oxobutyryloxy)methyl-3-cephem-4-carboxylic acid or its salt.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[C:20]([CH2:25][CH:26]3[S:30][C:29](=N)[NH:28][C:27]3=[O:32])[CH:21]=[N:22]2)=[CH:17][CH:16]=1.C([OH:35])C>Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[C:20]([CH2:25][CH:26]3[S:30][C:29](=[O:35])[NH:28][C:27]3=[O:32])[CH:21]=[N:22]2)=[CH:17][CH:16]=1
Reactant: CCO
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(CC3SC(=N)NC3=O)cnc2c1
Agent: Cl
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(CC3SC(=O)NC3=O)cnc2c1
Yield: 11 %

Procedure:
In a mixture of 3N hydrochloric acid (4 mL) and ethanol (2 mL) was dissolved 5-[[7-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-quinolyl]methyl]-2-iminothiazolidin-4-one (100 mg, 0.22 mmol.). The resulting solution was heated under reflux for 12 hours. After the completion of reaction was confirmed, ethanol was distilled off. To the residue were added ethyl acetate and aqueous sodium hydrogen carbonate. The organic portion was recovered, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/3), to give 11 mg of the desired compound as pale brown crystalline powder (yield 11%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH:13]2[C:18]([OH:20])=[O:19])[CH:5]=[CH:4][N:3]=1.[F:24][C:25]1[CH:26]=[C:27]([CH2:32][CH2:33][NH2:34])[CH:28]=[C:29]([F:31])[CH:30]=1>>[F:24][C:25]1[CH:26]=[C:27]([CH2:32][CH2:33][NH:34][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=3)[CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH:13]3[C:18]([OH:20])=[O:19])[CH:5]=[CH:4][N:3]=2)[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: NCCc1cc(F)cc(F)c1
Reactant: O=C(O)C1CNCCN1Cc1cccc(-c2ccnc(Cl)n2)c1
Product: O=C(O)C1CNCCN1Cc1cccc(-c2ccnc(NCCc3cc(F)cc(F)c3)n2)c1

Procedure:
Intermediate 137 was coupled with 2-(3,5-difluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 454. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.47 (s, 1H) 8.36 (d, 1H)) 8.33 (d, 1H) 7.87 (d, 1H) 7.71 (t, 1H) 7.65 (d, 1H) 7.00 (d, 2H) 6.77 (s, 1H) 4.63 (dd, 1H) 4.36 (s, 2H) 4.08 (t, 2H) 3.84 (dd, 2H) 3.65 (t, 2H) 3.47 (t, 2H) 3.09 (t, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:6]=[C:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH3:12].N1CCCC1>CO.[Ni].[H][H]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH3:12]
Reactant: [H][H]
Reactant: COc1ccc(C=C2CCCN2C)cc1OC
Agent: [Ni]
Solvent: CO
Solvent: C1CCNC1
Product: COc1ccc(CC2CCCN2C)cc1OC
Yield: 78 %

Procedure:
Dissolve 12.2 g of 3,4-dimethoxybenzylidene-1-methylpyrrolidine in methanol and reduce the pyrrolidine in the thus-obtained solution with Raney nickel/hydrogen. Filter off the catalyst and distil off the methanol before distilling the residue to obtain 9.6 g (79%) of the title compound with a b.p. of 90° at 0.005 mm of Hg. The m.p. of the picrate (from ethanol) is 105° to 106°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22]([CH2:25][OH:26])[S:23][CH:24]=1)=[CH:16][CH:15]=3.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22]([CH:25]=[O:26])[S:23][CH:24]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CO)n4)ccc3n(C)c21
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(C=O)n4)ccc3n(C)c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
258 mg (0.548 mmol) of compound from Example 9, 3-(2,4-dichlorophenyl)-6-(2-hydroxymethylthiazol-4-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one are suspended in 10 ml of CHCl3. 177 mg (0.82 mmol) of pyridinium chlorochromate (PCC) are added. The mixture is stirred at ambient temperature for 3 hours. The reaction medium is loaded directly onto a silica column and the mixture is purified, elution being carried out with 100% EtOAc.