Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:25][C:26]1[N:31]2[CH:32]=[CH:33][N:34]=[C:30]2[CH:29]=[CH:28][CH:27]=1)[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:35][C:36]([Cl:41])([Cl:40])[C:37](Cl)=[O:38].C(=O)([O-])O.[Na+]>CN(C1C=CN=CC=1)C.C(Cl)(Cl)Cl>[Cl:35][C:36]([Cl:41])([Cl:40])[C:37]([C:32]1[N:31]2[C:26]([CH2:25][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:9]3[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][NH:17][S:18]([C:21]([F:24])([F:22])[F:23])(=[O:20])=[O:19])=[CH:13][CH:14]=3)=[CH:27][CH:28]=[CH:29][C:30]2=[N:34][CH:33]=1)=[O:38]
Reactant: CC(C)(C)OC(=O)N(Cc1cccc2nccn12)c1ccc(CCNS(=O)(=O)C(F)(F)F)cc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12)c1ccc(CCNS(=O)(=O)C(F)(F)F)cc1
Temperature: 0 °C
Yield: 54.8 %

Procedure:
To a solution of 2.00 g of 5-[N-tert-butoxycarbonyl-N-[4-(2-trifluoromethanesulfonamidoethan-1-yl)phenyl] aminomethyl]imidazo[1,2-a]pyridine and 1.47 g (12.04 mmol) of 4-(N,N-dimethylamino)pyridine in 20 ml of chloroform was added dropwise 1.34 ml (12.04 mmol) of trichloroacetyl chloride at room temperature. The reaction mixture was heated for 18 hours under reflux. The reaction mixture was poured into ice-water. The mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and extracted with 100 ml of chloroform. The organic layer was washed with 100 ml of purified water three times and further with 100 ml of a saturated aqueous saline solution, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) to afford 1415 mg of the desired compound (54.8%, a yellow liquid).
Reaction SMILES: Cl.[CH3:2][C@H:3]1[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10].C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:57]1[N:61]2[CH:62]=[CH:63][CH:64]=[N:65][C:60]2=[C:59]([C:66](O)=[O:67])[CH:58]=1.CCN(C(C)C)C(C)C>C1COCC1>[CH3:2][C@@H:3]1[N:4]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[CH2:5][CH2:6][N:7]([C:66]([C:59]2[CH:58]=[N:57][N:61]3[CH:62]=[CH:63][CH:64]=[N:65][C:60]=23)=[O:67])[CH2:8]1
Reactant: C[C@H]1CNCCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1cnn2cccnc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(C(=O)c2cnn3cccnc23)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Yield: 69.7 %

Procedure:
To a solution of (2S)-2-methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine hydrochloride (may be prepared as described in Description 6) (100 mg, 0.270 mmol) in THF (5 ml) was added HOBT.H2O (41.3 mg, 0.270 mmol), HBTU (102 mg, 0.270 mmol) and pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (48.4 mg, 0.297 mmol). The mixture was stirred for 5 minutes before addition of DIPEA (0.118 ml, 0.674 mmol) and the resultant solution stirred at rt for 16 hours. The mixture was then concentrated and the residue partitioned between DCM (10 ml) and water (10 ml), the layers were separated using a hydrophobic frit and the organic layers concentrated to dryness and the crude material dissolved in DMSO and purified by MDAP to give the title compound (85.3 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[Cl:8][C:9]1[CH:21]=[CH:20][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:11][CH:10]=1>C(O)C>[Cl:8][C:9]1[CH:21]=[CH:20][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 92.8 %

Procedure:
Analogously to Example 1a, 30 g (0.3 mol) ethyl acrylate and 63.2 g 1-(4-chlorobenzyl)-piperazine are reacted in 200 ml ethanol to give 86.5 g (92.8% of theory) ethyl 3-[4-(4-chlorobenzyl)-piperazin-1-yl]-propionate; b.p. 150° - 160° C./0.1 mm Hg.
Reaction SMILES: [N+:1]([C:4]1[CH:45]=[CH:44][C:7]([CH2:8][CH:9]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-])=O)=[CH:37][CH:36]=2)[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20](=[O:33])[C:21]2[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[O:11])=[CH:6][CH:5]=1)([O-])=O>[Zn]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20](=[O:33])[C:21]2[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[O:11])=[CH:44][CH:45]=1
Reactant: COC(=O)/C=C/c1ccc(C(=O)OCCCCCCOC(=O)C(Cc2ccc([N+](=O)[O-])cc2)Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Zn]
Product: COC(=O)/C=C/c1ccc(C(=O)OCCCCCCOC(=O)C(Cc2ccc(N)cc2)Cc2ccc(N)cc2)cc1
Yield: 75.3 %

Procedure:
Preparation can be carried out analogously to Example 1 using 2.84 g (4.59 mmol) 6-({4-[(1E)-3-methoxy-3-oxoprop-1-enyl]benzoyl}oxy)hexyl 2-(4-nitrobenzyl)-3-(4-nitrophenyl)propanoate, 7.44 g (27.52 mmol) Ferric chloride hexahydrate and 3.00 g (45.89 mmol) Zinc powder yielded 1.93 g (72%) 6-({4 -[(1E)-3-methoxy-3-oxoprop-1-enyl]benzoyl}oxy)hexyl 2-(4-aminobenzyl)-3-(4 -aminophenyl)propanoate as yellow powder.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:18][C:19]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[N:26][C:25]=23)=[O:20])=[C:5]([C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[O:14][CH:15]([F:17])[F:16])[N:6]=1.[CH3:30][N:31]([CH3:38])[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CC(N(C)C)=O.CO>[Cl:13][C:11]1[CH:10]=[CH:9][C:8]([O:14][CH:15]([F:17])[F:16])=[C:7]([C:5]2[N:6]=[C:2]([N:35]3[CH2:36][CH2:37][CH:32]([N:31]([CH3:38])[CH3:30])[CH2:33][CH2:34]3)[S:3][C:4]=2[NH:18][C:19]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[N:26][C:25]=23)=[O:20])[CH:12]=1
Reactant: CN(C)C1CCNCC1
Reactant: O=C(Nc1sc(Br)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CN(C)C1CCN(c2nc(-c3cc(Cl)ccc3OC(F)F)c(NC(=O)c3cnn4cccnc34)s2)CC1
Temperature: 160 °C
Yield: 39.2 %

Procedure:
Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide (100 mg, 0.2 mmol) and 4-dimethylaminopiperidine (128 mg, 1 mmol) were dissolved in DMA (1 ml) and heated in a microwave at 160° C. for 1 hour. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. The resulting yellow glass was purified by MDAP (Method 1). Appropriate fractions were combined and evaporated to afford a yellow solid. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH to give the title compound as a yellow-orange solid (43 mg, 39%). LCMS (Method 5) [M+H]+=548.1, RT=3.20 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 10.23 (s, 1H), 9.36 (dd, 1H, J=1.6, 7.0 Hz), 8.68 (s, 1H), 8.63 (dd, 1H, J=1.6, 4.2 Hz), 7.66 (d, 1H, J=2.7 Hz), 7.59 (dd, 1H, J=2.6, 8.8 Hz), 7.41 (d, 1H, J=9.0 Hz), 7.31 (dd, 1H, J=4.2, 6.7 Hz), 7.18 (t, 1H, J=73.5 Hz), 3.93 (d, 2H, J=12.7 Hz), 3.02 (dd, 2H, J=10.3, 12.3 Hz), 3.05-2.95 (m, 1H), 2.40-2.26 (m, 6H), 1.92-1.89 (m, 2H), 1.58-1.47 (m, 2H).
Reaction SMILES: O.NN.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][CH2:14][NH:13][C:12](=[O:17])[C:11]=2[CH:18]=1)([O-])=O>[Pd].C(O)C>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][CH2:14][NH:13][C:12](=[O:17])[C:11]=2[CH:18]=1
Reactant: O=C1NCCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)C(=O)NCCC2
Yield: 91.3 %

Procedure:
Added 65 mL of ethanol, 10% Palladium on activated carbon (50% wet with water for safety) (513 mg), and hydrazine monohydrate (965 ul) to 8-Nitro-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (1.024 g, 4.966 mmol). Heated reaction to 60° C. for 16 hours. Filtered reaction through Celite, and concentrated under reduced pressure. Purified with normal phase silica gel chromatography to obtain a white solid, 8-Amino-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (799 mg, 91%). LCMS: m/z=177.03 (M+H+), 1H NMR (400 MHz, CD3OD) δ 7.00 (d, 1H, J=8.1 Hz), 6.96 (m, 1H), 6.80 (m, 1H), 3.33 (m, 3H), 3.06 (m, 2H), 2.71 (m, 2H), 1.96 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)[CH2:3][C:4]([OH:6])=[O:5].Cl>[OH-].[Na+].O.NN.[Ni]>[NH:13]1[C:8]2[C:7](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]([CH2:3][C:4]([OH:6])=[O:5])=[N:1]1
Reactant: NC(CC(=O)O)c1ccccc1[N+](=O)[O-]
Agent: [Ni]
Agent: Cl
Agent: NN
Solvent: O
Product: O=C(O)Cc1n[nH]c2ccccc12
Temperature: 80 °C
Yield: 54.5 %

Procedure:
3-Amino-3-(2-nitrophenyl) propionic acid (15 g, 71.4 mmol) was dissolved in a mixed solution of 5% sodium hydroxide solution (85 mL) and 85% hydrazine hydrate (5 mL). The reaction was heated to 80° C., and then Raney nickel (2×25 mg) was added carefully. After reacted for half an hour, it was cooled, adjusted to pH≈2 with 6 N hydrochloric acid. A solid precipitated was pumping filtered, dried in vacuum to obtain a yellow solid 6.86 g, at a yield of 54.5%.
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.C[C:7]([O:9][CH2:10][C:11]1[CH2:20][S:19][C@@H:14]2[C@H:15]([NH2:18])[C:16](=[O:17])[N:13]2[C:12]=1[C:21]([OH:23])=[O:22])=O.[B].N>O.CO>[NH2:18][CH:15]1[C:16](=[O:17])[N:13]2[C:12]([C:21]([OH:23])=[O:22])=[C:11]([CH2:10][O:9][CH3:7])[CH2:20][S:19][C@H:14]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: N
Agent: [B]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 60 °C

Procedure:
To 10 ml of carbon tetrachloride were added 2.72 g of 7-ACA, 4.3 g of a boron trifluoridediethylether complex, and 3.5 g of methanol. The mixture was heated at 60° C. for 35 min to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 5° C. To the reaction mixture was added 20 ml of cold water. Then, the mixture was adjusted to pH 7.5 with 28% aqueous ammonia at a temperature of 5° C. The resulting precipitate was filtered off, and then washed with water. The filtrate was combined with the washings. The resulting mixture was applied to the same column as used in Example 2. The elution was conducted using water as an eluent. The resulting eluate was adjusted to pH 3.5 with 36% hydrochloric acid to hereby form a precipitate. The precipitate was collected by filtration, and washed with 5 ml of cold water and, then, with 5 ml of cold methanol to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.27 g. The yield of the desired product was as low as 11.1%.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[NH2:10][C@@H:11]([CH2:15][OH:16])[CH:12]([CH3:14])[CH3:13].C(O)(=O)C.C([BH3-])#N>CO>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:10][C@H:11]([CH:12]([CH3:14])[CH3:13])[CH2:15][OH:16])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](N)CO
Reactant: O=Cc1cccc(Br)n1
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)[C@H](CO)NCc1cccc(Br)n1
Reaction time: 0.08 h
Yield: 59.7 %

Procedure:
To a solution of 6-bromopyridine-2-carbaldehyde (5.00 g, 26.9 mmol) in methanol (75 mL) at ambient temperature was added D-valinol (3.00 mL, 26.9 mmol) followed by acetic acid (6.2 mL, 110 mmol). After 5 minutes, MP-cyanoborohydride (2.49 mmol/g; 12 g) was added and stirred overnight. The mixture was filtered, concentrated. The residue was partitioned between 1N NaOH and CH2Cl2. The organic phase was dried (Na2SO4) and concentrated. The residue was purified by chromatography (50% ethyl acetate:CH2Cl2 to remove non polar impurites, then ethyl acetate to 20% acetone:ethyl acetate) to provide 4.39 g (60%) of the title compound. MS (DCI30 ) m/z 273/275 (M+H).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:21]2[N:25]([CH3:26])[N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:22]2[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:11][CH:10]=1>CN(C)C=O>[CH3:40][C:39]1([CH3:44])[N:22]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH:21]3[N:25]([CH3:26])[N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:23]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:22]3[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:11][CH:10]=2)[C:21]([CH2:16][CH2:15][CH3:12])=[N:25][C:1]1=[O:4]
Reactant: CN1C(c2ccccc2-c2ccc(CBr)cc2)N(c2ccccc2)N(c2ccccc2)N1c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC1=NC(=O)C(C)(C)N1Cc1ccc(-c2ccccc2C2N(C)N(c3ccccc3)N(c3ccccc3)N2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.6 %

Procedure:
A mixture of potassium carbonate (500 mg, 3.7 mmol), 2-propyl-4-4-dimethyl-1H-imidazol-5(4H)-one (0.6 g, 3.9 mmol), and 4'-bromomethyl-2-(triphenyl methyl tetrazol-5-yl)biphenyl (1.08 g, 1.9 mmol) in dimethyl formamide (5 mL) was allowed to stir at room temperature overnight. The mixture was chromatographed over silica gel eluting with ethyl acetate-hexane to give 1,5-dihydro-5,5-dimethyl-2-propyl-1-[(2'-(triphenyl methyl tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl]-4H-imidazol-4-one (70 mg, 14% ) M.S. m/e 631.5 (M+ +H) NMR (CDCl3 /TMS) δ0.88 (t, 3H, J=7 Hz, CH3), 1.38 (s, 6H, 2 CH3), 1.67 (m, 2H, CH2), 2.21 (t, 2H, J=7Hz, CH2), 4.56 (s, 2H, CH2), 6.92 (d, J= 7 Hz, 8H, Harom), 7.11 (d, J=7 Hz, 2H, Harom), 7.24-7.38 (m, 10H, Harom), 7.47 (m, 2H, Harom), 7.92 (m, 1H, Harom).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:21])[O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH2:17][NH:18]2)=[CH:13][CH:12]=1.[H-].[Na+].[CH3:24]I>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:21])[O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH2:17][N:18]2[CH3:24])=[CH:13][CH:12]=1
Reactant: O=C(Nc1ccccc1F)Oc1ccc2c(c1)NCCC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCc2ccc(OC(=O)Nc3ccccc3F)cc21
Reaction time: 0.5 h

Procedure:
A solution of 1,2,3,4-tetrahydroquinolin-7-yl 2-fluorophenylcarbamate (300 mg, 1.84 mM) in dry dimethylformamide (DMF, 5 mL) was added to the stirred solution of sodium hydride in dry DMF at −10° C. during 5 minutes under nitrogen environment. The reaction mixture was stirred for 30 minutes. Then, methyl iodide (285 mg/ml, 2 mM), was added to the stirring reaction mixture. The mixture was stirred further for 3 hours during which the temperature was allowed to reach the room temperature (37° C.). The reaction mixture was quenched with water, diluted with water, extracted with ethyl acetate and dried over sodium sulphate. The combined fractions of ethyl acetate were concentrated under vacuum and chromatographed using ethyl acetate:hexane (1:49) to afford the pure compound 8l as oil. Yield: 300 mg, 54.33%.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:17]([NH:18][C:19](=[O:43])[CH:20]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:21]([O:23]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:22])[C:16](=[O:44])[N:10]2[C:11]=1[P:12]([OH:15])(=[O:14])[OH:13])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.O.C([O-])(O)=O.[Na+:65]>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:17]([NH:18][C:19](=[O:43])[CH:20]([C:21]([OH:23])=[O:22])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:16](=[O:44])[N:10]2[C:11]=1[P:12]([O-:15])(=[O:13])[O-:14])(=[O:3])[CH3:2].[Na+:65].[Na+:65].[Na+:65]
Reactant: CC(=O)OCC1=C(P(=O)(O)O)N2C(=O)[C@@H](NC(=O)C(C(=O)OC(c3ccccc3)c3ccccc3)c3ccccc3)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC(=O)OCC1=C(P(=O)([O-])[O-])N2C(=O)[C@@H](NC(=O)C(C(=O)O)c3ccccc3)[C@H]2SC1

Procedure:
One gram of 3-acetoxymethyl-7β-(2-phenyl-2-benzhydryloxycarbonylacetamido)-3-cephem-4-phosphonic acid is dissolved in 2 ml. anisole and treated for two minutes at 0° with 10 ml. trifluoroacetic acid. The mixture is pumped at 0.1 mm at 25° until most of the anisole is removed, and then more anisole is added and pumped off to insure complete removal of TFA. The residue is taken up in 100 ml. water containing three equivalents of NaHCO3, washed with methylene chloride and lyophilized, affording the product, trisodium 3-acetoxymethyl-7β-(2-carboxy-2-phenylacetamido)-3-cephem-4-phosphonate.
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[SH:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].CC(C)([O-])C.[K+]>C1COCC1>[CH3:24][O:23][C:21](=[O:22])[CH2:20][CH2:19][S:18][C:2]1[CH:17]=[CH:16][C:5]([C:6](=[O:7])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][N:3]=1
Reactant: COC(=O)CCS
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CCSc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 3.9 %

Procedure:
To a solution of 6-chloro-N-(4-fluorophenyl)nicotinamide (0.25 g, 1.0 mmol) in 3 mL of THF was added methyl 3-mercaptopropionate (0.16 mL, 1.5 mmol) then potassium tert-butoxide (0.22 g, 2.0 mmol). The mixture was stirred for 3 h then poured into ice water and the solids washed with water and collected. Purification by trituration using ethyl acetate gave 13 mg (4%) of the titled product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.94 (m, 1H), 8.09 (m, 1H), 7.74 (m, 2H), 7.43 (m, 1H), 7.17 (m, 2H), 3.59 (s, 3H), 3.37 (m, 2H), 2.75 (m, 2H); MS (EI) m/z 333.10 (M−H)−.
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([CH2:15][CH:16]([CH3:18])[CH3:17])=[N:7][CH:6]=1)C.[ClH:20]>>[ClH:20].[CH2:11]([C:9]1[C:8]([CH2:15][CH:16]([CH3:18])[CH3:17])=[N:7][CH:6]=[C:5]([CH:10]=1)[C:4]([OH:19])=[O:3])[CH:12]([CH3:14])[CH3:13]
Reactant: CCOC(=O)c1cnc(CC(C)C)c(CC(C)C)c1
Agent: Cl
Product: CC(C)Cc1cc(C(=O)O)cnc1CC(C)C
Temperature: 25 °C

Procedure:
A solution of 5,6-diisobutyl-nicotinic acid ethyl ester (52 mg, 0.2 mmol) in 6 N aq. HCl (2 mL) is stirred at 65° C. for 15 h before it is cooled to rt and extracted with ether (2×10 mL). The aq. phase is evaporated and the residue is dried under HV to give 5,6-diisobutyl-nicotinic acid hydrochloride (0.12 g) as a colourless solid; LC-MS: tR=0.73 min; [M+1]+=236.40.
Reaction SMILES: [C:1]1(=[O:22])[N:5]([CH:6]([C:9]([F:16])([F:15])[CH2:10][CH2:11][CH2:12][O:13]C)[CH:7]=[CH2:8])[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]12.C[Si](I)(C)C.Cl>ClCCl>[C:4]1(=[O:17])[N:5]([CH:6]([C:9]([F:15])([F:16])[CH2:10][CH2:11][CH2:12][OH:13])[CH:7]=[CH2:8])[C:1](=[O:22])[C:2]2=[CH:21][CH:20]=[CH:19][CH:18]=[C:3]12
Reactant: C=CC(N1C(=O)c2ccccc2C1=O)C(F)(F)CCCOC
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: ClCCl
Product: C=CC(N1C(=O)c2ccccc2C1=O)C(F)(F)CCCO
Reaction time: 0.5 h

Procedure:
Under an atmosphere of nitrogen, a mixture of 3-phthalimido-4,4-difluoro-7-methoxy-1-heptene (440 mg, 1.43 mmoles) and trimethylsilyliodide (400 mg, 2 mmoles) in dry dichloromethane (10 ml) is heated overnight under reflux. 1N HCl (10 ml) is added to the reaction mixture which is kept under vigorous stirring for 1/2 hour. The organic layer is separated, washed successively with water, sodium bisulfite solution, and water, and is dried over sodium sulfate. 3-phthalimido-4,4-difluoro-7-hydroxy-1-heptene is obtained as a solid: 3.85 mg (91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:23]=3)[CH2:12][NH:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][CH:15]=3.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C=O>[C:31]([N:13]1[CH2:12][C:11]2[CH:23]=[C:7]([CH:8]=[CH:9][CH:10]=2)[NH:6][C:5]2=[N:21][C:20](=[C:2]([Cl:1])[CH:3]=[N:4]2)[NH:19][C:18]2=[CH:22][C:14]1=[CH:15][CH:16]=[CH:17]2)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Clc1cnc2nc1Nc1cccc(c1)NCc1cccc(c1)N2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1Cc2cccc(c2)Nc2ncc(Cl)c(n2)Nc2cccc1c2
Yield: 41.6 %

Procedure:
To a stirring solution of 6-chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene (20.0 mg, 0.0618 mmol) in N,N-dimethylformamide (0.24 mL) was added triethylamine (17.2 μL), followed by the addition of benzoyl chloride (17.4 mg, 0.12 mmol). The resultant solution was stirred at rt for 30 min. The mixture was quenched with H2O and concentrated. The residue was purified by silica gel column chromatography to give the desired product as an off-white powder (11 mg, 42%). LCMS for C24H19ClN5O (M+H)+: m/z=428.1. 1H NMR (300 MHz, DMSO-d6): δ 9.42 (s, 1H), 9.11 (s, 1H), 8.12 (s, 2H), 7.82 (s, 1H), 7.25 (m, 4H), 7.15 (m, 4H), 7.03 (m, 3H), 4.86 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[S:8].Br[CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:19]=O>CN(C)C=O>[CH3:16][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]1[CH:19]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:8][C:7]1=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)CCCNC(=S)Nc1ccccc1
Reactant: O=CC(Br)c1ccccc1
Solvent: CN(C)C=O
Product: CN(C)CCCn1cc(-c2ccccc2)sc1=Nc1ccccc1
Yield: 53.8 %

Procedure:
Using N-[3-(dimethylamino)propyl]-N′-phenylthiourea (650 mg) obtained in Reference Example 3 as described below, 2-bromo-2-phenylacetoaldehyde (600 mg) and N,N-dimethylformamide (11 ml), the title compound (497 mg) was obtained in a similar manner to in Example 1.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.[CH3:56][C:57]([CH3:61])([CH3:60])[CH:58]=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][N:53]([CH2:56][C:57]([CH3:61])([CH3:60])[CH3:58])[CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:39][CH:40]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1
Reactant: CC(C)(C)C=O
Reactant: Cc1cc(COc2ccc(C3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C3(N4CCN(CC(C)(C)C)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 5.5 %

Procedure:
Using a procedure analogous to Example 15, the product from example 14 (100 mg, 0.125 mmol) was treated with trimethylacetaldehyde (21.5 mg, 2.0 eq) to provide the title barbituric acid (6.0 mg, 5.5%). MS found: (M+H)+=530.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH:10]=[CH:11][C:5]=2[CH:4]=1.[I-:21].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][I:21])[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: [I-]
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)C=C2
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCI)C=C2
Yield: 96.8 %

Procedure:
A suspension of 12 g of 7,8-dimethoxy-3-[3-chloropropyl]-1,3-dihydro-2H-3-benzazepin-2-one obtained in accordance with the method described in the literature (Reiffer M. et al., J. Med. Chem. 1990; vol 33 (5): 1496-1504) and 6.2 g of sodium iodide in 50 cm3 of acetone are refluxed for 24 hours. After filtration and evaporation to dryness of the solvent, the residue is taken up in water and extracted with dichloromethane. The extract is separated off, dried over anhydrous magnesium sulphate and then concentrated in vacuo to yield 15.2 g of the desired compound.