Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[C:3](=[O:14])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].NCCC(O)=O.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CCCCCC.C(O)(=O)C.O>[CH3:1][CH:2]([CH3:15])[C:3](=[O:14])[C:4](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: CC(C)C(=O)CC(=O)Nc1ccccc1
Reactant: O=Cc1ccccc1
Agent: NCCC(=O)O
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: O
Product: CC(C)C(=O)C(=Cc1ccccc1)C(=O)Nc1ccccc1
Yield: 84.7 %

Procedure:
A suspension of 100 kg of 4-methyl-3-oxo-N-phenyl-pentanamide (Example A) in 660 kg of hexane was treated with agitation under nitrogen with 8 kg of β-alanine, 47 kg of benzaldehyde, and 13 kg of glacial acetic acid. The resulting suspension was heated to reflux with removal of water for 20 hours. An additional 396 kg of hexane and 3 kg of glacial acetic acid was added and reflux continued with water removal for 1 hour. The reaction mixture was cooled to 20° C. to 25° C., and the product was isolated by filtration. The product was purified by slurring in hexane at 50° C. to 60° C., cooling, and filtrating. The product was slurred twice with water at 20° C. to 25° C., filtered, and dried in vacuo to yield 110 kg of 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide, mp 143.7-154.4° C. VPC: 30 meter DB-5 capillary column 50° C. to 270° C. at 15° C./min; 19.33 minutes, 99.7% (area). GC/MS: M/Z 293 [M]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.C[O:16][C:17](=O)[C:18]([C:20]1[C:28]2[C:23](=[C:24]([O:29][CH3:30])[CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=O.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[NH:22][CH:21]=[C:20]2[C:18]1[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: COC(=O)C(=O)c1c[nH]c2c(OC)cccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cccc2c(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)c[nH]c12
Temperature: 25 °C
Yield: 17 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)-acetamide (0.491 g, 2.61 mmol) and (7-methoxy-1H-indol-3-yl)-oxo-acetic acid methyl ester (0.611 g, 2.62 mmol) in DMF (40 mL) under N2 was added a 1.0 M solution of potassium-tert-butoxide in THF (10 mL, 10 mmol) dropwise over 5 minutes. The mixture was heated at 65–70° C. for 15 h. The mixture was cooled to room temperature, quenched with 1N HCl (excess) and poured into EtOAc. The organic layer was separated, washed with water (3×), saturated aq NaHCO3, and brine, dried (MgSO4), filtered and concentrated to ˜40 mL. Upon standing, a bright orange solid precipitated which was isolated by filtration and dried under vacuum at 80–100° C. overnight affording the title compound (0.165 g, 17%). The mother liquor was concentrated onto SiO2 and flash chromatography (30–50% EtOAc/hex) afforded additional product (0.212 g, 22%). 1H NMR (400 MHz, DMSO-d6) 11.98 (br s, 1H), 11.13 (s, 1H), 7.76 (d, J=2.7 Hz, 1H), 7.60 (dd, J=8 Hz, 1H), 7.25 (d, J=3.1 Hz, 1H), 6.97 (dd, J=7, 7 Hz, 1H), 6.88 (dd, J=7, 1 Hz, 1H), 6.54 (d, J=7 Hz, 1H), 6.48 (d, J=3.1 Hz, 1H), 6.43 (dd, J=8, 8 Hz, 1H), 5.98 (d, J=8 Hz, 1H), 3.84 (s, 3H), 3.66 (s, 3H). MS (electrospray, m/z) 372.1 (M++1), 370.1 (M−−1). HRMS 372.1330 (M++1, calcd for C22H18N3O3 372.1348). Anal. Calcd for C22H17N3O3: C, 71.15; 4.61; N, 11.31. Found: C, 70.80; H, 4.58; N, 11.06.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[NH:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:14]([C:25]([OH:27])=[O:26])[C@@H:15]([CH3:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH:35]1(O)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[NH:13]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[C@H:14]([C:25]([O:27][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:26])[C@@H:15]([CH3:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OC1CCCCC1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)OC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
EDC.HCl (7.5 g, 40 mmol) was added to a stirring solution of Boc-Thr(Bzl)-OH (10 g, 32 mmol), cyclohexanol (5.0 mL, 48 mmol), and OMAP (0.66 g, 5.3 mmol) in OCM (75 mL) at 0° C. The mixture was warmed to room temperature (rt) over 30 min and stirred additionally overnight. After removal of the solvent in vacuo, the residue was dissolved in AcOEt, washed successively with 5% citric acid (3×), 5% NaHCO3 (3×) and saturated NaCl (3×), dried over MgSO4, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (AcOE:hexane 1:8) to yield oily Boc-Thr(Bzl)-OcHex (12 g, 30 mmol, 95%). 1H NMR (CDCl3 400 MHz) 67.34-7.25 (m, 5H), 5.28 (d, J=9.6 Hz, 1H), 4.83-4.77 (m, 1H), 4.54 (d, J=11.6 Hz, 1H), 4.38 (d, J=11.6 Hz, 1H), 4.26 (dd, J=2.2, 9.6 Hz, 1H), 4.15 (dq, J=2.2, 6.4 Hz, 1H), 1.84-1.81 (m, 1H), 1.78-1.62 (m, 4H), 1.56-1.46 (m, 1H), 1.45 (s, 9H), 1.44-1.28 (m, 4H), 1.26 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9][C:10]([F:13])([F:12])[F:11].C1N=CN([C:19](N2C=NC=C2)=[O:20])C=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([N:39]2[CH2:44][CH2:43][N:42]([C:19](=[O:20])[NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([O:9][C:10]([F:12])([F:11])[F:13])[CH:4]=3)[CH2:41][CH2:40]2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCNCC2)CC1
Reactant: Nc1ccc(Br)c(OC(F)(F)F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)Nc3ccc(Br)c(OC(F)(F)F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a solution of 4-bromo-3-trifluoromethoxy-phenylamine (500 mg, 2 mmol) in DCM (5 mL) was added N,N-carbonyldiimidazole (348 mg, 2.15 mmol). The reaction mixture was stirred at RT overnight and then 4-piperazin-1-yl-piperidine-1-carboxylic acid tert-butyl ester (579 mg, 2.15 mmol, Preparation 12) was added and the reaction mixture was stirred at RT for 15 min, and concentrated by rotary evaporation and purified by silica gel chromatography (80 g silica, 0-10% MeOH/DCM) to provide the title intermediate (776 mg, 70% yield) as a yellow powder. (m/z): [M+H]+ calcd for C22H30BrF3N4O4 551.14, found 551.3.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH:9]([NH2:13])[CH2:8][O:7]2)([O-:3])=[O:2].[F:14][C:15]([F:39])([F:38])[O:16][C:17]1[CH:37]=[CH:36][C:20]([O:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33](Cl)=[O:34])[CH2:24][CH2:23]2)=[CH:19][CH:18]=1>>[F:39][C:15]([F:14])([F:38])[O:16][C:17]1[CH:18]=[CH:19][C:20]([O:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33]([NH:13][C@@H:9]3[CH2:8][O:7][C:6]4=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][N:11]4[CH2:10]3)=[O:34])[CH2:24][CH2:23]2)=[CH:36][CH:37]=1
Reactant: O=C(Cl)CCOCCN1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1
Reactant: NC1COc2nc([N+](=O)[O-])cn2C1
Product: O=C(CCOCCN1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 38 %

Procedure:
Similar to the manipulation of example 22, with (S)-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine-6-amine (110 mg, 0.6 mmol) and 3-(2-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)ethoxy) propionyl chloride (296 mg, 0.72 mmol) as crude materials, title compound as 124 mg yellow powder was generated and yield was 38%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[C:32][Si](C)(C)C)[CH:26]=4)=[N:23][CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:37]([CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])=[N+:38]=[N-:39].[CH2:45]1OCCOC1>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[N:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]5[N:39]=[N:38][N:37]([CH:40]([Si:41]([CH3:44])([CH3:43])[CH3:42])[CH3:45])[CH:32]=5)[CH:26]=4)=[N:21][CH:20]=3)[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCO1
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(-c4cccc(C#C[Si](C)(C)C)c4)nc3)cn2)CC1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CC(n1cc(-c2cccc(-c3ncc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cn3)c2)nn1)[Si](C)(C)C
Reaction time: 8 h
Yield: 49 %

Procedure:
A solution of copper sulfate pentahydrate (2.2 mg; 0.01 mmol; 0.04 eq.) in water (0.2 mL) was added to a mixture of 4-{4-[2-(3-Trimethylsilanylethynyl-phenyl)-pyrimidin-5-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (intermediate 19, 110 mg; 0.22 mmol; 1.0 eq.), azidomethyl-trimethyl-silane (36 μl; 0.24 mmol; 1.1 eq.) and D-(−)-isoascorbic acid sodium salt (9 mg; 0.04 mmol; 0.2 eq.) in Dioxane-1,4 (3 mL). The vial was sealed and stirred overnight at 8000. The reaction mixture was then diluted with water and extracted with EtOAc (three times). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica afforded the title compound as a beige solid (60 mg, 49%). 1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 2H), 8.88 (t, J=1.6 Hz, 1H), 8.57 (s, 1H), 8.54 (s, 1H), 8.34 (dt, J=8.0 Hz, 1.6 Hz, 1H), 8.16 (s, 1H), 7.96 (dt, J=8.0 Hz, 1.6 Hz, 1H), 7.60 (t, J=8.0 Hz, 1H), 4.48-4.38 (m, 1H), 4.11-4.03 (m, 4H), 2.94 (m, 2H), 2.09-2.05 (m, 2H), 1.88-1.74 (m, 2H), 1.43 (s, 9H), 0.13 (s, 9H). MS (ESI+): 559.5.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13]([C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4C(O)=O)[NH:12][C:11]=3[N:10]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:9]2=[O:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(=O)C(Br)C(C1C=CC([C:48]2[NH:49][C:50]3N(CC4CCCCC4)C(=O)N(CC4CCCCC4)C(=O)[C:55]=3[N:56]=2)=CC=1)Br)C>CN(C)C=O.ClCCl>[CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13]([C:18]4[CH:19]=[CH:23][CH:24]=[C:25](/[CH:11]=[CH:15]/[C:16]([N:49]5[CH:50]=[CH:55][N:56]=[CH:48]5)=[O:17])[CH:26]=4)[NH:12][C:11]=3[N:10]([CH2:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)[C:9]2=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccccc1-c1nc2c(=O)n(CC3CCCCC3)c(=O)n(CC3CCCCC3)c2[nH]1
Reactant: CCOC(=O)C(Br)C(Br)c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(/C=C/c1cccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)c1)n1ccnc1
Reaction time: 18 h

Procedure:
A slurry of (E)-4-[(1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]benzoic acid (from part (a) of this example, 0.50 g) in anhydrous N,N-dimethylformamide (10 mL) was heated briefly to near reflux under nitrogen. N,N′-Carbonyldiimidazole (Aldrich, 0.211 g) was then added to the pale yellow slurry, which thinned and turned orange as a gas evolved. Within minutes the slurry turned a bright yellow and thickened as a yellow solid formed. The mixture was stirred for 18 h, diluted with dichloromethane (30 mL), and filtered. The bright yellow solid was washed with dichloromethane (30 mL), and dried at 40° C. to provide (E)-1,3-bis(cyclohexylmethyl)-8-[3-(2-(1H-imidazol-1-ylcarbonyl)vinyl)phenyl]-9H-purin-2,6(1H,3H)-dione as a yellow powder (0.32 g). A mixture of this sample (0.32 g), nonaethylene glycol monomethyl ether (from part (a) of example 10, 0.277 g) and anhydrous potassium carbonate (0.170 g) in acetonitrile (10 mL) was refluxed for 20 h. Chloroform (50 mL) was added and the solution was washed with 1N HCl, (20 mL). The organic layer was washed with brine, dried (magnesium sulfate), and eluted from a silica gel column with 10% methanol-chloroform. Evaporation of solvents left yellow waxy solid which was reprecipitated from ethyl acetate-hexanes. The yellow waxy solid precipitate was filtered and dried to (E)-4-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]benzoic acid nonaethylene glycol methyl ether ester (0.355 g, 65%); 1H-NMR (DMSO-d6) δ: 8.24 (d, J=8.4, 2,2 CH), 8.06 (d, I=8.6, 2, 2 CH), 4.40 (m, 2, CH2O), 3.90 (d, J=7.3, 2, CH2N), 3.75 (m, 4, CH2N and CH2O), 3.70-3.40 (m, 32, 16 CH2), 3.19 (s, 3, CH3), 2.1-1.6 and 1.4-1.0 (m, 22, cyclohexyl CH2 and CH).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:42]([O:44][C:45](=[O:48])[CH2:46][NH2:47])[CH3:43]>CN(C=O)C.O>[CH2:42]([O:44][C:45](=[O:48])[CH2:46][NH:47][C:15](=[O:17])[C:14]1[CH:13]=[CH:12][C:11]([OH:10])=[CH:19][CH:18]=1)[CH3:43]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
DIPEA (1.4 g, 10.86 mmol) was added drop wise to 4-hydroxy benzoic acid (500 mg, 3.62 mmol) in DMF (10 mL). EDCI (1.7 g, 9.05 mmol) and HOBT (586 mg, 4.34 mmol) were added consecutively and, after 15 minutes, glycine ethyl ester HCl (603 mg, 4.344 mmol) was added. The resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford (4-hydroxy-benzoyl amino)-acetic acid ethyl ester in 91% yield.
Reaction SMILES: [CH2:1]([O:15][C:16]([C:18]1[CH:22]=[CH:21][S:20][C:19]=1[CH:23]=O)=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH2:25][C:26]([C:28]([NH2:30])=[S:29])=[S:27]>>[CH2:1]([O:15][C:16]([C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]1[S:27][C:26]2[N:25]=[C:23]([C:19]3[S:20][CH:21]=[CH:22][C:18]=3[C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:17])[S:29][C:28]=2[N:30]=1)=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOC(=O)c1ccsc1C=O
Reactant: NC(=S)C(N)=S
Product: CCCCCCCCCCCCCCOC(=O)c1ccsc1-c1nc2sc(-c3sccc3C(=O)OCCCCCCCCCCCCCC)nc2s1
Temperature: 200 °C

Procedure:
To a 25 mL flask were added 0.978 g (2.8 mmol) of tetradecyl-2-formylthiophene-3-carboxylate and 110 mg (0.9 mmol) of dithiooxamide. This mixture was heated to 200° C. for 2 hours. The resulting mixture was purified by column chromatography using a mixture of hexane and dichloromethane to give the desired compound. The NMR data were obtained and were consistent with those of the desired compound.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[Br:34][CH2:35][C:36](Br)=[O:37]>O1CCCC1.C(OCC)(=O)C>[Br:34][CH2:35][C:36]([N:9]([CH:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:14][CH2:15]1)[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:23])[F:24])=[CH:8][CH:7]=1)=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)cc2)CC1
Reactant: O=C(Br)CBr
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)CBr)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of the product of Example 166A (480 mg, 1.39 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.486 mL, 2.79 mmol) in anhydrous tetrahydrofuran (10 mL) was cooled in an ice water bath for 10 minutes followed by the dropwise addition of bromoacetyl bromide (0.146 mL, 1.67 mmol) via syringe. The reaction was stirred for 30 minutes at 0° C., then 1 hour at ambient temperature and 3 hours at reflux. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate. The organic solution was washed with 1 N aqueous HCl and saturated NaHCO3 solution and brine, dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel (Analogix® Intelliflash™ 280; SF25-60 g column; 50% ethyl acetate/hexanes) which yielded the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.74 (d, J=8.4, 2H), 7.34 (d, J=8.2, 2H), 4.80-4.66 (m, 1H), 4.25-4.04 (m, 2H), 3.49 (s, 2H), 2.79 (t, J=12.4, 2H), 1.87-1.77 (m, 2H), 1.39 (s, 9H), 1.29-1.11 (m, 2H); MS (DCI+) m/z 482/484 (M+NH4)+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11].Cl.[CH:23]1([CH2:29][CH2:30][NH:31][CH2:32][CH2:33][S:34][CH3:35])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(OCC)(=O)C>O1CCCC1>[CH:23]1([CH2:29][CH2:30][N:31]([CH2:32][CH2:33][S:34][CH3:35])[C:10]([NH:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:11])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NCCN1CCCCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CSCCNCCC1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSCCN(CCC1CCCCC1)C(=O)NCCN1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(1-piperidyl) ethylamine (151 mg) in anhydrous tetrahydrofuran (5.9 ml), there was added 1,1′-carbonyl diimidazole (228 mg) in a nitrogen gas atmosphere and the resulting mixture was stirred at room temperature for 15 minutes. Then 2-cyclohexyl-N-[2-(methylthio) ethyl]-ethylamine hydrochloride (309 mg) was added to the foregoing mixture and the resulting mixture was refluxed with heating for 45 minutes. Ethyl acetate was added to the reaction solution with ice cooling, followed by washing the reaction solution with saturated aqueous solution of sodium hydrogen carbonate and then with saturated sodium chloride aqueous solution, drying over anhydrous sodium sulfate and concentration under reduced pressure. The resulting oily product was purified by the silica gel column chromatography to thus give the title compound (Compound 4-1).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11]1[C:12]([NH2:29])=[CH:13][C:14]2[CH:20]([CH3:21])[CH2:19][N:18]([C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH2:17][CH2:16][C:15]=2[N:28]=1>C(Cl)Cl>[Br:8][C:13]1[C:14]2[CH:20]([CH3:21])[CH2:19][N:18]([C:22](=[O:27])[C:23]([F:26])([F:24])[F:25])[CH2:17][CH2:16][C:15]=2[N:28]=[C:11]([O:10][CH3:9])[C:12]=1[NH2:29]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nc2c(cc1N)C(C)CN(C(=O)C(F)(F)F)CC2
Solvent: ClCCl
Product: COc1nc2c(c(Br)c1N)C(C)CN(C(=O)C(F)(F)F)CC2
Yield: 37 %

Procedure:
A solution of NBS (1.16 g, 6.50 mmol) in DCM (40 ml) was added dropwise to a stirred and cooled (0-5° C.) solution of 2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (1.97 g, 6.50 mmol) in DCM (40 ml) over a period of 20 min. After 30 minutes of stirring, the reaction was quenched with sat. aq. NaHCO3 and extracted with DCM. The organic layer was dried, concentrated in vacuo and purified by column chromatography to provide 920 mg (37%) of 4-bromo-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NMR (CDCl3) δ 4.36 (0.5H), 4.18 (2H), 4.00 (0.5H), 3.95 (3H), 3.79 (1H), 3.74 (1H), 3.70 (1H), 3.38 (1H), 3.23 (1H), 3.07 (1H), 1.19 (3H) ppm. 4-Bromo-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (57.0 mg, 0.15 mmol) of was deprotected using K2CO3 (62 mg, 0.45 mmol), MeOH (2.3 ml) and H2O (0.5 ml) at 55-60° C. for 30 minutes. After carefully removing MeOH under reduced pressure, the mixture was diluted with aq. NaHCO3 and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated in vacuo to give 37.0 mg (86%) of 4-bromo-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NMR (CDCl3) δ 3.96 (s, 3H), 3.54 (m, 1H), 3.26 (dd, 2H), 3.18 (dd, 1H), 3.02 (d, 1H), 2.94 (dd, 1H), 2.78 (dd, 1H), 1.32 (d, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[C:43]([NH2:51])(=[O:50])[C:44]1[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=1.C(OCC)(=O)C>CS(C)=O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][N+:47]4[CH:48]=[CH:49][C:44]([C:43](=[O:50])[NH2:51])=[CH:45][CH:46]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1nsc(N)n1
Reactant: NC(=O)c1ccncc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[n+]3ccc(C(N)=O)cc3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.9 %

Procedure:
To a stirred solution of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (IX-1) (E, 716 mg, 1 mmole) in dry DMSO (2 ml) was added isonicotinamide (244 mg, 2 mmoles). The mixture was stirred at room temperature for 1 hour and then poured into ethyl acetate (200 ml). The resulting precipitate was collected by filtration, washed well with ethyl acetate and dried. A stirred mixture of the quaternized material (400 mg) and sodium bisulfite (40 mg) in HCOOH (4 ml) was heated at 40°-50° C. for 1 hour, and evaporated to dryness under reduced pressure. The crude solid was dissolved in water (40 ml). After filtration of an insoluble material, the filtrate was chromatographed on a reverse phase column (packing of PrepPAK/C18, 100 ml) using water and 5%, 10%, 20% and 30% aqueous CH3OH as eluant. The fractions containing the desired compound were combined, evaporated and lyophilized to give 21 mg (3.8%) of the title compound (I-1H) (E) as a pale yellow powder. Mp. >180° C. (dec.).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][CH2:25][NH:26]2)=[CH:22][CH:21]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][CH2:25][N:26]2[C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:22][CH:21]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Fc1ccc2c(c1)NCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2ccc(F)cc21
Yield: 67.1 %

Procedure:
The product is prepared according to the procedure described in example 5, but using 200 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, 210 mg of 6-fluoro-2,3-dihydro-1H-indole, and 194 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.12 ml of pyridine and 3 ml of N,N-dimethylformamide. 184 mg of 2-[2-(6-fluoro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white powder, the characteristics of which are the following: