Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].C(N(C(C)C)CC)(C)C.Cl.[NH2:24][C:25]1[N:30]=[C:29]([OH:31])[C:28]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][OH:43])=[CH:35][C:34]=2[O:44][CH3:45])=[C:27]([CH3:46])[N:26]=1>C1COCC1.O>[CH3:13][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:31][C:29]1[C:28]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][OH:43])=[CH:35][C:34]=2[O:44][CH3:45])=[C:27]([CH3:46])[N:26]=[C:25]([NH2:24])[N:30]=1)(=[O:11])=[O:10]
Reactant: COc1cc(OCCCO)ccc1Cc1c(C)nc(N)nc1O
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OCCCO)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Yield: 88.1 %

Procedure:
2-Mesitylenesulfonyl chloride (2.7 g) was added to a suspension of diisopropylethylamine (4.6 mL) and the product from step (vi) (2.9 g) in THF (200 mL) and the mixture was stirred under reflux for 18 h. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by flash column chromatography on amino silica gel to afford the sub-title compound (3.6 g) as a white solid; 1H NMR (300 MHz, CDCl3); 6.92 (2H, s), 6.71 (1H, d), 6.40 (1H, d), 6.32 (1H, dd), 4.70 (2H, br s), 4.07 (2H, t), 3.88-3.82 (2H, m), 3.76 (3H, s), 3.73 (2H, s), 2.57 (6H, s), 2.29 (3H, s), 2.24 (3H, s), 2.06-1.98 (2H, m); LC-MS: m/z 502.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[F:12])[NH:8][C:7](=[O:14])[CH:6]=[CH:5]2.[H][H]>C(O)C.CN(C)C=O.[Ni]>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[F:12])[NH:8][C:7](=[O:14])[CH2:6][CH2:5]2
Reactant: O=c1ccc2cc(F)c(F)c(F)c2[nH]1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C1CCc2cc(F)c(F)c(F)c2N1
Yield: 95.9 %

Procedure:
24.35 g of 6,7,8-trifluorocarbostyril in suspension in a mixture of 450 cm3 of ethanol and 150 cm3 of dimethylformamide are hydrogenated, with stirring, at about 50° C., in the presence of 5 g of Raney nickel under a pressure of 1 atmosphere until the absorption of hydrogen has ceased. The W-2 grade Raney nickel used is washed beforehand with 50 cm3 of an aqueous 2% acetic acid solution, twice 50 cm3 of water and 3 times 50 cm3 of ethanol. 250 cm3 of dimethylformamide are added to the reaction mixture and the mixture is filtered at about 50 C. through diatomaceous silica. The filtrate is concentrated under reduced pressure (20 kPa) at about 70° C. The dry extract is taken up in 150 cm3 of water, drained and washed with twice 50 cm3 of water. 23.6 g of 6,7,8-trifluoro-3,4-dihydrocarbostyril are obtained in the form of a light beige solid melting at 217° C., which is used for the subsequent steps without further purification.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]([NH2:9])=[O:8])=[O:5])#[N:2].[C:10](O)(=O)[CH3:11].[C:14]([O-])(=O)C.[NH4+]>CC(C)=O>[C:1]([CH:3]([CH:10]([CH3:11])[CH3:14])[C:4]([NH:6][C:7]([NH2:9])=[O:8])=[O:5])#[N:2]
Reactant: CC(=O)[O-]
Reactant: N#CCC(=O)NC(N)=O
Reactant: CC(=O)O
Agent: [NH4+]
Solvent: CC(C)=O
Product: CC(C)C(C#N)C(=O)NC(N)=O

Procedure:
When acetone is used as a reaction solvent, the production method is almost the same as the one mentioned above, wherein cyanoacetylurea is suspended or dissolved in acetone, and acetic acid and ammonium acetate are added to allow reaction under reducing conditions to give N-(2-cyano-3-methylbutanoyl)urea. Preferably, the reaction is carried out in the presence of a reduction catalyst. The termination of the reaction can be confirmed and the objective product can be isolated after the reaction, according to the above-mentioned methods.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.C(O)(=O)C.C([BH3-])#N.[Na+].[CH2:26]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH2:27][CH2:28][CH3:29]>CN(C=O)C.C(OCC)(OCC)OCC>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:34][C:33]2[CH:35]=[CH:36][C:30]([CH2:26][CH2:27][CH2:28][CH3:29])=[CH:31][CH:32]=2)=[CH:10][CH:9]=1
Reactant: CCCCc1ccc(N)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Solvent: CN(C)C=O
Product: CCCCc1ccc(NCc2ccc(C(=O)NCCC(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.2 %

Procedure:
The above propionic acid methyl ester (2.0 g, 8.5 mmol) was dissolved in DMF (20 mL) and triethyl orthoformate (10 mL), glacial acetic acid (1 mL), sodium cyanoborohydride (0.81 g, 12.8 mmol) and 4-butylaniline 1.27 g, 8.5 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium chloride (3×100 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and heptane (3:1) to afford 1.54 g (49%) of 3-{4-[(4-butylphenylamino)methyl]-benzoylamino}propionic acid methyl ester as an oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Br[C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]=1>>[CH3:22][C:20]1[CH:19]=[CH:18][N:17]=[C:16]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])[CH:21]=1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: Cc1ccnc(Br)c1
Product: Cc1ccnc(C#Cc2c(-c3ccccc3)noc2C)c1
Yield: 52 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-4-methylpyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 72 mg, 52%) which was obtained as a light brown solid. MS: m/e=275.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[C:5]([CH3:27])[CH:6]=[C:7]([CH:19]([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1>ClCCCl.C(Cl)Cl.CO.O=[Mn]=O>[Cl:1][C:2]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[C:5]([CH3:27])[CH:6]=[C:7]([C:19]([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)=[O:20])[CH:8]=2)[N:3]=1
Reactant: Cc1cc(C(O)c2cncn2C)cc2c(Cl)c(-c3ccccc3)c(Cl)nc12
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CO
Product: Cc1cc(C(=O)c2cncn2C)cc2c(Cl)c(-c3ccccc3)c(Cl)nc12
Temperature: 70 °C

Procedure:
A suspension of crude (2,4-dichloro-8-methyl-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (801 mg, assume 1.46 mmol, Intermediate 48, step a) in DCE (15 mL) was stirred at 70° C. until a milky mixture resulted with no visible particulates. This was cooled to room temperature and treated with MnO2 (1.27 g, 14.5 mmol), and stirred under air (capped) at 70° C. for 35 hours. The reaction was diluted with 9:1 DCM/MeOH (10 mL) and Celite®, filtered on a bed of Celite®, and concentrated to provide an oil. This was flash chromatographed with a DCM to 100% EtOAc gradient to afford the title compound as a white foam.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:6]([C:7]([N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[OH-].[Li+].O.CO>C1COCC1>[N+:19]([C:17]1[CH:16]=[C:6]([C:7]([N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=[C:4]([CH:18]=1)[C:3]([OH:22])=[O:2])([O-:21])=[O:20]
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCN(CCC)C(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
Dissolve 5-nitro-N,N-dipropyl-isophthalamic acid methyl ester (1.000 g, 3.243 mmol) and lithium hydroxide (0.089 g, 3.730 mmol) in a mixture of THF (3.16 mL), water (1.58 mL) and methanol (1.58 mL). Stir the mixture at room temperature until the starting material is consumed. Concentrate and acidify with 1 N HCl. Extract with ethyl acetate, dry (magnesium sulfate) and concentrate to give the title compound (0.874 g, 92%).
Reaction SMILES: [NH:1]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@@H:2]([C:27](O)=[O:28])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:26])[NH:8][S:9]([C:12]1[C:24]([CH3:25])=[C:23]2[C:17]([O:18][C:19]([CH2:22]2)([CH3:21])[CH3:20])=[C:15]([CH3:16])[C:13]=1[CH3:14])(=[O:11])=[O:10].CN1CCOCC1.[NH2:44][C@H:45]([C:53]([NH:55][C@H:56]([C:69]([O:71][CH3:72])=[O:70])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[CH:60][CH:59]=1)=[O:54])[C@@H:46]([CH3:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49]>CN1C(=O)CCC1.C(Cl)(Cl)Cl>[NH:1]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@@H:2]([C:27]([NH:44][C@@H:45]([C:53]([NH:55][C@@H:56]([C:69]([O:71][CH3:72])=[O:70])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[CH:60][CH:59]=1)=[O:54])[C@H:46]([CH3:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:28])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:26])[NH:8][S:9]([C:12]1[C:24]([CH3:25])=[C:23]2[C:17]([O:18][C:19]([CH2:22]2)([CH3:20])[CH3:21])=[C:15]([CH3:16])[C:13]=1[CH3:14])(=[O:11])=[O:10]
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](N)[C@@H](C)OC(C)(C)C
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c(C)c2c1OC(C)(C)C2
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: COC(=O)[C@@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@H](NC(=O)[C@@H](CCCNC(=N)NS(=O)(=O)c1c(C)c(C)c2c(c1C)CC(C)(C)O2)NC(=O)OC(C)(C)C)[C@H](C)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
A clear solution of 3.73 g (7.08 mmoles) of Boc-D-Arg(Pbf)-OH (Bachem Feinchemikalien, cat. No A-3750) in 75 ml of dry NMP, comprising 0.85 ml (7.79 mmoles) of NMM was chilled to −10° C. under shaking. Then, 1.02 ml (7.79 mmoles) of IBCF diluted in 6 ml of CHCl3 were added drop-wise. After 30 minutes, a solution of 2.88 g (7.08 mmoles) of H-L-Thr(tBu)-L-Tyr(tBu)-OMe in 75 ml of CHCl3 was added drop-wise in 20 minutes. The reaction mixture was kept for 2 h at 0° C. and overnight at room temperature. The solvent was evaporated under vacuum and the crude material was purified by flash chromatography on silica gel column, using a mixture of AcOEt-hexane as eluent. There were thus obtained 5.58 g (6.08 mmoles, yield 86%) of Boc-D-Arg(Pbf)-D-Thr(tBu)-D-Tyr(tBu)-OMe, as pure oil (TLC and RP-HPLC).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.Cl[CH2:27][C:28](Cl)=[O:29].[OH-].[K+]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH:10]([C:12]2[CH:13]=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=2)[O:11][CH2:27][C:28]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(CNCc1ccccc1)c1ccc(Br)cc1
Reactant: O=C(Cl)CCl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1COC(c2ccc(Br)cc2)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.9 %

Procedure:
To a solution of 2-benzylamino-1-(4-bromo-phenyl)-ethanol (18.95 g; 62 mmol) and Et3N (9.6 mL; 68 mmol) in CH2Cl2 (500 mL) was added dropwise a solution of chloroacetyl chloride (5.4 mL; 68 mmol) in CH2Cl2 (20 mL), at 0° C. After 1 hour at 0° C. the reaction mixture was quenched with 1M aqueous HCl (200 mL). The layers were separated and the organic layer washed with a 5% aqueous NaHCO3 solution, dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in 2-propanol (200 mL) and KOH (4.2 g; 75 mmol) was added. The resulting mixture was stirred at RT for 3 hours and subsequently concentrated in vacuo. The crude product was partitioned between CH2Cl2 and 1M aqueous HCl. The layers were separated and the organic layer was washed with saturated aqueous NaHCO3 solution, dried (Na2SO4) and evaporated in vacuo to afford 4-benzyl-6-(4-bromo-phenyl)-morpholin-3-one (22.30 g) which was used as such in the next step.
Reaction SMILES: [SH2:1].[Na].[CH2:3]([C:8]([C:10]1[CH:15]=[CH:14][C:13](Cl)=[CH:12][CH:11]=1)=[O:9])[C:4]([CH3:7])([CH3:6])[CH3:5]>CN1CCCC1=O>[CH2:3]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([SH:1])=[CH:12][CH:11]=1)=[O:9])[C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)CC(=O)c1ccc(Cl)cc1
Reactant: S
Agent: [Na]
Solvent: CN1CCCC1=O
Product: CC(C)(C)CC(=O)c1ccc(S)cc1
Temperature: 140 °C

Procedure:
18.5 g (0.2 mol) of sodium hydrogen sulphide (NaSH·H2O) in 100 ml of N-methylpyrrolidone are introduced and the water is removed by partial distillation with xylene. The mixture is cooled to 140° C., 21.05 g (0.1 mol) of 4-(neopentylcarbonyl)-chlorobenzene are added, and the mixture is further reacted at 160° C. for 3 hours and worked up as described in Example I-1 to give 14 g (70% of theory) of the desired product of boiling point: 110°-115° C./0.1 mbar.
Reaction SMILES: [F:1][C:2]1[CH:19]=[N:18][C:5]2[O:6][C@@H:7]([CH3:17])[C:8](=[O:16])[N:9]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:4]=2[CH:3]=1.[C:20]([O:24][C:25](=[O:47])[C:26]([CH3:46])([CH3:45])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[CH:40]=[CH:39][C:38]([C:41](O)=[O:42])=[C:37]([F:44])[CH:36]=1)([CH3:23])([CH3:22])[CH3:21].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O.CN(C)C=O>[F:44][C:37]1[CH:36]=[C:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[O:28][CH2:27][C:26]([CH3:46])([CH3:45])[C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:47])[CH:40]=[CH:39][C:38]=1[C:41]([N:13]1[CH2:12][CH2:11][CH:10]([N:9]2[C:8](=[O:16])[C@H:7]([CH3:17])[O:6][C:5]3[N:18]=[CH:19][C:2]([F:1])=[CH:3][C:4]2=3)[CH2:15][CH2:14]1)=[O:42]
Reactant: CC(C)(C)OC(=O)C(C)(C)COc1ccccc1-c1ccc(C(=O)O)c(F)c1
Reactant: C[C@@H]1Oc2ncc(F)cc2N(C2CCNCC2)C1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1Oc2ncc(F)cc2N(C2CCN(C(=O)c3ccc(-c4ccccc4OCC(C)(C)C(=O)OC(C)(C)C)cc3F)CC2)C1=O
Reaction time: 24 h
Yield: 90.4 %

Procedure:
At room temperature, to an N,N-dimethylformamide solution (10 ml) of (3S)-7-fluoro-3-methyl-1-piperidin-4-yl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (Reference Example 2) (434 mg) and 2′-(3-tert-butoxy-2,2-dimethyl-3-oxopropoxy)-3-fluorobiphenyl-4-carboxylic acid (636 mg) were added 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (683 mg) and diisopropylethylamine (0.855 ml), followed by stirring for 24 hours. The reaction solution was poured into water (40 ml), and stirred for 6 hours. The precipitate was collected by filtration and dried to afford tert-butyl 3-{[3′-fluoro-4′-({4-[(3S)-7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl]piperidin-1-yl}carbonyl)biphenyl-2-yl]oxy}-2,2-dimethylpropanoate (940 mg).
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H].C([OH:20])C>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[C:12]([OH:15])(=[O:20])[CH3:13].[NH:8]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][CH2:10][CH2:9]1
Reactant: CCO
Reactant: O=C1CCN(Cc2ccccc2)CCN1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C1CCNCCN1
Yield: 96 %

Procedure:
1-Benzylhexahydro-(5H)-1,4-diazepine-5-one (1.5 g, 7.34 mmol) was dissolved in 12 mL of ethanol and 6 mL of acetic acid. After addition of 150 mg of 20% palladium hydroxide on carbon, the mixture was shaken under 40 psi of hydrogen for 4 h. The resulting mixture was centrifuged and the supernatant was filtered through a 0.45 micron membrane filter. The catalyst was washed with ethanol (3×10 mL), and the combined filtrate was concentrated in vacuo to give a yellow oil which began to crystallize. Swirling with 2 mL of methanol and 1 mL of ethyl acetate facilitated the crystallization, and evaporation of the solvent in vacuo gave 1.23 g (96%) of hexahydro-(5H)-1,4-diazepin-5-one acetic acid salt as light yellow crystals.
Reaction SMILES: [NH2:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[O:15])=[C:6]([C@H:9]3[CH2:13][CH2:12][CH2:11][O:10]3)[CH2:7][S:8][C@H:3]12.C1(N=C=NC2CCCCC2)CCCCC1.[C:43]([O:47][C:48]([NH:50][C@H:51]([C:55]1[CH:60]=[CH:59][C:58]([OH:61])=[CH:57][CH:56]=1)[C:52](O)=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44]>C1COCC1>[C:43]([O:47][C:48]([NH:50][C@H:51]([C:55]1[CH:60]=[CH:59][C:58]([OH:61])=[CH:57][CH:56]=1)[C:52]([NH:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[O:15])=[C:6]([C@H:9]3[CH2:13][CH2:12][CH2:11][O:10]3)[CH2:7][S:8][C@H:3]12)=[O:53])=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(O)cc1
Reactant: COc1ccc(COC(=O)C2=C([C@H]3CCCO3)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)C2=C([C@H]3CCCO3)CS[C@@H]3[C@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c4ccc(O)cc4)C(=O)N23)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Methoxybenzyl (6R,7R)-7-amino-3-[(R)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (136 mg, 0.35 mmol)(See example 6] in THF (10 ml) was stirred in an ice bath with dicyclohexylcarbodiimide (108 mg, 0.52 mmol) then (R)-2-t-butoxycarbonylamino-2-(4-hydroxyphenyl)acetic acid (139 mg, 0.52 mmol) in THF (3 ml) was added dropwise over 2 min. The mixture was stirred at 0° C. for 30 min then at room temperature for 30 min. It was filtered and evaporated and the residue chromatographed on silica gel eluting with ethyl acetate/hexane mixtures. The title compound was obtained as a white solid (212 mg, 95%); δH (CDCl3) 1.10-2.0 (4H,m), 1.42 (9H,s), 3.18 and 3.43 (2H,ABq, J 17 Hz), 3.80 (3H,s), 3.77-3.88 (2H,m), 4.89 (1H,d, J 5 Hz), 5.10 (1H,t, J 7 Hz), 5.11 (1H,d, J 5 Hz), 5.19 (2H, s), 5.65 (1H,d, J 5 Hz exch), 5.69 (1H,dd, J 4.9 Hz), 6.72 (2H,d, J 8 Hz), 6.81 (1H,d, J 9 Hz exch), 6.88 (2H,d, J 9 Hz), 7.10 (2H,d, J 8 Hz) and 7.33 (2H,d,J 9 Hz). [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (938)].
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([Cl:42])=[CH:11][C:12]([O:39][CH2:40][CH3:41])=[C:13]([C:15]2[N:16]([C:36](Cl)=[O:37])[C:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)([CH3:28])[C:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)([CH3:20])[N:19]=2)[CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.Cl.[CH3:52][S:53]([CH2:56][CH2:57][CH2:58][N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)(=[O:55])=[O:54]>C(Cl)Cl>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C@@:18]2([CH3:20])[C@:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)([CH3:28])[N:16]([C:36]([N:62]3[CH2:61][CH2:60][N:59]([CH2:58][CH2:57][CH2:56][S:53]([CH3:52])(=[O:54])=[O:55])[CH2:64][CH2:63]3)=[O:37])[C:15]([C:13]3[C:12]([O:39][CH2:40][CH3:41])=[CH:11][C:10]([Cl:42])=[C:9]([S:6]([NH:5][C:1]([CH3:3])([CH3:2])[CH3:4])(=[O:8])=[O:7])[CH:14]=3)=[N:19]2)=[CH:22][CH:23]=1
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(5-tert-butylsulfamoyl-4-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (260 mg, 0.39 mmol, example 45) and triethylamine (350 mg, 3.34 mmol) in methylene chloride (10 mL) was treated with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (110 mg, 0.39 mmol, prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C38H49N5O6S2Cl3 [(M+H)+] 840.2185, observed 840.2179
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][N:20]([CH2:34][C:35]3[C:36]([C:41]#[N:42])=[N:37][CH:38]=[CH:39][CH:40]=3)[CH2:21][CH2:22][N:23]3[CH:28]=[CH:27][C:26]4[O:29][C:30]([CH3:32])=[CH:31][C:25]=4[C:24]3=[O:33])[CH:17]=[CH:18][C:4]1=2)[CH3:2].C[C:44](C)=[O:45]>[Ni].C(O)=O>[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][N:20]([CH2:34][C:35]3[C:36]([CH2:41][NH:42][CH:44]=[O:45])=[N:37][CH:38]=[CH:39][CH:40]=3)[CH2:21][CH2:22][N:23]3[CH:28]=[CH:27][C:26]4[O:29][C:30]([CH3:32])=[CH:31][C:25]=4[C:24]3=[O:33])[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3cccnc3C#N)ccc21
Reactant: CC(C)=O
Agent: [Ni]
Solvent: O=CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3cccnc3CNC=O)ccc21
Temperature: 60 °C
Reaction time: 3 h

Procedure:
3-({N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)pyridine-2-carbonitrile (0.40 g) and Raney nickel (1.2 g) were suspended in formic acid (8 ml), and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was filtered to remove insoluble matter, and the filtrate was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=75:25→80:20). The purified product was condensed under reduced pressure. Acetone and ether were added to the residue. The precipitated insoluble matter was separated, washed with ether, and dried to give the title compound (33 mg) as a pale brown white amorphous.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[C:7]1([C:13]2[CH:14]=[C:15]3[N:20]([CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16]3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.C1COCC1>[O:3]=[C:2]([C:21]1[N:20]2[C:15]([CH:16]=[CH:17][CH:18]=[CH:19]2)=[CH:14][C:13]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:1]([Cl:6])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccc(-c2cc3ccccn3c2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cl)C(=O)c1c(-c2ccccc2)cc2ccccn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.3 %

Procedure:
Oxalyl chloride (2.23 mL, 25.9 mmol) was added to an ice-cold solution of 2-phenylindolizine (4.0 g, 20.7 mmol) in a mixture of toluene (40 mL) and THF (8 mL). The reaction mixture was stirred at r.t. for 5 h then concentrated in vacuo. The residue obtained was recrystallised from DCM-hexane to yield oxo-(2-phenyl-indolizin-3-yl)-acetyl chloride (4.6 g, 80%) as a solid.