Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])CCC.C[Si](C=[N+]=[N-])(C)C.[CH3:13][N:14]1[C:18]([CH:19]=O)=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:16]=[CH:15]1.[Cl-].[NH4+]>C1COCC1>[C:19]([C:18]1[N:14]([CH3:13])[CH:15]=[N:16][C:17]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)#[CH:1]
Reactant: [Li]CCCC
Reactant: Cn1cnc(-c2ccccc2)c1C=O
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#Cc1c(-c2ccccc2)ncn1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
n-Butyllithium (2M in pentane, 650 μL) was added dropwise to trimethylsilyldiazomethane (2M in hexane, 750 μL) in THF (1 mL), cooled to −78° C. and stirred for 30 minutes. 1-Methyl-4-phenyl-1H-imidazole-5-carbaldehyde (intermediate 2) (186 mg) was added dropwise over 5 minutes and stirring continued at −78° C. for 30 minutes, then warmed to 0° C. over 30 minutes and stirred for a further 30 minutes at 0° C. Saturated aqueous ammonium chloride (3 mL) was added, mixture extracted with diethyl ether (3×5 mL), organics combined dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with DCM:MeOH (50.1) afforded the title compound as yellow solid (61.3 mg, 34%);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[C:6]([C:8]2[C:9]([O:16][CH2:17][CH3:18])=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][C:63]=1[CH2:69][C:70](O)=[O:71]>CC(N(C)C)=O>[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][C:63]=1[CH2:69][C:70]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[C:6]([C:8]2[C:9]([O:16][CH2:17][CH3:18])=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1)=[O:71]
Reactant: CCOc1cc(=O)n(C)cc1-c1cc(N)ccc1Oc1ccc(F)cc1F
Reactant: O=C(O)Cc1cc(F)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCOc1cc(=O)n(C)cc1-c1cc(NC(=O)Cc2cc(F)ccc2Cl)ccc1Oc1ccc(F)cc1F

Procedure:
A solution of Example 1G and DIPEA (0.182 M and 0.52 M in DMA, respectively, 221 μL, 0.40 mmol Example 1G (1.0 equivalent) and 1.21 mmol DIPEA (3.0 equivalents)), HATU (0.182 M in DMA, 221 μL, 0.40 mmol, 1 equivalent) and 2-(2-chloro-5-fluorophenyl)acetic acid (0.40 M in DMA, 151 μL, 0.60 mmol, 1.5 equivalents) were mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL min−1 (10 minute residence time). Upon exiting the reactor, the solution was loaded directly into an injection loop and purified by preparative HPLC on a Phenomenex Luna C8(2) 5 μm 100 Å AXIA column (50 mm×21.2 mm), eluting with a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) at a flow rate of 30 mL/min (0-0.5 min 5% A, 0.5-6 5 min linear gradient 5-100% A, 6.5-8.5 min 100% A, 8.5-9.0 min linear gradient 100-5% A, 9.0-10 min 5% A) to provide the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 10.37 (s, 1H), 7.59-7.46 (m, 4H), 7.37-7.27 (m, 2H), 7.18 (td, J=8.5, 3.1 Hz, 1H), 7.14-6.93 (m, 2H), 6.90 (d, J=8.7 Hz, 1H), 5.82 (s, 1H), 3.92 (q, J=7.0 Hz, 2H), 3.85 (s, 2H), 3.36 (s, 3H), 1.14 (t, J=7.0 Hz, 3H). MS (APCI+) m/z 543.0 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][NH2+:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.C1COCC1.C([O-])(O)=O.[Na+].[CH:33]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1>O>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:38]([CH:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[O:39])[CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCC[NH2+]C3)c21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCN(C(=O)C4CCCC4)C3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To a solution of (S)-3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 2a, 528 mg, 1.52 mmol) in H2O:THF (20 mL, 2:1), was added NaHCO3 (640 mg, 7.60 mmol). Upon complete dissolution of the NaHCO3, cyclopentanecarbonyl chloride (945 uL, 7.60 mmol) was added dropwise. The reaction was stirred at room temperature overnight. The precipitate was collected by vacuum filtration and purified by preparative HPLC (10-90% acetonitrile in water). The pure fractions were combined, concentrated then dissolved in a solution of NaHCO3 (250 mg in 10 mL water). After complete dissolution, the mixture was cooled in an ice bath and neutralized with 1N HCl. The resulting white solid was collected by vacuum filtration to provide the desired product (322 mg, 52%) as a white solid. 1H NMR (DMSO-d6, 400 MHz, 80° C.): 1.43 (m, 2H), 1.51-1.80 (m, 10H), 1.90 (m, 1H), 2.09 (m, 1H), 2.96 (m, 2H), 4.01 (br m, 2H), 4.12 (d, J=6.4 Hz, 2H), 6.67 (d, J=7.8 Hz, 1H), 6.77 (d, J=8.3 Hz, 1H), 7.46 (t, J=8.3 Hz, 1H), 7.92 (br s, 2H), 10.70 (br s, 1H). MS=407 (MH+).
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4](C=O)=[CH:5][CH:6]=1.[NH2:9][N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15]>>[Cl:1][C:2]1[O:3][C:4](=[N:9][N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:5][CH:6]=1
Reactant: NN1CCNC1=O
Reactant: O=Cc1ccc(Cl)o1
Product: O=C1NCCN1N=C1CC=C(Cl)O1

Procedure:
2-Chlorofuran-5-aldehyde is reacted with 1-amino-2-oxo-imidazolidine as in Example 1.1. 1-(5-Chlorofurylideneamino)- 2-oxo-imidazolidine of melting point 173°-175° C. is obtained.
Reaction SMILES: [OH:1][C:2]1[O:3][C:4]2[CH:12]=[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:9][C:5]=2[C:6](=[O:8])[CH:7]=1.[N+:25]([O-])([OH:27])=[O:26]>C(O)(=O)C>[OH:1][C:2]1[O:3][C:4]2[CH:12]=[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:9][C:5]=2[C:6](=[O:8])[C:7]=1[N+:25]([O-:27])=[O:26]
Reactant: O=[N+]([O-])O
Reactant: CS(=O)(=O)Nc1cc2oc(O)cc(=O)c2cc1Oc1ccccc1
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc2oc(O)c([N+](=O)[O-])c(=O)c2cc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 20.4 %

Procedure:
3.47 g of 2-hydroxy-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was suspended in 50 ml of acetic acid. Thereto was added 1.67 ml of concentrated nitric acid (specific gravity: 1.38). The mixture was stirred for 20 minutes at 100°-110° C. The reaction mixture was introduced into 300 ml of ice water. The resulting crystal was collected by filtration, washed with water, and recrystallized from acetonitrile to obtain 800 mg (yield: 20.4%) of 2-hydroxy-7-methylsulfonylamino-3-nitro-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 228°-230° C. (decomposed).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([N:7]=[C:8]=[O:9])=[N:4][CH:3]=1.C1C=CC=CC=1.[Cl:16][CH2:17][NH:18][CH2:19][CH:20]=[O:21]>C(O)C.O>[Cl:16][CH2:17][N:18]([CH2:19][CH:20]=[O:21])[C:8]([NH:7][C:5]1[S:6][C:2]([Br:1])=[CH:3][N:4]=1)=[O:9]
Reactant: O=CCNCCl
Reactant: O=C=Nc1ncc(Br)s1
Solvent: CCO
Solvent: O
Solvent: c1ccccc1
Product: O=CCN(CCl)C(=O)Nc1ncc(Br)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Bromothiazol-2-yl isocyanate dimer (17.0 grams), benzene (70 ml) and the dimethyl acetal of 2-chloromethylaminoacetaldehyde (13.5 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is then stirred at room temperature for a period of about one hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent under reduced pressure, leaving an oil. This oil is dissolved in an ethanol-water mixture, and the solution is filtered. The filtrate is then stripped of solvents under vacuum to yield the desired product the dimethyl acetal of 2-[1-chloromethyl-3-(5-bromothiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [OH:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[S:5][C:4](=[O:14])[C:3]=1[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23].C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>O1CCCC1>[CH3:13][O:12][N:9]1[CH2:10][CH2:11][C:6]2([S:5][C:4](=[O:14])[C:3]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])=[C:2]2[O:1][C:32](=[O:33])[O:34][CH2:35][CH3:36])[CH2:7][CH2:8]1
Reactant: CCOC(=O)Cl
Reactant: CON1CCC2(CC1)SC(=O)C(c1c(C)cc(C)cc1C)=C2O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)SC12CCN(OC)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.7 %

Procedure:
94 mg 4-Hydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1-thia-8-aza-spiro[4.5]dec-3-en-2-one (from Step 7) and 43 mg triethylamine were dissolved in 10 ml tetrahydrofuran, and a solution of 32 mg ethyl chloroformate in 5 ml tetrahydrofuran was added dropwise. The mixture was stirred at ambient temperature for 18 hours, then partitioned between saturated aqueous sodium bicarbonate and t-butylmethyl ether, the organic layer dried over sodium sulfate, and the solvent evaporated. The residue was purified by chromatography on silica gel with ethylacetate/cyclohexane (1:2) as a solvent, to give 34 mg carbonic acid ethyl ester 8-methoxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1-thia-8-aza-spiro[4.5]dec-3-en-4-yl ester (title compound P1.7) as a solid, mp 87-89° C.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH3:9][C@@:10]12[C:16](=O)[C:15]([CH3:19])([CH3:18])[C@@H:13]([CH2:14]1)[CH2:12][CH2:11]2>O.CO>[CH3:9][C@@:10]12[CH2:14][CH:13]([CH2:12][CH2:11]1)[C:15]([CH3:19])([CH3:18])[C:16]2=[N:2][OH:3]
Reactant: CC1(C)C(=O)[C@@]2(C)CC[C@@H]1C2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)C(=NO)[C@@]2(C)CCC1C2
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 23 g of hydroxylamine hydrochloride and 41 g of sodium acetate in 200 ml of water is added at RT to a solution of 38.1 g of (1S)-(+)-fenchone in 120 ml of MeOH and the mixture is then refluxed for 48 hours. After cooling to RT, the precipitate formed is filtered off, washed with water and dried under vacuum to give 41 g of the expected product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=[C:5]2O.P(Cl)(Cl)([Cl:27])=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=[C:5]2[Cl:27]
Reactant: Cc1nc2ccc(Br)cc2c(O)c1Cc1ccc(C(F)(F)F)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A round-bottomed flask containing a mixture of 6-bromo-2-methyl-3-(4-(trifluoromethyl)benzyl)quinolin-4-ol (5.00 g, 12.6 mmol, Intermediate 57: step b), phosphorous oxychloride (5.90 mL, 63.1 mmol) and acetonitrile (42 mL) was warmed to 90° C. After 3 h, the reaction mixture was cooled to room temperature. The acetonitrile and excess phosphorous oxychloride was removed by rotary evaporation. The residue was dissolved in dichloromethane (100 mL) and the solution was cooled in an ice-water bath. Ice (100 mL) was added. Concentrated aqueous ammonia solution was added dropwise until the pH=˜9 by litmus paper test. The biphasic mixture was separated and the aqueous layer was extracted with dichloromethane (50 mL). The combined organics were dried with magnesium sulfate and the dried solution was filtered. Celite (5 g) was added to the filtrate and the solvents were removed by rotary evaporation to provide a free-flowing powder. The powder was loaded onto a silica gel column. Elution with hexanes initially, grading to 20% ethyl acetate-hexanes provided the title compound as an off-white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[N:2]1.[NH2:8][C:9]([CH3:31])([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[C:10]([NH:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])=[O:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>N1C=CC=CC=1>[NH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([CH2:21][C:9]([CH3:31])([NH:8][CH2:6][C:3]2[NH:2][N:1]=[CH:5][CH:4]=2)[C:10]([NH:12][CH:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])=[O:11])=[CH:23]1
Reactant: O=Cc1cc[nH]n1
Reactant: CC(NC(=O)C(C)(N)Cc1c[nH]c2ccccc12)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(NC(=O)C(C)(Cc1c[nH]c2ccccc12)NCc1ccn[nH]1)c1ccccc1
Yield: 10 %

Procedure:
To a stirred solution of pyrazole-3-carboxaldehyde (96 mg, 1 mmol, supplied as dimer) in pyridine (10 mL) was added 2-amino-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide (161 mg, 0.5 mmol) followed by sodium triacetoxyborohydride (848 mg, 4 mmol). After stirring over night at room temperature another portion of sodium triacetoxyborohydride (424 mg, 2 mmol) was added. After stirring over night at room temperature the pyridine was removed under reduced pressure. The residue was taken up in CH2Cl2 (100 mL) and saturated NaHCO3. The aqueous phase was extracted with CH2Cl2 (100 mL). The combined organic phases were washed with brine (50 mL), dried (MgSO4), and the solvent was removed under reduced pressure. The residue was initially purified by chromatography on normal phase silica using 95% EtOAc in heptane as eluent. The solvent was removed under reduced pressure and the residue was dissolved in aqueous acetonitrile and acidified using formic acid. Purification by chromatography on reverse phase silica using 25% CH3CN in H2O (0.1% formic acid in mobile phases) as eluent gave pure product. The solvent was removed under reduced pressure and the residue was suspended between EtOAc and saturated NaHCO3. The EtOAc was dried (MgSO4) and the solvent was removed under reduced pressure to give pure product as a glass (20 mg, 10%); IR (film): 3260, 3059, 2979, 2927, 1651, 1515, 1456, 1374, 1266, 1105, 1048, 1011, 932, 741 cm−1; NMR (DMSO-d6): δ1.22 (3H, s); 1.35 (3H, d, J=6.8 Hz); 2.26 (1H, s); 2.96-3.05 (2H, m); 3.50-3.75 (2H, m); 4.93 (1H, s); 6.10 (1H, s); 6.89-6.93 (2H, m); 7.00-7,04 (1H, m); 7.18-7.32 (6H, m); 7.35 (0.5H, s); 7.52 (1H, d, J=7.8 Hz); 7.60 (0.5H, s); 8.05-8.20 (1H, m); 10.82 (1H, s); 12.52 (0.5H, s); 12.73 (0.5H, s); MS m/e (ES+): 424.1 (27%); 402.1 (100%, M++H).
Reaction SMILES: NC1SC2C3C(CC=2[C:3]=1[C:14](N)=[O:15])=CC=CC=3.[NH2:17][C:18]1[S:22][C:21]2[C:23]3[C:28]([CH2:29][CH2:30][C:20]=2[C:19]=1[C:31]([NH2:33])=[O:32])=[CH:27][CH:26]=[CH:25][CH:24]=3>>[C:14]([NH:17][C:18]1[S:22][C:21]2[C:23]3[C:28]([CH2:29][CH2:30][C:20]=2[C:19]=1[C:31]([NH2:33])=[O:32])=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:15])[CH3:3]
Reactant: NC(=O)c1c(N)sc2c1CCc1ccccc1-2
Reactant: NC(=O)c1c(N)sc2c1Cc1ccccc1-2
Product: CC(=O)Nc1sc2c(c1C(N)=O)CCc1ccccc1-2

Procedure:
The title compound was prepared by the same procedure as Example 3 except that 2-amino-4H-indeno[1,2-b]thiophene-3-carboxylic acid amide was replaced with 2-amino-4,5-dihydro-naphtho[1,2-b]thiophene-3-carboxylic acid amide to give the above title compound as brown solid. ESMS m/z: 287 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]([C:17](=[O:22])N(OC)C)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[C:24]([NH:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[CH3:36])(C)([CH3:26])[CH3:25]>>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:17](=[O:22])[CH2:36][C:31]1[C:30]([C:29](=[O:37])[NH:28][CH:24]([CH3:25])[CH3:26])=[CH:35][CH:34]=[CH:33][N:32]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Reactant: Cc1ncccc1C(=O)NC(C)(C)C
Product: CC(C)NC(=O)c1cccnc1CC(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 2 with [(R)-2-(2-fluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (0.65 g, 2.0 mmol) and substituting N-isopropyl-2-methyl-nicotinamide for N-tert-butyl-2-methyl-nicotinamide gives the title compound.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:15]1([CH2:21][CH2:22][NH2:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.O>[C:15]1([CH2:21][CH2:22][NH:23][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(NCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of commercially available tert-butyl 4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 2-phenylethylamine (0.143 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-(2-phenylethyl)amino-piperidine carboxylate. Yield: 221 mg. To a solution of tert-butyl 4-(2-phenylethyl)amino-piperidine carboxylate (50 mg, 0.16 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and water (10 ml), dried (Na2SO4), filtered and concentrated to give N-(2-phenylethyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. N-(2-Phenylethyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2×15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 52 mg; 13C-NMR (CD3OD, rotamers): δ 27.1, 28.5, 34.9, 36.6, 40.2, 40.4, 44.1, 44.2, 44.4, 53.3, 54.2, 54.6, 114.0, 114.1, 126.2, 126.6, 127.2, 127.4, 128.3, 128.6, 128.79, 128.82, 129.7, 138.5, 139.5, 158.96, 159.0, 172.7, 173.1
Reaction SMILES: [CH3:1][C:2]1[N:21]=[C:5]2[N:6]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:14])[CH:7]=[C:8]([S:10][CH3:11])[CH:9]=[C:4]2[C:3]=1[CH3:22].C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(Cl)Cl>[CH3:1][C:2]1[N:21]=[C:5]2[N:6]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:14])[CH:7]=[C:8]([S:10]([CH3:11])=[O:31])[CH:9]=[C:4]2[C:3]=1[CH3:22]
Reactant: CSc1cc2c(C)c(C)nc-2n(CC(=O)c2ccccc2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc2n(CC(=O)c3ccccc3)cc(S(C)=O)cc-2c1C
Yield: 46 %

Procedure:
A solution of 2,3-dimethyl-5-methylthio-7-phenacylpyrrolo[2,3-b]pyridine (35 mg, 0.1 mmol) in 20 ml CH2Cl2 was cooled to -20° C. an treated with 71% m-CPBA (27 mg, 0.1 mmol) for 30 min. The volume was adjusted 50 ml with CH2Cl2 and the organic layer washed twice with 50 ml 5% Na2CO3 and once with 2M HCl (reextraction trice with 25 ml CH2Cl2). The organic layer was dried over MgSO4 and evaporated leaving 15 mg (41%) pure title compound.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[C:26]([Br:30])[C:27]([Br:29])=[CH:28][C:4]=2[N:3]=1>N.CO>[Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[C:26]([Br:30])[C:27]([Br:29])=[CH:28][C:4]=2[N:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Br)c(Br)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Br)c(Br)cc32)[C@H](O)[C@@H]1O

Procedure:
A solution of 569 mg (1 mmole) of (56) in 20 mL of NH3 /MeOH was stirred in a sealed flask at room temperature for 5 hr. Volatile materials were removed by evaporation. The residue was recrystallized from MeOH to give 337 mg (2 crops, 76%) of 57. Its 1H NMR spectrum was identical to that of (57) prepared by a direct bromination; see Method B.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH:35]C(OC(C)(C)C)=O)=[CH:30][CH:29]=2)[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:43]>CO>[ClH:43].[ClH:43].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:34][NH2:35])=[CH:32][CH:33]=2)[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CON=C(C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)c2csc(NC=O)n2)cc1
Agent: Cl
Solvent: CO
Product: NCc1ccc(CON=C(C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)c2csc(N)n2)cc1
Yield: 70.6 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-(4-tert-butoxycarbonylaminomethylbenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.4 g.), conc. hydrochloric acid (0.95 g.) and methanol (15 ml.) were treated in a similar manner to that of Example 4-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-(4-aminomethyl benzyloxyimino)acetamido]-3-cephem-4-carboxylic acid dihydrochloride (syn isomer, 0.9 g.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:7](Cl)(=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[Na+]>CCOCC>[C:7]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])(=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCC(=O)Cl
Reactant: NCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCCCC(=O)NCCC(=O)O

Procedure:
β-Alanine (20 mmol) was reacted with valeryl chloride (22 mmol) in the presence of NaOH (40 mmol) in a mixture of H2 0 and ether using the method described in Example 5. The crude crystalline product (2.75 g, 79%) was recrystallized from a mixture of isopropyl ether (150 ml) and ethyl acetate (10 ml) to give title acid (1.51 g, 44%), m.p. 73°-76° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[NH2:19][C:20]([CH3:39])([CH3:38])[CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:30][C:25]=2[N:24]=[CH:23]1>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][C:20]([CH3:39])([CH3:38])[CH2:21][N:22]2[C:26]3[CH:27]=[CH:28][C:29]([C:31]4[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=4)=[CH:30][C:25]=3[N:24]=[CH:23]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)(N)Cn1cnc2cc(C3=NNC(=O)CC3)ccc21
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Product: CC(C)COCCc1ccc(OCC(O)CNC(C)(C)Cn2cnc3cc(C4=NNC(=O)CC4)ccc32)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isobutoxyethyl)-phenoxy]-2,3-epoxypropane and 6-[1-(2-amino-2,2-dimethylethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.