Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=3)[C:16]([C:24]3[N:25]=[C:26]4[C:32]([C:33]([OH:35])=O)=[CH:31][N:30]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:27]4=[N:28][CH:29]=3)=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:45]([O:49][C:50](=[O:58])[NH:51][CH:52]1[CH2:56][CH2:55][CH:54]([NH2:57])[CH2:53]1)([CH3:48])([CH3:47])[CH3:46].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=3)[C:16]([C:24]3[N:25]=[C:26]4[C:32]([C:33](=[O:35])[NH:57][CH:54]5[CH2:55][CH2:56][CH:52]([NH:51][C:50]([O:49][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:58])[CH2:53]5)=[CH:31][N:30]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:42])[CH3:43])[C:27]4=[N:28][CH:29]=3)=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)C1
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(-c3cnc4c(n3)c(C(=O)O)cn4COCC[Si](C)(C)C)c3ccc(F)cc32)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cn(COCC[Si](C)(C)C)c3ncc(-c4nn(C5CCN(C(=O)OC(C)(C)C)CC5)c5cc(F)ccc45)nc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109 %

Procedure:
A 10 ml round-bottomed flask was charged with 2-[1-(1-tert-butoxycarbonyl-piperidin-4-yl)-6-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (85 mg, 0.14 mmol) and (3-aminocyclopentyl)-carbamic acid tert-butyl ester hydrochloride (50 mg, 0.21 mmol). Then, DMF (1 ml) was added followed by N,N-diisopropylethylamine (0.07 ml, 0.40 mmol) and HATU (59 mg, 0.155 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 12 g silica gel with EtOAc/hexanes (gradient: 0-50% EtOAc) to afford 121 mg (99%) of 4-{3-[7-(3-tert-butoxycarbonylamino-cyclopentylcarbamoyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-6-fluoro-indazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil. The isolated product was determined to be a single diastereomer of unknown relative stereochemistry by NMR analysis.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:49]=[N+:50]=[N-:51])(=O)=O)(C)C.C(O)(=O)C>C1COCC1>[CH3:20][O:19][C:17](=[O:18])[CH:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2])=[CH:15][CH:14]=1)[N:49]=[N+:50]=[N-:51]
Reactant: COC(=O)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C(N=[N+]=[N-])c1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
A solution of methyl 4-(N-BOC-aminomethyl)phenylacetate (9.34 g; 0.033 mol) in THF (100 mL) was stirred under argon at −78° C. and potassium bis(trimethylsilyl)amide (16.7 g, 0.084 mol) in THF (50 mL) was added. After stirring for 30 minutes, 2,4,6-triisopropylbenzene-sulfonyl azide (31.1 g, 0.101 mol) was added as a solid. After 5 minutes, acetic acid (10 mL, 0.175 mol) was added and the reaction warmed to room temperature. The reaction mixture was then partitioned between ethyl acetate (500 mL) and water (500 mL), separated and the organic layer dried (MgSO4). Evaporation of the solvent and purification of the residue by silica gel chromatography afforded the azide (7.1 g, 67%).
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16]C)=[CH:13][CH:14]=2)[CH:9]=[CH:8][N:7]=1.N>ClCCl>[NH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[CH:9]=[CH:8][N:7]=1
Reactant: COc1ccc2c(N)nccc2c1
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: Nc1nccc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 88.2 %

Procedure:
A solution of boron tribromide (18.2 ml, 370 mmol) in 20 ml dichloromethane was added dropwise to a stirred solution of 1-amino-6-methoxyisoquinoline (11.0 g, 63 mmol) in 150 ml of dichloromethane at 10° C. After stirring for 4 days at ambient temperature the reaction mixture was poured into ice and the pH was adjusted to 9 by adding concentrated aqueous ammonia. The precipitated material was collected by filtration and dried in vacuo to give 1-amino-6-hydroxyisoquinoline (8.9 g, 88%), EI-MS: 160 [M]+
Reaction SMILES: [NH:1]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:2]([C:24](O)=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1CCC([N:40]=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.N>C(Cl)Cl.CN(C)C=O>[NH:1]([C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])[C@H:2]([C:24]([NH2:40])=[O:25])[CH2:3][S:4][C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(N)=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of Boc-Cys(Trt)-OH (100 gm) in methylene chloride (1000 ml) at −10 to 0° C., was charged sequentially, a solution of DCC (57.9 g) in methylene chloride (125 ml) and HOBT (34.8 gm) in dimethyl formamide (70 ml). Stirred the solution for 30 minutes at the same temperature and then charged ammonia solution (120 ml). After completion of the reaction the resultant precipitate was filtered and the filtrate was taken and washed with 10% sodium bicarbonate solution. The separated organic layer was concentrated and crystallized the product Boc-Cys(Trt)-NH2 from ethyl acetate and hexane (Yield: 100 g, HPLC Purity 98%, Chiral purity: 99.9% and D-Cys: 0.1%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=O)=[O:6])C>CN(C=O)C.[Pd]>[Cl:14][C:12]1[CH:13]=[C:8]2[C:9](=[CH:10][C:11]=1[Cl:15])[N:16]([OH:18])[C:4](=[O:3])[C:5](=[O:6])[NH:7]2
Reactant: CCOC(=O)C(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2n(O)c1=O
Reaction time: 1.5 h
Yield: 87 %

Procedure:
This compound was prepared using an adaptation of the method of Loev, et al., supra. A mixture of ethyl-N-(4,5-dichloro-2-nitro-phenyl)oxamate (0.307 g, 1 mmol) and 0.04 g of 5% Pd-C in 5 mL of DMF was hydrogenated at 45 psi for 1.5 h. The reaction mixture was filtered and the liquid was added to water (18 mL). A white precipitation formed. The mixture was vacuum filtered. The solid was rinsed with water (5×2 mL), and air dried for 1 h to yield 215.14 mg (0.87 mmol) of 6,7-dichloro-N-hydroxy-1,4-dihydroquinoxaline-2,3-dione as a pale yellow solid (87%). The pale yellow solid (215 mg, 0.87 mmol) was dissolved in 4 mL of DMSO with heating. Water (0.8 mL) was added until precipitation appeared. The mixture was heated again to redissolve the precipitate. The yellow solution was cooled down. Pale yellow crystals came out which were collected by vacuum filtration and rinsed with water (5×2 mL) and dried in vacuum to yield 173 mg (0.70 mmol) of 6,7-dichloro-N-hydroxy-1,4-dihydroquinoxaline-2,3-dione as pale yellow crystals. Mp>300° C. (dec). 1H NMR (300 MHz, DMSO-d6) δ12.244 (br s, 1H, NH), 11.953 (br s, 1H, N--OH), 7.562 (s, 1H, H-8), 7.318 (s, 1H, H-5). HRMS calcd. for C8H4Cl2N2O3, 245.9599; found, 245.9600.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][C:5]=1[CH3:13].Cl.CN(C)CCCN=C=NCC.[CH3:27][Si:28]([CH2:31][NH2:32])([CH3:30])[CH3:29]>ClCCl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:32][CH2:31][Si:28]([CH3:30])([CH3:29])[CH3:27])=[O:9])=[CH:6][C:5]=1[CH3:13]
Reactant: C[Si](C)(C)CN
Reactant: COC(=O)c1ccc(C(=O)O)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NC[Si](C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-terephthalic acid 1-methylester (preparation see WO 2000/021920) (1.43 g) in dichloromethane (10 ml) was added N-(−3-dimethylaminopropyl)-N′-ethylcarbodiimid hydrochloride (1.84 g), N,N-dimethylaminopyridine (0.41 g) and trimethylsilylmethylamine (1 ml). The reaction mixture was stirred at ambient temperature. for 2 hours. The reaction mixture was concentrated and the residue purified by chromatography on silica gel (eluent: ethyl acetate/heptanes 1:3) to give 2-methyl-N-trimethylsilanylmethyl-terephthalamic acid methyl ester (1.85 g). 1H-NMR (400 MHz, CDCl3): 7.72 (d, 1H), 7.45 (s, 1H), 7.40 (d, 1H), 5.85 (s, 1H), 3.78 (s, 3H), 2.84 (d, 2H), 2.49 (s, 3H), 0.00 (s, 9H) ppm. 2-Methyl-N-trimethylsilanylmethyl-terephthalamic acid tert-butyl ester was obtained using a similar procedure. 1H-NMR (400 MHz, CDCl3): 7.82 (d, 1H), 7.48 (s, 1H), 7.39 (d, 1H), 5.70 (s, 1H), 2.82 (d, 2H), 2.48 (s, 3H), 1.48 (s, 9H), 0.00 (s, 9H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>CC1C=CC=CC=1>[Cl:16][CH2:17][CH2:18][CH2:19][C:20]([N:8]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:21]
Reactant: O=C(Cl)CCCCl
Reactant: Fc1ccc(Nc2ccc(F)cc2)cc1
Solvent: Cc1ccccc1
Product: O=C(CCCCl)N(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 2 h
Yield: 95 %

Procedure:
A mixture of 35 parts of 4-fluoro-N-(4-fluorophenyl)benzenamine, 107 parts of 4-chlorobutanoyl chloride and 130 parts of methylbenzene was stirred for 2 hours at reflux temperature. The reaction mixture was washed with a sodium chloride solution, dried, filtered and evaporated. The residue was distilled to remove the excess of 4-chlorobutanoyl chloride, yielding 47 parts (95.0%) of 4-chloro-N,N-bis(4-fluorophenyl)butanamide as a residue (int. 69).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C([O:17][CH:18]=[C:19]([C:25](OCC)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])C.C(OCC)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:7]([C:8]1[CH:13]=[C:12]2[C:11](=[CH:10][CH:9]=1)[NH:14][CH:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]2=[O:17])[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(Cc2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2ccc(Cc3ccccc3)cc2c1=O
Temperature: 110 °C

Procedure:
A mixture of 4-aminodiphenylmethane (20.3 g) and diethyl ethoxymethylenemalonate (24.3 mL) was heated at 110° C. for 3.5 hr under nitrogen. The resulting mixture was diluted with phenyl ether (50 mL) and heated at 220° C. for 7.5 hr. After cooling, ethyl ether was added to the reaction mixture. The precipitate was collected by filtration, and washed with ethyl ether to afford the title compound (12.6 g) as a pale brown powder: mp 265-270° C.; 1H NMR (400 MHz, CDCl3—CD3OD (1:1, v/v)) δ 1.39 (t, J=6.8 Hz, 3H), 4.12 (s, 2H), 4.35 (q, J=6.8 Hz, 2H), 7.14-7.33 (m, 4H), 7.47 (d, J=8.3 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.65-7.75 (m, 2H), 8.23 (s, 1H), and 8.59 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH:16](O)[CH:17]2[CH2:22][CH2:21][O:20][N:19]([CH3:23])[C:18]2=[O:24])[N:6]=1)([CH3:4])[CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:4][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[N:8]=[C:7](/[CH:16]=[C:17]2/[C:18](=[O:24])[N:19]([CH3:23])[O:20][CH2:21][CH2:22]/2)[N:6]=1)([CH3:1])[CH3:3]
Reactant: CN1OCCC(C(O)c2nc(C(C)(C)C)c(O)c(C(C)(C)C)n2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CN1OCC/C(=C\c2nc(C(C)(C)C)c(O)c(C(C)(C)C)n2)C1=O
Yield: 30 %

Procedure:
A mixture of 0.70 g (2.0 mmol) of 4-[[4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]hydroxymethyl]tetrahydro-2-methyl-2H-1,2-oxazin-3-one, Example 7, and 0.040 g (0.20 mmol) of p-toluenesulfonic acid monohydrate in 15 mL of toluene was stirred at reflux for 18 hours. The cooled reaction mixture was evaporated, and the residue was purified by flash chromatography (silica gel, 15% ethyl acetate in hexane elution) to yield 0.20 g (31%) of the title compound, mp 180°-181° C.; 1H NMR (deuteriochloroform) δ 1.46 (s, 18H), 3.36 (s, 3H), 3.46 (m, 2H), 4.21 (m, 2H), 5.25 (s, 1), 7.73 (s, 1H); MS m/e 334 (M+ +1).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[CH2:25][OH:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[Cl:27][C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][N:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>ClCCl.O1CCCC1>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:15])=[O:16])[CH2:11][C@H:10]2[CH2:25][O:26][C:31]2[CH:30]=[N:29][C:28]([Cl:27])=[CH:33][CH:32]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2CO)CC1
Reactant: Oc1ccc(Cl)nc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2COc2ccc(Cl)nc2)CC1
Reaction time: 8 h
Yield: 38.4 %

Procedure:
To a cold mixture (ice bath) of (1R,2R,4S)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-hydroxymethyl-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 155, 28.5 mg), 2-chloro-5-hydroxypyridine (19 mg) and triphenyl phosphine (28 mg) in dichloromethane (1 mL) was added a solution of di-tert-butyl-azodicarboxylate (25 mg) in tetrahydrofuran (1 mL). The reaction mixture was stirred overnight then adsorbed unto silica and was purified by flash chromatography on silica gel with a gradient of cyclohexane:ethyl acetate (4:1 to 1:1 v/v) as eluant to afford the title compound (14 mg, 36%) as a colorless solid. MS (EI): 512.0 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](Cl)=[N:16][N:15]=[CH:14]2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1)=[N:16][N:15]=[CH:14]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: NC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)C1CCN(c2nncc3cc(Br)ccc23)CC1
Yield: 92.7 %

Procedure:
A mixture of the isonipecotamide (71 mg, 554 μmol), 6-bromo-1-chlorophthalazine (Example 1, 90 mg, 370 μmol) and potassium carbonate (51 mg, 370 μmol) in 5 mL acetonitrile was added to a glass microwave reaction vessel. The reaction mixture was stirred and heated in a Smith Synthesizes microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 190° C. for about 20 min. at which the starting material was consumed, by TLC, to form product (M+1=335, 337). The mixture was concentrated and purified by column, eluting with a gradient of 2% 2M ammonia in MeOH/DCM to 10% 2M ammonia in MeOH/DCM to give 1-(6-bromophthalazin-1-yl)piperidine-4-carboxamide (0.115g) as a pale yellow solid. Found MS (ES+): 335, 337(M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:17]([O:21][C:22]([N:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>COCCOC.C(O)C>[C:17]([O:21][C:22]([N:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: O=[N+]([O-])c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1cccc1-c1cccc([N+](=O)[O-])c1
Yield: 51 %

Procedure:
A solution of 1-bromo-3-nitrobenzene (1.5 g 7.42 mmol) in anhydrous 1,2-dimethoxyethane (10 ml) was treated sequentially with 1,1-bistriphenylphosphine palladium II dichloride (260 mg, 0.371 mmol), 2M aqueous sodium carbonate (7.4 ml), and 1-(t-Butoxycarbonyl)pyrrole-2-boronic acid (1.88 g, 8.91 mmol) dissolved in ethanol (10 ml). The reaction was heated under reflux for 5 hours under argon. The solvent was evaporated and the residue dissolved in dichloromethane, washed with water, brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with a mixture of ether/hexane (5:95) to afford the title compound (1.09 g, 51%); MS (ES+) m/e 288 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][CH:18]=[O:19])[C:15](=[O:20])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].[C:21]1([C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N+]=[N-])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.CCOCC>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][CH:18]=[O:19])[C:15](=[O:20])[N:10]2[C:11]=1[C:12]([O:14][CH:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Yield: 40 %

Procedure:
A solution of (6R,7R)-3-acetoxymethyl-7-formamidoceph-3-em-4-carboxylic acid (6.20g, 20 mmole) in dry tetrahydrofuran (150 ml) was stirred with a solution of diphenyldiazomethane (20 mmole; prepared in ether solution, then evaporated) in dry tetrahydrofuran (20 ml) at +20° to +25° for 16 hrs. The solvent was evaporated and the solution of the residue in methylene chloride (150 ml) was washed successively with 2N-hydrochloric acid 3%-aqueous sodium bicarbonate solution. The solution was dried and evaporated leaving a foam which was chromatographed on kieselgel G (250g) in benzeneethyl acetate (9:1, then 1:1). The appropriate fractions were combined, evaporated, and triturated with ethyl acetate to give the title compound as a crystalline solid (3.789g, 8.1 mmole, 40%), m.p. 158.6 to 160.4(cap.); [α]D +32.8; λmax 261 nm (ε7,750); νmax 3410 (NH), 1788 (azetidin-2-one), 1732 (OCOCH3), 1705 (CO2R) and 1698 and 1502 cm-1 (CONH); τ 1.80 (1H,d,J9Hz, NH), 2.70(10H,m, [C6H5 ]CH), 3.03(1H,s, [C6H5 ]2CH), 4.10 (1H, dd,J9 and 4.5Hz, C7 -H), 4.90 and 5.23 (2H, ABq, J14Hz, CH 2 OCOCH3), 5.04 (1H, d, J5Hz, C6 -H), 6.38 and 6.72 (2H, ABq, J18Hz, C2 -H2), 8.00 (3H,s, OCOCH3). (Found: C, 62.1; H, 4.8; N, 5.8; S, 6.9. C24H22N2O6S(466.5) requires C, 61.8; H, 4.8; N, 6.0; S, 6.9%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:22]=[CH:21][C:16]([C:17](OC)=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][NH2:24]>C(O)C>[NH:23]([C:17]([C:16]1[CH:21]=[CH:22][C:13]([C:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:12][CH2:11][CH2:10]2)=[CH:14][CH:15]=1)=[O:18])[NH2:24]
Reactant: NN
Reactant: COC(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)NN)cc2)CCC1

Procedure:
To a solution of methyl 4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)benzoate (14.8 g, 48 mmol) in ethanol (100 mL) was added hydrazine (12 mL). The reaction mixture was stirred at reflux for 48 hours. The mixture was concentrated in vacuo and the residue was suspended ether (100 mL) and hexanes (50 mL). The suspension was stirred at room temperature for 2 hours and the solid was filtered off and dried under vacuum. The tert-butyl (1-(4-(hydrazinecarbonyl)phenyl)cyclobutyl)carbamate was obtained as a white solid (13.2 g, 89%). M.p.=146-147° C.; 400 MHz 1H NMR (DMSO-d6) δ: 9.70 (s, 1H), 7.75 (d, J=7.6 Hz, 2H), 7.67 (br.s, 1H), 7.42 (d, J=8.4 Hz, 2H), 4.51 (br.s, 2H), 2.37 (br.s, 4H), 2.1-1.9 (m, 1H), 1.85-1.7 (m, 1H), 1.33 (br.s, 9H); LCMS [M+H]: 306.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[C:9](Br)[CH:10]=2)[S:5][CH2:4][CH2:3]1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>[Pd+2].[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[C:9]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc2c(cc1Br)C(C)(C)CCS2
Agent: Cl[Pd]Cl
Agent: [Pd+2]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1C#C[Si](C)(C)C)C(C)(C)CCS2
Temperature: 85 °C
Reaction time: 15 h

Procedure:
A mixture of 624 mg (3.0 mmol) of 4,4,7-trimethyl-6-bromothiochroman (Compound 66) 314 mg (3.2 mmol) of trimethylsilyl acetylene, 40 mg (0.21 mmol) of cuprous iodide, 80 mg (0.11 mmol) of bis (triphenylphosphin) palladium (II) chloride and 1 ml of triethylamine was degassed under nitrogen and heated in a sealed tube at 85 degrees C. for 15 h. The mixture was then treated with a further 20 mg (0.11 mmol) of cuprous iodide and 40 mg (0.06 mmol) of the palladium (II) catalyst. The mixture was then heated under a nitrogen atmosphere in the sealed tube at 100 degrees C. for a further 64 h. The triethylamine was then removed under vacuum and the residue purified by flash chromatography (silica; hexanes) to give the title compound as a yellow oil. PMR (CDCl3): & 0.28 (9H, s), 1.30 (6H, s), 1.88-1.97 (2H, m), 2.33 (3H, s), 2.97-3.05 (2H, m), 6.92 (1H, s), 7.43 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:17][S:18]([O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([CH2:29]Br)[CH:23]=1)(=[O:20])=[O:19].CCOC(C)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:29][C:24]2[CH:23]=[C:22]([O:21][S:18]([CH3:17])(=[O:20])=[O:19])[CH:27]=[CH:26][C:25]=2[Cl:28])[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Oc1ccc(Cl)c(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(OS(C)(=O)=O)ccc2Cl)C(=O)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of piperazin-3-one-1-carboxylic acid tert-butyl ester (7.10 g, 35.3 mmol) in dry DMF (200 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 2.10 g, 53.0 mmol). The reaction mixture was stirred for 15 min, and then a solution of the benzylbromide from Step B (10.0 g, 35.3 mmol) in DMF (50 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature overnight. The reaction was poured into EtOAc (300 ml), and washed with H2O (3×50 ml). The organic layer was dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (60% ethyl acetate/hexane) to provide the title compound as a yellow oil.