Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][N:21]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:3]=12.[CH:29]1([S:32](Cl)(=[O:34])=[O:33])[CH2:31][CH2:30]1>N1C=CC=CC=1>[CH2:22]([N:21]1[C:3]2=[C:2]([NH:1][S:32]([CH:29]3[CH2:31][CH2:30]3)(=[O:34])=[O:33])[C:7]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=3[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCN2Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC2)c2n(c1=O)CCN2Cc1ccccc1
Yield: 6.7 %

Procedure:
Following the procedure set forth for the preparation of Example 1A, 8-amino-1-benzyl-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one (250 mg, 0.001 mol) in pyridine (4 mL) was reacted with cyclopropanesulfonyl chloride (144 mg, 0.001 mol) to afford the crude product. Purification by column chromatography on silica gel (80% ethylacetate in hexane) afforded 40 mg of the product (13.2% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11](Cl)=[N:10]1.[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)=[N:10]1
Reactant: c1nc[nH]n1
Reactant: CCOC(=O)C1=C(C)NC(Cl)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(C)NC(n2cncn2)=NC1c1ccc(F)cc1Br
Yield: 60 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-2-chloro-6-methyl-1,4-dihydropyrimidine-5-carboxylate (15.04 g, 40 mmol) was reacted with 1H-1,2,4-triazole (8.28 g, 120 mmol) according to the procedure as described in Example 48, Step A to give the title compound as a yellow solid (9.8 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: N(C([C:6]1[CH2:10][S:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[C:7]=1[N:23]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:24](=[O:26])[CH3:25])=O)=[N+]=[N-].[C:32]([N:37](C1C(CCCCC(N2CCCCC2)=O)SCC=1N=C=O)C(=O)C)([O:34][CH2:35]C)=[O:33]>CO>[C:27]([N:23]([C:7]1[CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[S:9][CH2:10][C:6]=1[NH:37][C:32]([O:34][CH3:35])=[O:33])[C:24](=[O:26])[CH3:25])([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)N(C(C)=O)C1=C(C(=O)N=[N+]=[N-])CSC1CCCCC(=O)N1CCCCC1
Reactant: CCOC(=O)N(C(C)=O)C1=C(N=C=O)CSC1CCCCC(=O)N1CCCCC1
Solvent: CO
Product: CCOC(=O)N(C(C)=O)C1=C(NC(=O)OC)CSC1CCCCC(=O)N1CCCCC1
Reaction time: 5 h
Yield: 85 %

Procedure:
2.8 g (.006 moles) of 4-azidocarbonyl-3-(N-carbethoxyacetamido)-2,5-dihydro-2-thiophenevaleric acid piperidide was dissolved in 50 ml. of methanol and brought slowly up to reflux over a 15 minute period. The reaction was allowed to proceed for 5 hrs. at this temperature. Formed as an intermediate in the reaction mixture was 3-(N-carbethoxyacetamido)-4-isocyanato-2,5-dihydro-2-thiophenevaleric acid piperidide. The methanol was then removed, and 2.33 g. (0.0056 mole, 85%) of 3-(N-carbethoxyacetamido)-4-carbomethoxyamino-2,5-dihydro-2-thiophenevaleric acid piperidide was obtained as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][CH:4]=1.[C:20](Cl)(=[O:22])[CH3:21].CN(C)C(=O)C>O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:8]=1)[C:20](=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: CNc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)N(C)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A mixture of 2-(6-methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.20 g, 0.74 mmol), acetyl chloride (0.18 g, 2.22 mmol) and N,N-dimethylacetamide (10 ml) was stirred at 80° C. for 1 hr. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated. The residue was recrystallized from tetrahydrofuran-hexane to give the titled compound (0.20 g, 86%).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH2:7]([O:14][C:15](=[O:35])[NH:16][CH:17]1[CH2:29][C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:30][C:31]([F:34])([F:33])[F:32])[CH:26]=3)[NH:21][C:20]=2[CH2:19][CH2:18]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[N:39]=1>CN(C=O)C.CCOC(C)=O>[CH2:7]([O:14][C:15](=[O:35])[NH:16][CH:17]1[CH2:29][C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:30][C:31]([F:34])([F:32])[F:33])[CH:26]=3)[N:21]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[N:39]=3)[C:20]=2[CH2:19][CH2:18]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Fc1cccc(CBr)n1
Reactant: O=C(NC1CCc2[nH]c3ccc(OC(F)(F)F)cc3c2C1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NC1CCc2c(c3cc(OC(F)(F)F)ccc3n2Cc2cccc(F)n2)C1)OCc1ccccc1
Temperature: 50 °C
Yield: 56.2 %

Procedure:
Add Cs2CO3 (6.44 g, 19.8 mmol) to a solution of (6-trifluoromethoxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carbamic acid benzyl ester (Preparation 43) (4.00 g, 9.88 mmol) and 2-bromomethyl-6-fluoropyridine (Preparation 44) (3.11 g, 13.8 mmol) in DMF (40 mL). Heat the resulting mixture to 50° C. for 18 h and then dilute with EtOAc (120 mL). Wash the organics with water (3×40 mL), dry (MgSO4), filter, and concentrate to give the crude product (5.40 g) as a brown oil. Purify the crude product on silica gel (120 g) eluting with 2545% EtOAc/hexanes to afford 2.85 g (56%) of the title compound as a tan oil. MS (ES): m/z 514 (M+1); HPLC (Method A): Rt=4.54 min (95%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[C:18]([NH:28]C(OCC)=O)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[Cl-].[NH4+]>CO>[NH2:28][C:18]1[N:17]=[C:16]([NH:15][C@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]2[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=1
Reactant: CCOC(=O)Nc1nc(N[C@H]2CCCC[C@H]2NC(=O)OC(C)(C)C)c2cc(OC)ccc2n1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CO
Product: COc1ccc2nc(N)nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
A solution of 300 mg of cis-N-tert-butoxycarbonyl-2-(2-ethoxycarbonylamino-6-methoxyquinazolin-4-yl)aminocyclohexylamine in 10 mL of methanol was combined with a 50 mg of potassium hydroxide powder, and stirred at room temperature for 3 hours. The reaction solution was neutralized by addition of a saturated aqueous solution of ammonium chloride, and then extracted with chloroform and dried. After the solvent was distilled off, the residue was purified by column chromatography on silica gel (chloroform:methanol=10:1) to obtain 250 mg of the desirable compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].CO.[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25]>C(N(CC)CC)C>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH:25][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CN(C)CCCN
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1NCCCN(C)C

Procedure:
139 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester (0.5 Mol.) of Example 1a are dissolved in about 500 ml. of methanol. 60 g. of triethylamine are added and the solution is heated at reflux temperature. At this point, 50.1 g. of [3-(dimethylamino)propyl]amine are added dropwise. After the addition is completed, heating is continued for ten minutes. The solvent is removed in vacuo and the residue is suspended in 200 ml. of water. The aqueous mixture is made alkaline with 10% sodium hydroxide solution and extracted three times with 200 ml. portions of ethyl acetate. The organic layer is dried over calcium chloride, evaporated to dryness and crystallized with petroleum ether to obtain 4-[[3-(dimethylamino)propyl]amino]-6-chloro-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester, yield: 102 g. (59%); m.p. 20°.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=O.[C:16]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:18])[CH3:17]>O1CCOCC1>[O:18]=[C:16]([CH3:19])[CH:17]=[CH:1][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc2c(C=O)c[nH]c2c1
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C=CC(C)=O)c[nH]c2c1
Yield: 17 %

Procedure:
To a stirred solution of methyl 3-formylindole-6-carboxylate (368 mg) in 1,4-dioxane (10 ml) was added acetylmethylene triphenylphosphorane (1.15 g), and the mixture was stirred under reflux for 12 hours. The resulting mixture was evaporated in vacuo, redissolved with ethyl acetate and washed with 1N hydrochloric acid and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of chloroform and ethyl acetate (1:2) to give methyl 3-(3-oxo-1-butenyl)indole-6-carboxylate (75 mg) as a solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([N:15](CC1C=CC(OC)=CC=1OC)[C:16]1[S:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].[Cl:38][C:39]1[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][C:40]=1B(O)O.O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:38][C:39]1[CH:44]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:42]=[CH:41][C:40]=1[C:10]1[CH:11]=[CH:2][CH:3]=[C:8]2[C:9]=1[CH:4]=[CH:5][C:6]([S:12]([NH:15][C:16]1[S:20][N:19]=[CH:18][N:17]=1)(=[O:13])=[O:14])=[CH:7]2
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cccc3c2)c(OC)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1ncns1)c1ccc2c(-c3ccc(C(F)(F)F)cc3Cl)cccc2c1
Temperature: 100 °C
Yield: 10 %

Procedure:
A pressure vessel was charged with 5-bromo-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (Intermediate D) (110 mg, 0.211 mmol), potassium carbonate (146 mg, 1.057 mmol), (2-chloro-4-(trifluoromethyl)phenyl)boronic acid (56.9 mg, 0.254 mmol), tetrakis(triphenylphosphine)palladium(0) (24.42 mg, 0.021 mmol), dioxane (1409 μl) and water (705 μl). The reaction was heated in a microwave at 100° C. for 30 min. The mixture was then cooled to room temperature and the organic layer was separated from the aqueous layer by pipet. The resulting organic layer was then injected as is onto a reverse phase HPLC (Column: Gemini 150×30 mm, 5 μm, Phenomenex, Torrance, Calif., Flow rate: 40 mL/min, Mobile phase: 0.1% TFA in ACN and water). The fractions containing product were combined and saturated aq. NaHCO3 (15 mL) was added. The aqueous layer was washed with ethyl acetate (1×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under a vacuum to provide 5-(2-chloro-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (10 mg, 0.021 mmol) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.22 (d, J=8.90 Hz, 1H) 7.36 (dd, J=7.09, 1.03 Hz, 1H) 7.43-7.58 (m, 4H) 7.65 (d, J=7.92 Hz, 1H) 7.85 (s, 1H) 7.99-8.09 (m, 2H) 8.31 (d, J=1.76 Hz, 1H); m/z (ESI) 470 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:3]1=[O:23].[CH2:24]([O:26][C:27](=[O:50])[C@H:28](OS(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)[CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[CH3:25].CN1CCOCC1>>[CH2:24]([O:26][C:27]([C@@H:28]([NH:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:3]1=[O:23])[CH2:29][CH2:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)=[O:50])[CH3:25]
Reactant: CCOC(=O)[C@@H](CCC1CCCCC1)OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC1CCc2ccccc2N(Cc2ccc([N+](=O)[O-])cc2)C1=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H](CCC1CCCCC1)N[C@@H]1CCc2ccccc2N(Cc2ccc([N+](=O)[O-])cc2)C1=O

Procedure:
The reaction of 15 g of 3-amino-1-(p-nitrobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one with 22.1 g of (R)-alpha-[[(4-nitrophenyl)sulfonyl]oxy]-4-cyclohexylbutyric acid ethyl ester and 6.45 ml N-methylmorpholine yields the two diastereoisomeric esters 3-(S)-[(1-(S)-ethoxycarbonyl-3-cyclohexyl-propyl)-amino]-1-(p-nitrobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one and 3-(R)-[(1-(S)-ethoxycarbonyl-3-cyclohexyl-propyl)-amino]-1-(p-nitrobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one. Rf values (eluant ethyl acetate/hexane 1:2) non-polar component 0.78, polar component 0.69.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][N:14]2[CH2:18][C@H:17]([CH:19]([CH3:21])[CH3:20])[N:16]([C:22]3[CH:27]=[CH:26][N:25]4[N:28]=[CH:29][C:30]([C:31]5[CH:36]=[CH:35][C:34]([C:37]6[N:41]=[CH:40][N:39]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[N:38]=6)=[CH:33][CH:32]=5)=[C:24]4[N:23]=3)[C:15]2=[O:50])(=O)=O)=CC=1.Cl.[F:52][C@@H:53]1[CH2:57][CH2:56][NH:55][CH2:54]1.C(N(C(C)C)C(C)C)C.[OH-].[Na+]>CN(C=O)C>[F:52][C@@H:53]1[CH2:57][CH2:56][N:55]([CH2:12][CH2:13][N:14]2[CH2:18][C@H:17]([CH:19]([CH3:20])[CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][N:25]4[N:28]=[CH:29][C:30]([C:31]5[CH:32]=[CH:33][C:34]([C:37]6[N:41]=[CH:40][N:39]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:47])([CH3:48])[CH3:49])[N:38]=6)=[CH:35][CH:36]=5)=[C:24]4[N:23]=3)[C:15]2=[O:50])[CH2:54]1
Reactant: Cc1ccc(S(=O)(=O)OCCN2C[C@H](C(C)C)N(c3ccn4ncc(-c5ccc(-c6ncn(COCC[Si](C)(C)C)n6)cc5)c4n3)C2=O)cc1
Reactant: F[C@@H]1CCNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[C@H]1CN(CCN2CC[C@@H](F)C2)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 40.2 %

Procedure:
To a solution of (S)-2-(4-isopropyl-2-oxo-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-1-yl)ethyl 4-methylbenzenesulfonate (0.070 g, 0.098 mmol) in DMF was added (R)-3-fluoropyrrolidine hydrochloride (0.044 g, 0.49 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.13 g, 0.98 mmol) and the reaction stirred for 4 days at ambient temperature. The reaction was poured into 1N NaOH and the aqueous layer extracted into EtOAc. The organics were washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The crude material was chromatographed using EtOAc to 3% MeOH/dichloromethane as eluent to yield (S)-1-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-4-isopropyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (0.025 g, 40%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH:10]=2)O1.Cl[C:21]1[CH:22]=[CH:23][C:24]([N+:29]([O-:31])=[O:30])=[C:25]([O:27][CH3:28])[CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:28][O:27][C:25]1[CH:26]=[C:21]([C:9]2[CH2:18][CH2:17][C:12]3([O:13][CH2:14][CH2:15][O:16]3)[CH2:11][CH:10]=2)[CH:22]=[CH:23][C:24]=1[N+:29]([O-:31])=[O:30]
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C2=CCC3(CC2)OCCO3)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
To a stirred solution of 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dioxaspiro[4.5]dec-7-ene (1.09 g, 4.13 mmol) in dioxane (17 mL) was added 5-chloro-2-nitroanisole (0.64 g, 3.44 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.12 g, 0.17 mmol) and 1.0 M Na2CO3 in H2O (10.32 mL, 10.32 mmol). The mixture was degassed by purging the reaction flask with vacuum/then N2 back-fill (5×). Under N2 the reaction was then heated to 80° C. and stirred overnight (approximately 16 h). The reaction was cooled to rt and diluted with EtOAc, then filtered through Celite, washing with EtOAc. The filtrate was concentrated under vacuum. The residue was taken up in EtOAc and H2O. The H2O layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, then concentrated and purified by silica gel chromatography to give the title compound of step C (911 mg, 3.13 mmol, 91%) as an amber oil. MS (ESI): 292 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[N:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>O1CCOCC1>[ClH:25].[ClH:25].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[N:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cnc3ccccc3c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2ncc(NC3CCNCC3)cc2c1

Procedure:
A solution of 4-(quinolin-3-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.77 g, 5.41 mmol) in dioxane (20 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 228.6 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:13]([NH:14][C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[O:16])[C:12](=[O:28])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10].ClS([N:33]=[C:34]=[O:35])(=O)=O>C(#N)C>[C:34]([O:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:13]([NH:14][C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[O:16])[C:12](=[O:28])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10])(=[O:35])[NH2:33]
Reactant: O=C(NC1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H]2SC1

Procedure:
3-Hydroxymethyl-7-(p-nitrobenzyloxycarbonylamino) 3-cephem-4-carboxylic acid (2.0 g.; 5 m. mole) was suspended in dry acetonitrile (100 ml) and with stirring was cooled to 0°-5° C. under nitrogen. Chlorosulphonylisocyanate (1.1 ml.; 12.5 m. mole) was added dripwise under nitrogen giving a clear solution almost immediately after the addition. The solution was stirred for 1 hour at 0°-5° C. and evaporated to dryness. The resulting gum was dissolved in aqueous sodium bicarbonate such that the final solution was at pH 1.5. This aqueous solution (150 ml) was layered with ethyl acetate (200 ml) and the mixture was stirred at 20° C. for 18 hours. The ethyl acetate layer was separated, washed with brine, dried over magnesium sulphate and evaporated to dryness to give 3-carbamoyloxymethyl-7-(p-nitrobenzyloxycarbonylamino)-3-cephem-4-carboxylic acid as a cream powder (1.73 g.; 77% of theory). Thin layer chromatography in chloroform, acetone, acetic acid (50:50:7) revealed a single spot at Rf =0.11. δ (DMSO) 8.64 (1H, d, CONH), AA'BB' 8.3 and ##STR13## 6.54 (2H, S, --CONH2 exchanges D2O), 5.55 (2H, m, H7 and α-protons), 5.28 (2H, s, benzylic CH2), 5.12 (1H, d, H6), AB quartet 4.9 and 4.6 (2H, 3-CH2), and 3.55 (2H, s, S-CH2 --), γ max (nujol) 1780 (β-lactam C=O) 1710 (broad), 1520 (NO2)cm-1 ; λ max (EtOH) 266 nm (εm 16220).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH3:24][C:25]1[N:34]([CH2:35][C:36]#[CH:37])[C:33](=[O:38])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:37]#[C:36][CH2:35][N:34]3[C:33](=[O:38])[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]3[CH3:24])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: C#CCn1c(C)nc2ccccc2c1=O
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=NC2
Product: Cc1nnc2n1-c1ccc(C#CCn3c(C)nc4ccccc4c3=O)cc1C(c1ccccc1F)=NC2
Yield: 57 %

Procedure:
This compound was obtained by coupling 6-(2-fluorophenyl)-8-iodo-1-methyl-4H-[1,2,-4]triazolo[4,3-a][1,4]benzodiazepine with 2-methyl-3-(2-propynyl)-4(3H)-quinazolinone [ref. B. Danielsson, L. Kronberg and B. Akerman, Acta Pharm. Suecica, 6, 379, (1969)] as described in ex. 17. It was isolated in 57% yield and crystallized from ethyl acetate. m.p. 241°-244° C. with decomposition. The crystals contained 0.66 molar amounts of water.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:13][C@H:12]([CH2:14]O)[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:10]1[CH2:23][OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>C1COCC1>[C:19]([O:18][C:16]([N:11]1[CH:10]2[CH:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH:12]1[CH2:14][O:24][CH2:23]2)=[O:17])([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CO)CC(OCc2ccccc2)[C@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2COCC1C(OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a solution of tert-butyl (2R,5R)-3-benzyloxy-2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate (1.15 g, 3.4 mmol) in THF (50 mL) was added NaH (60%, 0.409 g, 10.2 mmol). The mixture was stirred at room temperature for 30 minutes and cooled to 0° C. A solution of p-TsCl (0.65 g, 3.4 mmol) in THF (5 mL) was slowly added to the mixture. The reaction mixture was then stirred at room temperature for 12 hours and quenched by sat. NH4Cl solution (20 mL). The mixture was concentrated in vacuo, and the residue was taken up with water and EtOAc. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water and brine and dried over Na2SO4. The organic solvent was removed in vacuo to give the crude product, which was purified by flash chromatography on silica gel to give 6-benzyloxy-3-oxa-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (716 mg, 66%) as an off-white solid. 1H NMR (CDCl3, 300 MHz): 7.35-7.27 (m, 5H), 4.59-4.43 (m, 2H), 4.38-4.07 (m, 3H), 3.73-3.56 (m, 3H), 3.47 (t, 1H, J=9.8 Hz), 2.27 (m, 1H), 1.96 (m, 1H), 1.48 (s, 4.5H), 1.44 (s, 4.5H).