Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[S:10][C:9]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:21]([Cl:25])(=O)(=[O:23])[OH:22]>[OH-].[Na+]>[CH:1]1([C:6]2[S:10][C:9]([NH:11][C:12]([C:13]3[CH:18]=[C:17]([S:21]([Cl:25])(=[O:23])=[O:22])[CH:16]=[CH:15][C:14]=3[F:19])=[O:20])=[N:8][N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Nc1nnc(C2CCCC2)s1)c1ccccc1F
Reactant: O=S(=O)(O)Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(Nc1nnc(C2CCCC2)s1)c1cc(S(=O)(=O)Cl)ccc1F
Temperature: 200 °C

Procedure:
3-{[(5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}-4-fluorobenzenesulfonyl chloride was prepared from N-(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-2-fluorobenzamide using a Biotage Initiator 8 microwave set to high absorbance as follows. Using conditions described, the reaction reached a pressure of 12 barr. The pressure was reduced to 3 barr after cooling and was vented prior to decapping the reaction vessel. To a 5 ml Biotage microwave reaction tube was added N-(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-2-fluorobenzamide (0.305 g, 1.05 mmol) and a Teflon covered magnetic stir-bar. To this was added 2 ml of chlorosulfuric acid. The vessel was capped and heated to 200° C. for 3.25 min. After cooling to room temperature, the remaining pressure was vented into a 50 ml syringe and discharged into 30 ml 1M NaOH. Reaction was quenched by adding dropwise to 30 ml of crushed ice-water while stirring. The solid product was collected by vacuum filtration, washed with water (5 ml, 3×) and air-dried under vacuum, yielding 3-{[(5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}-4-fluorobenzenesulfonyl chloride as a off white solid (290 mg, 71%), Crude product was used to next step.
Reaction SMILES: OC1(C2C=CC=CC=2)[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[O:21][C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[N:19][C:18]=3[C:28]([F:31])([F:30])[F:29])=[O:16])=[CH:10][CH:9]=2)CC1.N[C:39]1C=C2C(=NC=1)NC=C2>>[NH:5]1[C:8]2=[N:13][CH:12]=[C:11]([NH:14][C:15]([C:17]3[O:21][C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH:24]([CH3:39])[CH2:23]4)=[N:19][C:18]=3[C:28]([F:30])([F:31])[F:29])=[O:16])[CH:10]=[C:9]2[CH:7]=[CH:6]1
Reactant: Nc1cnc2[nH]ccc2c1
Reactant: O=C(Nc1ccc(N2CCC(O)(c3ccccc3)CC2)nc1)c1oc(N2CCCCC2)nc1C(F)(F)F
Product: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3cnc4[nH]ccc4c3)o2)C1

Procedure:
Compound 54 was prepared by the general procedure for compound 1, by using compound A-10 and 5-amino-7-azaindole as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 11.67 (s, 1H), 10.21 (s, 1H), 8.37 (s, 1H), 8.23 (s, 1H), 7.50 (s, 1H), 6.46 (m, 1H), 4.13 (m, 2H), 3.07 (m, 1H), 2.75 (t, 1H, J=11.7 Hz), 1.77 (m, 2H), 1.67 (m, 1H), 1.54 (m, 1H), 1.15 (m, 1H), 0.94 (d, 3H, J=6.3 Hz). MS (M+1): 394.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[NH:13][CH2:12][CH2:11]3)[C@H:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.I[C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2>>[CH3:1][C:2]1([CH3:25])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[N:13]([C:27]2[CH:28]=[CH:29][CH:30]=[C:31]4[C:36]=2[N:35]=[CH:34][CH:33]=[CH:32]4)[CH2:12][CH2:11]3)[C@H:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Ic1cccc2cccnc12
Reactant: CC1(C)OC(=O)N(c2ccc3c(c2)CCNC3=O)[C@H]1c1ccccc1
Product: CC1(C)OC(=O)N(c2ccc3c(c2)CCN(c2cccc4cccnc24)C3=O)[C@H]1c1ccccc1
Yield: 68.6 %

Procedure:
The title compound was prepared as described in General Scheme A substituting (S)-5,5-dimethyl-3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-phenyloxazolidin-2-one and 8-iodoquinoline (commercially available from Synthonix, Wake Forest, N.C.). The final reaction mixture was filtered through Celite® brand filter aid with MeOH and DCM, concentrated, and purified (ISCO: 5 g cartridge, 12 g column, 0 to 40 to 80 to 100% EtOAc-heptanes) giving (S)-5,5-dimethyl-3-(1-oxo-2-(quinolin-8-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-phenyloxazolidin-2-one (68.1 mg, 0.147 mmol, 68.6% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.85-8.89 (m, 1H), 8.41-8.46 (m, 1H), 7.96-8.01 (m, 1H), 7.77-7.81 (m, 1H), 7.71-7.76 (m, 1H), 7.62-7.69 (m, 2H), 7.52-7.59 (m, 1H), 7.37-7.46 (m, 3H), 7.22-7.36 (m, 3H), 5.54-5.58 (m, 1H), 3.80-4.09 (m, 2H), 3.10-3.18 (m, 2H), 1.66 (s, 3H), 0.93 (s, 3H). m/z (ESI) 464.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[O:4][CH2:5][C:6]#[N:7].[F:12][C:13]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[CH:15][C:14]=1[C:28]1[CH:29]=[N:30][C:31]([NH2:34])=[N:32][CH:33]=1>>[NH2:34][C:31]1[N:32]=[CH:33][C:28]([C:14]2[CH:15]=[CH:16][C:17]([C:2]3[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=3[O:4][CH2:5][C:6]#[N:7])=[CH:18][C:13]=2[F:12])=[CH:29][N:30]=1
Reactant: N#CCOc1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: N#CCOc1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-(2-bromophenoxy)acetonitrile and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C18H13FN4O, 320.11; m/z found, 320.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J=1.5, 2H), 7.60-7.56 (m, 1H), 7.46-7.34 (m, 4H), 7.26 (d, J=8.0, 1H), 7.18-7.14 (m, 1H), 6.87 (s, 2H), 5.18 (s, 2H).
Reaction SMILES: NC[CH:3]1[CH2:11][CH2:10][CH:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4]1([CH3:13])[CH3:12].[CH:14]([N:17](CC)C(C)C)(C)C>C(O)C>[C:14]([CH:11]1[CH2:10][CH:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4]([CH3:12])([CH3:13])[CH2:3]1)#[N:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC1(C)C(CN)CCC2CCCN21
Solvent: CCO
Product: CC1(C)CC(C#N)CC2CCCN21
Yield: 74.8 %

Procedure:
(±) Equatorial aminomethyl-2,2-dimethylazabicyclo[4.3.0]nonane (0.1 g, 0.0006 mole) was treated with mutilin 14-toluenesulfonyloxyacetate (0.25 g, 0.0005 mole), (K Riedl, J Antibiotics 29 (2), 133, 1976) and N,N-diisopropylethylamine (0.1 ml, 0.0006 mole) in ethanol (20 ml) and heated under reflux for 6 hours. The mixture was then concentrated in vacuo and the residue partitioned between saturated sodium hydrogen carbonate solution and dichloromethane. The organics were separated and dried (Na2SO4). Chromatography on silica gel eluting with chloroform/methanol/35% ammonia solution (90:9:1) gave the title compound 0.08 g, (31%); 1H NMR (CDCl3) 0.71 (3H, d, J 6.5 Hz) 0.90 (3H, d, J 6.5 Hz), 0.95 (3H, s), 1.25-2.55 (38H, m), 2.85-2.97 (1H, m), 3.19-3.39 (2H, m), 5.15 (1H, d, J 16.5 Hz), 5.31 (1H, d, J 11.1 Hz), 5.78 (1H, d, J 8.6 Hz), 6.50 (1H, dd, J 15.0 and 11.1 Hz). MS (+ve ion electrospray) m/z 543 (MH+, 100%).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].N1C=CN=C1.[CH3:19][C:20]([Si:23](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:22])[CH3:21]>CN(C)C=O>[Si:23]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])([C:20]([CH3:22])([CH3:21])[CH3:19])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCCOCCOCCOCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCOCCOCCOCCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
A mixture of tetra(ethylene glycol) 9 (5.00 mL, 28.7 mmol) and imidazole (2.91 g, 42.6 mmol) was dissolved in 10 mL of N,N-dimethylformamide (DMF). TBDPSCl (7.80 mL, 29.4 mmol) was added to the solution dropwise over a 30 min-period using a syringe with an additional amount of DMF (total 20 mL) being added to avoid the reaction mixture becoming cloudy. The reaction was stirred at room temperature for 16 h. DMF was removed under reduced pressure and the crude product was chromatographed (SiO2, gradient, hexane/EtOAc 1:1 to 2:3) to give 6.05 g (14.0 mmol, 49%) of 10 as a light colorless oil. Rf 0.21 (hexane/EtOAc 1:1); 1H NMR (400 MHz, CDCl3) δ 7.68 (m, 4H, H-2 of phenyl), 7.44-7.35 (m, 6H, H-3 and H-4 of phenyl), 3.81 (t, 2H, J=5.5 Hz, CH2OSi), 3.71 (m, 2H, HOCH2CH2), 3.68-3.58 (m, 12H, HOCH2CH2(OCH2CH2)2OCH2CH2), 2.46 (br s, 1H, OH), 1.05 (s, 9H, C(CH3)3); MS (ESI) Calcd for C24H36O5SiNa (M+Na+): 455.2. Found: 455.2.
Reaction SMILES: Cl[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]2[C:13]([CH3:16])=[N:14][O:15][C:5]=2[C@H:4]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.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>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:6]3[C:13]([CH3:16])=[N:14][O:15][C:5]=3[C@H:4]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:3]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)C[C@@H]1N=C(Cl)c2ccccc2-c2c(C)noc21
Reactant: OB(O)c1ccc(Cl)cc1
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: [Na+]
Solvent: O
Product: COC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2ccccc2-c2c(C)noc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a 100 mL round bottom flask containing methyl 2-((4S)-6-chloro-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate (0.4701 g, 1.543 mmol) was added Pd(PPh3)4 (0.095 g, 0.082 mmol) and 4-chlorophenylboronic acid (0.393 g, 2.51 mmol). The flask was evacuated and purged with N2 (g) (3×), followed by addition of toluene (10 mL) and another cycle of evacuation and purging with N2 (g). To the heterogeneous mixture was added aqueous sodium carbonate (2.4 mL, 4.80 mmol, 2 M) in one portion and the flask was heated to 80° C. After ˜30 min, the reaction mixture was cooled to room temperature and diluted with water. The aqueous layer was extracted with EtOAc (3×), dried over Na2SO4, and concentrated to give a dark orange oil. The oil was purified on Biotage system (5% EtOAc:95% Hexanes to 35% EtOAc:65% Hexanes, then isocratic 35% EtOAc:65% Hexanes). The product methyl 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate (0.444 g, 1.166 mmol, 76% yield) was obtained as yellow foam after drying. LC/MS m/z 381 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[C:8]([CH3:15])([CH2:11][C:12]([CH3:14])=[CH2:13])[CH2:9][OH:10].CC1C=CC(S(O)(=O)=O)=CC=1>CCCCCCC>[CH3:13][C:12]1([CH3:14])[CH2:11][C:8]([CH3:15])([CH:3]2[CH2:4][CH:5]=[C:6]([CH3:7])[C:2]2([CH3:16])[CH3:1])[CH2:9][O:10]1
Reactant: C=C(C)CC(C)(CO)C1CC=C(C)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCC
Product: CC1=CCC(C2(C)COC(C)(C)C2)C1(C)C
Yield: 96.8 %

Procedure:
A 1 liter 3 neck round bottomed flask was charged with 600 ml of heptane, 155.3 g of 2-(2,2,3-trimethylcyclopent-3-en-1-yl)-2,4-dimethyl-4-pentenol at 97.7% (0.68 mole) and 0.9 g of p-TSA. The batch was refluxed under nitrogen for 26 hours. Then batch was cooled and washed with 500 ml of 10% sodium carbonate, 500 ml of water and 500 ml of brine. The batch was dried with magnesium sulfate, filtered, and concentrated in vacuo to afford 163.3 g of crude product. Distillation of the product afforded 150.3 g of purified product (92.7%). BP 84° C./0.5 mmHg; 1H-NMR (300 MHz), δ 0.92 (3H, s), 1.10 (3H, s), 1.20 (3H, s), 1.25 (3H, s), 1.33 (3H, s), 1.55 (4H, sharp m), 1.81-1.99 (2H, m), 2.16 (2H, br m), 3.60 (2H, AB quintet J=8.7 Hz), 5.24 (1H, s); 13C-NMR (75 MHz), δ 12.35, 22.03, 24.57, 25.66, 28.69, 29.96, 32.48, 47.38, 48.36, 50.58, 57.22, 77.63, 80.60, 121.20, 148.01; IR (Neat), 3020, 2980, 1450, 1060 cm-1 ; MS (m/e), 222 (M+), 207, 191, 95, 43;
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]([C:6]1[NH:7][C:8]([C@@H:11]([NH:13]C(OC(C)(C)C)=O)[CH3:12])=[N:9][CH:10]=1)=[O:5]>Cl.O1CCOCC1>[ClH:1].[CH3:2][O:3][C:4]([C:6]1[NH:7][C:8]([C@@H:11]([NH2:13])[CH3:12])=[N:9][CH:10]=1)=[O:5]
Reactant: COC(=O)c1cnc([C@H](C)NC(=O)OC(C)(C)C)[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cnc([C@H](C)N)[nH]1
Yield: 104.6 %

Procedure:
A solution of 2-((S)-1-tert-butoxycarbonylamino-ethyl)-3H-imidazole-4-carboxylic acid methyl ester hydrochloride (50 mg, 186 μmol) in 4M HCl in dioxane (2 mL) was stirred at room temperature for 15 h. The mixture was concentrated in vacuo, washed with ether to give 2-((S)-1-amino-ethyl)-3H-imidazole-4-carboxylic acid methyl ester hydrochloride (40 mg, quantitative) as a yellow oil, LCMS, [M+H]=170.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1.[CH2:23]1[O:33][C:32]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=2[O:24]1>>[O:33]1[C:32]2[CH:31]=[CH:30][C:27](/[CH:28]=[C:20](/[C:17]3[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:19][CH:18]=3)\[C:21]#[N:22])=[CH:26][C:25]=2[O:24][CH2:23]1
Reactant: N#CCc1ccc(OCCCCCCCCCCCO)cc1
Reactant: O=Cc1ccc2c(c1)OCO2
Product: N#C/C(=C\c1ccc2c(c1)OCO2)c1ccc(OCCCCCCCCCCCO)cc1
Yield: 85 %

Procedure:
(2Z)-3-(1,3-benzodioxol-5-yl)-2-{4-[(11-hydroxyundecyl)oxy]phenyl}prop-2-enenitrile is prepared starting from 4-[(11-hydroxyundecyl)oxy]-benzeneacetonitrile and commercial 3,4-(methylenedioxy)benzaldehyde according the same procedure following for example 1 in 85% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [NH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5](O)[C:4]=2[N:3]=[CH:2]1.P(Cl)(Cl)([Cl:17])=O.C(=O)(O)[O-].[Na+]>>[Cl:17][C:5]1[C:4]2[N:3]=[CH:2][NH:1][C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc2ccccc2c2[nH]cnc12
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1nc2ccccc2c2[nH]cnc12

Procedure:
A mixture of 500 mg of 1H-imidazo[4,5-c]quinolin-4-ol and about 6 mL of phosphorous oxychloride was heated on a steam bath for about 16 hours, then poured over ice. The mixture was neutralized with saturated sodium bicarbonate solution, then the solid was separated by filtration. The solid was dissolved in dilute hydrochloric acid, the mixture was filtered and the filtrate was neutralized with concentrated ammonium hydroxide to reprecipitate the product. Filtration and drying was followed by recrystallization from methanol to provide crystals of 4-chloro-1H-imidazo[4,5-c]-quinoline. Analysis: Calculated for C10 H6N3 : % C, 59.0; % H, 3.0; % N, 20.6; Found: % C, 59.5; % H, 3.0; % N, 20.2.
Reaction SMILES: [C:1]([C:5]([O:7][C:8]([C:10]([F:24])([F:23])[C@@:11](C(=O)C)([C@@H:13]([CH:15]([C:17](=[O:19])[CH3:18])[OH:16])[OH:14])[OH:12])=[O:9])=[O:6])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].C(O)(=O)C>O1CCCC1>[C:1]([C:5]([O:7][C:8]([C:10]([F:23])([F:24])[C@@H:11]([C@@H:13]([CH:15]([C:17](=[O:19])[CH3:18])[OH:16])[OH:14])[OH:12])=[O:9])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)C(O)[C@@H](O)[C@](O)(C(C)=O)C(F)(F)C(=O)OC(=O)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)C(O)[C@@H](O)[C@@H](O)C(F)(F)C(=O)OC(=O)C(C)(C)C
Temperature: -65 °C
Reaction time: 1 h
Yield: 137.7 %

Procedure:
To a solution of 0.5 g (approximately 1 mmol) crude 1-(t-butylcarbonyloxy)-3,5-bis(acetyl)-2-deoxy-2,2-difluororibose in tetrahydrofuran (5 ml) cooled to -65° C. were added 2.0 ml of a 1M solution of potassium t-butoxide in tetrahydrofuran (2 mmol) dropwise and the reaction mixture stirred 1 hour at -65° C. The reaction was then quenched with 0.23 ml of glacial acetic acid (4 mmol) and allowed to warm to room temperature. The reaction mixture was concentrated under reduced pressure to give 0.43 gm 1-(t-butylcarbonyloxy)-5-acetyl-2-deoxy-2,2-difluororibose. Mass spec. m/e=390=P+1.
Reaction SMILES: N12CCCN=C1CCCCC2.[NH:12]1[CH:16]=[C:15]([C:17]2[CH:18]=[N:19][C:20]3[N:21]([C:23]([CH2:26][C:27]4[CH:28]=[C:29]5[C:34](=[CH:35][CH:36]=4)[N:33]=[CH:32][CH:31]=[CH:30]5)=[CH:24][N:25]=3)[N:22]=2)[CH:14]=[N:13]1.[C:37]([CH:39]=[C:40]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]1)#[N:38]>C(#N)C>[C:37]([CH2:39][C:40]1([N:12]2[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][C:20]4[N:21]([C:23]([CH2:26][C:27]5[CH:28]=[C:29]6[C:34](=[CH:35][CH:36]=5)[N:33]=[CH:32][CH:31]=[CH:30]6)=[CH:24][N:25]=4)[N:22]=3)[CH:14]=[N:13]2)[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:44][CH2:45]1)#[N:38]
Reactant: c1cnc2ccc(Cc3cnc4ncc(-c5cn[nH]c5)nn34)cc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(-c3cnc4ncc(Cc5ccc6ncccc6c5)n4n3)cn2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (68 μL, 0.46 mmol) was added to a mixture of 6-[2-(1H-pyrazol-4-yl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylquinoline (50.0 mg, 0.153 mmol) and tert-butyl 4-(cyanomethylene)piperidine-1-carboxylate (0.068 g, 0.30 mmol) in acetonitrile (1 mL). The reaction was stirred at 60° C. overnight. After cooling to RT, the mixture was purified by chromatography on silica gel with EtOAc in CH2Cl2 (0-70%) to give the desired product (30 mg, 35.7%). LCMS: (M+H)=550.5.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.Cl[CH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: ClCc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: Cl
Product: Clc1ccc(-c2nn(Cc3ccncc3)c3c2CCNCC3)cc1
Yield: 19.7 %

Procedure:
The title compound (0.02 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.3 mmol) using 4-chloromethyl-pyridine hydrogen chloride (0.5 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C19H19ClN4, 338.13. found, m/z 339.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.49-8.48 (m, 2H), 7.43-7.41 (m, 2H), 7.33-7.31 (m, 2H), 6.90-6.89 (m, 2H), 5.28 (s, 2H), 2.92-2.87 (m, 2H), 2.75-2.73 (m, 1H), 2.66-2.64 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:15])[N:4]2[C:8](=[C:9]([C:11](=[O:14])[CH2:12][CH3:13])[CH:10]=1)[CH2:7][CH2:6][CH2:5]2.CCN(CC)CC.C1(N[S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])C=CC=CC=1>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[S:30]([O:1][C:2]1[C:3](=[O:15])[N:4]2[C:8](=[C:9]([C:11](=[O:14])[CH2:12][CH3:13])[CH:10]=1)[CH2:7][CH2:6][CH2:5]2)(=[O:32])=[O:31]
Reactant: CCC(=O)c1cc(O)c(=O)n2c1CCC2
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)c1cc(OS(=O)(=O)C(F)(F)F)c(=O)n2c1CCC2
Reaction time: 0.33 h
Yield: 99 %

Procedure:
To a stirred, cooled (0° C.) solution of 6-hydroxy-8-propionyl-2,3-dihydroindolizin-5-(1H)-one (1.10 g, 4.53 mmol) in CH2Cl2 (10 mL) was added Et3N. After stirring for 20 min., N-phenyltrifluoromethane sulfonamide was added in one portion. The mixture was stirred at RT for 6 h and quenched with H2O. the mixture was extracted with CH2Cl2 (3×) and the combined organic layers were dried over MgSO4, concentrated and purified by ISCO (40% EtOAc/Hexanes) to give the title compound as a white solid (1.50 g, 99%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C@@H:7]2[CH2:8][C@H:3]1[CH2:4][CH2:5][C:6]2=O.Cl.[CH3:12][O:13][NH2:14].N1C=CC=CC=1>C(O)C>[CH3:12][O:13][N:14]=[C:6]1[CH2:5][CH2:4][C@H:3]2[CH2:8][C@@H:7]1[C:2]2([CH3:10])[CH3:1]
Reactant: CC1(C)[C@@H]2CCC(=O)[C@H]1C2
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C1CC[C@H]2C[C@@H]1C2(C)C
Yield: 89.9 %

Procedure:
To a solution of (1S,5R)-6,6-dimethylnorpinan-2-one (3.09 g, 22.35 mmol) in ethanol (70 mL) was added O-methylhydroxylamine hydrochloride (2.05 g, 24.59 mmol) and pyridine (1.29 mL, 15.92 mmol). Heated reaction mixture to 80° C. for 4 hours. Removed solvent under reduced pressure. Diluted residue with 1N HCl and extracted twice with ether. The combined organic phases were washed with aqueous saturated NaHCO3, dried (MgSO4), filtered, concentrated in vacuo to afford 3.36 g of a colorless oil (mixture of oxime isomers) that was used without further purification.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][OH:11])=[CH:9][C:4]=2[N:3]=[CH:2]1>C1C=CC=CC=1.O=[Mn]=O>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: OCc1ccc2[nH]cnc2c1
Agent: O=[Mn]=O
Solvent: c1ccccc1
Product: O=Cc1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40.7 %

Procedure:
To a stirring solution of (1H-benzo[d]imidazol-5-yl)methanol (501 mg, 3.38 mmol) in benzene (35 mL) was added MnO2 (2.35, 27.0 mmol). After stirring at room temperature for 12 h the reaction was then filtered through celite and the filter cake was washed with THF (200 mL). The Filtrate was concentrated to give the title compound (1H-benzo[d]imidazole-5-carbaldehyde) (201 mg, 41%) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 12.90 (bs, 1H), 10.04 (s, 1H), 8.43 (s, 1H), 8.19 (s, 1H), 7.75 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[N:26]1([CH2:32][CH2:33][NH:34][C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][N:36]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([CH2:32][CH2:33][NH:34][C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:25]=[CH:24][C:5]4[C:6]5[N:7]=[C:8]([C:14]6[N:15]([CH2:19][C:20]([F:22])([F:23])[F:21])[N:16]=[CH:17][N:18]=6)[S:9][C:10]=5[CH2:11][CH2:12][O:13][C:4]=4[CH:3]=3)=[CH:37][N:36]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC1(C)OB(c2ccc(NCCN3CCOCC3)nc2)OC1(C)C
Product: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(-c3ccc(NCCN4CCOCC4)nc3)ccc1-2

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with (2-Morpholin-4-yl-ethyl)-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-amine to give 116. MS (ESI+) 558.2. 1H NMR (400 MHz, DMSO) δ 8.41 (d, J=2.1, 1H), 8.32 (d, J=8.4, 1H), 8.29 (s, 1H), 7.79 (dd, J=8.8, 2.4, 1H), 7.45 (dd, J=8.4, 1.7, 1H), 7.30 (d, J=1.6, 1H), 6.59 (dd, J=10.9, 7.1, 2H), 5.87 (q, J=8.7, 2H), 4.41 (t, J=4.9, 2H), 3.64-3.54 (m, 4H), 3.47 (t, J=4.9, 2H), 3.42 (dd, J=12.5, 6.4, 2H), 2.50-2.47, (m, 2H), 2.40-2.44 (m, 4H)
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[O:27][CH3:28])/[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([OH:23])=[O:22])=[C:15]([CH:18]=[CH:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:35]([O:41][CH2:42]I)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[O:27][CH3:28])/[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O:23][CH2:42][O:41][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC=CC1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Reactant: CC(C)(C)C(=O)OCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C/C=C\C1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 75.3 %

Procedure:
To a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1-propenyl)-3-cephem-4-carboxylic acid (Ia, R2 =CH3, R3 =H) (E/Z=1/17, 90 mg, 0.21 mmole) and potassium carbonate (44 mg, 0.32 mmole) in DMF (3 ml) was added at 0° C. pivaloyloxymethyl iodide (77 mg, 0.32 mmole). The mixture was stirred at 0° C. for 40 minutes, diluted with ethyl acetate (20 ml), washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was dissolved in CHCl3 and chromatographed on a silica gel column (silica gel: 3 g) by eluting with 1% methanol in CHCl3 to yield 85 mg (75%) of the title compound. Mp. 100°-104° C. Estimated purity 90% (by HPLC).