Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9](OS(C(F)(F)F)(=O)=O)[C@@:10]2([N:22]=[N+:23]=[N-:24])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH:8]=[CH:9][C@:10]2([N:22]=[N+:23]=[N-:24])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@@H](OS(=O)(=O)C(F)(F)F)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1[C@@H]2C=C[C@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Temperature: -50 °C
Reaction time: 3 h

Procedure:
To a solution of (1S,2R,3R,5R,6S)-2-azido-3-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXV) (1.36 g, 2.85 mmol) in THF (5.7 mL) was added DBU (0.47 mL, 3.13 mmol) and the mixture was stirred at -50° C. for 3 h. After dilution with ethyl acetate, the solution was washed with 1 N HCl-sol., sat. NaHCO3 -sol. and brine, followed by drying over MgSO4. Removal of the solvent in vacuum left the crude (1S,2R,5R,6S)-2-azido-bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXVI) (566 mg, 61%) as a brownish oil, sufficiently pure for further transformations. 1H-NMR (250 MHz, CDCl3) □1.27 (3H, t, J=7.1 Hz), 1.76 (1H, t, J=3.5 Hz), 2.59 (1H, dt, J=7, 3.5 Hz), 2.67 (1H, ddd, J=7, 3.5, 2 Hz), 4.14 (2H, q,J=7.1 Hz), 5.27 (2H, s), 5.53 (1H, d, J=5.5 Hz), 6.25 (1H, dd, J=5.5, 2Hz), 7.37 (5H, s); MS[ISP] 345 (M+NH4+); □D20 -7183.54° (c=1.08, CHCl3).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[CH:6][N:7]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]=1[CH3:9])[CH3:3].[CH3:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]([S:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)(=[O:41])=[O:40])[C:31]=1[CH2:48][CH:49]=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[CH3:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]([S:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)(=[O:41])=[O:40])[C:31]=1[CH2:48][CH2:49][NH:1][CH:2]([C:4]1[N:5]=[CH:6][N:7]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:8]=1[CH3:9])[CH3:3]
Reactant: Cc1c(CC=O)n(S(=O)(=O)c2ccccc2)c2ccccc12
Reactant: Cc1c(C(C)N)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(CCNC(C)c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C)n(S(=O)(=O)c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
A mixture of 4-(1-aminoethyl)-5-methyl-1-trityl-1H-imidazole (735 mg), 3-methyl-1-(phenylsulfonyl)-2-indoleacetaldehyde (626 mg) and molecular sieves 3A (100 mg) in dry methanol (30 ml) was stirred at ambient temperature for 30 minutes. Acetic acid (0.35 ml) and sodium cyanoborohydride (126 mg) were added and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was treated with cold water, extracted twice with ethyl acetate, which was washed with brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was chromatographed over silica gel (eluted with 3% methanol in chloroform) to give 3-methyl-2-[2-[[1-(5-methyl-1-trityl-1H-imidazol-4-yl)ethyl]amino]ethyl]-1-phenylsulfonylindole (947 mg) as an amorphous powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([N+:13]([O-])=O)=[CH:8][CH:9]=2)[N:4]=1>[Pd].CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([NH2:13])=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1ccc2ccc([N+](=O)[O-])cc2n1
Agent: [Pd]
Solvent: CO
Product: COc1ccc2ccc(N)cc2n1
Yield: 99.5 %

Procedure:
A methanol (10 ml) solution containing 2-methoxy-7-nitroquinoline (33 mg) obtained in the 1st step was prepared and subjected to a hydrogenation reaction (60° C.; 50 bar; flow rate: 1 ml/min; 10% Pd/C) using H-cube™. Then, the solvent was distilled away under reduced pressure, and a purple solid of 2-methoxyquinolin-7-amine (28 mg) was thus obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([S:48]([CH3:51])(=[O:50])=[O:49])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:47])[C@H:18]([NH:27][C:28]([C@@H:30]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][N:31]2C(OC(C)(C)C)=O)=[O:29])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:13][CH2:12]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][CH2:2][CH2:3][N:4]([S:48]([CH3:51])(=[O:49])=[O:50])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:47])[C@H:18]([NH:27][C:28]([C@@H:30]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][NH:31]2)=[O:29])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2N(CCN)S(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N(CCN)c1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2)CC1
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
The title compound was prepared according to the procedure described in Example 3 (Step b) from tert-butyl 3-{N-[(1R)-2-(4-(2-[(2-aminoethyl)-(methylsulfonyl)amino]phenyl}piperidyl)-1-[(4-chlorophenyl)methyl]-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step f) (294.8 mg, 0.4 mmol) and 50% TFA in CH2Cl2 (20 mL). Purification by reverse phase preparative HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min] provided the title compound (TFA salt) as a white solid (224 mg). MS (ESI, pos. ion) m/z: 638 (M+1); (ESI, neg. ion) m/z: 636 (M−1). Calc'd for C33H40ClN5O4S: 637.25. Anal. Calcd for C33H40ClN5O4S.2.5C2H3O2: C, 49.43; H, 4.64; N, 7.41. Found: C, 49.39; H, 4.78; N, 7.58.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=S)[S:10]CC(O)=O)=[CH:5][CH:4]=1.[OH-].[K+].O.[NH2:21][NH2:22].C(O)(=O)C>CO.O>[CH:5]1[C:6]([C:9]([NH:21][NH2:22])=[S:10])=[CH:7][CH:8]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:4]=1
Reactant: O=C(O)CSC(=S)c1ccc(C(F)(F)F)cc1
Reactant: NN
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: NNC(=S)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
[((4-(Trifluoromethyl)phenyl)thioxomethyl)thio]acetic acid (6.7 g) was dissolved in methanol (50 ml). Potassium hydroxide (1.34 g) in water (15 ml) was added followed by hydrazine hydrate (1.28 ml). The mixture was stirred for 4 hours at room temperature. Glacial acetic acid was added until the pH was 5 and the solvent was removed under reduced pressure. The product was extracted with diethyl ether (250 ml) and the solvent was evaporated under reduced pressure. The resulting solid was crystallised from cyclohexane as pale pink crystals (4.0 g) mp 114°-115.5°.
Reaction SMILES: [CH:1]1([NH:7][N:8]2[C:13](=[O:14])[C:12]([C:15]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([OH:25])=[CH:24][C:18]=4[S:17](=[O:27])(=[O:26])[N:16]=3)=[C:11]([OH:28])[C:10]3[S:29][CH:30]=[CH:31][C:9]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:39][C:40]([NH2:42])=[O:41].Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.O>[CH:1]1([NH:7][N:8]2[C:13](=[O:14])[C:12]([C:15]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([O:25][CH2:39][C:40]([NH2:42])=[O:41])=[CH:24][C:18]=4[S:17](=[O:27])(=[O:26])[N:16]=3)=[C:11]([OH:28])[C:10]3[S:29][CH:30]=[CH:31][C:9]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC(=O)CBr
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2sccc2n1NC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)COc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3sccc3n(NC3CCCCC3)c1=O)N2
Yield: 21.5 %

Procedure:
The product of Example 324E (0.209 g, 0.45 mmol) was reacted with cesium carbonate (0.589 g, 1.81 mmol), 2-bromoacetamide (0.125 g, 0.91 mmol) and a catalytic amount of tetrabutylammonium iodide in N,N-dimethylformamide (8 mL) at 25° C. for 18 hours. The reaction was diluted with 50 mL water, acidified to pH 2 with 1 M hydrochloric acid. The resulting precipitate was collected by filtration and purified by column chromatography on silica gel eluting with 5% methanol in chloroform to give the title compound (0.050 g, 21% yield). The sodium salt of the title compound was prepared according to the procedure of Example 1D. MS (ESI−) m/z 516 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.48 (m, 10 H) 4.59 (s, 2 H) 6.50 (s, 1 H) 7.39 (m, 2 H) 7.44 (s, 1 H) 7.48 (d, J=5.15 Hz, 1 H) 7.65 (s, 1 H) 7.70 (d, J=9.56 Hz, 1 H) 8.28 (d, J=5.15 Hz, 1 H) 14.13 (s, 1 H) 14.89 (s, 1 H).
Reaction SMILES: C([S:8][CH2:9][C:10]1([CH3:21])[CH2:14][CH2:13][N:12]([C@@H:15]([CH3:19])[C:16]([OH:18])=[O:17])[C:11]1=[O:20])C1C=CC=CC=1.O1CCCC1.N.[Na]>CO>[SH:8][CH2:9][C:10]1([CH3:21])[CH2:14][CH2:13][N:12]([C@@H:15]([CH3:19])[C:16]([OH:18])=[O:17])[C:11]1=[O:20]
Reactant: C[C@@H](C(=O)O)N1CCC(C)(CSCc2ccccc2)C1=O
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](C(=O)O)N1CCC(C)(CS)C1=O

Procedure:
Two grams of (αS)-3-(benzylmercaptomethyl)α,3-dimethyl-2-oxo-1-pyrrolidineacetic acid were dissolved in about 15 ml. of tetrahydrofuran. This solution was then added to liquid ammonia. Small pieces of sodium metal were added until a blue color persisted. The reaction was then quenched by the addition of about two grams of ammonium chloride. The ammonia was evaporated and water was added to the residue. The slurry was made acidic with hydrochloric acid, saturated with sodium chloride and the acidic solution was extracted with chloroform. The chloroform extract was washed with a saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness. Two crystallizations of the resulting solid from diethylether/Skelly B gave 0.5 g. of the desired title product, m.p. about 132°-133° C. [α]D25 =-23.78° (c=1, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]2[CH2:33][O:34][CH2:35][CH:29]2[CH2:28]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH:30]5[CH2:33][O:34][CH2:35][CH:29]5[CH2:28]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: BrCCCN1CCC2COCC2C1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2COCC2C1
Temperature: 80 °C
Yield: 23.3 %

Procedure:
A mixture of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (140 mg, 0.44 mmol, 1 eq), 5-(3-bromopropyl)octahydrofuro[3,4-c]pyridine (90 mg, 0.44 mmol, 1 eq) and K2CO3 (135 mg, 0.98 mmol, 2 eq) in DMF (10 mL) was heated at 80° C. overnight under N2 and cooled to rt. To this, 50 mL of CH2Cl2 was added. The mixture was washed with brine (20 mL×3) and water (20 mL×2). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (20:1 (v/v) CH2Cl2/MeOH) to afford the title compound as a yellow solid (50 mg, 25.00%), HPLC: 96.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 487.1 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.76-1.77 (1H, m), 2.24-2.48 (3H, m), 2.50-2.64 (2H, m), 2.68-2.71 (2H, m), 2.73-2.75 (2H, m), 2.96-3.03 (3H, m), 3.07-3.12 (1H, m), 3.61-3.90 (2H, m), 4.24-4.27 (2H, m), 7.06-7.10 (1H, m), 7.16 (1H, s), 7.76-7.82 (1H, m), 7.82 (1H, s), 8.09-8.11 (1H, m), 8.59 (1H, s) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[N:29][NH:30][C:31]([NH2:33])=[O:32])[CH2:7][CH:8]([NH:11]C(OCC1C2CC3C(=CC=CC=3)C=2C=CC=1)=O)[CH:9]=[O:10])([CH3:4])([CH3:3])[CH3:2].C(NCC)C>C(#N)C>[C:1]([O:5][C:6](=[N:29][NH:30][C:31]([NH2:33])=[O:32])[CH2:7][CH:8]([NH2:11])[CH:9]=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(CC(C=O)NC(=O)OCc1cccc2c1Cc1ccccc1-2)=NNC(N)=O
Solvent: CC#N
Solvent: CCNCC
Product: CC(C)(C)OC(CC(N)C=O)=NNC(N)=O
Reaction time: 2 h

Procedure:
(3S) 3-(1-Fluorenylmethoxycarbonylamino)-4-oxobutyric acid tert-butyl ester semicarbazone (4; 226 mg, 0.5 mmol; prepared in a similar manner as the benzyloxycarbonyl analog described in Graybill et al. Int. J. Protein Res., 44, pp. 173-82 (1994)) was dissolved in 10 ml of acetonitrile (20 ml) and diethylamine (2 ml) was added to the solution. The reaction was stirred for two hours, concentrated in vacuo, the resulting dissolved in acetonitrile and concentrated in vacuo again to give (3S) 3-amino-4-oxobutyric acid tert-butyl ester semicarbazone. A 5° C. solution of the semicarbazone and 3 (188 mg, 0.424 mmol) in methylene chloride/DMF (6 ml of 1:1) was treated with 1-hydroxybenzotriazole (HOBt; 57 mg, 0.424 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC; 115 mg, 0.6 mmol) and the reaction was stirred at room temperature for 16 hr. The reaction was diluted with ethyl acetate (100 ml) and washed with water, aqueous saturated NaHCO3 and aqueous saturated NaCl, dried over dried over anhydrous Na2SO4 and concentrated in vacuo. Chromatography (SiO2, 5% ammonium hydroxide/5% methanol/methylene chloride eluent) gave 250 mg of 5.
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:32][O:33]CC)[N:18]([CH2:19][C:20]([NH:23][C:24]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])([CH3:22])[CH3:21])[C:14]=2[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1>ClCCl>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:32][OH:33])[N:18]([CH2:19][C:20]([NH:23][C:24]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])([CH3:21])[CH3:22])[C:14]=2[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CCOCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)NC(=O)C1CCCCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(Cn1c(CO)nc2c(N)nc3cccnc3c21)NC(=O)C1CCCCC1
Temperature: 25 °C
Yield: 49.8 %

Procedure:
Boron tribromide (1.24 mL of 1 M in dichloromethane) was added dropwise to a chilled (ice bath) suspension of N-[2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-1,1-dimethylethyl]cyclohexanecarboxamide (500 mg, 1.18 mmol) in dichloromethane (15 mL). The reaction mixture was allowed to slowly warm to ambient temperature and then stirred over the weekend. Additional boron tribromide (1 mL) was added and the reaction mixture was stirred for 24 hours. The reaction was quenched with methanol (10 mL) and then concentrated under reduced pressure. The residue was combined with hydrochloric acid (15 mL of 6 M), heated to 50° C., and stirred for 2 hours. The resulting solution was cooled to ambient temperature and then neutralized (pH 7) with 10% sodium hydroxide. The resulting gummy precipitate was extracted with chloroform (3×15 mL). The combined extracts were washed with brine (15 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide an off white solid. This material was purified by prep HPLC (HORIZON HPFC system, eluting with a gradient of 10-50% CMA in chloroform) to provide a white solid. The solid was triturated with hot acetonitrile, allowed to cool, isolated by filtration, and dried under vacuum to provide 233 mg of N-[2-(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-1,1-dimethylethyl]cyclohexanecarboxamide as a fine white solid, mp 230-232° C.; 1H NMR (300 MHz, DMSO-d6, 350 K) δ 8.53 (dd, J=4.3, 1.6 Hz, 1H), 7.95 (dd, J=8.4, 1.5 Hz, 1H), 7.87 (s, 1H), 7.47 (dd, J=8.4, 4.4 Hz, 1H), 6.55 (s, 2H), 5.31 (s, 1H), 5.15 (s, 2H), 4.79 (d, J=5.4 Hz, 2H), 1.90-1.80 (m, 1H), 1.67-1.43 (m, 5H), 1.31 (s, 6H), 1.24-1.02 (m, 5H); 13C NMR (75 MHz, DMSO-d6) δ 175.9, 154.6, 152.8, 142.8, 140.8, 134.2, 133.5, 133.3, 129.3, 122.5, 56.4, 55.0, 52.3, 44.9, 29.4, 25.7, 25.6, 24.9; MS (ESI) m/z 397 (M+H)+; Anal. Calcd for C21H29N6O2: C, 63.62; H, 7.12; N, 21.20. Found: C, 63.77; H, 7.34; N, 21.50.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>C1COCC1.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.[Cu]I>[CH3:29][Si:30]([C:33]#[C:34][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1)([CH3:32])[CH3:31]
Reactant: N#Cc1cc(Br)ccn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Bromo-2-pyridinecarbonitrile [Cesko-Slovenska Farmacie 25(5),181(1976)] (0.73 g, 4.0 mmol) was dissolved in 18 mL dry THF. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (31 mg, 0.12 mmol) and bis(triphenylphosphine)palladium(II) chloride (141 mg, 0.20 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper(I) iodide (23 mg, 0.12 mmol) and trimethylsilyl-acetylene (590 mg, 6.0 mmol) were added. The reaction mixture was stirred at room temperature for 3 days. The solvent was evaporated. The residue was taken up in 100 mL water and extracted three times with 100 ml of ethyl acetate. The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/methylene chloride 1:2). The desired product was obtained as a yellow oil (329 mg, 41%), MS: m/e=201.3 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH:13]=2)[C:7](=[O:29])[C:6]=1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:43]2[NH:47][C:46](=[O:48])[O:45][N:44]=2)=[CH:33][CH:32]=1)[CH2:2][CH2:3][CH3:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>O1CCCC1>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][OH:21])[CH:13]=2)[C:7](=[O:29])[C:6]=1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:43]2[NH:47][C:46](=[O:48])[O:45][N:44]=2)=[CH:33][CH:32]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(-c2cccc(OCCO[Si](C)(C)C(C)(C)C)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nc(C)n(-c2cccc(OCCO)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 69.9 %

Procedure:
To a solution of 6-butyl-3-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (0.95 g) in tetrahydrofuran (7 mL) was added tetrabutylammonium fluoride (0.56 g), and the mixture was stirred at 50° C. for 12 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.55 g, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.C([Mg]Br)(C)C.[CH3:14][Si:15]([CH3:30])([CH3:29])[CH2:16][CH2:17][S:18]([N:21]1[CH2:26][CH2:25][CH2:24][CH:23]([CH:27]=[O:28])[CH2:22]1)(=[O:20])=[O:19]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:27]([CH:23]1[CH2:24][CH2:25][CH2:26][N:21]([S:18]([CH2:17][CH2:16][Si:15]([CH3:30])([CH3:29])[CH3:14])(=[O:19])=[O:20])[CH2:22]1)[OH:28]
Reactant: Brc1ccccc1I
Reactant: C[Si](C)(C)CCS(=O)(=O)N1CCCC(C=O)C1
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: C[Si](C)(C)CCS(=O)(=O)N1CCCC(C(O)c2ccccc2Br)C1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
A three neck 200-mL flask was charged with anhydrous THF (150 mL) and 1-bromo-2-iodobenzene (5.81 g, 20.5 mmol, 1.5 equiv), and cooled to −40° C. Isopropyl magnesium bromide (1.0 M in THF, 19.9 mL, 19.9 mmol, 1.45 equiv) was added to the solution via syringe at a rate such that the internal temperature did not rise above −35° C. An aliquot was removed, quenched with water and analyzed by LC-MS. The observed amount of bromobenzene showed >90% conversion to the desired Grignard reagent. A solution of 1-(2-trimethylsilyl-(ethanesulfonyl))piperidine-3-carbaldehyde (3.8 g, 13.7 mmol) in 20 mL of THF was added to solution containing the Grignard reagent at such a rate that the internal temperature did not rise above −35° C. The mixture was stirred for 1 h at −40° C.; after this period LC-MS analysis of an aliquot showed consumption of the aldehyde and formation of two peaks with the desired mass, consistent with formation of two diastereomers. The mixture was quenched with methanol and the THF removed in vacuo. The resulting solid was partitioned between EtOAc and water, and filtered through a pad of Celite to remove a sticky white solid. The layers were separated and the aqueous layer was extracted with additional EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and evaporated. The mixture of alcohols was purified by flash chromatography on 120 g silica, eluting with 0 to 50% EtOAc in hexanes. No attempt was made to separate the two diastereomers. This afforded (2-bromophenyl)(1-(2-(trimethylsilyl)ethanesulfonyl)piperidin-3-yl)methanol (3.64 g, 61%) as a white foam. 1H NMR (CDCl3) δ 0.01 (s, 9H), 0.95-2.06 (m, 8H), 2.6-3.0 (m, 6H), 3.6-3.9 (m, 3H), 4.96 (bs, 1H), 7.13 (m, 1H), 7.29 (m, 1H), 7.44 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH2:12][CH2:13][OH:14])=[CH:4][C:3]=1[F:19].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[F:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1)[N:9]([CH2:12][CH2:13][OH:14])[CH:8]=[C:7]([C:15]([OH:17])=[O:16])[C:6]2=[O:18]
Reactant: O=C(O)c1cn(CCO)c2cc(Cl)c(F)cc2c1=O
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CCO)CC1
Yield: 70.1 %

Procedure:
28 g of 7-chloro-6-fluoro-1-(2-hydroxyethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 40 g of 1-methyl piperazine and 200 cm3 of pyridine were heated for 18 hours under reflux. The solvent was removed by distillation under reduced pressure. The residue was taken up in 100 cm3 of water, the mixture was agitated and adjusted to pH 6.8 by the addition of acetic acid. The solid was filtered off, washed with water and recrystallised from DMF. 24 g of 6-fluoro-1-(2-hydroxyethyl)-7-(4-methyl-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, m.p. 270° C., were obtained.