Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NN1CCCC1.Cl[C:8]1[N:17]=[C:16]([O:18][CH3:19])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.Cl.[NH2:21][C@H:22]1[CH2:26][CH2:25][N:24]([C:27](=[O:40])[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)[CH2:23]1.C(N(CC)CC)C>C(Cl)(Cl)Cl.C1COCC1>[CH3:19][O:18][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([NH:21][C@H:22]2[CH2:26][CH2:25][N:24]([C:27](=[O:40])[CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][C:36]([F:37])([F:38])[F:39])=[CH:33][CH:34]=3)[CH2:23]2)[N:17]=1
Reactant: COc1nc(Cl)nc2ccccc12
Reactant: N[C@H]1CCN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C1
Agent: Cl
Agent: NN1CCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1nc(N[C@H]2CCN(C(=O)Cc3ccc(OC(F)(F)F)cc3)C2)nc2ccccc12
Temperature: 100 °C
Yield: 6.5 %

Procedure:
Metal sodium (35 mg) was added to methanol (1.5 mL) to prepare a solution, and the solution was concentrated under reduced pressure, followed by addition of THF (1.5 mL). This suspension was added to a solution of 2,4-dichloroquinazoline (0.30 g) in THF (1.5 mL), and the mixture was stirred at room temperature for 2 h. To the reaction mixture was added saturated brine, the mixture was extracted with chloroform, and the organic layer was dried with anhydrous magnesium sulfate. The desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=9:1) to obtain 2-chloro-4-methoxyquinazoline (0.27 g). (2) A mixture of 2-chloro-4-methoxyquinazoline (0.25 g), 1-((S)-3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (0.42 g), triethylamine (0.33 g), and THF (3.2 mL) was heated at 100° C. in a microwave reaction apparatus for 3 h. The reaction mixture was diluted with chloroform, washed with 1 M aqueous sodium hydroxide, and then dried with anhydrous magnesium sulfate. The desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (chloroform-chloroform/methanol=95:5, and silica gel, hexane/ethyl acetate=1:2−ethyl acetate) to obtain the title compound (37 mg).
Reaction SMILES: [CH:1]1([N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7](I)=[CH:6]2)[CH2:4][CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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>[CH:1]1([N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[N:23]4)=[CH:28][CH:27]=3)=[CH:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)cn2C1CCC1
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: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2C1CCC1

Procedure:
Following the general procedure for the Suzuki coupling, 7-cyclobutyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (142.5 mg, 0.4536 mmol) was reacted with 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (150.2 mg, 0.4533 mmol), Na2CO3 (120 mg, 1.13 mmol) and Pd(PPh3)4 (32 mg, 0.028 mmol) in DMF (10 mL)/water (2 mL). The crude material was purified by column chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with CH2Cl2 (1-12)→1% MeOH in CH2Cl2 (13-37)→2% MeOH in CH2Cl2 (38-61)], yielding the title compound as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ=1.88-2.00 (m, 2H), 2.44-2.56 (m, 2H), 2.56-2.65 (m, 2H), 5.27 (brs, 2H), 5.35 (quint, J=8.6 Hz, 1H), 7.35 (s, 1H), 7.46-7.51 (m, 1H), 7.52-7.58 (m, 2H), 7.70 (dd, J=1.8, 8.2 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 8.17-8.22 (m, 2H), 8.26 (d, J=8.4 Hz, 1H), 8.28-8.31 (m, 1H), 8.36 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=15.03 (−), 31.11 (2C, +), 48.26 (+), 101.15 (Cquart), 115.99 (Cquart), 118.99 (+), 120.86 (+), 125.97 (Cquart), 127.42 (+), 127.55 (2C, +), 128.26 (+), 128.48 (+), 128.87 (2C, +), 129.52 (+), 136.49 (Cquart), 136.55 (+), 139.43 (Cquart), 148.52 (Cquart), 150.79 (Cquart), 151.97 (+), 156.97 (Cquart), 158.12 (Cquart). MS (ES+): m/z 392.1 (17) [MH+], 338.2 (22) [MH+−cyclobutene]. HPLC: tR=3.0 min (OpenLynx, polar—5 min).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH:19]=O)[CH:13]=[CH:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(O)=O.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH2:19][N:25]1[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]1)[CH:13]=[CH:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2nc(C=O)ccc2c1
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(Cc2ccc3cc(O[Si](C)(C)C(C)(C)C)ccc3n2)CC1
Reaction time: 3 h
Yield: 77.6 %

Procedure:
6-((tert-butyldimethylsilyl)oxy)quinoline-2-carbaldehyde (5.74 g, 20 mmol), AcOH (3.6 g, 60 mmol, 3 eq) and ethyl 4-piperidinecarboxylate (6.28 g, 40 mmol, 2 eq) in DCE (100 mL) were stirred at room temperature for 30 min. Then NaBH(OAc)3 (12.7 g, 60 mmol, 3 eq) was added to the mixture at room temperature and stirred for 3 h. The reaction mixture was quenched with water (300 mL), and adjusted to pH=8 with conc. aq. NH3 solution. Then the mixture was extracted with DCM (3×400 mL). The combined organic layer was washed by brine (300 mL), dried (Na2SO4) and concentrated. The crude product was purified by silica gel chromatography (PE:EA=4:1) to give ethyl 1-((6-((tert-butyldimethylsilyl)oxy)quinolin-2-yl)methyl)piperidine-4-carboxylate as yellow oil (6.65 g, yield: 77%). ESI-MS (M+H)+: 429.3. 1H NMR (400 MHz, CDCl3) δ: 7.97 (d, J=8.4 Hz, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.27 (dd, J=9.2, 2.4 Hz, 1H), 7.12 (d, J=2.8 Hz, 1H), 4.12 (q, J=7.2 Hz, 2H), 3.78 (s, 2H), 2.92-2.89 (m, 2H), 2.30-2.25 (m, 1H), 2.20-2.15 (m, 2H), 1.91-1.79 (m, 4H), 1.25 (t, J=7.2 Hz, 3H), 1.02 (s, 9H), 0.25 (s, 6H).
Reaction SMILES: [S:1]([CH:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])([OH:4])(=[O:3])=[O:2].OO.[OH:27]P(O)(O)=O>>[S:1]([CH:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][OH:27])=[O:15])([OH:4])(=[O:3])=[O:2]
Reactant: CCCCCCCCC(CCCCCCCCC(=O)O)S(=O)(=O)O
Reactant: O=P(O)(O)O
Agent: OO
Product: CCCCCCCCC(CCCCCCCCC(=O)OO)S(=O)(=O)O
Temperature: 25 °C

Procedure:
To a 2.0 g mixture of 9 or 10-Sulfostearic acid was added 2.0 g of 50% H2O2. The mixture was stirred at room temperature until all the solid was dissolved. Then, 2.0 g of 75% H3PO4 was added, and the resulting solution was stirred at room temperature overnight. No attempt was made to isolate the pure 9 or 10-sulfoperoxystearic acid from solution. 13C NMR (D2O) of the solution showed a peracid peak (COOOH) at 174 ppm and the parent the carboxylic acid peak at 178 ppm. The iodometric titration (QATM-202) indicated 18.96% of sulfoperoxystearic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]=C)[CH:12]=[CH:11][C:10]=1[N:17]1[S:21](=[O:23])(=[O:22])[N:20]([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:19](=[O:30])[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:34]CC1.CC(O)(C)C.O.C([O-])(O)=O.[Na+]>CC(O)(C)C.O.O=[Os](=O)(=O)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:12]=[CH:11][C:10]=1[N:17]1[CH2:18][C:19](=[O:30])[N:20]([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[S:21]1(=[O:23])=[O:22])[CH:15]=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C=O)cc2OCc2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-(2-benzyloxy-4-vinylphenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (1.9 g, 4.3 mmol) in 1:1:1 THF/t-BuOH/H2O (60 mL) is added 1-methylmorpholine-N-oxide (551 mg, 4.74 mmol) and OsO4 (2 mL of a 2.5 wt % solution in t-BuOH, 0.17 mmol). The reaction is stirred for 4 h at ambient temperature, then diluted with water (15 mL) and treated with NaIO4 (4.5 g, 21.5 mmol) and NaHCO3 (3.6 g, 43 mmol). The mixture is stirred vigorously for 1 h, then filtered through Celite. The solution is extracted with EtOAc. The organic phase is washed with saturated NaCl. The solution is dried over MgSO4 and the solvent removed under reduced pressure, then purified via silica gel chromatography using a gradient of 0-40% EtOAc/hexanes to afford 3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-benzaldehyde as a white solid: MS (M+NH4)+=464.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]1)[N:7]=[CH:6]2.B(Br)(Br)Br.O=S(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH2:13][N:14]1[CH2:15][CH2:16][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:19]1)[N:7]=[CH:6]2
Reactant: COC(=O)C1CCN(Cc2ncc3cc(OC)ccc3n2)CC1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCN(Cc2ncc3cc(O)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.4 %

Procedure:
To a solution of methyl 1-((6-methoxyquinazolin-2-yl)methyl)piperidine-4-carboxylate (3.0 g, 9.5 mmol) in DCM (15 mL) was added BBr3 (9.5 mmol, 1.0 eq) at 0° C. under N2. The reaction was stirred at room temperature for 16 h. After the removal of solvent, SOCl2 (2.8 g, 0.238 mol, 1.5 eq) and MeOH (20 mL) was added at 0° C. The mixture was refluxed at 80° C. for 3 h, poured into the NaHCO3 aqueous solution and extracted with DCM (100 mL*3). The combined extracts were dried over anhydrous Na2SO4 and evaporated to dryness in vacuum. The crude product was purified by chromatography (eluting with DCM/MeOH=25/1) to give methyl 1-((6-hydroxyquinazolin-2-yl)methyl)piperidine-4-carboxylate (1.7 g, yield: 77%) as a yellow solid. 1HNMR (400 MHz, DMSO-d6) δ: 10.36 (s, 1H), 9.35 (s, 1H), 7.84 (d, J=9.2 Hz, 1H), 7.51 (dd, J=9.2, 2.4 Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 3.74 (s, 2H), 3.57 (s, 3H), 2.86˜2.84 (m, 2H), 2.27 (m, 1H), 2.16 (m, 2H), 1.77 (m, 2H), 1.56 (m, 2H); ESI-MS: m/z 302.1 ([M+1]+).
Reaction SMILES: [C:1]1([N:7]2[C:19](=[O:20])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[CH3:42][CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>C(Cl)Cl>[CH3:42][CH:43]1[CH2:48][CH2:47][N:46]([C:34]([N:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]3=[N:8][N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19](=[O:20])[C:10]3=[CH:11]2)=[O:40])[CH2:45][CH2:44]1
Reactant: CC1CCNCC1
Reactant: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(C(=O)n2cc3c(=O)n(-c4ccccc4)nc-3c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-phenyl-2,5-dihydro-pyrazolo-(4,3-c)quinolin-3-one (4a) (0.261 g, 1 mM) in 2 mL of anhydrous methylene chloride was stirred with N,N-diisopropylethylamine (0.145 g, 1.2 mM) and triphosgene (0.173 g, 0.55 mM) at 0° C. for 1 hour and 25° C. for 2 hours. N,N-diisopropylethylamine (0.145 g, 1.2 mM) and 4-methylpiperidine (0.208 g, 2 mM) were added at 0° C. and the reaction mixture was stirred overnight at room temperature. The reaction was quenched by addition of aqueous sodium bicarbonate solution. The organic layer was collected, washed with brine solution, dried over sodium sulfate, filtered and concentrated in vacuo. The product was obtained by column chromatography. 1H NMR (CDCl3) δ (ppm): 1.0 (3H, d, J=6.59), 1.6 (4H,m), 1.84 (1H,m), 3.14 (1H,m), 3.30 (1H,m), 4.01, (1H,m), 4.60 (1H,m), 7.20 (1H, t, J=8.57), 7.38 (1H, m), 7.68-7.42 (4H, m), 8.18 (2H, m), 8.28 (1H, s), 8.44 (1H, d, J=8.81 Hz). m/z 387.5 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[N:14][CH:15]=3)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1NC.[CH3:41][N:42](C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C(O[Na])(C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:20]1([CH2:19][CH2:18][NH:17][C:13]2[N:12]=[C:11]3[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:42][CH2:41][C:35]5[S:34][CH:38]=[CH:37][CH:36]=5)[CH:3]=4)[C:16]3=[CH:15][N:14]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)c2)c2cnc(NCCN3CCOCC3)nc21
Reactant: CNc1cccs1
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc(-c2cccc(NCc3cccs3)c2)c2cnc(NCCN3CCOCC3)nc21

Procedure:
To a stirred solution of [3-(3-bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 40 supra) (250 mg, 0.468 mmol), thiophen-2-yl-methylamine (80 mg, 0.70 mmol), DavePhos (30 mg, 0.076 mmol) and t-BuONa (70 mg, 0.73 mmol) in 1,4-dioxane (10 mL), Pd2(dba)3 (42 mg, 0.073 mmol) was added in one portion under N2 atmosphere. The resultant mixture was stirred at 100° C. for 4 hours. The mixture was cooled and filtered; the filtrate was evaporated under reduced pressure to give the crude product. It was purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH, 100:1, v/v) to give (2-morpholin-4-yl-ethyl)-[3-{3-[(thiophen-2-ylmethyl)-amino]-phenyl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-amine. (Yield 170 mg, 64.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH:14](=O)[CH2:15][CH2:16][CH3:17]>>[CH2:14]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCC=O
Reactant: COC(=O)CCc1ccc(N)cc1
Product: CCCCNc1ccc(CCC(=O)OC)cc1
Yield: 35.7 %

Procedure:
Following a procedure analogous to that for the synthesis Example 106, methyl 3-(4-aminophenyl)propanoate (Jakobsen, C. M. et al., J. Med. Chem., 44:4696-4703 (2001)) (896 mg, 5.00 mmol) and butyraldehyde (397 mg, 5.50 mmol) were converted to the title compound (420 mg, 44%). 1H NMR (CDCl3) δ 7.01 (d, J=8.4 Hz, 2H), 6.60-6.47 (m, 2H), 3.68 (s, 3H), 3.10 (t, J=7.2 Hz, 2H), 2.89-2.77 (m, 2H), 2.62-2.46 (m, 2H), 1.66-1.53 (m, 2H), 1.43 (qd, J=15.0, 7.3 Hz, 2H), 0.96 (t, J=7.3 Hz, 3H); MS (ESI+) m/z 236.0 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]([CH2:14][CH3:15])[C:11](Cl)=[S:12])[CH3:9].[F:16][C:17]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][N:18]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:8]([N:10]([CH2:14][CH3:15])[C:11]([O:23][C:22]1[C:17]([F:16])=[N:18][CH:19]=[CH:20][CH:21]=1)=[S:12])[CH3:9]
Reactant: CCN(CC)C(=S)Cl
Reactant: Oc1cccnc1F
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CC)C(=S)Oc1cccnc1F
Temperature: 75 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
36.2 g (358 mmol) of triethylamine and 54.3 g (358 mmol) of diethylthiocarbamoyl chloride are added in succession to a suspension of 36.7 g (325 mmol) of 2-fluoro-3-hydroxypyridine in 150 ml of toluene at room temperature, and the reaction mixture is heated at 75° C. After the reaction mixture has been stirred at this temperature for 1 hour, it is cooled to room temperature, diluted with ethyl acetate, washed 3 times with water, dried over Na2SO4 and concentrated in vacuo at 60° C.; 80 g of brown oil which, after recrystallization from Et2O/hexane, gave 64.2 g (86%) of brown crystals of m.p. 52°-54° C.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl[CH2:11][C:12]1[CH2:13][S:14][C@@H:15]2[C@H:35]([NH:36][C:37](=[O:45])[CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:34](=[O:46])[N:16]2[C:17]=1[C:18]([O:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].[SH:47][C:48]1[CH2:52][O:51][C:50](=[O:53])[CH:49]=1>ClCCl>[O:53]=[C:50]1[CH:49]=[C:48]([S:47][CH2:11][C:12]2[CH2:13][S:14][C@@H:15]3[C@H:35]([NH:36][C:37](=[O:45])[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:34](=[O:46])[N:16]3[C:17]=2[C:18]([O:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:52][O:51]1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: O=C1C=C(S)CO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSC3=CC(=O)OC3)CS[C@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
N,N-Diisopropylethylamine (0.52 ml) was added to a stirred solution of diphenylmethyl 3-chloromethyl-7β-phenylacetamidoceph-3-em-4-carboxylate (1.59 g) and 4-mercapto-2(5H)-furanone (400 mg) in dichloromethane (30 ml). The mixture was stirred at room temperature for 2 hours and then washed successively with aqueous citric acid solution, water, sodium bicarbonate solution, water and brine. The solution was dried over magnesium sulphate and evaporated. The title compound (1.64 g) was isolated by column chromatography of the residue using gradient elution (Kieselgel, 1:1 going to 3:7 hexane:ethyl acetate), m.p. 178°-180° C. from ethyl acetate/hexane (Found: C, 64.89; H, 4.61; N, 4.57; S, 10.30: C33H28N2O6S2 requires; C, 64.69; H, 4.61; N, 4.57; S, 10.47). υmax (CHCl3) 3400, 1780, 1745, and 1680 cm-1. δH (CDCl3) 3.36 (1H, d, J 18.3Hz), 3.57 (1H, d, J 18.3Hz), 3.62 (1H, d, J 16.2Hz), 3.70 (1H, d, J 16.2Hz), 3.86 (1H, d, J 12.5Hz), 4.01 (1H, d, J 12.5Hz), 4.71 (2H, s), 4.98 (1H, d, J 4.8Hz), 5.64 (1H, s), 5.88 (1H, dd, J 4.8 and 9.0Hz), 6.06 (1H, d, J 9.0Hz), 6.95 (1H, s), 7.2-7.4 (15H, m).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH2:9])[C:3]=1[N+:10]([O-:12])=[O:11].FC(F)(F)C(O)=O.[NH2:20][C@@H:21]1[C@@H:26]2[CH2:27][C@@H:23]([CH:24]=[CH:25]2)[C@@H:22]1[C:28]([NH2:30])=[O:29].C(N(CC)C(C)C)(C)C>C(O)(C)C>[NH2:9][C:4]1[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:20][C@@H:21]2[C@@H:26]3[CH2:27][C@@H:23]([CH:24]=[CH:25]3)[C@@H:22]2[C:28]([NH2:30])=[O:29])[C:7]([Cl:8])=[CH:6][N:5]=1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: NC(=O)[C@@H]1[C@H](N)[C@H]2C=C[C@@H]1C2
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2[N+](=O)[O-])[C@H]2C=C[C@@H]1C2
Temperature: 60 °C
Yield: 94.9 %

Procedure:
4,5-Dichloro-3-nitro-pyridin-2-ylamine (1.01 g, 4.86 mmol) and (1S,2S,3R,4R)-3-Amino-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide trifluoroacetic acid salt (1.5 g, 5.5 mmol) were combined with N,N-diisopropylethylamine (3.3 g, 26 mmol) in isopropanol (15 mL) and heated at 60° C. overnight. The reaction was permitted to cool to room temperature and the orange solid which had formed was isolated by filtration. The solid was washed with 3 mL cold isopropanol and was dried in an air stream to afford 1.493 g (95%) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].II>C(#N)C>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:3]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: CCOC(=O)C(C)Br
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)n1nc(C)cc1C
Reaction time: 24 h
Yield: 71.2 %

Procedure:
A suspension of 3,5-dimethyl-1H-pyrazole (ALDRICH, 8 g, 0.083 mol), anhydrous K2CO3 (ALDRICH, 11.50 g, 0.083 mol) and ethyl 2-bromopropanoate (ALDRICH, 15 g, 0.083 mol) in 50 mL of dry ACN was refluxed with mechanical stirring for 24 h. Reaction was checked by TLC (iodine), and starting material was detected. 0.2 equivalents of K2CO3 were added to the mixture which was refluxed over the weekend. Reaction was checked, starting material was still detected. 0.2 eq. of K2CO3 were added to the mixture, which was refluxed during 24 additional hours. Reaction mixture was filtered. Solvent was evaporated under reduced pressure. Residue was diluted with 50 ml of DCM, and washed with water. Organic layer was separated and aqueous fraction was extracted three times with 70 mL of DCM. Combined organic extracts were washed with brine, dried over Na2SO4 (anh), filtered and concentrated under reduce pressure. Residue was purified using a 70 g silica gel cartridge with a linear gradient of hexane/EtOAc 100/0 to 20/80 to yield the title compound (11.6 g 71%) as colourless oil. 1H NMR (300 MHz, CDCl3) δ ppm: 5.83 (s, 1H), 4.85 (q, 1H), 4.08-4.25 (m, 2H), 2.22-2.23 (m, 6H), 1.79 (d, 3H), 1.23 (t, 3H).
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.[CH3:26][N:27]([CH3:47])[CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1>>[CH3:47][N:27]([CH3:26])[CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]([F:23])([F:21])[F:22])[N:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)=[CH:34][N:33]=1
Reactant: CN(C)CCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CN(C)CCCOc1ccc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1

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 dimethyl-{3-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yloxy]-propyl}-amine to give 121. MS(ESI+) 531.2. 1H NMR (400 MHz, DMSO) δ 8.56 (d, J=2.2, 1H), 8.38 (d, J=8.3, 1H), 8.30 (s, 1H), 8.09 (dd, J=8.7, 2.5, 1H), 7.54 (dd, J=8.3, 1.8, 1H), 7.41 (d, J=1.7, 1H), 6.89 (d, J=8.6, 1H), 5.87 (q, J=8.7, 2H), 4.43 (t, J=4.9, 2H), 4.33 (t, J=6.6, 2H), 3.49 (t, J=4.9, 2H), 2.37 (t, J=7.1, 2H), 2.16 (s, 6H), 1.87 (p, J=6.8, 2H)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Li])CCC.[Li][CH:20]1C2N=CC(C)=CC=2CCC1(C)C.[C:33](=[O:35])=[O:34]>CCOCC.CCCCCC>[CH3:20][O:34][C:33]([CH:6]1[C:5]2[N:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:10]=2[CH2:9][CH2:8][C:7]1([CH3:13])[CH3:12])=[O:35]
Reactant: O=C=O
Reactant: Cc1cnc2c(c1)CCC(C)(C)C2
Reactant: [Li]C1c2ncc(C)cc2CCC1(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COC(=O)C1c2ncc(C)cc2CCC1(C)C
Reaction time: 0.5 h

Procedure:
3,7,7-Trimethyl-5,6,7,8-tetrahydroquinoline (17.5 g, 0.1 m) was dissolved in dry ether (200 ml.) and treated with a solution of n-butyl lithium in hexane (15% w/w solution, 56 ml.) under nitrogen. The reaction mixture containing 8-lithio-3,7,7-trimethyl-5,6,7,8-tetrahydroquinoline was allowed to stand at room temperature for 30 minutes and then treated with CO2 gas until the intense red colour was discharged. The reaction mixture was further treated as described in Example 36 of our copending U.S. Ser. No. 460,265 to give methyl-3,7,7-trimethyl-5,6,7,8-tetrahydroquinoline-8-carboxylate.