Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:18])[C:15]([F:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=O)[CH3:6])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:18])[C:15]([F:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[S:30])[CH3:6])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(C)N1C(=O)COc2cc(F)c(Br)cc21
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)N1C(=S)COc2cc(F)c(Br)cc21
Temperature: 25 °C
Yield: 80.2 %

Procedure:
To a mixture of 2-(6-bromo-7-fluoro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (43.0 g, 124 mmol) in toluene (300 mL) was added Lawesson's reagent (50.6 g, 124 mmol) and the mixture was heated at reflux overnight. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo The residue was purified by chromatography on silica gel (eluting with 5% EtOAc in petroleum ether) to give 2-(6-bromo-7-fluoro-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (36.0 g, 80%). 1H NMR (CDCl3, 400 MHz): δ 7.09 (d, J=6.4 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.62 (brs, 1H), 4.96 (dd, J=15.2 Hz, 2H), 4.23 (m, 2H), 1.72 (d, J=7.2 Hz, 3H), 1.21 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:18]3[CH:19]=[C:20]([CH:23]=O)[S:21][CH:22]=3)=[N:13][C:12]([CH:25]([CH3:27])[CH3:26])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.[OH-].[K+]>C(O)CO.O>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:18]3[CH:19]=[C:20]([CH3:23])[S:21][CH:22]=3)=[N:13][C:12]([CH:25]([CH3:27])[CH3:26])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc2c(c(-c3csc(C=O)c3)n1)CCN(Cc1ccccc1)C2
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1cc(-c2nc(C(C)C)nc3c2CCN(Cc2ccccc2)C3)cs1
Temperature: 200 °C
Reaction time: 6 h
Yield: 65.9 %

Procedure:
To a solution of the product of Step A (0.230 g) in ethylene glycol was added hydrazine hydrate (0.1 mL). The mixture was heated at 200° C. for 1 h, then KOH (0.150 g) was added and the heating continued for 6 h. The mixture was allowed to cool then was diluted with water and extracted with Et2O. The combined organic extracts were dried and concentrated to 0.210 g of pale yellow solid. Chromatography on SiO2 (EtOAc/hexanes) afforded 0.146 g of the title compound. MS (ESI): exact mass calcd. for C22H25N3S, 363.18; found m/z 364.4 [M+H]+. 1H NMR (MeOH-d4): 7.85-7.84 (m, 1H), 7.65-7.63 (m, 2H), 7.56-7.55 (m, 3H), 7.37-7.36 (m, 1H), 4.60 (br s, 2H), 4.44 (br s, 2H), 3.46-3.32 (m, 2H), 3.22-3.17 (m, 1H), 2.55 (s, 3H), 1.34 (d, J=7.2, 6H).
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9]OC(OC)OC>C1(C)C(S(O)(=O)=O)=CC=CC=1>[CH3:9][O:8][C:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C1CCCCCC1
Reactant: COC(OC)OC
Agent: Cc1ccccc1S(=O)(=O)O
Product: COC1=CCCCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71 %

Procedure:
At 0° C., cycloheptanone (1) (5 cm3, 42.61 mmol, 1 eq.), trimethylorthoformate (5.2 cm3, 46.88 mmol, 1.1 eq.) and anhydrous toluenesulphonic acid (40 mg, 0.213 mmol, 0.05 eq.) were allowed to warm to room temperature and left to stand for 2 days. Crude 1H-NMR spectroscopy indicated formation of the intermediate ketal. Distillation, initially at atmospheric pressure, then at water aspirator pressure (ca. 15 mm/Hg) afforded the product 2 (3.82 g, 71%) as a colourless liquid (b.p. 130-140° C./15 mm/Hg). δH (250 MHz, CDCl3) 1.35-1.55 (4H, m, CH), 1.59-1.74 (2H, m, CH2), 1.97-2.08 (2H, m, CH2), 2.12-2.25 (2H, m, CH2), 3.39 (3H, s, CH3), 4.67 (1H, t, J 7.0 Hz, CH); m/z (CI) 127 (MH+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=O.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:16][C:17]([OH:19])=[O:18])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][O:13][CH3:14]
Reactant: COCCOc1ccc(C=O)cc1F
Reactant: O=C(O)CC(=O)O
Product: COCCOc1ccc(C=CC(=O)O)cc1F

Procedure:
Similar procedure as described in example 343a was used, starting from 3-Fluoro-4-(2-methoxy-ethoxy)-benzaldehyde and malonic acid to give 3-[3-Fluoro-4-(2-methoxy-ethoxy)-phenyl]-acrylic acid. LC-MS: m/e 241 (MH+).
Reaction SMILES: O[CH:2]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:3][CH3:4].P(Br)(Br)[Br:20]>C(Cl)(Cl)Cl>[Br:20][CH:2]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:3][CH3:4]
Reactant: CCC(O)c1ccc(-c2ccc(C#N)cc2)cn1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: CCC(Br)c1ccc(-c2ccc(C#N)cc2)cn1
Temperature: 25 °C
Yield: 145.5 %

Procedure:
To a solution of 4-(6-(1-hydroxypropyl)pyridin-3-yl)benzonitrile (0.10 g, 0.21 mmol) in chloroform (4 mL) was added PBr3 (0.34 g, 0.63 mmol) at 0-5° C. This temperature was maintained for 15 min, was slowly allowed to rt and was then maintained at rt for another 90 min. The contents were diluted with chloroform (100 mL) and washed with bicarbonate solution (2×30 mL). The organic layer was separated, dried over sodium sulphate and evaporated to provide 4-(6-(1-bromopropyl)pyridin-3-yl)benzonitrile (92 mg, 73% yield).
Reaction SMILES: [NH2:1][C@H:2]1[C@H:5]([CH3:6])[N:4]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]1=[O:15].C1(C)C(S([O-])(=O)=O)=CC=CC=1.[CH3:27][O:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[C:30]=1[C:31](Cl)=[O:32]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:39][O:38][C:34]1[CH:35]=[CH:36][CH:37]=[C:29]([O:28][CH3:27])[C:30]=1[C:31]([NH:1][C@H:2]1[C@H:5]([CH3:6])[N:4]([O:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:3]1=[O:15])=[O:32]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: C[C@H]1[C@H](N)C(=O)N1OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cc1ccccc1S(=O)(=O)[O-]
Solvent: ClCCl
Product: COc1cccc(OC)c1C(=O)N[C@@H]1C(=O)N(OCc2ccccc2)[C@H]1C
Reaction time: 5 h

Procedure:
To a cold (-10° C.) solution of (3S-trans)-3-amino-4-methyl-1-(phenylmethoxy)-2-azetidinone, toluenesulfonate (0.95 g; see example 2D) in methylene chloride (50 ml) is added 2,6-dimethoxybenzoyl chloride (0.60 g) and 4-dimethylaminopyridine (0.61 g). The reaction is stirred under nitrogen and allowed to rise to 26° C. over five hours. The reaction mixture is concentrated to an oil and partitioned between ethyl acetate and aqueous hydrogen sulfate solution. The organic layer is washed with aqueous sodium bicarbonate, and brine, dried over sodium sulfate and concentrated to a foam (0.848 g).
Reaction SMILES: Cl.[F:2][C:3]([F:13])([F:12])[C:4]1[N:5]=[C:6]([C:9]([NH2:11])=[NH:10])[S:7][CH:8]=1.C([O:16][C:17]([C:19]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:20][O-])=O)C.[Na+].CC[O-].[Na+]>CCO>[O:22]([C:19]1[C:17]([OH:16])=[N:10][C:9]([C:6]2[S:7][CH:8]=[C:4]([C:3]([F:2])([F:12])[F:13])[N:5]=2)=[N:11][CH:20]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N=C(N)c1nc(C(F)(F)F)cs1
Reactant: CCOC(=O)C(=C[O-])Oc1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Oc1nc(-c2nc(C(F)(F)F)cs2)ncc1Oc1ccccc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of compound 282 (280 mg, 1 eq.) in dry EtOH (6 mL) was added compound 291 (1.38 g, 5 eq.) under nitrogen, followed by NaOEt (165 mg, 1 eq.). The reaction mixture was stirred at 90° C. for 2 hrs. EtOH was evaporated and a DCM/water mixture was added. Aqueous layer was acidified to pH 5 with aqueous 1N HCl and was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo, and purified by chromatography on silica gel (DCM/MeOH) to yield compound AI1 as a beige oil in 81% yield. MS (ESI, EI+): m/z=340 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[S:11][CH:12]=[CH:13][C:14]=2[CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)O)=[CH:4][CH:3]=1.C[Si](I)(C)C.[I-].[Na+].Cl[Si](C)(C)C.[OH-].[Na+]>C(#N)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:10]2[S:11][CH:12]=[CH:13][C:14]=2[CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:6][CH:7]=1
Reactant: OC(c1ccc(F)cc1)c1sccc1CCN1CCCC1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)I
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Fc1ccc(Cc2sccc2CCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
(4-Fluorophenyl)(3-(2-(pyrrolidin-1-yl)ethyl)thiophen-2-yl)methanol from step (ii) was reduced with trimethylsilyliodide in accordance with published procedure (See reference: Tetrahedron 1995, 51 (41), 11043-11062.) A dry three-necked flask equipped with an addition funnel and a nitrogen inlet was charged with sodium iodide (0.87 g, 5.8 mmol) and acetonitrile (5.0 mL). Then, chlorotrimethylsilane (0.73 mL, 5.8 mmol) was added via syringe and the reaction mixture was allowed to stir at ambient temperature for about 15 min. At that time, the bright yellow mixture was cooled to 0° C. and a solution of (4-fluorophenyl)(3-(2-(pyrrolidin-1-yl)ethyl)thiophen-2-yl)methanol (353 mg, 1.16 mmol) in acetonitrile (5 mL) was added dropwise over the course of an hour. The reaction mixture was allowed to warm to room temperature over 16 h and then cooled back down below 5° C. before work-up. A solution of NaOH (5 N, 1.5 mL, 7.5 mmol) was added and the reaction mixture cooled to rt before it was diluted with EtOAc and stirred for an additional 10 min. The layers were separated and the aqueous layer extracted with another portion of EtOAc. The combined organic layers were washed with a solution of saturated aqueous Na2S2O3.5H2O, water, and brine, dried over MgSO4, and concentrated. The resulting residue was purified by flash chromatography, eluting with 1-10% (0.5 M ammonia in MeOH)/dichloromethane to afford the product as a pale yellow oil (160 mg, 0.56 mmol, 48% yield). MS (M+H)+ 290.
Reaction SMILES: [CH2:1]([N:5]1[C:17]([CH2:18][CH2:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])=[C:16]2[C:7]([C:8]([NH2:26])=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)=[N:6]1)[CH2:2][CH2:3][CH3:4]>FC(F)(F)C(O)=O.[Pt](=O)=O>[CH2:1]([N:5]1[C:17]([CH2:18][CH2:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:21])=[O:22])=[C:16]2[C:7]([C:8]([NH2:26])=[N:9][C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=32)=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc2c(N)nc3ccccc3c2c1CCS(=O)(=O)CCC
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCn1nc2c(N)nc3c(c2c1CCS(=O)(=O)CCC)CCCC3
Reaction time: 20 h
Yield: 81.3 %

Procedure:
A solution of 2-butyl-1-[2-(propylsulfonyl)ethyl]-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 60, 0.50 g, 1.3 mmol) in trifluoroacetic acid (6 mL) was treated with platinum (IV) oxide (0.5 g) and shaken under hydrogen pressure (50 psi, 3.4×105 Pa) for 20 hours on a Parr apparatus. The reaction mixture was filtered through a layer of CELITE filter agent, and the CELITE filter agent was rinsed with dichloromethane (100 mL) until the rinses were clear. The filtrate was concentrated under reduced pressure. The oil was suspended in water (20 mL) and treated with 50% aqueous sodium hydroxide to adjust the mixture to pH 14, causing a precipitate to form. The mixture was stirred for 1 hour, then the precipitate was isolated by filtration and washed with water. The white powder was recrystallized from acetonitrile (5 mL). The crystals were isolated by filtration, washed with acetonitrile, and dried under vacuum at 65° C. to afford 0.40 g of 2-butyl-1-[2-(propylsulfonyl)ethyl]-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine as white crystals, mp 173-175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:35])C=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([C:18]4[CH:23]=[CH:22][N+:21]([O-:35])=[CH:20][CH:19]=4)[CH2:14]3)=[O:12])[CH2:9][CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(N1CC[C@@H](c2ccncc2)C1)C1(c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Product: O=C(N1CC[C@@H](c2cc[n+]([O-])cc2)C1)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4-((3S)-1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-yl)pyridine (20 mg, 0.00006 mol, example 24) was dissolved in dichloromethane (1 mL, 0.02 mol) and to this solution was added m-chloroperbenzoic acid (44 mg, 0.00015 mol). The reaction mixture was stirred at 25° C. for 2.5 h. The reaction mixture then was concentrated and the residue was diluted with NaHCO3 and methanol. The crude product was purified by prep-HPLC. LCMS: m/z 343.4 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1C=[C:17]2C([C:21]([OH:25])([OH:24])[C:22](=O)[C:16]2=[CH:15]C=1)=O>Cl>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:2][NH:1][C@H:22]([C:21]([OH:25])=[O:24])[CH:16]([CH3:17])[CH3:15]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Product: CN[C@H](C(=O)O)C(C)C

Procedure:
Constituent amino acids: K-4 is hydrolyzed in 6N hydrochloric acid at 110° C. for 20 hours and the resulting mixture is analyzed by an amino acid automatic analyzer, whereby phenylalanine and an unidentified ninhydrin reaction-positive substance are detected. Separately, a solution of K-4 in 20% hydrochloric acid is stirred at 110° C. for 21 hours and then concentrated under reduced pressure. The residue is chromatographed on a column of silica gel (developing solvent: n-butanol:acetic acid:water=4:1:1) to give phenylalanine, N-methylvaline and the aforesaid ninhydrin reaction-positive substance.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CCN(CC)CC.[F:27][C:28]1[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[CH:33][C:29]=1[C:30](Cl)=[O:31]>C(Cl)Cl>[F:27][C:28]1[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[CH:33][C:29]=1[C:30]([NH:2][C@H:3]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])=[O:31]
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(F)c(F)c(F)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To an ice-cold solution of di-tert-butyl L-glutamate hydrochloride (6.6 g, 22.4 mmol) and Et3N (6.9 ml, 50 mmol) in dry CH2Cl2 (70 ml) was added, over a period of 1.5 hr, 2,3,4,5-tetrafluorobenzoyl chloride (5.0 g, 23.5 mmol) in dry CH2Cl2 (20 ml) and thirty minutes later the solution was allowed to warm to room temperature. Sixteen hours later the solution was washed with H2O, dried (MgSO4) and evaporated to dryness. 1H NMR δ 1.40+1.42 (2s, 18H, t-butyl), 1.85+1.95 (2m, 2H, CH2CH), 2.34 (t, 2H, CH2CO, J=7.5 Hz), 4.3 (m, 1H, CH), 7.57 (m, 1H, H6), 8.80 (d, 1H, NH, J=7.5 Hz); 19F NMR δ −138.6+139.0 (2m, 2F, F2+5), −152.4 (m, 1H, F4), −154.9 (t, 1F, F3, J=20 Hz).
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[O:10]1[CH2:13][C:12](=[O:14])[CH2:11]1>>[Cl:9][C:3]1[C:2]([C:12]2([OH:14])[CH2:13][O:10][CH2:11]2)=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=1
Reactant: Cc1ccc(Br)c(Cl)n1
Reactant: O=C1COC1
Product: Cc1ccc(C2(O)COC2)c(Cl)n1
Yield: 70.8 %

Procedure:
In analogy to the procedure described in Example 130 a), 3-bromo-2-chloro-6-methylpyridine (CAN 185017-72-5, 5 g, 24.2 mmol) was reacted with oxetan-3-one (CAN 6704-31-0, 1.75 g, 1.42 mL, 24.2 mmol) to give the title compound (3.42 g, 71%) as off-white solid, MS (ESI): m/e=200.5 [MH+].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[NH:11][CH2:10][CH2:9][N:8]([C:12](OCC)=O)[CH2:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH3:12][N:8]1[CH2:9][CH2:10][NH:11][CH:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH2:7]1
Reactant: CCOC(=O)N1CCNC(c2cccs2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CN1CCNC(c2cccs2)C1
Temperature: 25 °C

Procedure:
A solution of ethyl 3-(2-thienyl)piperazine-carboxylate (27.2 g, 0.11 mol; Preparation 2) in diethyl ether (300 ml) is added to a stirred suspension of lithium aluminum hydride (10.8 g, 0.28 mol) in diethyl ether (1300 ml). The mixture is refluxed for 12 h, cooled to room temperature and worked up as described in "Reagents for Organic Synthesis" , Fieser, L. F. and Fieser, M., John Wiley and Sons, Inc., New York, N.Y. 1967, p. 583. The ether solution is dried (potassium carbonate) and evaporated to give 1-methyl-3-(2-thienyl)piperazine as a light yellow oil, which is characterized as the maleate salt (m.p. 123°-124.5° C.), which is prepared in the manner described in Preparation 2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:18](=O)[CH2:19]Br)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:22][CH3:23])[CH:7]=1)=[O:5])[CH3:2].[C:24]([N:27]([CH2:29][C:30]([NH2:32])=[S:31])[CH3:28])(=[O:26])[CH3:25]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:18]3[N:32]=[C:30]([CH2:29][N:27]([C:24](=[O:26])[CH3:25])[CH3:28])[S:31][CH:19]=3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:22][CH3:23])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2cc(C(=O)CBr)c(F)cc2c1=O
Reactant: CC(=O)N(C)CC(N)=S
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2cc(-c3csc(CN(C)C(C)=O)n3)c(F)cc2c1=O

Procedure:
According to example 30, reacting 7-bromoacetyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester with 2-(N-acetyl-N-methylamino)thioacetamide in ethanol gave 1-ethyl-6-fluoro-7-[2-(N-acetyl-N-methylaminomethyl)-4-thiazolyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, mp 173°-175° C. which was then hydrolyzed in refluxing 6N hydrochloric acid to give the title compound, mp 230°-234° C. (dec).
Reaction SMILES: [CH3:1][S:2][CH:3]1[NH:6][C:5](=[O:7])[CH2:4]1.Br[CH2:9][C:10](=[O:21])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>>[CH3:1][S:2][CH:3]1[N:6]([CH2:9][C:10](=[O:21])[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)[C:5](=[O:7])[CH2:4]1
Reactant: O=C(CBr)Cc1ccc([N+](=O)[O-])cc1
Reactant: CSC1CC(=O)N1
Product: CSC1CC(=O)N1CC(=O)Cc1ccc([N+](=O)[O-])cc1

Procedure:
4-Methylthioazetidin-2-one (470 mg., 4 mmole) and 1-bromo-3-p-nitrophenylpropan-2-one (1.05 g., 4.07 mmole) were converted into the title compound using the process described in Example 1.1. The title compound was obtained as a yellow gum (176 mg., 15% yield). νmax (CHCl3): 1765 (β-lactam C=O), 1735 (ketone C=O), 1605 (aromatic C=C), 1530 and 1355 (aromatic NO2) cm-1. δ(CDCl3): 1.98 (s, 3H, SCH3), 2.98 (dd, J 15, J' 3Hz, 1H, β-lactam CHH), 3.42 (dd, J 15, J' 6Hz, 1H, β-lactam CHH), 3.80 (d, J 18Hz, 1H, NCHH), 3.88 (s, 2H, COCH2Ar), 4.38 (d, J 18Hz, 1H, NCHH), 4.82 (dd, J 6, J' 3Hz, 1H β-lactam CH), 7.43 (d, J 8.5Hz, 2H, Ar-H), 8.22 (d, J 8.5Hz, 2H, Ar-H).
Reaction SMILES: CO[C:3](=[O:13])[CH2:4][CH2:5][O:6][N:7]=[C:8]([O:10][CH2:11][CH3:12])[CH3:9].[CH2:14]([NH2:17])[CH2:15][CH3:16]>CO>[CH2:11]([O:10][C:8](=[N:7][O:6][CH2:5][CH2:4][C:3](=[O:13])[NH:17][CH2:14][CH2:15][CH3:16])[CH3:9])[CH3:12]
Reactant: CCOC(C)=NOCCC(=O)OC
Reactant: CCCN
Solvent: CO
Product: CCCNC(=O)CCON=C(C)OCC
Temperature: 55 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
To a known compound, 3-(1-ethoxy-ethylideneaminooxy)-propanoic acid methyl ester (CAS No. 97164-30-2, 300 mg, 1.585 mmol) were added methanol (3 ml) and n-propylamine (1.3 ml), and the mixture was stirred at 55° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give N-(2-propylcarbamoyl-ethoxy)-acetimidic acid ethyl ester (296 mg, 86% yield).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:15]2[CH:14]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:12]=[CH:11][C:10]=2[C:9]2[N:25]([CH:28]3[CH2:32][CH2:31][O:30][CH2:29]3)[N:26]=[CH:27][C:8]=2[C:7]1=[O:33].Cl.O1CC(NN)COCC1.Br[C:51]1[C:56]([CH3:57])=[CH:55][N:54]=[C:53]([O:58][CH3:59])[C:52]=1[CH3:60].C(=O)([O-])[O-].[Cs+].[Cs+]>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.O1CCOCC1>[CH3:59][O:58][C:53]1[C:52]([CH3:60])=[C:51]([C:13]2[CH:12]=[CH:11][C:10]3[C:9]4[N:25]([CH:28]5[CH2:32][CH2:31][O:30][CH2:29]5)[N:26]=[CH:27][C:8]=4[C:7](=[O:33])[NH:6][C:15]=3[CH:14]=2)[C:56]([CH3:57])=[CH:55][N:54]=1
Reactant: COc1ccc(Cn2c(=O)c3cnn(C4CCOC4)c3c3ccc(B4OC(C)(C)C(C)(C)O4)cc32)c(OC)c1
Reactant: COc1ncc(C)c(Br)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: NNC1COCCOC1
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(C)c(-c2ccc3c(c2)[nH]c(=O)c2cnn(C4CCOC4)c23)c1C
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of (±)-5-(2,4-dimethoxybenzyl)-1-(tetrahydrofuran-3-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one obtained in Preparation Example 5 (219 mg), 4-bromo-2-methoxy-3,5-dimethylpyridine obtained in Preparation Example 28 (134 mg), Pd(PPh3)4 (23.8 mg) and cesium carbonate (403 mg) was reacted in a mixed solvent of 1,4-dioxane (8 mL) and water (2 mL) using a microwave reactor at 130° C. for 70 minutes. The reaction mixture was cooled to mom temperature and then directly purified by silica gel column chromatography (ethyl acetate/n-heptane, 10% to 90%). The resulting coupling product was dissolved in TFA (4 mL), and the mixture was stirred at 70° C. for two hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. A saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM, 100%, then ethyl acetate/n-heptane, 50% to 100%) to give the title compound (78 mg).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7](Cl)(=[O:9])=[O:8].[H-].[Na+].[CH3:13][C:14]([CH3:27])([CH3:26])[C:15]([O:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16]>>[CH3:13][C:14]([CH3:27])([CH3:26])[C:15]([O:17][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[S:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[Br:1])(=[O:9])=[O:8])=[O:16]
Reactant: CC(C)(C)OC(=O)NOC(=O)C(C)(C)C
Reactant: O=S(=O)(Cl)c1sccc1Br
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(OC(=O)C(C)(C)C)S(=O)(=O)c1sccc1Br

Procedure:
N-[(tert-Butoxy)carbonyl]3-bromothiophene-2-sulfonamido 2,2-dimethylpropanoate (106) is synthesised from 3-bromothiophene-2-sulfonyl chloride (synthesised according to the method detailed in Bioorganic and Medicinal Chemistry Letters 1996, 6, 2651-2656), sodium hydride and [(tert-Butoxy)carbonyl]amino 2,2-dimethylpropanoate according to Scheme 2. δH (500 MHz, DMSO-d6) 8.25 (1H, d, 5.2 Hz), 7.44 (1H, d, 5.2 Hz), 1.39 (9H, s), 1.29 (9H, s).