Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH:10]3[CH2:15][CH2:14][N:13](C(=O)C(F)(F)F)[CH2:12][CH2:11]3)[CH2:7][C:6]=2[CH:22]=1.[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25].C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][CH:8]([CH:10]4[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]4)[CH2:7][C:6]=3[CH:22]=2)=[CH:29][CH:28]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: O=C(N1CCC(C2Cc3cc(Br)ccc3O2)CC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2ccc3c(c2)CC(C2CCNCC2)O3)cc1
Temperature: 90 °C

Procedure:
To a mixture of 1-[4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidin-1-yl]-2,2,2-trifluoro-ethanone (2.50 g) and 4-(methanesulfonyl)phenyl boronic acid (1.45 g) in N,N-dimethylformamide (25 mL) a 2 M aqueous Na2CO3 solution (8.26 mL) is added. The mixture is sparged with argon for 10 min and PdCl2[1,1′-bis(diphenylphosphino)-ferrocene].CH2Cl2 complex (540 mg) is added. The resulting mixture is stirred over night at 90° C. After cooling to room temperature, water (50 mL) and ethyl acetate (100 mL) are added and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water and brine, dried (MgSO4), and the solvent is evaporated. The residue is chromatographed on silica gel [dichloromethane/(methanol/NH4OH 9:1) 90:10-80:20] to give the title compound, since the trifluoroacetyl group is removed under the reaction conditions. LC (method 1): tR=0.88 min; Mass spectrum (ESI+): m/z=358 [M+H]+.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:7](=[O:18])[N:6]([CH3:19])[C:5](=[O:20])[CH:4]=1)[NH2:2].O=P(Cl)(Cl)Cl.[CH3:26]O>CN(C=O)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:8]2[C:3]3[NH:1][N:2]=[CH:26][C:4]=3[C:5](=[O:20])[N:6]([CH3:19])[C:7]2=[O:18])=[CH:11][CH:12]=1
Reactant: CO
Reactant: COc1ccc(Cn2c(NN)cc(=O)n(C)c2=O)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)n(C)c(=O)c3cn[nH]c32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 6-hydrazinyl-1-(4-methoxybenzyl)-3-methylpyrimidine-2,4(1H,3H)-dione (0.45 g, 1.6 mmol) in DMF (2 mL), POCl3 (0.3 mL, 3.3 mmol) is added dropwise at 0° C. After the reaction mixture is stirred at 0° C. for 1 hour, the mixture is treated with methanol carefully to give white solid. The solid is further purified by chromatography to give 0.4 g product (Yield: 85%). 1H NMR (DMSO-d6) δ 3.23 (s, 3H), 3.71 (s, 3H), 5.05 (s, 2H), 6.85 and 7.31 (AB, 4H, J=11.6 Hz), 8.47 (s, 1H), 13.5 (br, 1H). MS (FAB) m/z 287.21 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CC(C)([O-])C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:8][C:5]1[N:4]=[C:3]([O:9][CH3:10])[C:2]([N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1nc(Cl)ccc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COc1nc(Cl)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
3-bromo-6-chloro-2-methoxypyridine (1.15 g, 5.17 mmol), tert-butyl piperazine-1-carboxylate (900 mg, 4.8 mmol), sodium tert-butoxide (1.39 g, 14.5 mmol), Pd2(dba)3 (130 mg, 0.15 mmol) and XantPhos (250 mg, 0.44 mmol) were taken up in toluene (36 mL) under Ar. The reaction mixture was heated to 70° C. and was stirred for 18 h. The mixture was cooled and partitioned between water and EtOAc. The phases were separated, and the organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-3% Et2O in DCM) to afford tert-butyl 4-(6-chloro-2-methoxypyridin-3-yl)piperazine-1-carboxylate 7.10. LCMS-ESI+ (m/z): [M+H]+ calcd for C15H23ClN3O3: 328.1; found: 328.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=1)[CH3:2]>CO.[C].[Pd]>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc(C)n1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1cccc(C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
To a solution of 1.39 g (7.85 mmol) of 3-(6-methylpyridin-2-yl)acrylic acid ethyl ester in methanol (50 mL) was added 200 mg of 10% palladium-carbon, and stirred for 4 hours at room temperature under an atmosphere of hydrogen. The solution was filtered through Celite and the obtained filtrate was concentrated under a reduced pressure. The residue was purified by silica gel chromatography (developing solvent; hexane:ethyl acetate=3:1 to 2:1) to obtain 1.09 g (6.09 mmol) of 3-(6-methylpyridin-2-yl)propionic acid ethyl ester (IX-129) as colorless oil. Its physical property is shown below.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C([NH:26][C:27]1[S:28][CH:29]=[C:30](/[C:32](=[N:36]/[O:37][C@H:38]2[CH2:42][CH2:41][NH:40][C:39]2=[O:43])/[C:33]([OH:35])=O)[N:31]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:44][C@@H:45]1[C:62](=[O:63])[N:47]2[C:48]([C:59]([O-:61])=[O:60])=[C:49]([CH2:52][N+:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH2:50][S:51][C@H:46]12.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C>C(Cl)(Cl)Cl.O.C(N(CC)CC)C.CN(C)C=O>[NH2:26][C:27]1[S:28][CH:29]=[C:30](/[C:32](=[N:36]/[O:37][C@H:38]2[CH2:42][CH2:41][NH:40][C:39]2=[O:43])/[C:33]([NH:44][C@@H:45]2[C:62](=[O:63])[N:47]3[C:48]([C:59]([O-:61])=[O:60])=[C:49]([CH2:52][N+:53]4[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=4)[CH2:50][S:51][C@H:46]23)=[O:35])[N:31]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12
Reactant: O=C(O)/C(=N\O[C@H]1CCNC1=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc(/C(=N/O[C@H]2CCNC2=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(C[n+]4ccccc4)CS[C@H]23)cs1
Reaction time: 0.25 h

Procedure:
1.81 g of oxalyl chloride are added at 5° to 0° C. to 45 ml of chloroform containing 1.15 ml of dimethylformamide, and the mixture is stirred at the same temperature for 15 minutes. A solution of 4.90 g of (Z)-2-(2-tritylaminothiazol-4-yl)-2-[((3S)-2-pyrrolidon-3-yl)oxyimino]acetic acid and 0.97 g of triethylamine in 45 ml of chloroform is added to said mixture at -30° C. The mixture is stirred at the same temperature for 5 minutes. Then, a solution of (6R, 7R)-7-amino-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate in chloroform (said solution is prepared by suspending 5.8 g of the dihydrochloride of said cephem compound in 45 ml of chloroform and adding 12.7 ml of N,O-bis(trimethylsilyl)acetamide thereto to dissolve said salt therein) is added to the mixture at -30° to -10° C. After the mixture is stirred at the same temperature for 30 minutes, said mixture is concentrated to dryness under reduced pressure. 100 ml of 80% aqueous formic acid are added to the residue, and the aqueous mixture is stirred at room temperature for one hours. 110 ml of water are added to the mixture, and insoluble materials are filtered off. The filtrate is washed with ethyl acetate and is concentrated to dryness under reduced pressure. The residue thus obtained is dissolved in water and chromatographed on a column of non-ionic polymer resin Diaion HP-20 (resistered trade mark, manufactured by Mitsubish Chemical Industries Ltd., Japan). The column is washed with water, followed by elution with 20% aqueous methanol. The franctions containing the cephalosporin compound are collected and concentrated to dryness under reduced pressure. Acetone is added to the residue, and the resulting powder is collected by filtration. 2.22 g of (6R, 7R)-7-{(Z)-2-(2-aminothiazol-4-yl)-2-[((3S)-2-pyrrolidon-3-yl)oxyimino]acetamido}-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.FC(S(O)(=O)=O)(F)F.[I:20]N1C(=O)CCC1=O>ClCCl>[Cl:11][C:4]1[CH:3]=[C:2]([CH3:1])[C:10]([I:20])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccc(C(=O)O)c(Cl)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Cl)c(C(=O)O)cc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
To a solution of 4-methyl-2-chlorobenzoic acid 1 (2.50 g, 14.7 mmol) and (trifluoromethyl) sulfonic acid (65.0 mL, 73.3 mmol) in dichloromethane (20 mL) at 0° C. was added N-iodosuccinimide (3.50 g, 15.4 mmol) portion wise over a period of 10 minutes. The mixture was stirred at room temperature for 30 minutes, quenched with ice, then water (60 mL) and extracted into EtOAc (100 mL). The layers were separated and the aqueous layer was washed with EtOAc (2×50 mL). The combined organic layers were washed with 10% aqueous sodium sulfite solution (60 mL), dried over magnesium sulphate and concentrated in vacuo to afford the title compound (2.5 g, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:24][C@H:25]4[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[CH2:22][F:23])=[N:16][C:12]=3[CH:11]=[C:10]([C:32](=[NH:42])[NH:33][NH:34][C:35](OC(C)(C)C)=[O:36])[N:9]=2)[CH:5]=[N:6][CH:7]=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:24][C@H:25]4[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[CH2:22][F:23])=[N:16][C:12]=3[CH:11]=[C:10]([C:32]3[NH:42][C:35](=[O:36])[NH:34][N:33]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NNC(=N)c1cc2nc(N3CCC[C@H]3CF)n(C[C@H]3CC[C@H](C)CC3)c2c(-c2cncc(Cl)c2)n1
Solvent: CC#N
Product: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3CF)nc3cc(-c4n[nH]c(=O)[nH]4)nc(-c4cncc(Cl)c4)c32)CC1

Procedure:
A solution of crude tert-butyl 2-((4-(5-chloropyridin-3-yl)-2-((S)-2-(fluoromethyl)pyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)(imino)methyl)hydrazinecarboxylate (19.0 mg, 0.032 mmol) in acetonitrile (793 μL) was stirred at 80° C. for 72 hr. Purification of the reaction by mass triggered reverse phase HPLC (C-18), eluting with acetonitrile/water containing 0.1% TFA afforded 5-{4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-2,4-dihydro-3H-1,2,4-triazol-3-one (TFA salt). 1H NMR (600 MHz, CD3OD) δ 8.83 (d, J=1.8 Hz, 1H), 8.72 (d, J=2.3 Hz, 1H), 8.38 (t, J=2.1 Hz, 1H), 7.96 (s, 1H), 4.70 (dd, J=3.3, 9.9 Hz, 0.5H), 4.65-4.51 (m, 2H), 4.45 (dd, J=4.1, 9.9 Hz, 0.5H), 3.90 (dd, J=8.4, 14.9 Hz, 1H), 3.85-3.74 (m, 2H), 3.55 (dd, J=6.0, 14.9 Hz, 1H), 2.32-2.24 (m, 1H), 2.19-2.11 (m, 1H), 2.05-1.93 (m, 2H), 1.50-1.42 (m, 2H), 1.27-1.19 (m, 1H), 1.15-1.04 (m, 1H), 1.04-0.97 (m, 1H), 0.73 (d, J=6.6 Hz, 3H), 0.72-0.63 (m, 1H), 0.63-0.50 (m, 4H). MS ESI calc'd. for C26H30ClFN8O [M+H]+ 525. found 525.
Reaction SMILES: C([C:5]1[CH:10]=[C:9](C)[CH:8]=[C:7]([C:12]([CH3:15])(C)C)[C:6]=1O)(C)(C)C.BrC1C=CC([CH:22]=[O:23])=CC=1.C([Sn](CCCC)(CCCC)C=C)CCC.F.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1.O1CCCC1.C(OCC)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1>[CH:12]([C:7]1[CH:6]=[CH:5][C:10]([CH:22]=[O:23])=[CH:9][CH:8]=1)=[CH2:15]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=Cc1ccc(Br)cc1
Agent: [Pd]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: F
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
A few crystals of 2,6-di-tert-butyl-4-methylphenol (BHT), 4-Bromobenzaldehyde (2.00 g, 10.8 mmol), and tetrakis(triphenylphosphine) palladium(0) (250 mg, 2 mol %) are dissolved in toluene (20 mL). Tri-n-butyl-vinyl tin(IV) (3.47 mL, 3.77 g, 11.9 mmol) is added and the mixture is heated to reflux for 3 hr. After cooling to room temperature, the dark green/black reaction mixture is treated as follows: pyridine (4.4 mL) is added, then 9.3 mL of pyridinium hydrofluoride in tetrahydrofuran (˜1.2N, made by adding 0.88 g of pyridinium polyhydrofluoride into 20 mL dry THF containing 3.13 g of pyridine); the mixture is then stirred at room temperature overnight. The treated reaction mixture is diluted with diethyl ether (200 mL), washed with water (50 mL), 10% aqueous hydrochloric acid (2×50 mL), saturated aqueous NaHCO3 (50 mL), and then dried over MgSO4. Concentration in vacuo gives a crude oil, which is purified by flash chromatography (silica, 10% ethyl acetate/hexanes) to give pure 4-vinylbenzaldehyde as a pale yellow oil (1.16 g, 81.3%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:9]2[C:21]([CH:22]=[O:23])=[C:20]([OH:24])[CH:19]=[CH:18][C:10]=2[S:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].S(C1C=CC(C)=CC=1)(O[CH2:29][C@@H:30]1[O:32][CH2:31]1)(=O)=O.O>CN(C)C=O>[Cl:7][C:8]1[C:9]2[C:21]([CH:22]=[O:23])=[C:20]([O:24][CH2:29][C@@H:30]3[O:32][CH2:31]3)[CH:19]=[CH:18][C:10]=2[S:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: CCOC(=O)c1sc2ccc(O)c(C=O)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sc2ccc(OC[C@H]3CO3)c(C=O)c2c1Cl
Temperature: 60 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
Potassium carbonate (2.62 g) was added to a stirred solution of ethyl 3-chloro-4-formyl-5-hydroxybenzo[b]thiophene-2-carboxylate (4.90 g, prepared as described above) in dry dimethylformamide (50 ml) and then a solution of (R)-glycidyl tosylate (4.12 g) in dry dimethyl formamide (50 ml) was added slowly. The mixture was then stirred at 60° C. for 3 hours, cooled and poured into water (1200 ml). The resulting pale-green solid was collected by filtration, washed with water (200 ml) and dried to give ethyl (R)-3-chloro-5-(2,3-epoxypropoxy)-4-formylbenzo[b]thiophene-2-carboxylate (5.15 g).
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:16][CH3:17])[C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:5][N:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[F:24][C:25]([F:31])([F:30])[CH2:26][C:27](O)=[O:28].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:6]([N:7]([CH2:16][CH3:17])[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:27](=[O:28])[CH2:26][C:25]([F:31])([F:30])[F:24])[CH2:12][CH2:11]2)=[O:9])=[CH:5][N:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1
Reactant: CCN(C(=O)C1CCNCC1)c1cn(-c2cccnc2)nc1Cl
Reactant: O=C(O)CC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Product: CCN(C(=O)C1CCN(C(=O)CC(F)(F)F)CC1)c1cn(-c2cccnc2)nc1Cl

Procedure:
In an appropriate reaction vessel, to N-(3-chloro-1-(pyridin-3-yl)-1H -pyrazol-4-yl)-N-ethylpiperidine-4-carboxamide may be added 3,3,3-trifluoropropanoic acid (about 1.0 to about 2.0 eq), DMAP (about 2.0 to about 3.0 eq), and EDCI (about 1.5 to about 3.0 eq) in a solvent, such as CH2Cl2 (at a concentration between about 0.01 M to about 1 M). The reaction may be stirred at a temperature from about 0° C. to about 50° C. until determined to be completed. After completion of the reaction, the product may be obtained using standard organic chemistry techniques for workup and purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:22]4[C:23](=O)[CH2:24][N:25]([CH3:29])[S:26](=[O:28])(=[O:27])[C:21]=4[CH:20]=[CH:19]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[NH2:32][OH:33]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:22]4[C:23](=[N:32][OH:33])[CH2:24][N:25]([CH3:29])[S:26](=[O:28])(=[O:27])[C:21]=4[CH:20]=[CH:19]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN1CC(=O)c2c(ccn2CCCCN2CCN(c3ccc(F)cc3)CC2)S1(=O)=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC(=NO)c2c(ccn2CCCCN2CCN(c3ccc(F)cc3)CC2)S1(=O)=O
Temperature: 80 °C
Reaction time: 24 h
Yield: 88.4 %

Procedure:
A suspension of 174 mg (0.4 mmol) of Compound 23 and 111 mg (1.6 mmol) of hydroxylamine hydrochloride in 10 ml of pyridine was stirred for 24 hours over an oil bath of 80° C. Post-treatment and purification were conducted in a similar manner as in Example 21, whereby 159 mg of the title compound were obtained (yield: 88%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([Br:11])=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH2:18][C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][C:20]=1[OH:28]>C(Cl)Cl.O.CCCC[N+](CCCC)(CCCC)CCCC.[Br-].[Cl-].[Na+].O>[Br:11][C:6]1[C:5]([C:3]2([OH:4])[NH:18][C:19]3[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][C:20]=3[O:28][CH2:2]2)=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1cccnc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cccc2c1NC(O)(c1cccnc1Br)CO2
Temperature: 40 °C
Yield: 90.2 %

Procedure:
A solution of 2-bromo-1-(2-bromopyridin-3-yl)ethanone (2.15 g, 7.71 mmol) in methylene chloride (77.1 mL) and water (19.3 mL) was treated with potassium carbonate (2.13 g, 15.4 mmol), tetra-N-butylammonium bromide (500 mg, 1.50 mmol), and 2-amino-3-nitrophenol (1.31 g, 8.48 mmol), and heated at 40° C. for 5 h. The reaction mixture was then diluted with brine. The aqueous layer was separated and extracted with dichloromethane (2×100 mL). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography (100% hexanes to 35% ethyl acetate/hexanes) gave the desired product (2.45 g, 90%) as a racemic mixture. LCMS calculated for C13H11BrN3O4 (M+H)+: m/z=352.0, 354.0. found: 351.7, 353.8.
Reaction SMILES: O.O.Cl[Sn]Cl.[CH2:6]([O:8][C:9]1[CH:10]=[C:11]([C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([N+:28]([O-])=O)[CH:21]=2)=[CH:18][CH3:19])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[CH3:7].[OH-].[Na+]>C(O)C.C(OCC)(=O)C>[CH2:6]([O:8][C:9]1[CH:10]=[C:11]([C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([NH2:28])[CH:21]=2)=[CH:18][CH3:19])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[CH3:7]
Reactant: CC=C(c1ccc(OC)c(OCC)c1)c1ccc(OC)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC=C(c1ccc(OC)c(N)c1)c1ccc(OC)c(OCC)c1
Temperature: 70 °C
Yield: 72.8 %

Procedure:
SnCl2.2H2O (3.98 g, 17.6 mmol) was added to a stirred suspension of (E/Z) 4-[1-(3-ethoxy-4-methoxy-phenyl)-propenyl]-1-methoxy-2-nitro-benzene (1.10 g, 3.2 mmol) in ethanol (200 proof, 20 mL) and ethyl acetate (10 mL). The reaction mixture was heated at 70° C. for 1 h. The solution was cooled down to room temperature, poured into ice water (100 mL), and basified with 10 N NaOH (20 mL) to pH ˜12. The aqueous layer was extracted with ethyl acetate (5×35 mL). The combined organic layers were washed with water (60 mL), brine (50 mL) and dried (MgSO4). Removal of solvent and chromatography (Silica Gel) gave a mixture of (E/Z) 5-[1-(3-ethoxy-4-methoxy-phenyl) -propenyl]-2-methoxy-phenylamine as a solid (0.73 g, 73% yield): mp, 108-110° C.; 1H NMR (CDCl3) δ 1.39-1.46 (m, 6H, 2CH3), 1.72-1.77 (m, 6H, 2CH3), 3.71-3.75 (bp, 4H, 2NH2), 3.83-3.90 (m, 12H, 4OCH3), 3.99-4.09 (m, 4H, 2CH2), 5.97-6.05 (m, 2H, 2CH), 6.54-6.61 (m, 12H, Ar); 13C NMR (CDCl3) δ 14.79, 15.67, 15.72, 55.45, 55.52, 55.90, 55.95, 64.21, 64.26, 109.90, 109.95, 110.97, 111.01, 112.13, 114.11, 114.80, 116.83, 117.51, 119.89, 120.35, 121.81, 121.98, 122.44, 132.86, 132.93, 135.52, 135.57, 136.28, 136.49, 141.93, 142.02, 146.25, 146.53, 147.75, 148.02, 148.34; Anal. Calcd for C19H23NO3: C, 73.82; H, 7.40; N, 4.47. Found: C, 72.57; H, 7.47; N, 4.40.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[CH3:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=O>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][C:15]([C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[O:12][CH3:11])=[N:10][C:4]=2[CH:3]=1
Reactant: COc1ccccc1C(=O)O
Reactant: Nc1cc(F)c(F)cc1N
Product: COc1ccccc1-c1nc2cc(F)c(F)cc2[nH]1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate c, from 4,5-difluoro-benzene-1,2-diamine (CAS Reg. No. 76179-40-3) and 2-methoxy-benzoic acid (CAS Reg. No. 579-75-9). Brown solid (41%). MS (Turbo Spray): m/z=261.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([NH:14][CH3:15])[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19].[CH2:20]([NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[CH3:21]>C(#N)C>[CH2:20]([NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][N:26]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:19])[C:6]([C:16]([OH:18])=[O:17])=[CH:7][N:8]3[NH:14][CH3:15])=[CH:3][C:2]=2[F:1])[CH2:25]1)[CH3:21]
Reactant: CCNCC1CCNC1
Reactant: CNn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(NC)c3c2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To 0.75 g (2.75 mmol) of the 6,7,8-trifluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid in 15 ml of acetonitrile was added 0.44 g (1.05 equivalent) of 1,8-diazobicyclo[5.4.0]undec-7-ene, and 0.352 g (1.0 equivalent) of N-ethyl-3-pyrrolidinemethanamine. The mixture was refluxed for one hour and then stirred at room temperature overnight. The solids were filtered to give 0.68 g of 7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid, mp 222°-224° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:21]2[O:22][C:23]([CH2:26]Cl)=[N:24][N:25]=2)[CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(#N)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:21]2[O:22][C:23]([CH2:26][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[N:24][N:25]=2)[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CCl)o4)cc(Br)cc32)cc1
Reactant: C1COCCN1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CN5CCOCC5)o4)cc(Br)cc32)cc1
Temperature: 80 °C

Procedure:
A stirred mixture of 6-bromo-4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-methylphenyl)sulfonyl]-1H-indazole (0.1 g, 0.214 mmol) and morpholine (0.056 ml, 0.641 mmol) in acetonitrile (2.5 ml) was heated at 80° C. in the microwave (biotage initiator) for 45 mins. The mixture was evaporated and the residual solid triturated with ether (10 ml) to afford the title compound as a cream coloured solid which was collected by filtration (0.07 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([OH:10])=O)[S:6][CH:7]=1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]([NH2:23])=[O:22])[C:16](=[O:24])[CH2:15]2>CN(C1C=CN=CC=1)C.S(Cl)(Cl)=O>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]([NH2:23])=[O:22])[C:16](=[O:24])[CH:15]2[C:8](=[O:10])[C:5]1[S:6][CH:7]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: COc1csc(C(=O)O)c1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: COc1csc(C(=O)C2C(=O)N(C(N)=O)c3ccc(Cl)cc32)c1

Procedure:
The title compound was prepared according to the procedure of Example 32. A 1.30 g (8.22 mmoles) sample of 4-methoxy-2-thiophenecarboxylic acid (prepared according to Gronowitz, S., Arkiv. for Kemi. 12:239 (1958)) was converted to 1.19 g of pure acid chloride (b.p. 58-60° C., 0.03 mm) with 10 ml of thionyl chloride. The acid chloride was coupled to 1.18 g (5.61 mmoles) of 5-chloro-2-oxindole-1-carboxamide in the presence of 1.73 g (14.15 mmoles) 4-(N,N-dimethylamino)pyridine to give 1.88 g of crude product on acidic workup. Recrystallization gave 1.39 g (3.96 mmoles, 71% yield) of pure 5-chloro-3-(4-methoxy-2-thenoyl)-2-oxindole-1-carboxamide as a yellow solid, m.p. 221-223° C. (acetic acid).