Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.[CH2:11]([N:14]=[C:15]=[S:16])[CH:12]=[CH2:13]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH2:13][CH:12]([CH2:11][N:14]=[C:15]=[S:16])[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: ON=Cc1ccc(Br)cc1
Reactant: C=CCN=C=S
Product: S=C=NCC1CC(c2ccc(Br)cc2)=NO1

Procedure:
A 10 g. portion of 4-bromobenzaldoxime was chlorinated and reacted with 10 g. of allylisothiocyanate to prepare 15 g. of product, m.p. 123°-125°.
Reaction SMILES: C[O:2][C:3](=[O:10])[CH2:4][C:5]([CH3:9])([CH3:8])[CH:6]=[CH2:7].[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH3:9][C:5]1([CH3:8])[CH:6]([CH2:7][C:16]([C:15]2[CH:19]=[CH:20][C:12]([Cl:11])=[CH:13][CH:14]=2)=[O:17])[O:2][C:3](=[O:10])[CH2:4]1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: C=CC(C)(C)CC(=O)OC
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)CC(=O)OC1CC(=O)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
71 g (0.5 mol) of 3,3-dimethyl-4-pentenoic acid methyl ester were added dropwise to a mixture of 87.5 g (0.5 mol) of p-chlorobenzoyl chloride and 130.3 g (0.5 mol) of tin tetrachloride at 20° C., while cooling with ice. After being left to stand overnight, the reaction mixture had solidified. It was taken up in methylene chloride, the methylene chloride mixture was filtered and the filtrate was extracted by shaking with dilute hydrochloric acid. After drying and stripping off the solvent in vacuo, 111.1 g of crude product (about 83%), which crystallized completely, were obtained. Recrystallization from 120 ml of ethanol gave 3,3-dimethyl-4-(4'-chloro-phenacyl)-γ-butyrolactone of melting point 76°-80° C.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[C:4]([C:24]([O:26]C)=[O:25])[CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO.O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)=[C:4]([C:24]([OH:26])=[O:25])[CH:3]=1
Reactant: COC(=O)c1cc(F)c2ccccc2c1OCc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(F)c2ccccc2c1OCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 99.1 %

Procedure:
To a stirred solution of 0.22 g of 4-fluoro-1-[4-(trifluoromethyl)benzyloxy]-naphthalene-2-carboxylic acid, methyl ester in 4.5 ml of THF and 0.86 ml of methanol was added 1.7 ml of 1M sodium hydroxide. The mixture was stirred at ambient temperature for 11 h. The mixture was diluted with water, acidified to pH 1-2 with 1M HCl, extracted twice with ethyl acetate, dried (sodium sulphate), filtered and concentrated to provide 0.21 g of 4-fluoro-1-[4-(trifluoromethyl)benzyloxy]naphthalene-2-carboxylic acid as a white solid.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7]/[N:8]=[C:9](/[C:13]1[N:14]=[C:15]([NH:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:16][CH:17]=1)\[C:10]([O-:12])=O.[Na+].[NH2:39][C@@H:40]1[C:60](=[O:61])[N:42]2[C:43]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[C:44]([C@H:47]3[O:51][C:50](=[O:52])[CH2:49][CH2:48]3)[CH2:45][S:46][C@H:41]12.N1C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C>[CH3:6][O:7]/[N:8]=[C:9](/[C:13]1[N:14]=[C:15]([NH:18][C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:16][CH:17]=1)\[C:10]([NH:39][C@@H:40]1[C:60](=[O:61])[N:42]2[C:43]([C:53]([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:54])=[C:44]([C@H:47]3[O:51][C:50](=[O:52])[CH2:49][CH2:48]3)[CH2:45][S:46][C@H:41]12)=[O:12]
Reactant: CC(C)(C)OC(=O)C1=C([C@@H]2CCC(=O)O2)CS[C@@H]2[C@H](N)C(=O)N12
Reactant: CO/N=C(\C(=O)[O-])c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)(C)C)=C([C@@H]3CCC(=O)O3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -10 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
Methanesulphonyl chloride (23 μl, 0.3 mmol) was added to sodium 2-(Z)-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetate (0.12 g,0.25 mmol) in DMF (0.5 ml) at -40° C. The mixture was allowed to warm to -10° C. over 0.5 h then cooled to -30° C. and t-butyl (6R,7R)-7-amino-3-[(5S)-2-oxotetrahydrofuran-5-yl]ceph-3-em-4-carboxylate (68 mg, 0.2 mmol) in DMF (1 ml) and pyridine (24 μl, 0.3 mmol) was added. The reaction was stirred for 1 h without cooling, then diluted with ethyl acetate, washed twice with water and brine, dried, concentrated and flash chromatographed, eluting with 40,50% ethyl acetate in hexane, to give the title compound (92 mg,60%), δH (CDCl3) 1.53 (9H,m), 1.9-2.1 (1H,m), 2.5-2.8 3H,m), 3.27 and 3.57 (2H,ABq,J18.7 Hz), 4.07 (3H,s), 5.06 (1H,d,J5Hz), 5.6-5.8 (1H,m), 5.98 (1H,dd,J5,9 Hz), 6.72 (1H,d,J9 Hz), 6.74 (1H,s), 7.02 (1H,s), 7.2-7.4 (15H,m); [mass spectrum: +ve ion (thioglycerol)MH+, 766].
Reaction SMILES: [F:1][CH:2]([F:33])[O:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([O:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[N:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[N:24]=3)[C:14]=2[C:15]([OH:17])=[O:16])[N:5]=1.[H-].[Na+].Cl[CH2:37][O:38][CH3:39]>CN(C)C=O>[F:33][CH:2]([F:1])[O:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([O:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[N:24]=[C:25]([O:31][CH3:32])[CH:26]=[C:27]([O:29][CH3:30])[N:28]=3)[C:14]=2[C:15]([O:17][CH2:37][O:38][CH3:39])=[O:16])[N:5]=1
Reactant: COCCl
Reactant: COc1cc(OC)nc(Oc2cccc(Oc3nc(OC)cc(OC(F)F)n3)c2C(=O)O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOC(=O)c1c(Oc2nc(OC)cc(OC)n2)cccc1Oc1nc(OC)cc(OC(F)F)n1
Yield: 82.5 %

Procedure:
0.9 g of (1.9 mmol) of 2-(4-difluoromethoxy-6-methoxypyrimidin-2-yl)oxy-6-(4,6-dimethoxypyrimidin-2-yl)oxybenzoic acid, 0.1 g of 60% sodium hydride and 0.2 g of chloromethylmethylether were reacted in N,N-dimethylformamide, treated and purified in the same manner as in Example 1 to obtain 0.8 g of a colorless transparent viscous liquid having a refractive index of nD20 =1.5389.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=2)[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:3]1.C(N=[C:23]=[O:24])C>N1C=CC=CC=1>[C:14]1([C:4]2[C:5]3[C:8]4[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=4[C:23](=[O:24])[NH:7][C:6]=3[N:2]([CH3:1])[N:3]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCN=C=O
Reactant: Cn1nc(-c2ccccc2)c(C2=CCCCC2)c1N
Solvent: c1ccncc1
Product: Cn1nc(-c2ccccc2)c2c3c(c(=O)[nH]c21)CCCC3
Reaction time: 8 h
Yield: 72.4 %

Procedure:
The compound of Example 3A (2 g, 8 mmol) and ethyl isocyanate (1.67 g, 24 mmol) were dissolved in pyridine (30 mL) at room temperature. The mixture was warmed, refluxed and stirred overnight. The reaction was stopped. The solvent was rotary-evaporated. A small amount of ethanol was added. A large amount of solids were precipitated. The solids were filtered in vacuo. The solvent was rotary-evaporated. The residue was purified by column chromatography to give 1.618 g of the pure title compound. MS (ESI): m/z 280 (M+H)+
Reaction SMILES: [OH:1][CH:2]([CH3:7])[C:3]([NH:5][OH:6])=[NH:4].[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=O>N1C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]([C:12]2[O:6][N:5]=[C:3]([CH:2]([OH:1])[CH3:7])[N:4]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CC(O)C(=N)NO
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: c1ccncc1
Product: CC(O)c1noc(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 59.9 %

Procedure:
To a solution of 3.19 g (30.6 mmol) 2,N-dihydroxy-propionamidine in 25 ml pyridine was added 4.3 ml (33.7 mmol) 3-chloro-benzoyl chloride at 0° C. Cooling was removed and the mixture was stirred at room temperature for 25 min and at reflux for 25 min. After cooling the mixture was poured into water and extracted twice with CH2Cl2. The organic phase was dried and concentrated. Recrystallization from heptane/EtOAc afforded 4.12 g (60%) of a white solid. 1H NMR (CDCl3), d (ppm): 1.68 (d, 3 H) 2.67 (m, 1 H) 5.09 (m, 1 H) 7.46 (t, 1 H) 7.56 (d, 1 H) 8.01 (d, 1 H) 8.13 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[F:18][CH:19]([F:29])[C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([NH2:28])[CH3:27])=[CH:22][CH:21]=1>>[F:18][CH:19]([F:29])[C:20]1[CH:21]=[CH:22][C:23]([C@@H:26]([NH:28][CH2:16][CH2:15][C:2]2([OH:1])[CH2:3][CH2:4][C:5]3([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]3)[CH2:13][CH2:14]2)[CH3:27])=[CH:24][CH:25]=1
Reactant: C[C@H](N)c1ccc(C(F)F)cc1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Product: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(C(F)F)cc1
Yield: 77 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(4-difluoromethyl-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 77% of theory; LC (method 8): tR=1.10 min; Mass spectrum (ESI+): m/z=398 [M+H]+.
Reaction SMILES: F[C:2]1[N:3](C)C(=O)C(NC2C=CC=CC=2)=C(SC)C=1C([O-])=O.Br[C:23]1[C:28](=[O:29])[N:27]([CH3:30])[C:26]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([S:38][CH3:39])=[CH:34][C:33]=2[F:40])=[C:25]([C:41]([O:43][CH3:44])=[O:42])[CH:24]=1>CCOC(C)=O.O.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].[C-]#N.[C-]#N.[Zn+2]>[C:2]([C:23]1[C:28](=[O:29])[N:27]([CH3:30])[C:26]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([S:38][CH3:39])=[CH:34][C:33]=2[F:40])=[C:25]([C:41]([O:43][CH3:44])=[O:42])[CH:24]=1)#[N:3]
Reactant: COC(=O)c1cc(Br)c(=O)n(C)c1Nc1ccc(SC)cc1F
Reactant: CSc1c(C(=O)[O-])c(F)n(C)c(=O)c1Nc1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [C-]#N
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C#N)c(=O)n(C)c1Nc1ccc(SC)cc1F
Temperature: 120 °C
Yield: 29 %

Procedure:
Methyl 5-cyano-2-(2-fluoro-4-(methylthio)phenylamino-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate: A mixture of methyl 5-bromo-2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (0.020 g, 0.050 mmol), tris(dibenzylideneacetone)-dipalladium(0) (0.046 g, 0.050 mmol), 1,1′-bis(diphenylphosphine)-ferrocene (0.055 g, 0.100 mmol) and Zn(CN)2 (0.006 g, 0.055 mmol) was heated at 120° C. for 2 hours. The reaction mixture was diluted with EtOAc and H2O and the layers separated. The EtOAc layer was washed with saturated NH4Cl and saturated NaCl, dried (Na2SO4) and concentrated under reduced pressure to a dark yellow gum. Purification by flash column chromatography (methylene chloride/EtOAc, 10:1) gave 0.005 g (29%) pure desired product as a yellow solid. MS APCI (−) m/z 346 (M−1) detected; 1H NMR (400 MHz, CDCl3) δ 10.84 (s, 1H), 8.39 (s, 1H), 6.95-7.06 (m, 3H), 3.90 (s, 3H), 3.17 (s, 3H), 2.50 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C@H:3]([C@@H:14]([CH3:21])[C@@H:15]([O:19][CH3:20])/[CH:16]=C/C)[C@@H:4]([CH3:13])[CH2:5][O:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].[O:22]=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:1][O:2][C@H:3]([C@@H:14]([CH3:21])[C@@H:15]([O:19][CH3:20])[CH:16]=[O:22])[C@@H:4]([CH3:13])[CH2:5][O:6][C:7](=[O:12])[C:8]([CH3:9])([CH3:10])[CH3:11]
Reactant: O=[O+][O-]
Reactant: C/C=C/[C@H](OC)[C@H](C)[C@@H](OC)[C@@H](C)COC(=O)C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CO[C@H]([C@@H](C)[C@H](C=O)OC)[C@@H](C)COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (2,2-Dimethyl-propionic acid (E)-(2S,3S,4S,5S)-3,5-dimethoxy-2,4-dimethyl-oct-6-enyl ester (2.0 g, 6.94 mmol) in anhydrous dichloromethane (60 ml) at −78° C., ozone was bubbled through until a pale blue colour persisted. Nitrogen was then bubbled through until the solution turned colourless. Triphenylphosphine (2.7 g, 10.4 mmol) was added and the reaction was warmed to room temperature and stirred overnight. The reaction was concentrated in vacuo and the product purified by flash chromatography (SiO2, iHex/EtOAc, 20:1 then 4:1) to afford 1.62 g (81%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 9.51 (d, J=4.1 Hz, 1H), 4.14 (dd, J=10.8 Hz, 3.3 Hz, 1H), 4.00 (dd, J=10.8 Hz, 5.9 Hz, 1H), 3.36-3.29 (m, 2H), 3.33 (s, 3H), 3.32 (s, 3H), 1.93 (m, 2H), 1.20 (s, 9H), 0.84 (d, J=7.0 Hz, 3H), 0.78 (d, J=7.0 Hz, 3H).
Reaction SMILES: [Cu]C#N.[Br-].[Li+].[I-].[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[Zn+])#[N:8].[Br:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22].[NH4+].[Cl-]>C1COCC1.O>[Br:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=1[C:7]#[N:8])=[O:22]
Reactant: N#Cc1c(F)cccc1[Zn+]
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: N#C[Cu]
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(F)cccc1C(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A solution of copper(I) cyanide (4.70 g, 52.50 mmol) and lithium bromide (2.63 mL, 105.00 mmol) in THF (65 mL) was added to (2-cyano-3-fluorophenyl)zinc(II) iodide (100 mL, 50 mmol) at −78° C. under an argon atmosphere. The mixture was stirred at r.t. for 1 h and then cooled to −78° C. 3-Bromobenzoyl chloride (6.94 mL, 52.50 mmol) was added dropwise and the mixture was stirred at r.t. for 4 h. NH4Cl (50 mL, sat aq) was added followed by water (50 mL). The THF was removed in vacuo and the aqueous residue was diluted with water (100 mL) and DCM (150 mL). A precipitate was filtered off and the filtrate was added to a separation funnel. The organic layer was separated and the water phase extracted with DCM (100 mL). The combined organics were washed with brine (150 mL), dried over MgSO4, concentrated and purified on a silica gel column eluted with DCM to give the title compound (13.37 g, 88% yield): MS (ES+) m/z 304, 306 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].O1CCCC1.[H][H]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Cl-].[Ru+2].C(O)C>[CH3:1][O:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C=CCCCC=CCOC
Reactant: [H][H]
Agent: [Ru+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCC=CCOC
Reaction time: 6 h

Procedure:
1000 g of 1-methoxy-2,7-octadiene, 500 ml of tetrahydrofuran, 500 ml of ethanol and 2.5 g of tris(triphenylphosphine)ruthenium(II) chloride were placed in a 3 l Büchi autoclave. The temperature was set to 30° C. and the autoclave was pressurized to 30 bar by means of hydrogen. The reaction was followed via the amount of hydrogen taken up and by means of GC analyses. After 6 hours, the reaction was stopped. According to GC analysis, 98% of the 1-methoxy-2,7-octadiene had reacted to form 1-methoxy-2-octene (cis and trans) with a selectivity of 89%. The 1-methoxy-2-octene was separated from solvents and catalyst by distillation.
Reaction SMILES: Cl.[CH:2]([O:5][N:6]=[C:7]([C:31]1[N:32]=[C:33]([NH:36]C=O)[S:34][CH:35]=1)[C:8]([NH:10][CH:11]1[C:29](=[O:30])[N:13]2[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH2:18][S:19][C:20]3[N:24]([CH3:25])[N:23]=[N:22][N:21]=3)[CH2:16][S:17][C@H:12]12)=[O:9])([CH3:4])[CH3:3]>O1CCCC1.CO>[CH:2]([O:5][N:6]=[C:7]([C:31]1[N:32]=[C:33]([NH2:36])[S:34][CH:35]=1)[C:8]([NH:10][CH:11]1[C:29](=[O:30])[N:13]2[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH2:18][S:19][C:20]3[N:24]([CH3:25])[N:23]=[N:22][N:21]=3)[CH2:16][S:17][C@H:12]12)=[O:9])([CH3:4])[CH3:3]
Reactant: CC(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 56.1 %

Procedure:
Conc. hydrochloric acid (1 ml) was added to a solution of 7-[2-isopropoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(1.5 g) in a mixture of tetrahydrofuran (12 ml) and methanol (12 ml). The mixture was stirred for 3.5 hours at ambient temperature and then concentrated to dryness. Water was added to the residue and to the mixture was added sodium bicarbonate to give a solution. The solution was adjusted to pH 3.0 with conc. hydrochloric acid under ice-cooling. Precipitates were collected by filtration, washed with water and dried to give 7-[2-isopropoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(0.8 g).
Reaction SMILES: O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH3:34])[CH2:29][C@@H:28]1[C:35]([OH:37])=O)=[O:26])([CH3:23])([CH3:22])[CH3:21].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>ClCCl>[CH2:33]([N:30]1[CH2:31][CH2:32][N:27]([C:25]([O:24][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:26])[C@@H:28]([C:35]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[O:37])[CH2:29]1)[CH3:34]
Reactant: C1CNCCN1
Reactant: CCN1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCN1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)N2CCNCC2)C1
Reaction time: 18 h
Yield: 50.4 %

Procedure:
4-(4,6-Dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (253 mg, Acros chemicals) was added to a solution of (2R)-1-(tert-butoxycarbonyl)-4-ethylpiperazine-2-carboxylic acid (212 mg) in dry dichloromethane (6 ml) followed by addition on N-methyl morpholine (0.28 ml) and stirring under argon for 1 h piperazine (234 mg) was then added and stirring was continued for 18 h. Dichloromethane (30 ml) was added and extracted with 1M NaOH (2×10 mL). The organic layer was dried (MgSO4), filtered and evaporated. Purification by chromatography (5-50% MeOH:DCM) afforded the title compound (135 mg) as a foam
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[N:12]=[C:11]([C:13]([NH:15][NH2:16])=[O:14])[CH:10]=[CH:9][CH:8]=1.[Cl:22][C:23]([Cl:27])([Cl:26])[CH:24]=O.C1C=CC=CC=1>C(OCC)(=O)C>[Cl:22][C:23]([Cl:27])([Cl:26])[CH:24]=[N:16][NH:15][C:13](=[O:14])[C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([O:6][C:5]2[CH:17]=[CH:18][CH:19]=[C:3]([C:2]([F:20])([F:1])[F:21])[CH:4]=2)[N:12]=1
Reactant: NNC(=O)c1cccc(Oc2cccc(C(F)(F)F)c2)n1
Reactant: O=CC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: O=C(NN=CC(Cl)(Cl)Cl)c1cccc(Oc2cccc(C(F)(F)F)c2)n1

Procedure:
6-[3-(trifluoromethyl)phenoxy] picolinic acid hydrazide (0.15 g, 0.000505 mol) was mixed with trichloroacetaldehyde (0.22 g, 0.000505×3.0 mol) and benzene (about 20 ml). The obtained mixture was refluxed for about 3 hours. The obtained reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water, and the organic phase separated from the solution was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated. The obtained concentrated solution was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.[Cl:16][C:17]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:21][N:20]=[C:19]2[N:29]([CH2:33][CH2:34][N:35]3[CH2:39][CH2:38][C@@H:37]([F:40])[CH2:36]3)[N:30]=[C:31](I)[C:18]=12>>[Cl:16][C:17]1[C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:21][N:20]=[C:19]2[N:29]([CH2:33][CH2:34][N:35]3[CH2:39][CH2:38][C@@H:37]([F:40])[CH2:36]3)[N:30]=[C:31]([C:4]3[CH2:3][CH2:2][O:1][CH2:6][CH:5]=3)[C:18]=12
Reactant: F[C@@H]1CCN(CCn2nc(I)c3c(Cl)c(-c4ccccc4)nnc32)C1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Product: F[C@@H]1CCN(CCn2nc(C3=CCOCC3)c3c(Cl)c(-c4ccccc4)nnc32)C1

Procedure:
Compound Iq was synthesized according to Example 1, but using 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 4-chloro-1-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethyl]-3-iodo-5-phenyl-pyrazolo[3,4-c]pyridazine instead of 4-chloro-3-iodo-1-(2-(4-methylpiperazin-1-yl)ethyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine in Step 8.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH:13]=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10]1)=O)(C)(C)C.[OH-].[Na+].[ClH:21]>CO.O>[ClH:21].[NH2:8][CH:9]1[CH2:14][CH:13]=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10]1
Reactant: COC(=O)C1=CC(NC(=O)OC(C)(C)C)CC=C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC1C=C(C(=O)O)C=CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.4 g of methyl 3-(tert-butoxycarbonylamino)-1,5-cyclohexadienecarboxylate is treated with 164 mg of sodium hydroxide in 2 ml of methanol and 1 ml of water. The solution is stirred at about 25° C. for 3 hours, acidified to a pH of 3 with dilute hydrochloric acid and evaporated to dryness in vacuo. The residue is treated with 7 ml of methanol and 3.5 ml of 5% hydrochloric acid for 24 hours at 25° C. after which the solution is concentrated and washed with ether. The aqueous phase is evaporated in vacuo, and the residue is recrystallized from methanol-ether to afford 20 mg of 3-amino-1,5-cyclohexadiene carboxylic acid hydrochloride. M.P. 180°-184° C.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH2:16][NH2:17])=[CH:18][CH:19]=3)[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(OC2CCN(C3CCC3)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(OC2CCN(C3CCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.1 %

Procedure:
A solution of 4-(1-Cyclobutyl piperidin-4-yloxy)benzonitrile (8.22 g, 0.032 moles) in dry tetrahydrofuran (50 mL) was added to a stirred solution of lithium aluminium hydride (3.74 g, 0.098 moles) in dry tetrahydrofuran (30 mL), at 10 to 15° C. under nitrogen atmosphere. The resulting mass was further stirred for 20 minutes at ambient temperature and then refluxed for 4 hours. After completion of reaction, the mass was cooled to 10-15° C., quenched with water and basified with 4N sodium hydroxide solution. Reaction mass was filtered through celite and cake was washed with ethyl acetate. The separated organic layer was dried over sodium sulphate and concentrated under reduced pressure to obtain the title compound 7.17 g (Yield: 86.2%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[S:11](N)([NH2:14])(=[O:13])=[O:12]>O1CCOCC1>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([S:11]([NH2:14])(=[O:13])=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)N1CCC2(CC1)OCCO2

Procedure:
A solution of 1,4-dioxa-8-aza-spiro[4.5]decane (2 mL) and sulfamide (1.65 g) in 1,4-dioxane (28 mL) was heated at reflux for 48 h, then the volatiles were evaporated to afford the title compound as a pale yellow solid. Yield: 3.4 g
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].NC1C2C(=CC(CN3CC[C@@H](NC([NH:28][C:29]4S[C:31]([Cl:34])=[CH:32][CH:33]=4)=O)C3=O)=CC=2)N=CN=1.FC(F)(F)C(O)=O.[NH2:43][C:44]1[C:53]2[C:48](=[CH:49][C:50]([CH2:54][N:55]3[CH2:59][CH2:58][C@@H:57]([NH:60][C:61]([C:63]4S[C:65](Cl)=[CH:66][CH:67]=4)=O)[C:56]3=[O:69])=[CH:51][CH:52]=2)[N:47]=[CH:46][N:45]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:43][C:44]1[C:53]2[C:48](=[CH:49][C:50]([CH2:54][N:55]3[CH2:59][CH2:58][C@@H:57]([NH:60][CH2:61][C:63]4[NH:28][C:29]5[C:66]([CH:67]=4)=[CH:65][C:31]([Cl:34])=[CH:32][CH:33]=5)[C:56]3=[O:69])=[CH:51][CH:52]=2)[N:47]=[CH:46][N:45]=1
Reactant: Nc1ncnc2cc(CN3CC[C@@H](NC(=O)c4ccc(Cl)s4)C3=O)ccc12
Reactant: Nc1ncnc2cc(CN3CC[C@@H](NC(=O)Nc4ccc(Cl)s4)C3=O)ccc12
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2cc(CN3CC[C@@H](NCc4cc5cc(Cl)ccc5[nH]4)C3=O)ccc12

Procedure:
1-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]-3-(5-chlorothiophen-2-yl)urea trifluoroacetate and 5-Chlorothiophene-2-carboxylic acid [1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amide trifluoroacetate;