Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([CH3:29])=[CH:4][CH2:5][CH2:6][C:7]([CH3:28])=[CH:8][CH2:9][CH2:10][C:11]([CH3:27])=[CH:12][CH:13]=[C:14]([CH:24]([CH3:26])[CH3:25])[CH:15]([O:18][CH:19]([O:21][CH2:22][CH3:23])[CH3:20])[C:16]#[N:17].[Cl-].[NH4+]>CCCCCC.C1C=CC=CC=1.C1C=CC=CC=1>[CH2:22]([O:21][CH:19]([O:18][C:15]1([C:16]#[N:17])[CH2:2][C:3]([CH3:29])=[CH:4][CH2:5][CH2:6][C:7]([CH3:28])=[CH:8][CH2:9][CH2:10][C:11]([CH3:27])=[CH:12][CH:13]=[C:14]1[CH:24]([CH3:26])[CH3:25])[CH3:20])[CH3:23]
Reactant: CCOC(C)OC(C#N)C(=CC=C(C)CCC=C(C)CCC=C(C)CCl)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: c1ccccc1
Product: CCOC(C)OC1(C#N)CC(C)=CCCC(C)=CCCC(C)=CC=C1C(C)C
Reaction time: 0.08 h
Yield: 51.5 %

Procedure:
A solution of hexamethyldisilazane lithium amide (205 mg, 1.11 mmol) in dry hexane/benzene (1:4) solution (5 ml) is stirred on an oil bath at 90° C. and thereto is dropwise added a solution of cyanohydrin ethoxyethyl ether which is 15-chloro-2-(1-ethoxyethoxy)-3-(1-methylethyl)-6, 10,14-trimethyl-3,5,9,13-pentadecatetraenenitrile (115 mg, 0.26 mmol) in dry benzene (6 ml) over 20 minutes. After stirring the mixture at this temperature for 5 minutes, a saturated aqueous ammonium chloride solution is added while stirring on an ice-water bath. The organic layer is extracted with ether (20 ml ×2) and the solvent is removed by distillation under reduced pressure to give 1-(1-ethoxyethoxy)-2-(1-methylethyl)-5,9,13-trimethyl-2,4, 8,12-cyclotetradecatetraene-1-carbonitrile (51.6 mg, 50%) as a mixture of diastereomers. This product is subjected to silica gel column chromatography (n-hexane/ether=20:1) to give one isomer of the above formula.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(#N)C>[C:26]([O:25][C:23]([N:17]1[CH2:22][CH2:21][N:20]([CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10])[CH2:19][CH2:18]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)C(Br)C(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C(=O)OC)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.7 %

Procedure:
19.5 g (141 mmol) of potassium carbonate and then 19.5 ml (134 mmol) of dimethyl bromomalonate are added to a solution of 25 g (134 mmol) of tert-butyl piperazine-1-carboxylate in 300 ml of acetonitrile. The reaction medium is stirred at ambient temperature for 24 h and then filtered in order to remove the insoluble salts, and concentrated under vacuum. The crude residue obtained is purified by chromatography on silica gel, elution being carried out with a 70/30 heptane/ethyl acetate mixture. 41 g (97%) of dimethyl 2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate are obtained in the form of a light oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1.[C:25]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:25]([C:29]1[CH:30]=[CH:31][C:32]([NH:33][C:20]([C:19]2[CH:23]=[CH:24][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[O:21])=[CH:34][CH:35]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: COc1cc2nccc(Oc3ccc(C(=O)O)cc3)c2cc1OC
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(C(=O)Nc4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 38.3 %

Procedure:
4-[6,7-Dimethoxy-4-quinolyl)oxybenzoic acid (54 mg) and commercially available 4-tert-butylaniline (102 mg) were dissolved in N,N-dimethylformamide (3 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (106 mg) was added, and the admixture was stirred at room temperature for 6 hours, after which the reaction mixture was purified in the same manner as described in Example 51 to obtain 29 mg of the title compound (yield: 35%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.Cl.[O:26]=[S:27]1(=[O:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CO>[O:26]=[S:27]1(=[O:33])[CH2:32][CH2:31][N:30]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH2:29][CH2:28]1
Reactant: O=S1(=O)CCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCS(=O)(=O)CC3)n2n1
Temperature: 25 °C
Yield: 37 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 110 mg, 0.319 mmol), S,S-dioxidothiomorpholine hydrochloride (164 mg, 0.957 mmol) and N,N-diisopropylethylamine (181 mg, 1.40 mmol) in DMF (1.28 mL) was stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was diluted with methanol, and was then purified by preparatory HPLC (20-30% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (52.4 mg, 37%). 1H NMR (DMSO-d6) δ: 10.92 (s, 1H), 8.00 (d, J=8.8 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 7.42 (s, 1H), 6.21 (s, 1H), 4.25 (br. s., 4H), 3.41 (br. s., 4H), 2.39 (s, 3H), 1.45 (s, 6H); ESI-MS: m/z 444.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]Cl)=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2].[C:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[SH:28])#[N:17]>O1CCOCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][S:28][C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]=2[C:16]#[N:17])=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Reactant: N#Cc1c(S)ccc2ccccc12
Solvent: C1COCCO1
Product: N#Cc1c(SSc2ccc([N+](=O)[O-])cc2C(Cl)(Cl)Cl)ccc2ccccc12
Yield: 81.3 %

Procedure:
30.7 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride in 500 ml of dioxane is reacted with 18.5 g of 1-cyano-2-mercaptonaphthalene. There is obtained 37 g (81% of theory) of 2-(4-nitro-2-trichloromethylphenyldithio)-1-cyanonaphthalene; m.p.: 170° C. (recrystallized from toluene).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11]2)=[CH:4][C:3]=1[N:16]1[C:20](=[O:21])[C:19]2[CH2:22][CH2:23][CH2:24][CH2:25][C:18]=2[C:17]1=[O:26].[CH2:27]([NH2:31])[CH:28]([CH3:30])[CH3:29].C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11]2)=[CH:4][C:3]=1[NH:16][C:20](=[O:21])[C:19]1[CH2:22][CH2:23][CH2:24][CH2:25][C:18]=1[C:17]([NH:31][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:26]
Reactant: CC(C)CN
Reactant: CC1CCC(Oc2cc(N3C(=O)C4=C(CCCC4)C3=O)c(F)cc2Cl)C1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)CNC(=O)C1=C(C(=O)Nc2cc(OC3CCC(C)C3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
N-{2-Fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrophthalimide (1.20 g, 3.18 mmol), isobutylamine (0. 360 g, 4.92 mmol), triethylamine (0.450 g, 4.44 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-N'-isobutyl-3,4,5,6-tetrahydrophthalamide as white crystals (0.700 g, 48.7% yield).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[NH2:7][CH2:8][CH2:9][CH2:10][NH2:11]>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: NCCCN
Solvent: ClCCl
Product: C=C(C)C(=O)NCCCN
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
Methacryloyl chloride (8.0 g, 0.078 mmol) in methylene chloride (10 ml) was added to a solution of 1,3-diaminopropane (35 ml) in methylene chloride (200 ml) at 0° C. After 15 min. stirring at 0° C. and 16 hours at 25° C. the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silicagel, chloroform/methanol (8:2)) to give (72%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([OH:14])=O)[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:34][CH2:35][C:36]([C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)=[O:37].C(N(CC)CC)C>CN(C=O)C.O>[O:37]=[C:36]([C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)[CH2:35][NH:34][C:12]([C:10]1[S:11][C:7]2[C:6]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:14]
Reactant: NCC(=O)c1cccs1
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)O)nc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(C(=O)NCC(=O)c3cccs3)nc12
Yield: 44.1 %

Procedure:
0.40 g 4-Methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 0.25 g 1,1′-carbonyl-diimidazole in 40 ml DMF were stirred at room temperature for 1.5 hours. 0.27 g 2-amino-1-(2-thienyl)ethanone hydrochloride and 0.15 g triethylamine were added and stirring was continued over night at room temperature. 350 ml water was added and the mixture was extracted with ethylacetate. Chromatography on silicagel with ethylacetate/hexane 4:6 yielded 0.25 g (43%) 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid (2-oxo-2-thiophen-2-yl-ethyl)-amide as a yellow solid; MS (ISP): m/e=418 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8]=[CH2:9])=[C:4]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[C:16]([F:19])[CH:15]=[CH:14][CH:13]=3)[CH:3]=1.C([O-])(O)=O.[Na+].[ClH:25].O1CCOCC1>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][CH2:9][Cl:25])=[C:4]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[C:16]([F:19])[CH:15]=[CH:14][CH:13]=3)[CH:3]=1
Reactant: Cl
Reactant: C=Cc1nnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Fc1cccc2[nH]c(-c3cc(Cl)nnc3CCCl)cc12
Reaction time: 0.25 h
Yield: 66 %

Procedure:
A solution of 2-(6-chloro-3-vinylpyridazin-4-yl)-4-fluoro-1H-indole (80 mg, 0.29 mmol) in HCl-dioxane (5 mL) was stirred at 50° C. After 15 minutes, NaHCO3 (a.q) was added. The mixture was extracted with DCM. The organic phase was dried over Na2SO4. After being concentrated in vacuo, the residue was purified by prep-TLC (DCM) to give the product of 2-(6-chloro-3-(2-chloroethyl)pyridazin-4-yl)-4-fluoro-1H-indole (60 mg, yield: 66%). 1H-NMR (CDCl3, 400 MHz) δ 9.04 (s, 1H), 7.63 (s, 1H), 7.28˜7.31 (m, 1H), 7.22˜7.26 (m, 1H), 6.99 (d, J=1.6 Hz, 1H), 6.84˜6.93 (m, 1H), 4.24 (t, J=6.4 Hz, 2H), 3.66 (t, J=6.5 Hz, 2H). MS (M+H)+: 310/312.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[C:7]([O:14]C)[CH:8]=[CH:9][C:10]=2[O:12]C)[C:5]([F:16])=[C:4]([F:17])[C:3]=1[F:18].[F:19][C:20]1[C:28]([F:29])=[C:27]([F:30])[C:26]([F:31])=[C:25]2[C:21]=1[C:22](=[O:33])O[C:24]2=[O:32].[Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Na+].Cl>>[F:31][C:26]1[C:25]2[C:24](=[O:32])[C:9]3[C:8](=[C:7]([OH:14])[C:6]4[C:11]([C:10]=3[OH:12])=[C:2]([F:1])[C:3]([F:18])=[C:4]([F:17])[C:5]=4[F:16])[C:22](=[O:33])[C:21]=2[C:20]([F:19])=[C:28]([F:29])[C:27]=1[F:30]
Reactant: COc1ccc(OC)c2c(F)c(F)c(F)c(F)c12
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1c2c(F)c(F)c(F)c(F)c2C(=O)c2c1c(O)c1c(F)c(F)c(F)c(F)c1c2O
Reaction time: 1 h
Yield: 79.3 %

Procedure:
1,2,3,4-tetrafluoro-5,8-dimethoxynaphthalene (6) (4.77 g, 18.3 mmol), 4,5,6,7-tetrafluoroisobenzofuran-1,3-dione (2) (4.77 g, 21.7 mmol), aluminum chloride (23.1 g, 173 mmol), and sodium chloride (3.56 g, 60.9 mmol) were thrown into a 200 mL autoclave and heating was made at 200° C. for 1 hour. After the completion of the reaction, cooling was made down to room temperature, the reaction mixture was poured into dilute hydrochloric acid, and stirring was made at 100° C. for 1 hour. Subsequently, the mixture was filtered and the residue was washed with water, methanol and ether in order. The obtained solid was recrystallized from dichloromethane so as to obtain 6.3 g (yield of 79%) of 1,2,3,4,7,8,9,10,-octafluoro-6,11-dihydroxynaphthacene-5,12-dione (7).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C@:27]1([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[CH:48]=[CH2:49])=[CH:38][CH:37]=2)[CH2:31][NH:30][C@H:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:28]1.[CH3:50][C:51]([CH3:66])([CH3:65])[C@H:52]([NH:56][C:57]([O:59][CH2:60][CH2:61][CH2:62][CH:63]=[CH2:64])=[O:58])[C:53](O)=[O:54].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:50][C:51]([CH3:66])([CH3:65])[C@H:52]([NH:56][C:57]([O:59][CH2:60][CH2:61][CH2:62][CH:63]=[CH2:64])=[O:58])[C:53]([N:30]1[CH2:31][C@:27]([O:26][CH3:25])([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[CH:48]=[CH2:49])=[CH:38][CH:37]=2)[CH2:28][C@H:29]1[C:32]([O:34][CH3:35])=[O:33])=[O:54]
Reactant: C=CCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: C=Cc1ccccc1-c1ccc([C@@]2(OC)CN[C@H](C(=O)OC)C2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCCOC(=O)N[C@H](C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3C=C)cc2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Yield: 75.2 %

Procedure:
HATU (248 mg, 0.652 mmol) was added to a solution of (2S,4R)-methyl 4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (200 mg, 0.593 mmol), (S)-3,3-dimethyl-2-((pent-4-enyloxy)carbonylamino)butanoic acid (180 mg, 0.741 mmol) and DIEA (0.311 mL, 1.778 mmol) in DCM (8 mL) and stirred at r.t. 60 hours. The reaction was evaporated and purified on the Biotage (10-40% EtOAc:Hex) to give the product (2S,4R)-methyl 1-((S)-3,3-dimethyl-2-((pent-4-enyloxy)carbonylamino)butanoyl)-4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (251 mg, 0.446 mmol, 75% yield) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.96-1.00 (m, 1H) 1.04-1.10 (m, 1H) 1.11-1.21 (m, 7H) 1.64-1.79 (m, 2H) 2.06-2.20 (m, 2H) 2.52 (dd, J=13.30, 8.78 Hz, 1H) 2.83-3.04 (m, 4H) 3.72-3.82 (m, 3H) 3.96-4.12 (m, 3H) 4.15-4.21 (m, 1H) 4.31-4.41 (m, 1H) 4.86-5.10 (m, 3H) 5.19-5.30 (m, 1H) 5.41 (d, J=9.79 Hz, 1H) 5.67-5.87 (m, 2H) 6.61-6.76 (m, 1H) 7.28-7.44 (m, 7H) 7.61-7.71 (m, 1H). LCMS: r.t.=2.18 min., [M+H]+=563 Phenomenex Luna S10 (3×50 mm); Solvent A=95% water—5% methanol—10 mM ammonium acetate, Solvent B=5% water—95% methanol—10 mM ammonium acetate; gradient=0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 ml/min; inj. vol.=10 ul; wavelength=220 nm.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH:5]([CH3:22])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14]C2C=CC=CC=2)[CH2:10][CH:9]1[CH3:21])=[O:7].C=O.[H][H]>[Pd].CO>[ClH:2].[Cl:2][CH2:3][CH2:4][CH:5]([CH3:22])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]1[CH3:21])=[O:7]
Reactant: [H][H]
Reactant: CC(CCCl)C(=O)N1CCN(Cc2ccccc2)CC1C
Agent: [Pd]
Agent: C=O
Agent: Cl
Solvent: CO
Product: CC(CCCl)C(=O)N1CCN(C)CC1C
Yield: 72.6 %

Procedure:
A mixture of 16 parts of 1-(4-chloro-2-methyl-1-oxobutyl)-2-methyl-4-(phenylmethyl)piperazine monohydrochloride, 200 parts of methanol and 7 parts of a formaldehyde solution 40% was hydrogenated at normal pressure and at 60° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol and 2,2'-oxybispropane, yielding 9 parts (72.6%) of 1(-4-chloro-2-methyl-1-oxobutyl)-2,4-dimethylpiperazine monohydrochloride (int. 26).
Reaction SMILES: COC1C(C)=CC(OB(O)O)=CC=1C.[F-].[K+].C(OC(C1N=C2C=CC(Br)=CN2C=1)=O)C.C([O:34][C:35]([C:37]1[N:38]=[C:39]2[CH:44]=[CH:43][C:42]([C:45]3[CH:50]=[C:49]([CH3:51])[C:48]([O:52][CH3:53])=[C:47]([CH3:54])[CH:46]=3)=[CH:41][N:40]2[CH:55]=1)=[O:36])C.[OH-].[Na+].COC1C(C)=CC(C2C=CC3N(C=C(C(O)=O)N=3)C=2)=CC=1C.[ClH:80]>C(#N)C.C(O)C.[Pd].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>[ClH:80].[CH3:53][O:52][C:48]1[C:49]([CH3:51])=[CH:50][C:45]([CH:42]2[CH2:41][N:40]3[CH:55]=[C:37]([C:35]([OH:36])=[O:34])[N:38]=[C:39]3[CH2:44][CH2:43]2)=[CH:46][C:47]=1[CH3:54]
Reactant: CCOC(=O)c1cn2cc(-c3cc(C)c(OC)c(C)c3)ccc2n1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)c1cn2cc(Br)ccc2n1
Solvent: CC#N
Solvent: CCO
Product: COc1c(C)cc(C2CCc3nc(C(=O)O)cn3C2)cc1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-Methoxy-3,5-dimethylphenylboric acid (3.15 g; 17.5 mmol) followed by KF solution (2M in water, 15 ml) and finally Pd(PPh3)4 (607 mg; 0.525 mmol; 3 mol %) were added under a nitrogen atmosphere to a solution of 6-bromoimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (4.71 g; 17.5 mmol) in acetonitrile (30 ml) in a Milestone 100 ml high-pressure vessel. The reaction vessel was rinsed with nitrogen, closed and irradiated in a microwave at 160° C. for 5 min. (DC control: n-hexane-ethyl acetate 1:1). Four batches of the same size were run in parallel and combined prior to processing. The precipitated product was filtered out and washed with diethyl ether. The black crystalline product was taken up in chloroform and filtered over celite. The clear filtrate was concentrated to small volume and used for the next reaction without further purification. Yield: 22.7 g (quantitative). Stage 2. The 6-(4-methoxy-3,5-dimethylphenyl)-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (22.7 g, 70 mmol) was dissolved in ethanol (300 ml) and NaOH solution (20% in water, 30 ml) was added. The reaction batch was refluxed for 24 hours. On completion of the reaction the solvent was removed in a rotary evaporator and the residue taken up in as small an amount of water as possible. The solution was carefully adjusted to pH 3-4 with HCl solution (10% in water). The precipitated product was filtered and washed with water. Yield: 21.2 (quantitative). Stage 3. Palladium on activated carbon (1 g) was added to a solution of 6-(4-methoxy-3,5-dimethylphenyl)-imidazo[1,2-a]pyridine-2-carboxylic acid (4.74 g; 16 mmol) in a blend of HCl (4% in water, 70 ml) and ethanol (140 ml). The mixture was poured into an autoclave (stainless steel), the autoclave was closed and rinsed a few times with nitrogen. The autoclave was filled with hydrogen (8 bar) and the reaction batch stirred for 12 h at room temperature. On completion of the reaction the catalyst was filtered out over celite and the solvent drawn off in a rotary evaporator at room temperature. The product was crystallized out of acetonitrile. Yield: 2.3 g (43%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][C:14]3=[O:19])=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:20][NH:21][CH:22]=[O:23])[O:3]1.ClCCl.[N+](C1C=CC([C:36]2[CH:40]=[C:39]([Cl:41])[S:38][C:37]=2C([O-])=O)=CC=1)([O-])=O.[OH-].[Na+]>O.CO.C(O)(=O)C>[CH:11]1[C:10]([N:13]2[C:14](=[O:19])[CH2:15][O:16][CH2:17][CH2:18]2)=[CH:9][CH:8]=[C:7]([N:6]2[C:2](=[O:1])[O:3][C@@H:4]([CH2:20][NH:21][C:22]([C:37]3[S:38][C:39]([Cl:41])=[CH:40][CH:36]=3)=[O:23])[CH2:5]2)[CH:12]=1
Reactant: O=CNC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Reactant: O=C([O-])c1sc(Cl)cc1-c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1

Procedure:
N-({(5 S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)formamide (1 g) taken in a dichloromethane(10 ml) and stirred reaction mass at 25 to 30° C. for 30 minutes. To this mixture added solution of 4-nitrophenyl-5-chlorothiophene-2-carboxylate (1.06 g) in a dichloromethane (10 ml) and sodium hydroxide (0.38 g) in water (5 ml) simultaneously through addition funnel. Obtained reaction mass then stirred for 1 to 2 h at 25 to 30° C. After completion of reaction, Separated organic layer and concentrated under reduced pressure to obtain residue. Added acetic acid and methanol to residue stirred for 30 minutes and obtained solid is filtered off. Washed solid with methanol.
Reaction SMILES: Cl.[NH:2]=[C:3]1[NH:7][C:6]([C:8](=[N:29][OH:30])[C:9]([NH:11][CH:12]2[C:27](=[O:28])[N:14]3[C:15]([C:24]([OH:26])=[O:25])=[C:16]([CH2:19]OC(=O)C)[CH2:17][S:18][C@H:13]23)=[O:10])=[CH:5][S:4]1.[CH3:31][N:32]1[C:36]([SH:37])=[N:35][N:34]=[N:33]1.C(=O)([O-])O.[Na+:42].O>P([O-])([O-])([O-])=O>[NH:2]=[C:3]1[NH:7][C:6]([C:8](=[N:29][OH:30])[C:9]([NH:11][CH:12]2[C:27](=[O:28])[N:14]3[C:15]([C:24]([O-:26])=[O:25])=[C:16]([CH2:19][S:37][C:36]4[N:32]([CH3:31])[N:33]=[N:34][N:35]=4)[CH2:17][S:18][C@H:13]23)=[O:10])=[CH:5][S:4]1.[Na+:42]
Reactant: Cn1nnnc1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(=N)[nH]3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NO)c3csc(=N)[nH]3)[C@H]2SC1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
In 20 ml of phosphate buffer (0.2M, pH 6.4) there was dissolved 0.883 g of 7-[2-(2-imino-4-thiazolin-4-yl)-2-hydroxyimino-acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid hydrochloride together with 0.232 g of 1-methyl-1H-tetrazole-5-thiol and 0.336 g of sodium hydrogen carbonate and the mixed solution was stirred at 70° C. for 3 hours. The reaction mixture was subjected to column chromatography on polystyrene resin (Amberlite XAD-2, Rohm and Haas Co.), development being carried out with water. The fractions containing the desired product were pooled and lyophilized. By the above procedure there was obtained 0.217 g of the captioned compound.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C:5]1[CH:17]=[C:16]([CH3:18])[C:15]([O:19][CH3:20])=[C:14]2[C:6]=1[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=1[CH:13]2[CH2:21]C=O>C(O)C.C(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH3:4][C:5]1[CH:17]=[C:16]([CH3:18])[C:15]([O:19][CH3:20])=[C:14]2[C:6]=1[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=1[CH:13]2[CH:21]=[N:2][OH:3]
Reactant: COc1c(C)cc(C)c2c1C(CC=O)C1=C2CCCC1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1c(C)cc(C)c2c1C(C=NO)C1=C2CCCC1

Procedure:
500 Milligrams of hydroxylamine hydrochloride was added to an ethanol-chloroform (5:1) solution containing 910 mg of 5,7-dimethyl-8-methoxy-9-formylmethyl-1,2,3,4-tetrahydro-9H-fluorene in 18 ml of ethanol-chloroform and the mixture was refluxed with heating for 2 hours. The reaction mixture was diluted with chloroform and then washed with saturated aqueous sodium chloride solution and subsequently the solvent was distilled off. The residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:10) to obtain 670 mg of 5,7-dimethyl-8-methoxy-9-hydroxyiminomethyl-1,2,3,4-tetrahydro-9H-fluorene