Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[CH:17]12[C:25](=O)[CH:21]([CH2:22][CH2:23][CH2:24]1)[CH2:20][CH2:19][CH2:18]2.O.C([O-])([O-])=O.[K+].[K+]>C1COCC1.Cl[Ti](Cl)(Cl)Cl.[Zn]>[CH:17]12[C:25](=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[CH:21]([CH2:22][CH2:23][CH2:24]1)[CH2:20][CH2:19][CH2:18]2
Reactant: O=C1C2CCCC1CCC2
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(C(=C2C3CCCC2CCC3)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
In a 3-neck round-bottomed flask equipped with a reflux condenser and a nitrogen inlet, TiCl4 (0.51 mL, 4.67 mmol) was slowly added to a suspension of zinc powder (0.63 g, 9.60 mmol) in dry THF (13 mL) at room temperature. The reaction mixture was heated at reflux for 2.5 h. The reaction mixture was taken out of the oil bath and a solution of (4-bromophenyl)(4-hydroxyphenyl)methanone (2) (0.35 g, 1.26 mmol) and bicyclo[3.3.1]nonan-9-one (0.52 g, 3.79 mmol) in dry THF (13 mL) was added. The reaction mixture was heated at reflux for 2 h. The reaction mixture was allowed to cool at RT. Water (10 mL) was added to the reaction mixture via a syringe followed by 10% K2CO3 (10 mL). The reaction mixture was filtered through a pad of Celite. The pad of Celite washed with EtOAc. The filtrate was transferred to a separatory funnel and the layers were separated. The organic layer washed with brine, dried (MgSO4), filtered, and the filtrate was concentrated to give an oily residue. The crude product was adsorbed onto silica and purified by flash column chromatography using SiO2 and a hexanes:EtOAc gradient (100:0 to 75:25) to afford compound 43 as a white powder (0.32 g, 67%). 1H NMR (400 MHz, DMSO-d6): δ 1.50-1.54 (m, 2H), 1.71-1.73 (m, 8H), 1.93-1.99 (m, 2H), 2.60 (s, 1H), 6.67 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 7.02 (d, J=8.5 Hz, 2H), 7.46 (d, J=8.3 Hz, 2H), 9.32 (s, 1H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)[N:3]=1.[NH4+].[Cl-]>CO.[Zn]>[F:24][C:21]([F:22])([F:23])[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[C:9]([NH2:11])[C:10]=3[CH:2]=[N:3]2)=[N:16][CH:17]=1
Reactant: O=[N+]([O-])c1cccc2c1c(I)nn2Cc1ccc(C(F)(F)F)cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1cccc2c1cnn2Cc1ccc(C(F)(F)F)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To a solution of 3-iodo-4-nitro-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazole (0.464 g, 1.04 mmol) in MeOH (10 mL) at 0° C. was added Zn dust (0.339 g, 5.18 mmol) followed by saturated aqueous NH4Cl (10 mL). The mixture was stirred at 0° C. for 1 hour, then warmed to ambient temperature and stirred for an additional 1 hour. The mixture was diluted with MeOH and filtered. Saturated aqueous NH4OAc was added to the filtrate and the mixture was concentrated to remove bulk MeOH. The mixture was extracted with EtOAc, and the combined organic extracts were washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The product was purified by column chromatography (25 to 100% EtOAc/hexane) to afford 0.230 g (76%) of the product as yellow/orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.CCCCCC.[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]([C@H:29]1[CH2:33][CH2:32][O:31][C:30]1=[O:34])[CH2:24][CH2:23][CH2:22]2>C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]([C@@H:29]([CH2:33][CH2:32][OH:31])[C:30]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:34])[CH2:24][CH2:23][CH2:22]2
Reactant: O=C1OCC[C@@H]1N1CCCc2cc(Cl)ccc21
Reactant: Nc1ccccc1
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(Nc1ccccc1)[C@H](CCO)N1CCCc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.7 %

Procedure:
Prepared using general procedure 60: To a solution of aniline (1.0 mL, 11.1 mmol) in CH2Cl2 (25 mL) under nitrogen at RT was added a solution of trimethylaluminum in hexane (2.0 M, 5.5 mL, 11.0 mmol) over 5 min. After stirring at RT for 20 min, a solution of (S)-3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-dihydrofuran-2(3H)-one (2.32 g, 9.2 mmol) in CH2Cl2 (25 mL) was added over 10 min. Stirring was continued for 18 h at RT, then the reaction mixture was cooled to 0° C. and quenched by careful addition of aqueous 1M HCl (25 mL). Phases were separated, and the aqueous phase was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried over MgSO4 and concentrated. Purification via silica gel chromatography using 2-10% MeOH in CH2Cl2 gave (S)-2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-4-hydroxy-N-phenylbutanamide as a white solid (2.56 g, 81%). 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 7.60 (dd, J=1.0, 8.5 Hz, 2H), 7.29 (dd, J=1.8, 14.1 Hz, 2H), 7.07-6.95 (m, 3H), 6.80 (d, J=9.0 Hz, 1H), 4.67 (t, J=4.9 Hz, 1H), 4.56 (t, J=7.2 Hz, 1H), 3.47 (dd, J=6.1, 11.2 Hz, 2H), 3.39-3.34 (m, 1H), 3.31-3.25 (m, 1H), 2.71-2.68 (m, 2H), 2.15-2.04 (m, 1H), 1.94-1.80 (m, 3H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=345.3; tR=3.44 min.
Reaction SMILES: [C:1]([C:5]1[C:19]([OH:20])=[C:18]([CH:21]([CH3:24])[CH:22]=[CH2:23])[C:8]2[CH2:9][C:10]3([O:17][C:7]=2[CH:6]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([C:5]1[C:19]([OH:20])=[C:18]([CH:21]([CH3:24])[CH2:22][CH3:23])[C:8]2[CH2:9][C:10]3([O:17][C:7]=2[CH:6]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(C)c1c(O)c(C(C)(C)C)cc2c1CC1(CCCCCC1)O2
Agent: [Pd]
Solvent: CCO
Product: CCC(C)c1c(O)c(C(C)(C)C)cc2c1CC1(CCCCCC1)O2
Yield: 71 %

Procedure:
0.07 g of 6-t-butyl-5-hydroxy-4-(1-methyl-2-propenyl)-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane synthesized in Example 12 was dissolved in 10 ml of ethanol and he solution was treated with 0.01 g of 10% palladium on carbon in the same manner as in Example 9 to give 0.05 g of 6-t-butyl-5-hydroxy-4-(1-methylpropyl)-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane as a pale yellow oil (yield 71%).
Reaction SMILES: [C:1]([CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH2:17]O.C(=O)([O-])O.[Na+]>C(O)C>[CH2:2]([C:1]1[O:7][N:17]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)CC(=O)C(=O)OCC
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCCCc1cc(C(=O)OCC)no1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
A mixture of 38 g of ethyl hexanoylpyruvate in 190 ml of ethanol in the presence of 14.4 g of hydroxylamine hydrochloride and 16 g of sodium hydrogencarbonate was heated under reflux for 3 hours. After the reaction mixture was cooled to room temperature, the insoluble materials were separated by filtration, and the remaining filtrate was concentrated. The resulting residue was dissolved in chloroform (500 ml), which was washed with water, concentrated to give 5-pentyl-3-carboethoxyisoxazole as a liquid (36 g).
Reaction SMILES: N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:13]N1C(=O)CCC1=O.[CH2:21]([O:25][C:26]([N:28]([C:45]1[C:50]([O:51][CH3:52])=[N:49][C:48]([CH3:53])=[CH:47][N:46]=1)[S:29]([C:32]1[C:33]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)=[CH:34][CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])=[O:27])[CH:22]([CH3:24])[CH3:23]>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:44][C:41]1[CH:42]=[CH:43][C:38]([C:33]2[C:32]([S:29]([N:28]([C:26]([O:25][CH2:21][CH:22]([CH3:23])[CH3:24])=[O:27])[C:45]3[C:50]([O:51][CH3:52])=[N:49][C:48]([CH3:53])=[CH:47][N:46]=3)(=[O:31])=[O:30])=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:39][CH:40]=1
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1-c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Yield: 70.9 %

Procedure:
Azobis(isobutyronitrile) (150 mg) and N-bromosuccinimide (1.68 g) were added to a solution of N-(isobutoxycarbonyl)- N-(3-methoxy-5-methylpyrazin-2-yl)-4'-methyl-2-biphenylsulphonamide (4.44 g) in carbon tetrachloride (150 ml). The mixture was heated under reflux for 4 hours and then allowed to cool and filtered. The filtrate was concentrated by evaporation and the residue was purified by flash chromatography on silica (150 g), eluting with 20% ethyl acetate in isohexane. Fractions containing the product were combined and evaporated to give 4'-bromomethyl- N-(isobutoxycarbonyl)- N-(3-methoxy-5-methylpyrazin-2-yl)-2-biphenylsulphonamide (3.67 g); 1H NMR (d6 -DMSO): 0.6 (s, 6H), 1.6-1.7 (m, 1H), 3.8 (d, 2H), 3.95 (s, 3H), 4.8 (s, 2H), 7.3-7.5 (m, 5H), 7.7-7.8 (m, 2H), 8.15 (s, 1H), 8.45-8.55 (m, 1H); mass spectrum (+ve FAB, methanolBA): 548 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13](=O)[CH2:14][CH3:15])=[C:6](OS(C)(=O)=O)[CH:7]=1.[CH:17]1([NH:23][NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C([O-])(=O)C.[NH4+]>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:13]([CH2:14][CH3:15])=[N:24][N:23]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: NNC1CCCCC1
Reactant: CCC(=O)c1ccc(Br)cc1OS(C)(=O)=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CCc1nn(C2CCCCC2)c2cc(Br)ccc12
Temperature: 135 °C
Yield: 76.6 %

Procedure:
Methanesulfonic acid 5bromo-2-propionyl-phenyl ester (36.6 g, 119 mmol) was combined with cyclohexylhydrazine (27.2 g, 238 mmol) and ammonium acetate (23.0 g, 299 mmol) in xylenes (220 mL). The reaction mixture was heated to 135° C. in a Dean-Stark apparatus for 48 hours. The reaction was cooled to room temperature and concentrated to a low volume under reduced pressure. The crude product was filtered through a pad of silica gel (weight ratio product/silica gel 1/5) eluting first with hexanes then with a 10/90 mixture of ethyl acetate and hexanes. The fractions containing principally 6-bromo-1-cyclohexyl-3-ethyl-1H-indazole were collected. A second crop was obtained by repeating the above silica treatment with the mixed fractions. The two crops were combined and dried under vacuum to yield 28.0 g of 6-bromo-1-cyclohexyl-3-ethyl-1H-indazole (76% yield). 1H NMR (400 MHz, CDCl3) δ 1.35 (t, 3, J=7.7), 1.39-2.06 (m, 10), 2.95 (q, 2, J=7.7), 4.21-4.28(m, 1), 7.15 (d, 1, J=8.5), 7.51 (d, 1, J=8.5), 7.56 (s, 1). 13C NMR (100 MHz, CDCl3) δ 13.95, 20.50, 25.35, 25.84, 32.44, 58.15, 112.01, 120.10, 121.37, 121.65, 122.82, 140.37, 146.60. IR 2934, 2855, 1606, 1502, 1451, 1048, 951, 834 cm-1. Analysis calculated for C15H19BrN2 : C, 58.64; H, 6.23; N, 9.12. Found: C, 58.82; H, 6.20; N, 9.01.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([O:25]CC)=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][C:29]1=[O:34].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([OH:25])=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][C:29]1=[O:34])[CH:16]=2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COCCN1
Reactant: CCOC(=O)c1nc2cc(Br)ccc2cc1NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: O=C(Nc1cc2ccc(N3CCOCC3=O)cc2nc1C(=O)O)OCc1ccccc1
Temperature: 100 °C
Yield: 25.8 %

Procedure:
A mixture of ethyl 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylate (316 mg, 0.736 mmol), morpholin-3-one (100 mg, 1 mmol), Pd(OAc)2 (20 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.041 g, 0.071 mmol), and Cs2CO3 (0.31 g, 0.95 mmol) in dioxane (1.0 mL) was purged with nitrogen and then heated at 100° C. in a sealed vial for 3 h. To the cooled mixture, 5 mL of MeOH and 2 mL of 2 M NaOH were added. The resulting mixture was heated at 80° C. for 30 min. The solution was allowed to cool and NH4Cl solution and 10 mL of MeOH were added. The resulting mixture was filtered and the filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 60 mL/min.) to afford the sub-title compound (0.080 g, 20%). LCMS calc. for C22H20N3O6 [M+H]+: m/z=422.1. found: 422.2.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[CH:17]=[C:18]([CH3:23])[C:19](=[O:22])[NH:20][CH:21]=2)[CH2:3][CH2:2]1.CS(O[CH2:29][C:30]1[N:31]=[CH:32][O:33][CH:34]=1)(=O)=O.CS(OCC1COC1)(=O)=O>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[CH:17]=[C:18]([CH3:23])[C:19](=[O:22])[N:20]([CH2:29][C:30]3[N:31]=[CH:32][O:33][CH:34]=3)[CH:21]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)OCc1cocn1
Reactant: Cc1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)c[nH]c1=O
Agent: CS(=O)(=O)OCC1COC1
Product: Cc1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)cn(Cc2cocn2)c1=O

Procedure:
The title compound from Example 242, step 1 was reacted in a manner similar to Example 245 except that 1,3-oxazol-4-ylmethyl methanesulfonate was substituted for oxetan-3-ylmethyl methanesulfonate to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.82 (s, 5H), 7.52 (s, 1H), 7.01 (d, J=9.2 Hz, 1H), 5.11 (s, 2H), 3.94 (d, J=6.8 Hz, 1H), 3.06 (s, 3H), 2.21 (s, 3H), 1.27-1.24 (m, 1H), 0.68-0.65 (m, 2H), 0.37-0.36 (m, 2H). LCMS: 415.1 (M+1)+
Reaction SMILES: C(O)(=O)C.C(O[C:8]1(O[Si](C)(C)C)[CH2:10][CH2:9]1)C.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[N:27][N:26]3[C:37]=2[C:38]2[CH:43]=[CH:42][N:41]=[N:40][CH:39]=2)=[CH:19][CH:18]=1.C([BH3-])#N.[Na+]>CO.O1CCCC1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:32][CH2:33][N:34]([CH:8]5[CH2:10][CH2:9]5)[CH2:35][CH2:36]4)=[N:27][N:26]3[C:37]=2[C:38]2[CH:43]=[CH:42][N:41]=[N:40][CH:39]=2)=[CH:19][CH:18]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: Fc1ccc(-c2nc3ccc(N4CCNCC4)nn3c2-c2ccnnc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: Fc1ccc(-c2nc3ccc(N4CCN(C5CC5)CC4)nn3c2-c2ccnnc2)cc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 57.1 %

Procedure:
0.15 ml of acetic acid and 0.32 ml (1.6 mmol) of (1-ethoxycyclopropoxy)trimethylsilane are added, in a reactor, to 0.10 g (0.27 mmol) of 2-(4-fluorophenyl)-6-(piperazin-1-yl)-3-(pyridazin-4-yl)imidazo[1,2-b]pyridazine in 3 ml of methanol. 1.2 ml (1.2 mmol) of a molar solution of sodium cyanoborohydride in tetrahydrofuran are then added. After stirring for 15 minutes, the mixture is heated at 50° C. for 2 hours. After cooling, the product is extracted with dichloromethane, and the organic phase is filtered over a hydrophobic cartridge and then concentrated under reduced pressure. The residue is chromatographed on a silica gel column, to give 0.064 g of product. The latter is crystallized from diisopropyl ether, to give 0.053 g of light yellow crystals after drying.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([NH:18][C:19]1[CH:20]=[C:21]([N:26]2[CH2:31][CH2:30][N:29]([C:32]([C@H:34]3[CH2:39][CH2:38][CH2:37][CH2:36][N:35]3C(OC(C)(C)C)=O)=[O:33])[CH2:28][CH2:27]2)[CH:22]=[CH:23][C:24]=1[F:25])[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([NH:18][C:19]1[CH:20]=[C:21]([N:26]2[CH2:27][CH2:28][N:29]([C:32]([C@H:34]3[CH2:39][CH2:38][CH2:37][CH2:36][NH:35]3)=[O:33])[CH2:30][CH2:31]2)[CH:22]=[CH:23][C:24]=1[F:25])[CH3:17]
Reactant: C[C@@H](Nc1cc(N2CCN(C(=O)[C@H]3CCCCN3C(=O)OC(C)(C)C)CC2)ccc1F)c1ccc(Cl)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](Nc1cc(N2CCN(C(=O)[C@H]3CCCCN3)CC2)ccc1F)c1ccc(Cl)cc1Cl
Reaction time: 1 h
Yield: 62.9 %

Procedure:
Trifluoroacetic acid (1.5 mL) was added to a solution (R)-t-butyl 2-(4-(3-((R)-1-(2,4-dichlorophenyl)ethylamino)-4-fluorophenyl)piperazine-1-carbonyl)piperidine-1-carboxylate (0.080 g, 0.14 mmol) in dichloromethane (5 mL) at room temperature, and the solution was stirred for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane. The organic layer was neutralized with aqueous saturated sodium bicarbonate solution, and the aqueous layer was further extracted with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound as a white solid (0.042 g, 0.088 mmol, 64%). 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.60-8.55 (m, 1H), 7.56 (dd, J=8.4, 8.4 Hz, 2H), 7.38 (dd, J=2.4, 8.4 Hz, 1H), 6.92 (dd, J=9.2, 11.2 Hz, 1H), 6.26-6.09 (m, 3H), 4.83 (dd, J=6.4, 13.6 Hz, 1H), 4.37 (t, J=11.2 Hz, 1H), 3.76-3.48 (m, 4H), 3.21 (d, J=11.2 Hz, 1H), 3.09-3.05 (m, 2H), 2.90-2.84 (m, 2H), 1.95 (d, J=13.6 Hz, 1H), 1.73-1.60 (m, 3H), 1.45 (d, J=6.8 Hz, 3H); MS: (ES) m/z calculated for C24H30Cl2FN4O [M+H]+479.2. found 479.4.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[CH:2].[C:10]([NH:17][CH2:18][CH:19]=O)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(Cl)Cl.C(O)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:6][CH2:19][CH2:18][NH:17][C:10](=[O:11])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=[CH:8][CH:9]=1)#[CH:2]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: C#Cc1cccc(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C#Cc1cccc(NCCNC(=O)OC(C)(C)C)c1
Reaction time: 0.5 h

Procedure:
To a solution of 3-ethynylaniline (100 mg) and N-Boc-2-aminoacetaldehyde (407 mg) in ethyl acetate (5 mL) and methylene chloride (5 mL), acetic acid (2 drops) and sodium triacetoxyborohydride (543 mg) were added at room temperature, and the mixture was stirred at the same temperature for 3 hours and 30 minutes. To the reaction mixture, N-Boc-2-aminoacetaldehyde (200 mg) and sodium triacetoxyborohydride (200 mg) were added at room temperature, and the mixture was stirred at the same temperature. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent, 75% hexane/25% ethyl acetate) to obtain tert-butyl (2-((3-ethynylphenyl)amino)ethyl)carbamate (G27).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)=[CH:5][C:4]([C:14]([F:17])([F:16])[F:15])=[N:3]1.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:12][C:10]3[S:11][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:5]=4)=[CH:8][CH:9]=3)[CH2:31][CH2:30]2)[CH:24]=1)=[O:21]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: Cn1nc(C(F)(F)F)cc1-c1ccc(C=O)s1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-c4cc(C(F)(F)F)nn4C)s3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thiophenecarbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 491.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:19]([CH2:21][NH2:22])[OH:20].Cl>C(O)C.C(OCC)C.O>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:22]([CH2:21][CH2:19][OH:20])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: NCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCO
Yield: 44.94 %

Procedure:
A solution of the product from (1) in ethanol:water (300 ml:300 ml) containing 5% aqueous sodium hydroxide (2 ml) was treated with ethanolamine (17 ml) and then refluxed for 18 hours with rapid stirring. The resultant solution was cooled and adjusted to pH 1 with concentrated hydrochloric acid. The solid which formed on cooling was extracted with hot absolute ethanol and the precipitate obtained on cooling was taken up in diethylether, the solution being filtered and evaporated to dryness by rotary evaporation to give the title compound in 44.94% yield, m.p. 191.5°-193° C.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:13][CH:14]=2)=[CH:6][CH:5]=1)=[N+]=[N-]>C(OCC)C.[Pd]>[O:16]([CH2:15][C:12]1[NH:13][CH:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[N:11]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: [N-]=[N+]=Nc1ccc(-c2c[nH]c(COc3ccccc3)n2)cc1
Agent: [Pd]
Solvent: CCOCC
Product: Nc1ccc(-c2c[nH]c(COc3ccccc3)n2)cc1

Procedure:
In a 100 ml reactor, 549 mg of 4-(4-azidophenyl)-2-(phenoxymethyl)-1H-imidazole (0.00188 mol) are hydrogenated over 18 hours under a hydrogen pressure of 2.5 bars with a catalytic quantity of palladium adsorbed on carbon (10% by mass). After filtration on a millipore filter then rinsing with ethanol and concentration to dryness, the residue thus obtained is treated with diethyl ether. After stirring in diethyl ether, the solid is filtered. After drying a white-coloured powder is obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:27]([O:31][CH:32](Br)[CH3:33])(=[O:30])[CH2:28][CH3:29].[I-].[Na+].O>CS(C)=O.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O:20][CH:32]([O:31][C:27](=[O:30])[CH2:28][CH3:29])[CH3:33])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CCC(=O)OC(C)Br
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCC(=O)OC(C)OC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOC)c3csc(N)n3)C(=O)N12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
To a solution of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer, 4.0 g) in dimethylsulfoxide (40 ml) were added 1-bromoethyl propionate (1.8 g) and sodium iodide (0.18 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into a mixture of cold water and ethyl acetate, and the organic layer was separated. The remaining aqueous layer was extracted with ethyl acetate. The extract and the organic layer were combined, washed with water and dried over magnesium sulfate. The solvent was then distilled off and the residue was subjected to column chromatography using silica gel (50 g), elution being carried out with a mixture of benzene and ethyl acetate (3:2, v/v). The fractions containing the desired product were combined and the solvent was distilled off to give 1-propionyloxyethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 0.83 g), mp 113°-116° C. (decompn.).