Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]([CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)=[CH2:4].[C:11]([C:15]1[CH:16]=[C:17]([O:25][C@H:26]([CH3:30])[C:27](Cl)=[O:28])[CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1)([CH3:14])([CH3:13])[CH3:12].O>C1(C)C=CC=CC=1>[C:11]([C:15]1[CH:16]=[C:17]([O:25][C@@H:26]([CH3:30])[C:27]([N:9]2[C@H:5]([CH:3]=[CH2:4])[CH2:6][CH2:7][C:8]2=[O:10])=[O:28])[CH:18]=[C:19]([C:21]([CH3:23])([CH3:22])[CH3:24])[CH:20]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: C[C@@H](Oc1cc(C(C)(C)C)cc(C(C)(C)C)c1)C(=O)Cl
Reactant: C=CC1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C[C@@H]1CCC(=O)N1C(=O)[C@H](C)Oc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: 25 °C
Yield: 49.3 %

Procedure:
To 60% sodium hydride (336 mg, 10 mmol) in toluene (20 mL) at 0° C. was added dropwise a solution of 5-vinylpyrrolidin-2-one (1.0 g, 9.0 mmol) in toluene (10 mL) over a 5 min period. The cooling bath was removed and the solution was allowed to warm to 25° C. to ensure complete generation of the anion. To the anion at 25° C. was added dropwise a solution of (2R)-2-(3,5-di-t-butylphenyloxy)propanoyl chloride (11, 3.20 g, 9.8 mmol) in toluene (10 mL) over a 5 min period. TLC indicated that the reaction was complete upon addition of the acid chloride (silica gel plates; hexane and ethyl acetate, 2:1). Water (60 mL) was added to the reaction mixture and the phases were separated. The aqueous phase was extracted with ethylene chloride (1×40 mL). The combined organic phases were washed with a saturated aqeous sodium bicarbonate solution (1×70 mL) and dried (MgSO4). Concentration and purification by flash chromatography on silica gel (EM silica gel 60, 0.040-0.063 partical size, 230-400 Mesh, column size: 6.5 cm diameter×18 cm length) using hexane and ethyl acetate (19:1) afforded 1.65 g (46%) of (5S)-N-((2S)-2-(3,5 -di-t-butylphenyloxy)propanoyl)-5-ethenylpyrrolidin-2-one (15a) as an oil: 1H NMR (CDCl3) δ1.20 (s, 18 H), 1.60-1.62 (d, 3 H), 1.92-2.04 (m, 1 H), 2.21-2.32 (m, 1 H), 2.52-2.80 (m, 2 H), 4.9-4.96 (q, 1 H), 5.11-5.21 (m, 2 H), 5.77-5.88 (m, 1 H), 5.98-6.04 (q, 1 H), 6.71 (s, 2 H), 7.00 (s, 1 H); 13C NMR (CDCl3) δ175.2, 172.7, 157.1, 152.1, 135.2, 115.9, 115.6, 109.6, 72.3, 58.0, 34.9, 31.6, 31.4, 24.4, 18.1; IR (neat) 2966 (vs), 1740 (vs), 1715 (vs), 1593 (s), 1380 (s), 1229 (vs), 706 (w) cm-1.
Reaction SMILES: Cl[C:2](=[CH2:5])[C:3]#[N:4].[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1[NH:18][NH2:19].C(N(CC(O)=O)CC(O)=O)CN(CC([O-])=O)CC([O-])=O.[Na+].[Na+].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CO>[NH2:4][C:3]1[N:18]([C:8]2[C:7]([Cl:6])=[CH:12][C:11]([C:13]([F:14])([F:16])[F:15])=[CH:10][C:9]=2[Cl:17])[N:19]=[CH:5][CH:2]=1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: C=C(Cl)C#N
Agent: O=C([O-])CN(CCN(CC(=O)O)CC(=O)O)CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CO
Product: Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
25 ml (27.6 g/0.3 mol) of 2-chloro-acrylonitrile are added dropwise to 24.5 g (0.1 mol) of 2,6-dichloro-4-trifluoromethylphenylhydrazine and 20 mg of disodium ethylenediamine-tetraacetate (Titriplex III) in 150 ml of methanol at the reflux temperature. When the addition has ended, the mixture is heated at the reflux temperature for a further 8 hours, 9 ml (0.16 mol) of 96% strength sulphuric acid are added dropwise and the mixture is heated at the reflux temperature for a further 6 hours. 33.5 g (0.3 mol) of anhydrous sodium carbonate are added to the cooled reaction mixture. After 4 hours, the solvent is removed in vacuo, the residue is taken up in 500 ml of water and the mixture is stirred at room temperature for 10 hours. The precipitate which has separated out is filtered off, rinsed with water and dried in vacuo at 50° C. 28.5 (96% of theory) of 5-amino- 1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole of melting point 103°-105° C. are obtained.
Reaction SMILES: C([Sn]([CH2:14][O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])(CCCC)CCCC)CCC.C([Li])CCC.[CH3:27][Si:28]([CH3:37])([CH3:36])[C:29]1[O:33][CH:32]=[C:31]([CH:34]=[O:35])[CH:30]=1>O1CCCC1>[OH:35][CH:34]([C:31]1[CH:30]=[C:29]([Si:28]([CH3:37])([CH3:36])[CH3:27])[O:33][CH:32]=1)[CH2:14][O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21]
Reactant: CCCC[Sn](CCCC)(CCCC)COCOCCOC
Reactant: C[Si](C)(C)c1cc(C=O)co1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOCOCC(O)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
A solution of 2-methoxyethoxymethyl tributylstannylmethyl ether (620 mg, 1.5 mmole) in tetrahydrofuran (THF) (5 ml) at -78° C. was treated with n-butyl lithium (92.5M solution in hexane: 0.67 ml, 1.67 mmole). After 10 min., a solution of 5-trimethylsilyl-3-furaldehyde (254 mg, 1.5 mmole) in THF (2 ml) was added. The solution was stirred for 3 hours while the cooling bath warmed to room temperature. The mixture was quenched with water and the aqueous phase extracted with ethyl ether. The combined organic portions were dried over MgSO4, filtered and concentrated. Purification by flash chromatography (silica, 50% ethyl ether/hexane) gave 216.5 mg of the title compound as a light yellow oil.
Reaction SMILES: CC1(C)CCC(=O)CC1.C([N:20]1[CH2:24][CH2:23][C@H:22]([N:25]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:21]1)(OCC1C=CC=CC=1)=O>>[NH:20]1[CH2:24][CH2:23][C@H:22]([N:25]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:21]1
Reactant: COC(=O)CN(C1CCCCC1)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: CC1(C)CCC(=O)CC1
Product: COC(=O)CN(C1CCCCC1)[C@H]1CCNC1

Procedure:
The title compound was prepared following the procedure described in Step B of Intermediate 3 using the product of Step A, methyl 2-[(3S)-1-Cbz-pyrrolidin-3-yl (cyclohexyl) amino]acetate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].COC(OC)OC.[C:16]1([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29](/[C:32](/[CH3:36])=[CH:33]/[CH:34]=O)=[CH:28][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH4-].[Na+].[ClH:39].N>CO.O1CCCC1.O.C(Cl)(Cl)Cl>[ClH:39].[C:16]1([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29](/[C:32](/[CH3:36])=[CH:33]/[CH2:34][NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[CH:30][CH:31]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCCC(=O)O
Reactant: C/C(=C\C=O)c1ccc(OCCCc2ccccc2)cc1
Agent: Cl
Agent: N
Agent: [BH4-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: COC(OC)OC
Product: C/C(=C\CNCCC(=O)O)c1ccc(OCCCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of β-alanine (433 mg) in methanol (30 ml), sodium hydroxide (204 mg) was added. Then, trimethoxymethane (532 μl) was added to the mixture at 0° C. Further, a solution of (2E)-3-[4-(3-phenylpropoxy)phenyl]but-2-enal (1.43 g) in a mixture of methanol (30 ml) and tetrahydrofuran (10 ml) was added. The reaction mixture was stirred at 0° C. for 30 minutes. To the mixture, sodium borohydride (221 mg) was added at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes. After adding 2 N hydrochloric acid (5.5 ml), the reaction mixture was concentrated. To the residue thus obtained, a mixed solvent of chloroform:methanol:aqueous ammonia=80:10:1 was added, followed by filtration. To the precipitate thus obtained, water was added and the mixture was centrifuged to give a precipitate. The obtained residue was purified by silica gel column chromatography (chloroform:methanol:aqueous ammonia=80:20:4). To a suspension of the purified product in dioxane (100 ml) and water (15 ml), a 4 mol/l hydrogen chloride-dioxane solution (0.9 ml) was added at 0° C. The reaction mixture was concentrated and the residue was washed with diethyl ether and dried to give the title compound (1.16 g) having the following physical properties.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].[Br:28][C:29]1[C:34]([F:35])=[CH:33][C:32]([NH2:36])=[C:31]([F:37])[CH:30]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C2C=CC=CC=2)C=CC=C(P(C(C)(C)C)C(C)(C)C)C=1>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([NH:36][C:32]3[CH:33]=[C:34]([F:35])[C:29]([Br:28])=[CH:30][C:31]=3[F:37])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Nc1cc(F)c(Br)cc1F
Reactant: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1cccc(-c2ccccc2)c1)C(C)(C)C
Solvent: C1COCCO1
Product: Cc1c(Nc2cc(F)c(Br)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 120 °C
Yield: 41 %

Procedure:
A mixture of 4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (1.03 g, 3.28 mmol), palladium acetate (74 mg, 0.33 mmol), biphenyl-3-yl-di-tert-butyl-phosphane (9.7 mg, 0.033 mmol), sodium tert-butoxide (708 mg, 7.36 mmol), and 4-bromo-2,5-difluoro-phenylamine (706 mg, 3.39 mmol) in 15 mL dioxane was heated in microwave for 1 hour at 120° C. Solids were filtered off and mixture was purified by column chromatography (hexane/AcOEt) and crystallized from hexane/AcOEt to give compound A86 as a tanned solid (652 mg, 41%). 1H NMR (CDCl3, 400 MHz) δ 1.04-1.05 (d, 6H), 1.50-1.61 (m, 2H), 1.74-1.82 (m, 2H), 1.89 (s, 3H), 3.16-3.22 (m, 2H), 3.51-3.60 (m, 2H), 4.69-4.76 (m, 1H), 5.09-5.15 (m, 1H), 6.34-6.36 (m, 1H), 7.07-7.11 (m, 1H), 8.15(s, 1H), 8.34-8.38(m, 1H). Exact mass calculated for C20H23BrF2N4O3 484.09, found 485.2 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:14](=[O:15])[CH2:13][NH:12][C:11]2=[O:16])[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[C:14](=[O:15])[CH2:13][NH:12][C:11]2=[O:16])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CNC(=O)N1c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(N2C(=O)CNC2=O)c1
Reaction time: 2 h
Yield: 99.4 %

Procedure:
A solution of 3-(3-nitrophenyl)-2,4-imidazolidinedione (4.4 g, 20 mmol) and methanol (100 mL) was treated with 10% Pd/C (1.0 g) and placed under H2 (40 psi) for 2 h. The mixture was then filtered through celite and concentrated to afford the title compound (3.8 g).
Reaction SMILES: [OH:1][C:2]12[CH2:6][C:4]([NH:7][C:8](=[O:10])[CH3:9])([CH2:5]1)[CH2:3]2.[H-].[Na+].I[CH2:14][CH3:15]>C1COCC1>[CH2:14]([O:1][C:2]12[CH2:6][C:4]([NH:7][C:8](=[O:10])[CH3:9])([CH2:5]1)[CH2:3]2)[CH3:15]
Reactant: CCI
Reactant: CC(=O)NC12CC(O)(C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC12CC(NC(C)=O)(C1)C2

Procedure:
To a anhydrous THF (5 mL) solution of N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1) (1 mmol) is added NaH (60% dispersion in mineral oil, 3 mmol) portionwise at 0° C. After addition, the mixture is stirred until the evolution of gas stops. Iodoethane (1 mmol) is then added by syringe slowly. The reaction is monitored by LCMS and TLC. After consumption of starting material, the reaction mixture is quenched by adding water (3 mL) and extracted with ethyl acetate (3×). The organic layers are combined, dried (magnesium sulfate), filtered, and concentrated. The crude residue is subjected to flash chromatography (silica gel, EtOAc/hexanes) to afford compound 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[CH:15]=[C:16]([OH:19])[CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:28].[N:29]1([CH2:35][CH2:36]O)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[CH:15]=[C:16]([O:19][CH2:36][CH2:35][N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:28]
Reactant: OCCN1CCNCC1
Reactant: O=C1CCc2c(-c3ccc(F)cc3F)cc(O)cc2N1c1c(Cl)cccc1Cl
Product: O=C1CCc2c(-c3ccc(F)cc3F)cc(OCCN3CCNCC3)cc2N1c1c(Cl)cccc1Cl

Procedure:
1-(2,6-Dichlorophenyl)-5-(2,4-difluorophenyl)-3,4-dihydro-7-[2-(1-piperazinyl)ethoxy]-2(1H)-quinolinone was prepared from 1-(2,6-dichlorophenyl)-5-(2,4-difluorophenyl)-3,4-dihydro-7-hydroxy-2(1H)-quinolinone (INTERMEDIATE 3) and 1-piperazine ethanol by a procedure analogous to that described in EXAMPLE 2. Mass spectrum (ESI) 532.3 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.51 (d, J=8.5 Hz, 2H); 7.36 (t, J=8 Hz, 1H); 7.29 (q, J=6 Hz, 1H); 6.96 (m, 2H); 6.52 (s, 1H); 5.90 (s, 1H); 3.96 (t, J=5.5 Hz, 2H); 2.88 (m, 4H); 2.70 (m, 4H); 2.47 (br, 4H); 2.10 (br, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][CH:13]([C:18]#[N:19])[CH2:12]2.[C:20](OC(=O)C)(=O)[CH3:21]>C(O)(=O)C>[C:18]([CH:13]1[CH2:12][C:11]2[C:15](=[CH:16][CH:17]=[C:9]([N:8]3[C:7]4[CH:6]=[CH:5][N:4]=[CH:3][C:2]=4[N:1]=[C:20]3[CH3:21])[CH:10]=2)[CH2:14]1)#[N:19]
Reactant: N#CC1Cc2ccc(Nc3ccncc3N)cc2C1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1nc2cnccc2n1-c1ccc2c(c1)CC(C#N)C2
Yield: 79 %

Procedure:
A mixture of 5-(3-aminopyrid-4-ylamino)-2-cyanoindane (12.28 g, ca 44.5 mmol from step (d) above), acetic acid (70 ml) and acetic anhydride (70 ml) was heated at reflux under nitrogen for 1.75 hours, cooled, and concentrated under reduced pressure. The residual brown gum was dissolved in 2M hydrochloric acid (40 ml) and washed with ethyl acetate (50 ml). The aqueous layer was rendered basic by the addition of 2M aqueous sodium hydroxide, and the product was extracted into dichloromethane. The combined extracts were wahsed with water (50 ml), dried over magnesium sulphate and the solvent evaporated. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/methanol (7:1), to give a brown gum, which was recrystallised from ethyl acetate/methanol, to give the 2-cyano-5-(2-methylimidazo[4,5-c]pyrid-1-yl)indane as an off-white powder (9.67 g, 79%), m.p. 174°-176° C. Found: C,74.4; H,5.2; N,20.7. C17H14N4 requires C,74.4; H,5.1; N,20.4%.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CC([O-])=O.CC([O-])=O.[Pd+2].C(#N)C>[NH2:4][C:3]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:2]=1/[CH:15]=[CH:14]/[C:13]([O:17][CH3:18])=[O:16]
Reactant: C=CC(=O)OC
Reactant: Nc1cc(C(F)(F)F)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(C(F)(F)F)cc1N
Temperature: 90 °C
Yield: 35.5 %

Procedure:
A 100 ml 3-neck flask with magnetic stirrer was charged with 2-bromo-5-(trifluoromethyl)aniline (500 mg, 2.08 mmol), methyl acrylate (538 mg, 6.25 mmol), Pd(OAc)2 (23.3 mg, 0.104 mmol), P(o-tolyl)3 (64 mg, 0.21 mmol), triethylamine (422 mg, 4.7 mmol) and acetonitrile (20 mL). The flask was purge with N2 and heated to 90° C. overnight. Saturated aqueous NH4Cl (40 mL) was added, and the mixture was extracted with ethyl acetate (10 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduce pressure. The crude product was purified by silica gel chromatography to give (E)-methyl 3-(2-amino-4-(trifluoromethyl)phenyl)acrylate (180.9 mg, 37%) as a light green solid. 1H NMR (400 MHz, CDCl3): δ 7.71 (d, J=16 Hz, 1H), δ 7.38 (d, J=8 Hz, 1H), δ 6.92 (d, J=8 Hz, 1H), δ 6.86 (s, 1H), δ 6.34 (d, J=8 Hz, 1H), δ 4.05 (s, 2H), δ 3.73 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[S:13][N:12]=[C:11]([C:14](=[N:32][O:33][C:34]([C:37]([OH:39])=[O:38])([CH3:36])[CH3:35])[C:15]([NH:17][C@@H:18]2[C:30](=[O:31])[N:20]3[C:21]([C:27]([OH:29])=[O:28])=[C:22]([CH2:25]Cl)[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1.[CH3:40][N:41]([CH2:43][C:44]1[CH2:49][C:48](=[O:50])[C:47]([OH:51])=[CH:46][N:45]=1)[CH3:42].C(OCC)(=O)C>CN(C)C=O>[NH2:8][C:9]1[S:13][N:12]=[C:11]([C:14](=[N:32][O:33][C:34]([C:37]([OH:39])=[O:38])([CH3:36])[CH3:35])[C:15]([NH:17][C@@H:18]2[C:30](=[O:31])[N:20]3[C:21]([C:27]([O-:29])=[O:28])=[C:22]([CH2:25][N+:41]([CH3:42])([CH3:40])[CH2:43][C:44]4[NH:45][CH:46]=[C:47]([OH:51])[C:48](=[O:50])[CH:49]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1
Reactant: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CCl)CS[C@H]12)c1nsc(N)n1)C(=O)O
Reactant: CN(C)CC1=NC=C(O)C(=O)C1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+](C)(C)Cc3cc(=O)c(O)c[nH]3)CS[C@H]12)c1nsc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 29.2 %

Procedure:
To a solution of 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylic acid trifluoroacetate (syn isomer) (1.0 g) in N,N-dimethylformamide (10 ml) was added 2-(N,N-dimethylamino)methyl-5-hydroxy-4pyridone (1.09 g). After being stirred for 5 hours at ambient temperature, the mixture was poured into ethyl acetate (150 ml). The resulting precipitate was collected by filtration, washed with ethyl acetate and dried under reduced pressure. The precipitate was suspended in water (50 ml) at pH 2.0 and stirred for 30 minutes. After removal of insoluble material, the aqueous solution was subjected to column chromatography on Diaion HP-20. The column was washed with water and the elution was carried out with 30% aqueous methanol. The fractions containing desired product was combined and methanol was evaporated in vacuo. The resulting aqueous layer was lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl}ammonio]methyl-3-cephem-4carboxylate (syn isomer) (0.30 g) as a powder.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)[C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)=[CH:8][CH:7]=1)=[O:5])[CH3:2].ClC(OCC(C)C)=O.C([N:47](CC)CC)C.N>ClCCl>[CH2:35]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)[C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH2:47])=[O:18])=[CH:10][CH:11]=1)=[O:5])[CH3:36]
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(C(=O)O)c2)N2CCN(Cc3ccccc3)CC2)cc1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(C(N)=O)c2)N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C

Procedure:
To a solution of INTERMEDIATE 9 (100 mg, 0.21 mmol) in dichloromethane (3 mL) at −20° C. was added isobutyl chloroformate (41 μL, 0.31 mmol) and triethylamine (43 μL, 0.31 mmol). After 10 minutes a solution of ammonia in dichloromethane (1.5M, 4.5 mL, 3 mmol) was added. Reacton was warmed to room temperature and washed with brine. The organic layer was dried (MgSO4), filtered and concentrated to give COMPOUND 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[N:14]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:17]1[CH:18]=[CH:13][N:14]=[C:15]([NH:19][CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[N:16]=1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: Cc1cc(F)cc2cc[nH]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Cc1cc(F)cc2c(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)c[nH]c12

Procedure:
The title compound was prepared as described in Example 215, starting from SEM-protected 5-Fluoro-7-methyl-1H-indole (prepared by Sugasawa synthesis starting from 4-fluoro-2-methyl-phenylamine, J. Med. Chem. 1990, 33, 2777) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by cleavage of the SEM protecting group with TBAF. Yield: 2.00 g (69%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([C:13]1([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=2)[CH2:15][CH2:14]1)#N.[OH:25]S(O)(=O)=O>C1C=CC=CC=1.CCCCCCC>[CH2:23]([O:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2([CH:11]=[O:25])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1)[CH3:24]
Reactant: CCOc1ccc(C2(C#N)CC2)cc1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: c1ccccc1
Solvent: CCCCCCC
Product: CCOc1ccc(C2(C=O)CC2)cc1

Procedure:
1M Diisobutylaluminium hydride (14 ml) is added over 3 min. to a stirred solution of 1-cyano-1-(4-ethoxyphenyl)-cyclopropane (1.4 g) in dry benzene (35 ml) and dry n-heptane (14 ml) at 25° C. under an atmosphere of nitrogen. After 3 h the mixture is poured onto 2N H2SO4 (100 ml), extracted with diethyl ether (x3), dried and the solvent removed under reduced pressure. Yield 1 g, nD 1.5272.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(C)=O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f50) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH:18]([NH:29][OH:30])[C:19]#[C:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:31](OC(=O)C)=[O:32]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH:18]([N:29]([OH:30])[CH:31]=[O:32])[C:19]#[C:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C#CC(CS(=O)(=O)N2CCN(c3ccc(F)cc3)CC2)NO)c1
Reactant: CC(=O)OC=O
Solvent: C1CCOC1
Product: COc1cccc(C#CC(CS(=O)(=O)N2CCN(c3ccc(F)cc3)CC2)N(O)C=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
A solution of 1-(4-fluorophenyl)-4-{[2-(hydroxyamino)-4-(3-methoxyphenyl)but-3-yn-1-yl]sulfonyl}piperazine (349 mg; 0.81 mmol) and acetyl formate (prepared as described by Koller et al., 1983, above 8; 0.58 mL of a 1.39 M solution in THF; 0.81 mmol) was stirred at rt for 1 h. THF was removed under reduced pressure and replaced by MeOH. The solution was heated at 60° C. for 1 h and concentrated under reduced pressure. Purification of the crude by flash chromatography on silica (EtOAc:c-Hex 60:40 to 100:0) gave the title compound as an orange oil (90 mg, 24% yield). HPLC, Rt: 3.69 min (purity: 99.3%). LC/MS, M+(ESI): 462.3. 1H NMR (DMSO-d6) δ: 8.45 (brs, 0.4H), 8.13 (brs, 0.6H), 7.19 (m, 1H), 6.97-7.04 (m, 7H), 5.80 (brs, 0.4H), 5.25 (brs, 0.6H), 3.77 (s, 3H), 3.68 (brs, 1H), 3.44 (m, 6H), 3.14 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][C:22]=1[N+:30]([O-:32])=[O:31]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([Cl:20])=[C:22]([N+:30]([O-:32])=[O:31])[CH:23]=2)=[CH:4][CH:3]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
2-(4-Chlorophenyl)ethanamine (2.3 ml, 16 mmol) was diluted with DCM (40 mL) followed by the addition of DIEA (2.9 ml, 16 mmol) and 4-chloro-3-nitrobenzoyl chloride (3.0 g, 14 mmol) in 10 mL of DCM. After stirring for 30 minutes the reaction was loaded directly onto a biotage 40M cartridge and eluted with hexanes:ethyl acetate (2:1) to yield N-(4-chlorophenethyl)-4-chloro-3-nitrobenzamide (4.0 g, 86% yield) as a white solid.