Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C@H:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH3:30][C:31]([CH3:33])=O>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C@H:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:19][CH2:20][N:21]([CH:31]([CH3:33])[CH3:30])[CH2:22][CH2:23]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: O=C(N[C@@H](COCC1CCNCC1)c1ccccc1)c1ccc2c(Cl)c[nH]c2c1
Reactant: CC(C)=O
Product: CC(C)N1CCC(COC[C@H](NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2)CC1

Procedure:
Using alkylation method A, 3-chloro-N-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (8.97 mmol) and acetone (6.6 mL, 90 mmol) afforded, after purification (SiO2: 8:2:1 hexane:EtOAc:isopropylamine), 2.2 g (54%) of the title compound.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:23])[C:15]3[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[N:17][CH:16]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:26][CH:27]=[C:28]1[C:32](=O)[O:31][C:30]([CH3:34])=[N:29]1)C>C(O)C>[C:30]([NH:29][C:28]1[C:27](=[O:26])[N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:12][CH:11]=3)=[O:23])=[CH:16][N:17]=2)[NH:22][CH:32]=1)(=[O:31])[CH3:34]
Reactant: CCOC=C1N=C(C)OC1=O
Reactant: NNc1ccc(C(=O)Nc2ccc(C3CCCCC3)cc2)cn1
Solvent: CCO
Product: CC(=O)Nc1c[nH]n(-c2ccc(C(=O)Nc3ccc(C4CCCCC4)cc3)cn2)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 5.5 %

Procedure:
N-(4-Cyclohexylphenyl)-6-hydrazinonicotinamide (0.20 g) and 4-(ethoxymethylene)-2-methyl-1,3-oxazol-5(4H)-one (0.12 g) were dissolved in ethanol (30 mL), and the solution was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, and diisopropyl ether was added to the residue. The deposited solid was collected by filtration and washed with diisopropyl ether. The solid was dried under reduced pressure to obtain the title compound (0.015 g) as a white solid (yield: 5.5%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[N:12]=[CH:11][C:10]=2[NH2:16])[C:5]([F:8])=[N:6][CH:7]=1.Br.[N:18]1([CH2:24][C:25]2[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(#N)C.[F-].[K+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:15][C:13]1[N:12]=[CH:11][C:10]([NH2:16])=[C:9]([C:4]2[C:5]([F:8])=[N:6][CH:7]=[C:2]([C:28]3[CH:27]=[CH:26][C:25]([CH2:24][N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:30][CH:29]=3)[CH:3]=2)[CH:14]=1
Reactant: Nc1cnc(Cl)cc1-c1cc(Br)cnc1F
Reactant: OB(O)c1ccc(CN2CCCCC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Agent: [F-]
Solvent: O
Solvent: CC#N
Product: Nc1cnc(Cl)cc1-c1cc(-c2ccc(CN3CCCCC3)cc2)cnc1F
Temperature: 100 °C
Yield: 53.7 %

Procedure:
A degassed mixture of 5-bromo-6′-chloro-2-fluoro-[3,4′]bipyridinyl-3′-ylamine (1.35 g, 4.46 mmol), 4-(piperidin-1-ylmethyl)phenylboronic acid hydrobromide (2.28 g, 7.59 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.29 g, 0.35 mmol) in acetonitrile (70 mL) and 1N aqueous potassium fluoride solution (12 mL) was heated under microwave irradiation at 100° C. for 30 minutes. The cooled reaction was diluted with water (100 mL) and extracted with DCM (3×50 mL). The combined organic layer was dried over sodium sulfate, filtered, and evaporated to afford a residue which was purified by flash chromotagraphy (silica, 25 g column, Biotage, 0-10% methanol in (DCM containing 1% 2M ammonia in methanol)) to afford the title compound as a yellow/orange solid (0.95 g, 54%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39]O)=[CH:33][C:32]=2[CH3:41])=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=O)C.[NH2:45][CH2:46][CH2:47][OH:48].NC(C)(C)CO>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][NH:45][CH2:46][CH2:47][OH:48])=[CH:33][C:32]=3[CH3:41])=[C:28]([CH:42]([CH3:43])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCCO
Agent: CC(C)(N)CO
Product: Cc1cc(OCCNCCO)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 57 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-hydroxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-aminoethanol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-1-propanol, respectively.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11](S(C)(=O)=O)[N:10]3[N:17]=[CH:18][CH:19]=[C:9]3[CH:8]=2)=[CH:3][CH:2]=1.[C:26]([O:30][C:31](=[O:50])[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)=[CH:36][CH:35]=1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31](=[O:50])[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40](=[O:49])[NH:41][C:42]2[CH:43]=[CH:44][C:45]([NH:48][C:11]3[N:10]4[N:17]=[CH:18][CH:19]=[C:9]4[CH:8]=[C:7]([C:4]4[CH:5]=[CH:6][C:1]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:2][CH:3]=4)[N:12]=3)=[CH:46][CH:47]=2)=[CH:36][CH:35]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccc(N)cc2)cc1
Reactant: CS(=O)(=O)c1nc(-c2ccc(-c3ccccc3)cc2)cc2ccnn12
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccc(Nc3nc(-c4ccc(-c5ccccc5)cc4)cc4ccnn34)cc2)cc1
Temperature: 130 °C

Procedure:
Under an inert gas atmosphere at 130° C. bath temperature is heated neat a mixture of 5-biphenyl-4-yl-7-methanesulfonyl-pyrazolo[1,5-c]pyrimidine (compound B1) and [4-(4-amino-phenylcarbamoyl)-benzyl]-carbamic acid tert-butyl ester (compound G1) overnight. The crude product is purified by silica gel flash chromatography.
Reaction SMILES: [F:1][C:2]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1.CCCCCC>C1(C)C=CC=CC=1>[F:1][C:2]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][CH:4]=[C:3]1[SH:23]
Reactant: CCOC(=O)C1(F)CCCCC1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)C1(F)CCCC=C1S
Reaction time: 5 h
Yield: 18 %

Procedure:
Referring to the process described in Bulletin des Societe Chimiques Belges volume 87, page 223 (1978), 5.4 g (30 mmol) of ethyl 1-fluoro-2-oxocyclohexanecarboxylate was dissolved in 50 ml of toluene, to this was added 6.0 g (15 mmol) of Lawesson's reagent, and reaction was carried out at 100° C. for 5 hours. 100 ml of hexane was added, the precipitate was filtered out and the solvent was distilled away. The filtrate was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate=15/1) to obtain 1.1 g (yield: 18 % of ethyl 1-fluoro-2-mercapto-2-cyclohexenecarboxylate.
Reaction SMILES: [C:1]([C:3]1([C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[H][H]>CO.[Ni]>[NH2:2][CH2:1][C:3]1([C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: Cc1cccnc1C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Ni]
Solvent: CO
Product: Cc1cccnc1C1(CN)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A solution of tert-butyl 4-cyano4-(3-methylpyridin-2-yl)piperidine-1-carboxylate (2 g, 6.6 mmol) in methanol (70 mL containing 2 M ammonia) was reacted with Raney nickel (1 mL of 50% slurry in water) under 45 psi hydrogen for 24 hours. The catalyst was filtered off and washed thoroughly with methanol. Evaporation of solvent afforded the desired product: tert-butyl 4-aminomethyl)4-(3-methylpyridin-2-yl)piperidine-1-carboxylate: 1H NMR δ (ppm)(CDCl3): 8.44 (1 H, br s), 7.41 (1 H, d, J=7.4 Hz), 7.07 (1 H, br s), 3.80 (2 H, br s), 3.01 (4 H, br s), 2.66 (2 H, s), 2.48 (3 H, s), 1.62-1.54 (2 H, m), 1.44 (9 H, s).
Reaction SMILES: [CH3:1][C@H:2]([OH:6])[CH2:3][C:4]#[CH:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.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.[Cu]I>[F:7][C:8]1[C:9]([C:5]#[C:4][CH2:3][C@@H:2]([OH:6])[CH3:1])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CC[C@H](C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC[C@H](C)O)c21

Procedure:
Using Method C above, (S)-pent-4-yn-2-ol (44 mg, 0.52 mmol) (see below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg, 0.01 mmol) and CuI (2 mg) in a mixture of DMF (5 mL) and Et3N (5 mL) as a solvent at 80° C. for 7 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-1,3-Dihydro-5-fluoro-4-(4-hydroxy-1-pentynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-70% EtOAc in hexanes gradient and trituration with Et2O. (Yield 30 mg, 65%).
Reaction SMILES: [Cl-].[Cl-].[Ca+2].O.[F:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-])=O)[CH:7]=1.C1C=CC=CC=1>CCO.[Zn].CCOC(C)=O>[F:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([NH2:13])[CH:7]=1
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(F)cc1N

Procedure:
4-Fluoro-1,2-diaminobenzene was prepared using an adaptation of the method of Tsuji et al. (Tsuji, Y. et al., J. Org. Chem. 55: 580 (1990)). A suspension of Zn powder (10.5 g, 0.160 mol), CaCl2 (1.05 g) and H2O in 40 ml EtOH was heated to reflux with stirring under N2. To this was added slowly dropwise a solution of 4-fluoro-2-nitroaniline (2.00 g, 12.8 mmol) in 10 mL EtOH. The reaction mixture was refluxed 8 h. TLC analysis (silica gel, 2:1 benzene:EtOAc) indicated complete disappearance of the starting material. The Zn was removed by vacuum filtration, and the solvent rotary evaporated. The residue was dissolved in 50 mL Et2O and the solution extracted with 3×25 mL 1N HCl. The aqueous layers were combined and basified with 50% aq. NaOH (6 g) and the resulting solution extracted with 3×25 mL Et2O. The Et2O layers were combined and dried (MgSO4). The solvent was rotary evaporated to yield 1.36 g (84%) of a brown solid. mp 90°-92° C. 1H NMR (CDCl3) δ 3.18 (brs, 2H, NH2); 3.58 (brs, 2H, NH2); 6.44 (m, 2H, ArH), 6.61 (m, 1H, ArH).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=O.[CH2:14]([Mg]Br)[CH:15]=[CH2:16]>O1CCCC1.CCOCC>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]=[C:7]2[CH2:16][CH:15]=[CH2:14]
Reactant: O=C1CCCc2c(F)cc(F)cc21
Reactant: C=CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC1=CCCc2c(F)cc(F)cc21

Procedure:
A solution of 5, 7-difluoro-1-tetralone [110931-79-8] (prepared in accordance with DE-A 3702039) in tetrahydrofuran is added to an equimolar amount of an allylmagnesium bromide solution in ether at 0° C. The reaction mixture is subjected to conventional aqueous acidic workup (Mohammadi et al., J. Lab. Cpd. Radiopharm. XXIV, 317 (1987)) and distillation. The 5,7-difluoro-1-(1-propen-3-yl)-3,4-dihydronaphthalene obtained is reacted with an equimolar amount of thexyl-borane in terahydrofuran to give B-thexyl6,8-difluoro-2,3,4,4a,9,9a,10-octahydro-1-boraphenanthrene which is reacted with equimolar amounts of sodium cyanide at room temperature without further characterization. After 2 h, an equimolar amount of trifluoroacetic anhydride (TFAA) is added dropwise at −75° C., and the mixture is brought to room temperature with stirring. 3 equivalents of NaOH are added and the mixture is oxidized with 50% H2O2, finally at 50° C.; extraction and chromatography yield 1-keto6,8-difluoro-1,2,3,4,4a,9,9a,10-octahydrophenanthrene. As described by Mohammadi et al., J. Lab. Cpd. Radiopharm. XXIV, 317 (1987), this product can be converted into 1-keto-6,8-difluoro-2-propyl-1,2,3,4,4a,9,9a,10-octahydrophenanthrene by reacting with lithium diisopropylamide (LDA) followed by addition of n-propyl bromide. This product can be converted into 6,8-difluoro-1,2,3,4,4a,9,9a,10-octahydrophenanthrene by reducing with triethylsilane in trifluoroacetic acid. 6,8-Di-fluoro-7-pentyl-2-propyl-1,2,3,4,4a,9,9a,10-octahydrophenanthrene is obtained by ortho metalation using “Schlosser base” (i.e. butyllithium and potassium tert-butylate; see, for example: F. Mongin, M. Schlosser, Tetrahedron Lett. 1996, 37, 6551-6554) at −75° C., quenching with n-pentyl bromide and conventional workup by hydrolysis, extraction, chromatography (silica gel, dichloromethane) and repeated recrystallization (to increase the proportion of the desired isomer, among other things).
Reaction SMILES: Cl[C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11]([SH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:11]([S:18][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1cccc(O)c1Cl
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(O)c1SCc1ccccc1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
174 g of 2-chloro-3-hydroxybenzaldehyde are dissolved in 1 l of dimethylformamide, 126 ml of benzylmercaptan and 174 g of potassium carbonate are added, and the mixture is stirred for 2 days at 100° C. The reaction mixture is poured into ice-water and extracted using diethyl ether, and the organic phase is washed with saline, dried over sodium sulfate, filtered and concentrated. Silica gel chromatography with ethyl acetate/hexane (1:4) as the mobile phase gives 51.6 g of 2-benzylthio-3-hydroxybenzaldehyde. 31.6 g of this are emulsified in 66 ml of water, and 16.1 g of hydroxylamine-O-sulfonic acid and 1.84 g of sodium sulfate are added. After one hour, 32 ml of each water and methylene chloride are added, and the mixture is treated with 40.4 g of sodium hydrogen carbonate in portions. The reaction mixture is stirred for 2 hours at room temperature and then taken up in methylene chloride, and the organic phase is extracted using 1N potassium hydroxide solution. The aqueous-basic phase is brought to a pH of 1 using concentrated hydrochloric acid and extracted using methylene chloride. The organic phase is dried over sodium sulfate, filtered and concentrated. Recrystallisation from toluene gives 5.93 g of 7-hydroxy-1,2-benzisothiazole of m.p. 185°-187° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH3:26][S:27][CH2:28][CH2:29][NH2:30].O>C(#N)C>[CH3:26][S:27][CH2:28][CH2:29][NH:30][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: CSCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CSCCNc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 97.6 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.16 mmol) in acetonitrile (5 mL) was added potassium carbonate (321 mg, 1.55 mmol) and 2-(methylthio)ethylamine (127 mg, 1.39 mmol), and this was heated to reflux for 3 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (373 mg, 98% yield) as red crystals.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:29]([N:30]=[C:31](Br)Br)[C:28](=[O:34])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:3])[CH3:2].[C:35]1([NH2:42])[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH2:41]>C1COCC1>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:29]([NH:30][C:31]3[NH:41][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[N:42]=3)[C:28](=[O:34])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N=C(Br)Br)[C@H]2SC1
Reactant: Nc1ccccc1N
Solvent: C1CCOC1
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(Nc3nc4ccccc4[nH]3)[C@H]2SC1
Reaction time: 4 h
Yield: 70.3 %

Procedure:
To a solution of diphenylmethyl 3-acetoxymethyl-7-dibromomethyleneaminoceph-3-em-4-carboxylate (0.608 g., 1 mmole) in THF stirred under nitrogen at ambient temperature was added orthophenylenediamine (0.216 g., 2 mmole) in THF and the reaction was allowed to continue stirring for 4 hours. The solution was then evaporated to dryness and the residue was dissolved in CH2Cl2 containing a little methanol. This solution was chromatographed on silica gel (50 g.) at -40° using CH2Cl2 /MeOH 85:15 v/v as eluant to give diphenylmethyl 3-acetoxymethyl-7-(benzimidazol-2-yl)aminoceph-3-em-4-carboxylate (0.39 g.). The product had the following n.m.r. spectrum in CDCl3 : 1.92(s,3H); 3.25(m,2H); 4.57(d,1H); 4.97(d,1H); 5.15(d,1H); 5.90(d,1H); 6.85(s,1H); 3.25(m,10H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:4][N:3]=[CH:2]1.C1CCCCC=1>[Pd].C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)=[O:11])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(NCCCn1ccnc1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: Nc1ccc(C(=O)NCCCn2ccnc2)cc1
Reaction time: 1 h
Yield: 67.3 %

Procedure:
A mixture of 4-{N-[3-(imidazol-1-yl)propyl]carbamoyl}nitrobenzene (Method 41; 2.0 g, 7.30 mmol), 10% palladium on carbon (100 mg) cyclohexene (40 ml) and ethanol (80 ml) was heated under reflux under an atmosphere of nitrogen for 4 hours. Two further portions of cyclohexene (40 ml) were added and heating was continued for 1 hour after each addition. The mixture was left to cool and the catalyst was removed by filtration. The filtrate was concentrated by evaporation and the residue was recrystallized from a mixture of ethanol and ether to give the product (1.2 g, 67%). NMR: 1.9-2.0 (m, 2H), 3.1-3.2 (m, 2H), 4.0 (t, 2H), 5.6 (br s 2H), 6.55 (d, 2H), 6.85 (s, 1H), 7.2 (s, 1H), 7.55 (d, 2H), 7.65 (s, 1H), 8.0 (br t, H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:8][C:7](=[O:23])[NH:6]2.[Br-].[Li+].[H-].[Na+].[CH3:28][O:29][CH:30]([O:34][CH3:35])[CH2:31][CH2:32]Br>CN(C)C=O.C(OCC)(=O)C>[CH3:28][O:29][CH:30]([O:34][CH3:35])[CH2:31][CH2:32][N:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]([C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[CH2:8][C:7]1=[O:23]
Reactant: COc1ccc2c(c1)NC(=O)CN2C(=O)OCc1ccccc1
Reactant: COC(CCBr)OC
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)N(CCC(OC)OC)C(=O)CN2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl 6-methoxy-3-oxo-3,4-dihydroquinoxalin-1(2H)-carboxylate (291 mg, 0.932 mmol) in N,N-dimethylformamide (5 ml), lithium bromide (89 mg, 1.025 mmol) and subsequently sodium hydride (55%, 45 mg, 1.025 mmol) were added under a nitrogen gas atmosphere in an ice bath. The solution was stirred at room temperature for 1 hour. The reaction solution was cooled on ice again and 3-bromopropionaldehyde dimethyl acetal (0.184 ml, 1.212 mmol) was added thereto. After stirring overnight at room temperature, the reaction solution was diluted with ethyl acetate and washed sequentially with a saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride solution. After drying the resultant over anhydrous sodium sulfate, the solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to yield 386 mg (quantitative) of the title compound in the form of a yellowish brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:12]=[C:13]2[NH:17][C@@H:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:15][S:14]2)[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].[CH2:22](Br)[CH:23]([CH3:25])[CH3:24]>>[CH3:1][C:2]1[CH:3]=[C:4]([N:12]=[C:13]2[N:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[C@@H:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:15][S:14]2)[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(N=C2N[C@@H](CC(C)C)CS2)cc(C)c1[N+](=O)[O-]
Reactant: CC(C)CBr
Product: Cc1cc(N=C2SC[C@H](CC(C)C)N2CC(C)C)cc(C)c1[N+](=O)[O-]

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 3,5-Dimethyl-4-nitroaniline was converted to 3,5-Dimethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 3,5-Dimethyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(3,5-dimethyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(3,5-dimethyl-4-nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:16]=[C:15](I)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][C:20]1=[O:24].C(N)CN.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.ClCCl.[Cu]I>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:16]=[C:15]([N:19]2[CH2:23][CH2:22][CH2:21][C:20]2=[O:24])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: O=C1CCCN1
Reactant: CCCN(C)C(=O)c1cc(I)cc(C(=O)OC)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: NCCN
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCN(C)C(=O)c1cc(C(=O)OC)cc(N2CCCC2=O)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
Mix 5-iodo-N-methyl-N-propyl-isophthalamic acid methyl ester (220 mg, 0.61 mmol), 2-pyrrolidone (56 μL, 0.73 mmol), ethane-1,2-diamine (4 μL, 0.061 mmol), cesium carbonate (398 mg, 1.22) and copper (I) iodide (12 mg, 0.061 mmol) in 1,4-dioxane (4 mL). Heat the mixture to 110° C. for 1 h then stir at room temperature overnight. Dilute with dichloromethane and filter through a filtering agent. Concentrate and purify (silica gel chromatography, eluting with ethyl acetate and hexanes) to give the title compound (100 mg, 52%).