Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[C:20]3[CH:19]=[C:18]([C:21](=[O:23])[CH3:22])[CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[C:20]3[CH:19]=[C:18]([CH:21]([OH:23])[CH3:22])[CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc2c(c1)C(Cc1ccncc1)(Cc1ccncc1)c1ccccc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1ccc2c(c1)C(Cc1ccncc1)(Cc1ccncc1)c1ccccc1-2
Temperature: 25 °C

Procedure:
To 300 mg of 9,9-bis(4-pyridinylmethyl)-2-acetylfluorene was dissolved in 5 ml of ethanol cooled to 0° was added 100 mg of sodium borohydride. The reaction mixture was warmed to room temperature overnight, quenched with water and methanol and the solvents evaporated. The residue was partitioned between ethyl acetate and 1N NaOH, washed with water, brine, dried (MgSO4) and evaported. Recrystallization from ethanol yielded product. NMR (CDCl3, 200 MHz) δ: 1.50(d,J=6.5 Hz,3H), 3.39(s,4H), 4.92(q,J=6.4 Hz,1H), 6.43(2d,4H), 7.08-7.58(m, arom.), 7.87(d,2H), 7.97(d,2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:21][C:22]([CH3:30])([CH3:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-].C1CCCCC=1>[Pd].CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:21][C:22]([CH3:29])([CH3:30])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CC(C)(C)Cc1ccc(OCCCNc2cccc[n+]2[O-])c(OC)c1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CC(C)O
Product: CCOC(=O)CC(C)(C)Cc1ccc(OCCCNc2ccccn2)c(OC)c1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
A mixture of the product of STEP 7 (81.5 mg, 0.2mmol), 10% Pd/C (50 mg, 0.05 mmol), cyclohexene (0.5 ml, 4.9 mmol), and 2-propanol (5 ml) was heated at reflux for 3 h. The reaction was cooled to room temperature, filtered through a short column of Celite®, and washed with 2-propanol. The filtrate was concentrated to give 67.5 mg pale brown oil. The NMR spectra were consistent for the proposed structure.
Reaction SMILES: [C:1]1([CH2:14][OH:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>N1C=CC=CC=1>[C:1]1([CH2:14][O:15][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)O1
Reactant: OCc1cccc2c1Cc1ccccc1-2
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)OCc1cccc2c1Cc1ccccc1-2
Reaction time: 8 h
Yield: 64.4 %

Procedure:
Fluorenylmethanol (0.90 g, 4.5 mmol) and dimethylaminopyridine (50 mg) were dissolved in 10 ml dry pyridine. Succinic anhydride (0.50 g, 5.0 mmol) was added and the solution stirred overnight. The solvent was removed under reduced pressure, sodium bicarbonate added (50 ml), the solution extracted with ethyl acetate (50 ml), and the organic layer discarded. The aqueous layer was acidified to pH 2, extracted with ethyl acetate (2×100 ml), washed with brine, and the solvent removed under reduced pressure. The residue was purified by flash chromatography (ethyl acetate/hexane 2:1 as eluant) to give 0.86 g product (2.9 mmol, 64%). 1H NMR: (CDCl3, 200 MHz) δ7.8-7.26 (8H, m, ArH), 4.43 (2H, d, J=6.5 Hz, CHCH2OCO), 4.23 (1H, t, J=6.5 Hz, CHCH2OCO), 2.70 (4H, s, OCOCH2CH2COO).
Reaction SMILES: [CH:1]1([N:6]([CH3:40])[C:7]2[CH:8]=[C:9]([C:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH:28]=3)[CH:10]=[C:11]([C:14](=[O:26])[NH:15][CH2:16][C:17]3[C:18](=[O:25])[NH:19][C:20]([CH3:24])=[CH:21][C:22]=3[CH3:23])[C:12]=2[CH3:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([N:6]([CH3:40])[C:7]2[C:12]([CH3:13])=[C:11]([CH:10]=[C:9]([C:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH:28]=3)[CH:8]=2)[C:14]([NH:15][CH2:16][C:17]2[C:18](=[O:25])[NH:19][C:20]([CH3:24])=[CH:21][C:22]=2[CH3:23])=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCNCC3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a stirred solution of tert-butyl 4-(3-(cyclopentyl(methyl)amino)-5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-4-methylphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.800 g, 1.45 mmol) in DCM was added TFA (3 mL) and the reaction mixture was stirred at RT for 2 h. On completion, reaction was concentrated to dryness. Residue was basified with aqueous sodium bicarbonate till pH 8 and aqueous layer extracted with 20% MeOH/DCM. Combined organic layers were dried over sodium sulfate and concentrated to afford crude material which was purified by preparative HPLC to afford the desired compound (0.620 g, 95%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:21]=[CH:20][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>C(#N)C.CN(C)C1C=CN=CC=1>[S:29]([O:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:21]=[CH:20][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:8][CH:7]=1)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]
Reactant: OCCC#Cc1ccc(OCCCN2CCCCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OCCC#Cc2ccc(OCCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81975.1 %

Procedure:
To a solution of 1-{3-[4-(4-hydroxybut-1-yn-1-yl)phenoxy]propyl}piperidine (393 mg) in acetonitrile (10 mL) are added successively triethylamine (0.446 mL), 4-dimethylaminopyridine (18 mg) and tosyl chloride (617 mg). The mixture is stirred overnight at room temperature, concentrated under reduced pressure and purified by chromatography over silica gel to give 495 g of 1-{3-[4-(4-tosyloxybut-1-yn-1-yl)phenoxy]propyl}piperidine.
Reaction SMILES: C([N:8]1[C@H:12]([C:13]#[CH:14])[CH2:11][C@@H:10]([OH:15])[CH2:9]1)(OC(C)(C)C)=O.[C:16]([C:19]1[CH:20]=[C:21](/[CH:24]=[C:25]2\[C:26](=[O:36])[NH:27][C:28]3[C:33]\2=[C:32](I)[C:31]([F:35])=[CH:30][CH:29]=3)[NH:22][CH:23]=1)(=[O:18])[CH3:17]>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>[C:16]([C:19]1[CH:20]=[C:21](/[CH:24]=[C:25]2\[C:26](=[O:36])[NH:27][C:28]3[C:33]\2=[C:32]([C:14]#[C:13][C@@H:12]2[CH2:11][C@@H:10]([OH:15])[CH2:9][NH:8]2)[C:31]([F:35])=[CH:30][CH:29]=3)[NH:22][CH:23]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
Reactant: C#C[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(C#C[C@@H]4C[C@@H](O)CN4)c32)c1
Reaction time: 2 h

Procedure:
Using Method C above, (3R,5S)-N-Boc-3-Hydroxy-5-ethynyl-pyrrolidine (240 mg, 1.13 mmol) (Example 99C above) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (150 mg, 0.38 mmol) (Example 90B) using (Ph3P)4Pd (43 mg, 0.04 mmol) and a catalylic amount of CuI in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 0-100% EtOAc in hexanes gradient. The resulting intermediate was dissolved in 6 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.4 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the solution was poured in ammonium hydroxide and extracted with a 5:1 (V/V) mixture of EtOAc and DMF. The organic layer was dried over Na2SO4 and concentrated. (Z)-3-[(4-Acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-[(2S,4R)-(4-hydroxy-pyrrolidin-2-yl)ethynyl]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-10% MeOH in CH2Cl2 gradient and trituration with CH2Cl2. (Yield 50 mg, 35%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].[Br:11]Br>C(O)(=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6]
Reactant: Nc1ccccc1CCO
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1ccc(Br)cc1CCO
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of 2-aminophenethyl alcohol (10.0 g, 72.9 mmol) in acetic acid (60 mL) at 10° C. was added Br2 (3.8 mL, 72.9 mmol) in acetic acid (5 mL). Additional acetic acid (30 mL) was added and the reaction was stirred for 1 hour. The mixture was filtered and the filter cake washed with diethyl ether. The solid was then partitioned between ethyl acetate and aqueous 3N NaOH. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide the titled compound (15.8 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].FC(F)(F)S(O[C@@H:22]([CH2:30][CH3:31])[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])(=O)=O.C(OCC)(=O)C>C(#N)C>[CH:11]([C:10]1[CH:9]=[C:8]([CH:15]=[CH:14][CH:13]=1)[O:7][C@H:22]([CH2:30][CH3:31])[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])=[O:12]
Reactant: CCCCOC(=O)[C@H](CC)OS(=O)(=O)C(F)(F)F
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCOC(=O)[C@@H](CC)Oc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Potassium carbonate (473 mg) was added to a solution of 3-hydroxybenzaldehyde (418 mg) in acetonitrile (10 mL). Subsequently, n-butyl (S)-2-trifluoromethanesulfonyloxybutyrate (1.0 g) was added to the mixture, followed by stirring at room temperature for 12 hours. Ethyl acetate was added to the reaction mixture, and the resultant mixture was washed sequentially with water and saturated brine, followed by drying over sodium sulfate anhydrate. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography (hexane/ethyl acetate=4/1), to thereby yield 904 mg of a colorless, oily substance (99.9%).
Reaction SMILES: [Mg].Br[CH:3]([CH3:8])[CH2:4][CH2:5][CH:6]=[CH2:7].[CH2:9]1[O:12][C@H:10]1[CH3:11]>C1COCC1.[Cu](Br)Br.II>[CH3:7][CH:6]([CH2:5][CH2:4][CH:3]=[CH2:8])[CH2:9][C@@H:10]([OH:12])[CH3:11]
Reactant: C[C@H]1CO1
Reactant: C=CCCC(C)Br
Agent: Br[Cu]Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCC(C)C[C@H](C)O
Reaction time: 8 h
Yield: 36.2 %

Procedure:
To magnesium turnings (7.44 g, 0.020 moles) in dry THF (100 mL) and was added iodine (100 mg) at room temperature. To this reaction mass was added a solution of 5-bromohex-1-ene (50.0 g, 362 mmoles) in THF (200 mL). The reaction mass was heated with hot air gun to initiate the reaction. Upon completion of the reaction the solution was transferred by cannula to a solution of (S)-propylene oxide (14 g, 241 mmol) and copper bromide (3.45 g, 24 mmol) in THF (100 mL) at −78° C. The reaction mass was allowed to come to room temperature and was stirred overnight. The reaction mass was quenched with saturated aq. ammonium chloride solution and extracted with diethyl ether (200 mL×3). The combined organic layers were dried over anhydrous Na2SO4; filtered; then concentrated in vacuo at room temperature to get crude compound. The crude compound was purified by column chromatography (Silica gel, 10% TBME in pet ether) to get (2S)-4-methyloct-7-en-2-ol (12.4 g, 30%) as an oil. 1H NMR (400 MHz, CDCl3): δ ppm 5.84-5.77 (m, 1H), 5.02-4.92 (m, 2H), 4.05-3.85 (sb, 1H), 2.08-2.06 (m, 2H), 1.29-1.20 (m, 2H), 1.19-1.16 (m, 4H), 0.97-0.87 (m, 6H).
Reaction SMILES: [OH-:1].[Na+].Cl.[NH2:4]O.[CH2:6]([O:8][C:9](=[O:18])[C:10](=[O:17])[CH:11]([CH3:16])[C:12](=O)[CH2:13][CH3:14])[CH3:7]>O>[CH2:6]([O:8][C:9](=[O:18])[C:10](=[O:17])[CH:11]([CH3:16])[C:12](=[N:4][OH:1])[CH2:13][CH3:14])[CH3:7]
Reactant: NO
Reactant: CCOC(=O)C(=O)C(C)C(=O)CC
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(=O)C(C)C(CC)=NO
Yield: 53.8 %

Procedure:
Sodium hydroxide (1.58 g, 39.4 mmol) was dissolved in 8.5 mL of water. Hydroxylamine hydrochloride (2.74 g, 39.4 mmol) was added and the reaction mixture was stirred until complete dissolution was achieved. 3-Methyl-2,4-dioxo-hexanoic acid ethyl ester (6.37 g, 34.2 mmol) was added and the resulting mixture was stirred at ambient temperature for 16 h. The reaction mixture was extracted with EtOAc (3×50 mL) and the organic layers were combined, dried over MgSO4 and concentrated. The crude oil was purified by chromatography (0-40% EtOAc/hexanes) to give 3.7 g of the title compound. MS: (+) m/z 202.35 (M+1).
Reaction SMILES: CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.CS(N)(=O)=O.[CH2:64]([O:66][C:67]([C:69]1[CH2:78][CH2:77][C:76]2[C:71](=[CH:72][CH:73]=[CH:74][C:75]=2[O:79][Si:80]([C:93]([CH3:96])([CH3:95])[CH3:94])([C:87]2[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=2)[C:81]2[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=2)[CH:70]=1)=[O:68])[CH3:65].S([O-])([O-])=O.[Na+].[Na+].[OH2:103]>C(O)(C)(C)C>[OH:103][C@H:70]1[C:71]2[C:76](=[C:75]([O:79][Si:80]([C:93]([CH3:95])([CH3:94])[CH3:96])([C:87]3[CH:88]=[CH:89][CH:90]=[CH:91][CH:92]=3)[C:81]3[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=3)[CH:74]=[CH:73][CH:72]=2)[CH2:77][CH2:78][C@:69]1([OH:22])[C:67]([O:66][CH2:64][CH3:65])=[O:68]
Reactant: CCOC(=O)C1=Cc2cccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2CC1
Reactant: O
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: CS(N)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCOC(=O)[C@@]1(O)CCc2c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cccc2[C@@H]1O
Reaction time: 1 h

Procedure:
A solution of AD-mix-α (trade name, Aldrich) (9.2 g) in a mixture of t-butyl alcohol (30 ml) and water (30 ml) was stirred for 1 hour and then methanesulfonamide (0.62 g) and 2-ethoxycarbonyl-5-t-butyldiphenylsilyloxy-3,4-dihydronaphthalene (3.0 g) were added to the solution at room temperature. After being stirred for 20 hours at the same temperature, sodium sulfite (9.0 g) was added, and the mixture was stirred for 30 minutes. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford (1S,2R)-1,2-dihydroxy-2-ethoxycarbonyl-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (3.1 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([CH2:13][C:14]#[N:15])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.F[C:17]1C=CC(NN)=CC=1.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[NH:33][NH2:34]>>[NH2:15][C:14]1[N:33]([C:27]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=2[F:25])[N:34]=[CH:17][C:13]=1[C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:12]
Reactant: N#CCC(=O)c1ccc2ncccc2c1
Reactant: NNc1ccc(F)cc1F
Reactant: NNc1ccc(F)cc1
Product: Nc1c(C(=O)c2ccc3ncccc3c2)cnn1-c1ccc(F)cc1F

Procedure:
Proceeding as described in Example 1, step 2, but replacing 2-(3-bromobenzoyl)acetonitrile with 2-(6-quinolinoyl)acetonitrile and substituting 4-fluorophenylhydrazine in step 3 with 2,4-difluorophenylhydrazine was obtained 5-amino-1-(2,4-difluorophenyl)-4-(6-quinolinoyl)-pyrazole.HCl (117) (mpt. 220-259.2).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[CH:20](Br)Br)[C:13]([O:15]C)=[O:14].[OH-:23].[Na+]>CN(C=O)C.O>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][CH:20]([O:23][CH2:3][C:2]([F:6])([F:5])[F:1])[C:19]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[Cl:9]
Reactant: COC(=O)c1ccc(C(Br)Br)c(Cl)c1
Reactant: [OH-]
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(C(OCC(F)(F)F)OCC(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,2,2-trifluoroethanol (109 μL, 1.50 mmol) in DMF (2.63 mL) was added NaH (64 mg, 1.6 mmol). The mixture was stirred at room temperature for 1 h before methyl 3-chloro-4-(dibromomethyl)benzoate (342 mg, 1.00 mol) was added. The mixture was stirred at room temperature for 2 h before it was poured into water and was extracted with EtOAc (3×). The organics were combined, washed with water, brine, dried (Na2SO4) and evaporated to dryness. The material was taken up in MeOH and powdered NaOH (160 mg, 4.00 mol) was added and the mixture was stirred at room temperature for 1 h. The mixture was evaporated and treated with 1N HCl (until the solution was strongly acidic). The precipitated product was washed with water and dried to give 4-(bis(2,2,2-trifluoroethoxy)methyl)-3-chlorobenzoic acid. ESI-MS m/z calc. 394.4, found 394.5 (M+1)+; Retention time: 1.74 minutes (3 min run).
Reaction SMILES: [CH3:1][CH2:2][C:3]([NH:5][CH:6]1[C:25](=[O:26])[N:8]2[C:9]([C:22]([OH:24])=[O:23])=[C:10]([CH2:13][S:14][C:15]3[S:16][C:17]([CH2:20][NH2:21])=[N:18][N:19]=3)[CH2:11][S:12][C@H:7]12)=[S:4].[OH-].[Na+:28].[S:29](=[O:32])([OH:31])[O-:30].[Na+].[CH2:34]=O>O>[CH3:1][CH2:2][C:3]([NH:5][CH:6]1[C:25](=[O:26])[N:8]2[C:9]([C:22]([O-:24])=[O:23])=[C:10]([CH2:13][S:14][C:15]3[S:16][C:17]([CH2:20][NH:21][CH2:34][S:29]([OH:31])(=[O:30])=[O:32])=[N:18][N:19]=3)[CH2:11][S:12][C@H:7]12)=[S:4].[Na+:28].[Na+:28].[CH3:1][CH2:2][C:3]([NH:5][CH:6]1[C:25](=[O:26])[N:8]2[C:9]([C:22]([O-:24])=[O:23])=[C:10]([CH2:13][S:14][C:15]3[S:16][C:17]([CH2:20][NH:21][CH2:34][S:29]([OH:31])(=[O:30])=[O:32])=[N:18][N:19]=3)[CH2:11][S:12][C@H:7]12)=[S:4]
Reactant: O=S([O-])O
Reactant: CCC(=S)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CN)s3)CS[C@H]12
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(=S)NC1C(=O)N2C(C(=O)[O-])=C(CSc3nnc(CNCS(=O)(=O)O)s3)CS[C@H]12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a suspension of 7-(2-methylthioacetamido)-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (4.05 g.) in water (20 ml.) was added 1 N aqueous sodium hydroxide solution (9 ml.) under ice cooling to dissolve. Sodium bisulfite (3.12 g.) and 39% formaldehyde (2.25 ml.) were added to water (7.5 ml.) and, the solution was warmed at 60° C. for 5 minutes and adjusted to the total amount of 50 ml. by water. Thus obtained solution (22.5 ml.) was added to the solution above prepared all at once. The mixed solution was stirred at room temperature for 2 hours, and an insoluble product was filtered off and then the filtrate was concentrated under reduced pressure. The residue was dissolved in water (10 ml.) and purified on a column of an adsorption resin (Amberlite XAD-2: made by Rohm & Haas Co.) to give di-sodium 7-(2-methylthioacetamido)-3-(5-sulfomethylaminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate (983 mg.) m.p. 145° to 150° C. (dec.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:8]([C:10]1[CH:11]=[C:12]2[N:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[N:16]([CH3:29])[C:13]2=[N:14][CH:15]=1)=[O:9].[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+].C(OCC)(=O)C.C(O)C.N>CO>[ClH:36].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:8]([C:10]1[CH:11]=[C:12]2[N:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27](=[NH:41])[NH2:28])=[CH:25][CH:26]=3)[N:16]([CH3:29])[C:13]2=[N:14][CH:15]=1)=[O:9]
Reactant: COC(=O)CCN(C(=O)c1cnc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)CCN(C(=O)c1cnc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 75 %

Procedure:
Prepared analogously to Example 1 from 3-methyl-2-[2-(4-cyanophenyl)ethyl]imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)amide, methanolic hydrochloric acid, methanol, and ammonium carbonate. Yield: 75% of theory, C26H27N7O3 (485.55); Rf value: 0.31 (silica gel; ethyl acetate/ethanol/ammonia=50:45:5); EKA mass spectrum: (M+H)+=486.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.O>CS(C)=O>[N:14]1([CH2:13][CH2:12][NH:11][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: NCCN1CCOCC1
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(NCCN2CCOCC2)c1
Temperature: 100 °C
Reaction time: 60 h

Procedure:
28.2 g 3-fluoronitrobenzene and 143 g 4-(2-aminoethyl)morpholine were dissolved in 300 ml dimethyl sulfoxide, and the batch was stirred for 60 h at 100° C. After cooling, the batch was poured into 1 l water. The mixture was extracted several times with methyl tert-butyl ether, and the combined organic phases were reduced to dryness in a rotary evaporator, yielding a dark liquid.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6](OC)=[O:7].C([O-])(O)=O.[Na+].O.CCOC(C)=O>C1COCC1>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[NH:1][C:6](=[O:7])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(OC)c1C1CCCC(=O)N1
Temperature: 25 °C
Reaction time: 327 h

Procedure:
A yellow solution of the chlorhydrate salt of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate (14.96 mmol) in THF (92 ml) was treated with a solution of aq. sat. NaHCO3 (23.5 ml). The resulting heterogeneous mixture was further stirred at rt, under nitrogen, for 327 h. This reaction mixture was then treated with a solution of aq. sat. NaHCO3 (25 ml), water (50 ml), and AcOEt (200 ml). The layers were separated and the slightly yellow aq. layer was further extracted with AcOEt (50 ml). The mixed yellow organic layers were then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=20/1) afforded 6-(2,6-dimethoxyphenyl)-piperidin-2-one as a beige solid. LC-MS (conditions B): tR=0.83 min.; [M+H]+: 236.49 g/mol.