Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][C:27]=1[CH3:35].CCN(C(C)C)C(C)C.[CH3:45][C@:46]([NH:56][CH3:57])([CH:53]([CH3:55])[CH3:54])[CH2:47][N:48]1[CH2:51][CH:50]([OH:52])[CH2:49]1.[OH-].[K+]>CN(C=O)C.C(Cl)Cl.CO>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:56]([C@@:46]([CH3:45])([CH:53]([CH3:54])[CH3:55])[CH2:47][N:48]2[CH2:49][CH:50]([OH:52])[CH2:51]2)[CH3:57])=[O:32])=[CH:28][C:27]=1[CH3:35]
Reactant: Cc1cc(C(=O)O)ccc1F
Reactant: CN[C@](C)(CN1CC(O)C1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1cc(C(=O)N(C)[C@](C)(CN2CC(O)C2)C(C)C)ccc1F
Reaction time: 0.17 h
Yield: 0.6 %

Procedure:
HATU (0.408 g, 1.07 mmol) was added to a mixture of 4-fluoro-3-methylbenzoic acid (5.34 ml, 1.07 mmol) and DIPEA (2 mL, 11.45 mmol) in DMF (10 mL). After 10 min was (S)-1-(2,3-dimethyl-2-(methylamino)butyl)azetidin-3-ol (Compound Y) (0.1 g, 0.54 mmol) in DCM added. The resultant mixture was stirred at rt over night. The mixture was concentrated and the residue dissolved in DCM. The organic phase was washed with NaHCO3 (saturated) and brine. The filtrate was dried (Na2SO4) and concentrated under reduced pressure. MeOH (10 mL) and KOH (2.221 ml, 3.22 mmol) was added and the resultant mixture was stirred at rt for 3 days. The solvent was removed and the residue was purified by preparative HPLC to give the title compound (1.1 mg, 0.5%). Mixture of rotamers: 1H NMR (400 MHz, CDCl3) δ 0.91, 1.01, 2.29, 2.34-2.43, 2.81, 2.96, 3.03-3.56, 3.65-3.79, 3.79-3.96, 4.00-4.12, 4.28, 4.43-4.57, 6.92-7.06, 7.16-7.25. Total no of protons: 27. HRMS (M+H)+: calculated 323.2135. found 323.2113.
Reaction SMILES: C[Si](I)(C)C.C1(C[O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][C:28]=3[C:29]3[CH:34]=[CH:33][C:32]([O:35]CC5C=CC=CC=5)=[CH:31][CH:30]=3)[NH:25][N:24]=[C:23]4[NH:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47])=[CH:16][CH:15]=2)C=CC=CC=1>CO>[OH:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][C:28]=2[C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)[NH:25][N:24]=[C:23]3[NH:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47])=[CH:18][CH:19]=1
Reactant: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3ccc(OCc4ccccc4)cc3)cc12
Agent: C[Si](C)(C)I
Solvent: CO
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(O)cc3)c(-c3ccc(O)cc3)cc12
Yield: 46.1 %

Procedure:
10 cm3 of trimethylsilyl iodide are added to 700 mg of N-[5,6-bis[4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide, prepared in Example 97, and the mixture is refluxed for 18 hours. 30 cm3 of methanol are added and the reaction medium is refluxed for 15 minutes and is then concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is taken up in 75 cm3 of ethyl acetate and the organic phase is washed with 2×75 cm3 of 10% sodium thiosulphate solution and then with 75 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2 kPa; 50° C.) to give 900 mg of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a cyclohexane/ethyl acetate mixture (60/40 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) and the residue is taken up in 20 cm3 of diisopropyl ether, filtered off, washed with 3 cm3 of ethyl acetate, then with 2×10 cm3 of diisopropyl ether and dried (90 Pa; 45° C.) to give 220 mg of N-[5,6-bis(4-hydroxyphenyl)-1H-indazol-3-yl]butanamide in the form of a white powder melting at 180° C.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][O:12]2)=[CH:7][CH:6]=1)(=O)C.N1C=CN=C1.O1C2C(=CC=C(O)C=2)C=C(C2C=CC(O)=CC=2)C1>C(O)C>[O:12]1[C:13]2[C:8](=[CH:7][CH:6]=[C:5]([OH:4])[CH:14]=2)[CH:9]=[C:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11]1
Reactant: CC(=O)Oc1ccc2c(c1)OCC(c1ccccc1)=C2
Agent: Oc1ccc(C2=Cc3ccc(O)cc3OC2)cc1
Agent: c1c[nH]cn1
Solvent: CCO
Product: Oc1ccc2c(c1)OCC(c1ccccc1)=C2

Procedure:
Isoflav-3-ene-7-ol was prepared from 7-acetoxyisoflav-3-ene (0.2 g, 0.75 mmol) and imidazole (0.24 g) in ethanol (3.5 ml) as described for isoflav-3-ene-4′,7-diol. Yield: (0.11 g, 66%) m.p. 120° C. 1H NMR (d6-DMSO): δ 5.07 (s, 2H, H2), 6.24 (d, 1H, J 2.2 Hz, H8), 6.33 (dd, 1H, J 1.9 Hz, 7.9 Hz, H6), 6.96 (d, 1H, J 7.9 Hz, H5), 7.00 (s, 1H, H4), 7.26-7.47 (m, 5H, ArH), 9.65 (bs, 1H, OH). Mass spectrum: m/z 224 (m, 74%); 223 (100), 175 (28); 165 (23); 147 (41).
Reaction SMILES: [CH:1]([C:4]1([CH3:20])[NH:8][C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[N:6][C:5]1=[O:19])([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.CN([CH:37]=[O:38])C>CCOCC.CCCCCC.O.C(O)C.C(O)(=O)C>[CH:1]([C:4]1([CH3:20])[NH:8][C:7]([C:9]2[C:18]([CH:37]=[O:38])=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[N:6][C:5]1=[O:19])([CH3:3])[CH3:2]
Reactant: CC(C)C1(C)NC(c2ccc3ccccc3n2)=NC1=O
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CC(C)C1(C)NC(c2nc3ccccc3cc2C=O)=NC1=O
Temperature: -63 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a mixture of 5-isopropyl-5-methyl-2-(2-quinolyl)-2-imidazolin-4-one (3 g, 0.0112 mol) in ether (150 ml) is added tetramethylethylenediamine (3.4 g, 0.00225 mol). n-Butyllithium (17 ml, 0.027 mol) in hexane is added dropwise to the reaction mixture cooled to -63° C. An intense red color is generated and after the addition the mixture is maintained at -10° to -20° C. for 21/2 hours. Dry DMF (5 ml) is added at -10° C. and the mixture is allowed to attain room temperature, while stirring overnight. The mixture is diluted with water (75 ml) and is neutralized with acetic acid. A pale yellow solid 2.57 g (78%) is obtained with mp 226°-227° C. after crystallization* from 95% ethanol. Anal. calcd. for C17H17N3O2 : C, 69.13; H, 5.80; N, 14.23. Found: C, 68.98; H, 5.88; N, 14.25. The oxime of this aldehyde, prepared in the usual way, has mp 255°-257° C.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)=[N:8][C:7]=2[N:6]([CH2:27][CH2:28][CH3:29])[C:5]1=[O:30])[CH2:2][CH3:3].Br[CH2:32][C:33]([CH:35]1[CH2:39][N:38]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=2)[C:37](=[O:50])[CH2:36]1)=[O:34].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[O:34]=[C:33]([CH:35]1[CH2:36][C:37](=[O:50])[N:38]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:47])[F:48])[CH:41]=2)[CH2:39]1)[CH2:32][N:25]1[CH:26]=[C:22]([C:9]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:21])[CH3:19])[C:11]3[C:12](=[O:13])[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:30])[N:6]([CH2:27][CH2:28][CH3:29])[C:7]=3[N:8]=2)[CH:23]=[N:24]1
Reactant: CCCn1c(=O)c2c(nc(-c3cn[nH]c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Reactant: O=C(CBr)C1CC(=O)N(c2cccc(C(F)(F)F)c2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCn1c(=O)c2c(nc(-c3cnn(CC(=O)C4CC(=O)N(c5cccc(C(F)(F)F)c5)C4)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Temperature: 95 °C
Yield: 27.8 %

Procedure:
A mixture of 1,3-dipropyl-8-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.200 g, 0.462 mmol), 4-(2-Bromo-acetyl)-1-(3-trifluoromethyl-phenyl)-pyrrolidin-2-one (0.240 g, 0.693 mmol), Cs2CO3 (0.30 g, 0.924 mmol) and acetonitrile (2 ml) were heated at 90-100° C. in a sealed tube for 6 hrs. Reaction mixture was cooled to 20-25° C. and filtered off. The organic volatiles were evaporated. The crude product was purified by preparative TLC to obtain pure 8-(1-{2-oxo-2-[5-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-yl]-ethyl}-1H-pyrazol-4-yl)-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.090 g, 28%) as a brown mass.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:10]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Oc1ccccc1O
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCOc1ccccc1O
Yield: 47696.8 %

Procedure:
A mixture of 740 mL of methyl ethyl ketone, 120 g (1.09 mol) of catechol, 178 g (1.09 mmol) of 1-bromohexane, and 211 g (1.53 mol, 1.4 eq.) of potassium carbonate was refluxed for 25 hours. After being cooled, the mixture was filtered and the solvent was evaporated. The residue of 202 g was purified by silica-gel column chromatography and was then distilled. As a result, 101 g of a transparent liquid was obtained.
Reaction SMILES: [CH3:1][C:2](=[CH2:5])[CH2:3]O.[C:6]([O:14]CC)([O:11][CH2:12][CH3:13])(OCC)[CH3:7].C(O)(=O)CC>CCCCCC.C(OCC)C>[CH3:3][C:2](=[CH2:1])[CH2:5][CH2:7][C:6]([O:11][CH2:12][CH3:13])=[O:14]
Reactant: CCOC(C)(OCC)OCC
Reactant: C=C(C)CO
Solvent: CCCCCC
Solvent: CCC(=O)O
Solvent: CCOCC
Product: C=C(C)CCC(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 0.1 %

Procedure:
A solution of 2-methyl-2-propen-1-ol (12.9 g, 0.18 mol), triethyl orthoacetate (230.0 mL, 1.3 mol) and propionic acid (0.9 mL, 0.12 mol) was heated to 170° C. (external). The reaction apparatus was equipped with a Vigreaux Claisen adapter with a collection flask to remove the ethanol produced. The reaction mixture was left under reflux overnight. The excess amount of triethyl orthoacetate was gently distilled off at 130 mm Hg until the temperature in the reaction flask began to increase. After the reaction was cool, the remaining liquid was treated with 300 mL of 10% monobasic potassium phosphate and the left reaction was stirred for 90 min at ambient temperature. The reaction mixture was extracted with diethyl ether (3×100 mL). The combined organic phase was dried over Na2SO4 and concentrated in vacuo to give a yellow oil. Flash column chromatography of this oil (silica gel, 4:1 hexane/diethyl ether) afforded compound 7 as a colorless oil (17.0 g, 0.12 mmol, 67%) (Gen et al. (1973) J. Am. Chem. Soc. 95, 2656-2663).
Reaction SMILES: [C:1]([S:9][C@@H:10]([CH2:14][CH2:15][CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])[C:11](O)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29]([CH3:45])([CH3:44])[C@H:30]([NH:35][C:36](=[O:43])[C@@H:37]([NH2:42])[CH2:38][CH:39]([CH3:41])[CH3:40])[C:31](=[O:34])[NH:32][CH3:33]>C(OCC)(=O)C.O>[CH3:45][C:29]([CH3:28])([CH3:44])[C@H:30]([NH:35][C:36](=[O:43])[C@@H:37]([NH:42][CH2:11][C@@H:10]([S:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:14][CH2:15][CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])[CH2:38][CH:39]([CH3:41])[CH3:40])[C:31](=[O:34])[NH:32][CH3:33]
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)C(C)(C)C
Reactant: O=C(S[C@@H](CCCN1C(=O)c2ccccc2C1=O)C(=O)O)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC[C@H](CCCN1C(=O)c2ccccc2C1=O)SC(=O)c1ccccc1)C(C)(C)C
Reaction time: 0.17 h

Procedure:
(S)-2-Benzoylsulfanyl-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid (62.6 g, 0.163 mol) and (S)-2-amino-4-methylpentanoic acid (2,2-dimethyl-1-(S)-methylcarbamoylpropyl)amide (40 g, 0.155 mol) were dissolved in a biphasic mixture of ethyl acetate (480 mL) and water (240 mL) at 45° C. and stirred to equilibrate for 10 min. An HPLC reference sample was removed for t=0. The PeptiCLEC-TR enzyme (40 mL) is added to the reaction and the reaction is stirred at 45° C. Samples are removed at regular intervals for HPLC analysis which shows that the reaction is complete in 2 hours. Filtration of tile enzyme followed by acidic then basic aqueous washes gives a solution of (S)-2-[(S)-2-benzoylsulfanyl-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanylamino]-4-methylpentanoic acid (2,2-dimethyl-1(S)-methylcarbamoylpropyl)amide which is then evaporated to dryness to give the product as a glass foam 80 g, 83%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[N:21]1([C:27]2[C:32]([CH:33]=O)=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:33]([C:32]3[C:27]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[N:28][CH:29]=[CH:30][CH:31]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1cccnc1N1CCOCC1
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4cccnc4N4CCOCC4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 42.4 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and 2-Morpholin-4-yl-pyridine-3-carbaldehyde (31.2 mg, 0.163 mmol) were reacted to produce 32 mg (42%) of the title compound. mp: 150° C., 1H NMR (300 MHz, DMSO-d6): 12.95 (s, 1H), 8.33 (d, J=5 Hz, 1H), 8.04 (s, 1H), 7.98 (d, J=8 Hz, 1H), 7.73 (s, 1H), 7.19 (s, 1H), 7.09 (m, 1H), 6.34 (s, 1H), 6.32 (s, 1H), 5.21 (t, J=8 Hz, 1H), 3.64 (s, 4H), 3.29 (s, 1H), 3.06 (m, 4H), 2.87 (s, 1H), 2.78 (s, 1H), 2.59 (d, J=8 Hz, 1H), 2.26 (d, J=8 Hz, 1H), 1.39 (d, J=8 Hz, 1H). MS: 510, 512 (M+H), HPLC: 2.02 min (G method).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.[C:12](Cl)(=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O1CCCC1>[C:12]([NH:4][CH2:3][CH2:1][OH:2])(=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: NCCO
Reactant: CCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)NCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
A solution of ethanolamine (3.42 ml, 56.6 mmol) and triethylamine (5.51 ml, 39.5 mmol) in dry tetrahydrofuran (150 ml) was cooled in ice bath and decanoyl chloride (5.44 ml, 26.3 mmol) in tetrahydrofuran (50 ml) was added dropwise. The reaction mixture was stirred at room temperature overnight and filtered. The filtered solution was concentrated in vacuo. The residue was diluted with ethyl acetate (300 ml) and washed with 0.1% HCl (50 ml×3), saturated NaHCO3 (50 ml×3), brine (50 ml), and water (50 ml). The organic solution was dried over MgSO4 and solvent was removed on a rotovap. The crude product was purified by flash column chromatography, eluting with a gradient of dichloromethane/methanol (95:5) to dichloromethane/methanol (9:1) to give 5.57 g of a white solid NAE-10:0 (99% yield): Rf=0.35 in dichloromethane/methanol (95:5); 1H NMR (CDCl3) 6 6.11 (br, 1H), 3.72 (m, 2H), 3.42 (m, 2H), 3.08 (br, 1H), 2.20 (t, J=7.9 Hz, 2H), 1.64 (m, 2H), 1.26–1.29 (m, 12H), 0.88 (t, J=6.8 Hz, 3H); FT-IR (Table 1).
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[C:4]([N+:23]([O-])=O)[CH:3]=1.O.NN>C(O)C.[Ni]>[NH2:23][C:4]1[CH:3]=[C:2]([F:1])[C:7]([CH3:8])=[CH:6][C:5]=1[NH:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]1
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1F
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)cc1F
Temperature: 45 °C
Yield: 91.7 %

Procedure:
1,1-Dimethylethyl 4-[(4-fluoro-5-methyl-2-nitrophenyl)amino]-1-piperidinecarboxylate (D27) (0.96 mmol, 340 mg) in ethanol (20 mL) was treated under argon at room temperature with Raney Nickel (suspension, 50% in water, 0.5 mL) then dropwise with hydrazine hydrate (9.6 mmol, 10 eq) in ethanol over 15 min. The mixture was heated at 45° C. for 50 min. The Raney nickel was filtered off and washed with ethanol. The reaction mixture was concentrated under vacuum to give the title compound (0.88 mmol, 284 mg, 92% yield). M+H=324.16.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C([O-])(=O)C.[NH4+].[N+:18]([CH2:21][CH3:22])([O-:20])=[O:19]>>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:5]([CH:6]=[C:21]([N+:18]([O-:20])=[O:19])[CH3:22])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc(C=C(C)[N+](=O)[O-])cc1OC
Temperature: 105 °C
Yield: 50 %

Procedure:
4.99 g (30.0 mmol) 3,4-dimethoxybenzaldehyde (Aldrich, Milwaukee, Wis.), 15.0 g (194 mmol) ammonium acetate (Fluka), and 70 g (930 Mmol) nitroethane, 98% (Aldrich) were combined in a 100 ml round bottom flask equipped with magnetic stirrer and nitrogen inlet. The reaction mixture was heated to 105° C. for 90 minutes and the solvent was removed under vacuum to give a dark yellow liquid which was recrystallized from cold methyl alcohol three times to give yellow-orange needles in 50% yield. 1H NMR spectra is shown in FIG. 3.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][S:15][C:8]=2[C:7]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:18][CH2:17]1)=[O:5])[CH3:2].[H-].[Na+].[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([F:31])=[CH:33][CH:34]=2)[C:9]2[CH:13]=[CH:14][S:15][C:8]=2[C:7]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:18][CH2:17]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2sccc2[nH]c1=O
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2sccc2n(Cc2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
A solution of 5-oxo-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (5) (232 mg, 0.55 mmol) in dry DMF was added to a suspension of NaH (60% in mineral oil, 24 mg, 0.61 mmol) at room temperature. The solution was stirred at room temperature for 15 min. 4-Fluorobenzylbromide (76 μL, 0.61 mmol) was added to the solution through a syringe and further stirred at room temperature for 1 h. The solution was poured into ice water and the solids formed were filtered, washed by cold water, and dried. The crude product was purified by flash chromatography eluting with 0-2% methanol in CH2Cl2 gradient to yield 207 mg (90%) of 4-(4-fluoro-benzyl)-5-oxo-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester as white solids. 1H NMR (400 MHz, DMSO-d6) δ 1.28 (t, J=7.2 Hz, 3H), 3.34 (m, 4H), 3.80 (m, 4H), 4.27 (q, J=7.2 Hz, 2H), 5.34 (s, 2H), 7.14-7.18 (m, 3H), 7.29-7.35 (m, 3H), 7.48 (dd, J=1.2, 3.6, Hz, 1H), 7.80 (dd, J=1.2, 5.2 Hz, 1H), 8.04 (d, J=5.6 Hz, 1H) ppm; MS m/z=526 amu (M++1). Anal. (C26H24FN3O4S2) C, H, N.
Reaction SMILES: [C:1]([CH:3]=[CH:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18](=[O:31])[N:9]2[C:10]=1[C:11]([O:13]C(C)(C)C)=[O:12])#[N:2]>C(O)=O>[C:1]([CH:3]=[CH:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:18](=[O:31])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])#[N:2]
Reactant: CC(C)(C)OC(=O)C1=C(C=CC#N)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12
Solvent: O=CO
Product: N#CC=CC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1

Procedure:
Each of the cis-and trans-isomers of tert-butyl 3-(2'-cyanovinyl)-7-phenoxyacetamido-3-cephem-4-carboxylate from Example 17 was in turn treated with 98-100 percent formic acid for 1 hour at room temperature to cleave the tert-butyl ester groups therefrom. After evaporation under reduced pressure of the excess formic acid, the acid residue was separated as an oil. Each product [the cis-or trans-isomer of the titled compound] showed a large antibiotic activity zone at 1 microgram/milliliter on a bioautograph test against B. subtilis.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)[CH:16]=4)[C:4]=2[C:3]=1[CH3:27])[CH:12]=[CH:11][CH:10]=[CH:9]3.[H-].[Na+].[CH3:30][S:31][C:32]1[N:37]=[C:36]([C:38]2[S:42][C:41]([S:43](Cl)(=[O:45])=[O:44])=[CH:40][CH:39]=2)[CH:35]=[CH:34][N:33]=1>>[CH:22]1([C:17]2[CH:16]=[C:15]([C:14]3[C:4]4[C:3]([CH3:27])=[C:2]([CH3:1])[S:6][C:5]=4[CH:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)[CH:20]=[CH:19][C:18]=2[O:21][S:43]([C:41]2[S:42][C:38]([C:36]3[CH:35]=[CH:34][N:33]=[C:32]([S:31][CH3:30])[N:37]=3)=[CH:39][CH:40]=2)(=[O:44])=[O:45])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: Cc1sc2cc3ccccc3c(-c3ccc(O)c(C4CCCC4)c3)c2c1C
Reactant: CSc1nccc(-c2ccc(S(=O)(=O)Cl)s2)n1
Agent: [H-]
Agent: [Na+]
Product: CSc1nccc(-c2ccc(S(=O)(=O)Oc3ccc(-c4c5ccccc5cc5sc(C)c(C)c45)cc3C3CCCC3)s2)n1
Yield: 57.8 %

Procedure:
The title compound was prepared according to the procedure in Example 10, step 1, using 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenol (0.300 g, 0.805 mmol), 60% sodium hydride/mineral oil (0.032 g, 0.805 mmol) and commercial 5-[2-(methylthio)pyrimidin-4-yl]thiophene-2-sulphonyl chloride (0.272 g, 0.886 mmol). Purification on Biotage KP-Sil eluting with 25% EtOAc/pet. ether gave 0.299 g (58%) of the title compound as a yellow solid, mp 100-110° C. 1H NMR (DMSO-d6) δ 1.32-1.37 (m, 2 H), 1.45-1.65 (m, 8 H), 1.84-1.90 (m, 1 H), 2.37 (s, 3 H), 2.55 (s, 3 H), 3.15 (quintet, 1 H), 7.25-7.38 (m, 5 H), 7.44 (ddd, 1 H), 7.90 (d, 1 H), 7.96 (d, 1 H), 8.08 (d, 1 H), 8.27 (d, 1 H), 8.48 (s, 1 H), 8.77 (d, 1 H). mass spectrum (+APCI) m/z 643 (M+H). C34H30N2O3S4 : C, 63.52; H, 4.70; N, 4.36. Found: C, 63.18; H, 4.46; N, 4.19.
Reaction SMILES: [OH:1][C:2]([C@@H:5]1[CH2:10][C@H:9]([N:11]([CH:13]([CH3:15])[CH3:14])[CH3:12])[CH2:8][CH2:7][C@@H:6]1[N:16]1[CH2:20][CH2:19][C@H:18]([NH:21]C(=O)OCC2C=CC=CC=2)[C:17]1=[O:32])([CH3:4])[CH3:3]>CO.[Pd]>[NH2:21][C@H:18]1[CH2:19][CH2:20][N:16]([C@H:6]2[CH2:7][CH2:8][C@@H:9]([N:11]([CH:13]([CH3:15])[CH3:14])[CH3:12])[CH2:10][C@H:5]2[C:2]([OH:1])([CH3:4])[CH3:3])[C:17]1=[O:32]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](C(C)(C)O)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](C(C)(C)O)C1
Reaction time: 7 h

Procedure:
A solution of benzyl (S)-1-((1S,2R,4R)-2-(2-hydroxypropan-2-yl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (224 mg) in MeOH (15 mL) was charged with 10% Pd/C, Degussa (˜100 mg). The reaction flask was evacuated and then back-filled with hydrogen; this was repeated two more times. The reaction was stirred under 60 psi of H2 for 7 h and then filtered and concentrated in vacuo to afford the desired (S)-3-amino-1-((1S,2R,4R)-2-(2-hydroxypropan-2-yl)-4-(isopropyl(methyl)amino)cyclohexyl)pyrrolidin-2-one as an oil. MS found: (M+H)+=312.2.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([CH:18]=[O:19])[C:12]=3[CH:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1.[BH4-].[Na+].O>CO.C(Cl)Cl>[CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:17]3[C:12](=[C:13]([CH2:18][OH:19])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(-n2ccc3c(C=O)cccc32)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CSc1nccc(-n2ccc3c(CO)cccc32)n1
Reaction time: 1 h
Yield: 69 %

Procedure:
1-(2-Methylsulfanyl-pyrimidin-4-yl)-1H-indole-4-carbaldehyde (14.38 g, 53.39 mmol) was suspended in a mixture of MeOH (200 mL) and DCM (100 mL), cooled in an ice bath, treated with NaBH4, and stirred for 1 h. Water was then added, and the solvents concentrated in vacuo. The residue was them partitioned between water and EtOAc, filtered, and the precipitate was triturated with ether, filtered and solvent removed in vacuo overnight to yield [1-(2-methylsulfanyl-pyrimidin-4-yl)-1H-indol-4-yl]-methanol (10 g).