Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:4])#[N:2].N[CH2:16][CH2:17][OH:18]>C(O)CCC.O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C>[CH3:4][CH:3]([C:1]1[O:18][CH2:17][CH2:16][N:2]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCC(C)C#N
Reactant: NCCO
Agent: CC(=O)[O-]
Agent: [Cd+2]
Solvent: CCCCO
Solvent: O
Product: CCCCCCCCCCC(C)C1=NCCO1

Procedure:
100 mmoles of 2-cyanododecane is treated with 120 mmoles of 2-aminoethanol in 50 ml of 1-butanol in presence of 2.5 mmoles of cadmium acetate dihydrate as outlined under Example 1 to give 2-(2-dodecyl)-2oxazoline.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].CC1(C)COC2=CC3OCC4(C=3C=C12)C1C(=CC=CC=1)NC4=O.Br[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]([F:57])([F:56])[F:55])=[CH:49][CH:48]=1.BrCC1OC(C(F)(F)F)=CC=1>>[F:55][C:54]([F:56])([F:57])[O:53][C:50]1[CH:51]=[CH:52][C:47]([CH2:46][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])=[CH:48][CH:49]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2ccc(OC(F)(F)F)cc2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.21, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 1-(bromomethyl)-4-(trifluoromethoxy)benzene to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (50%) as a white solid: mp 99-101° C.; MS (ES+) m/z 456.3 (M+1).
Reaction SMILES: [C:1]([O-:4])(O)=O.[Na+].BrC[C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16]>CS(C)=O.O>[I:14][C:11]1[CH:12]=[CH:13][C:8]([CH:1]=[O:4])=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: O=[N+]([O-])c1cc(I)ccc1CBr
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(I)cc1[N+](=O)[O-]
Temperature: 86 °C
Reaction time: 19 h
Yield: 60.9 %

Procedure:
NaHCO3 (3.32 g, 39.48 mmol) was added to a solution of 1-bromomethyl-4-iodo-2-nitrobenzene (2.25 g, 6.58 mmol) in anhydrous DMSO (150 mL). The mixture was stirred at 86° C. for 19 hours under a nitrogen atmosphere, then cooled down to room temperature, diluted with water (300 mL), and extracted with methylene chloride four times (250 mL). The combined organic phase was dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to yield 4-iodo-2-nitrobenzaldehyde (1.11 g, 61%). 1HNMR (400 MHz, CDCl3): δ 10.38 (d, 1 H, J=1.6 Hz, CHO), 8.45 (d, 1 H, J=1.5 Hz, Ph-H), 8.15 (dd, 1 H, J=1.5 and 8.0 Hz, Ph-H), 7.67 (d, 1 H, J=8.1 Hz, Ph-H); 13C NMR (100 MHz, CDCl3): δ 187.28 (CH), 143.18 (CH), 133.29 (CH), 130.67 (CH), 130.28 (C), 109.60 (C), 99.78 (C).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([CH3:25])([CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:2].[BH4-].[Na+].O>CO>[CH2:19]([O:18][C:16](=[O:17])[C:15]([CH3:21])([CH3:22])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([OH:23])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:25])([CH3:24])[C:4]([O:3][CH2:1][CH3:2])=[O:26])[CH3:20]
Reactant: CCOC(=O)C(C)(C)CCCCC(=O)CCCCC(C)(C)C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)C(C)(C)CCCCC(O)CCCCC(C)(C)C(=O)OCC
Reaction time: 2 h
Yield: 91.3 %

Procedure:
7-Oxo-2,2,12,12-tetramethyltridecanedioic acid diethyl ester (9.2 g, 25 mmol) was dissolved in methanol (200 mL) and the solution was cooled in an ice-water bath. Sodium borohydride (0.95 g, 25 mmol) was added. After 2 h, another portion of sodium borohydride (0.95 g, 25 mmol) was added and stirring was continued for 2 h. The reaction mixture was hydrolyzed with water (200 mL). The aqueous solution was extracted with dichloromethane (3×150 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give the product (8.5 g, 92%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.11 (q, 4H, J=7.0 Hz), 3.60-3.50 (m, 1H), 1.66-1.32 (m, 11H), 1.24 (pseudo-t, 12H, J=7.0 Hz), 1.15 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 178.0, 71.7, 60.1, 42.1, 40.6, 37.3, 26.0, 25.1, 24.9, 14.2. HRMS (LSIMS, nba): Calcd. for C21H41O3 (MH+): 373.2954. found: 373.2936. HPLC: 88.90% purity.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10](I)=[C:9]([C:12]2[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:15]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:14][C:13]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:8][N:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[CH:44]([C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1)=[O:45]>CN(C=O)C.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>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:49]2[CH:50]=[CH:51][C:46]([CH:44]=[O:45])=[CH:47][CH:48]=2)=[C:9]([C:12]2[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:15]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:14][C:13]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1noc(-c2cc(CC(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1I
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)c1noc(-c2cc(CC(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(2,4-Bis-benzyloxy-5-isobutyl-phenyl)-4-iodo-isoxazole-3-carboxylic acid ethylamide (1 eq) was dissolved in DMF and 1M Na2CO3 (aq) (3 eq) was added, followed by 4-formylphenylboronic acid (2 eq) and catalytic PdCl2(PPh3)2. Nitrogen was bubbled through the solution for ten minutes at ambient temperature, after which time, the temperature was elevated to 80° C. under a nitrogen atmosphere, for 2 hours. The reaction mixture was allowed to cool to room temperature and the reaction mixture was diluted with ethyl acetate. This solution was washed with brine, then dried over magnesium sulfate, filtered and concentrated in vacuo to give an oil which was purified by column chromatography, eluting with 10% EtOAc in hexane, to give 5-(2,4-bis-benzyloxy-5-isobutyl-phenyl)-4-(4-formyl-phenyl)-isoxazole-3-carboxylic acid ethylamide as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([O:20][CH3:21])=[C:4]([CH:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:15]([O:14][C:13]([NH:12][CH:10]([C:4]1[C:3]([O:20][CH3:21])=[C:2](/[CH:24]=[CH:23]/[C:22]([O:26][CH3:27])=[O:25])[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=1)[CH3:11])=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: C=CC(=O)OC
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1c(C)c(Cl)cc(C(C)NC(=O)OC(C)(C)C)c1OC
Temperature: 130 °C
Yield: 68.1 %

Procedure:
Into a sealed tube was placed a suspension of tert-butyl[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]carbamate [from Example 113, step 1, peak 2] (1.0 g, 2.6 mmol) in DMF (15 mL) that was degassed with nitrogen and treated with methyl acrylate (0.83 mL, 9.2 mmol), triphenylphosphine (97 mg, 0.37 mmol), and palladium acetate (59 mg, 0.26 mmol). Lastly, triethylamine (1.1 mL, 7.9 mmol) was added and the reaction mixture was heated at 130° C. for 16 hours. After cooling to room temperature, the mixture was filtered over Celite and the Celite was washed with EtOAc (100 mL). The EtOAc was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated to a crude foam. The crude material was dissolved in 2:1 hexane/dichloromethane and purified by flash column chromatography using EtOAc in hexanes (0%-30% over 30 min) to give the desired product (0.68 g, 68%) as a white foam. LCMS for C14H16ClO3 (M−NHBoc)+: m/z=267.1. Found: 266.9.
Reaction SMILES: [NH2:1][C@@H:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH:9]=[CH2:10])[CH2:7][S:8][C@H:3]12.C[Si](C)(C)NC(=O)C.[NH2:24][C:25]1[S:26][C:27]([Cl:39])=[C:28](/[C:30](=[N:34]/[O:35]C(=O)C)/[C:31](Cl)=[O:32])[N:29]=1.CO>ClCCl>[NH2:24][C:25]1[S:26][C:27]([Cl:39])=[C:28](/[C:30](=[N:34]/[OH:35])/[C:31]([NH:1][C@@H:2]2[C:14](=[O:15])[N:4]3[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH:9]=[CH2:10])[CH2:7][S:8][C@H:3]23)=[O:32])[N:29]=1
Reactant: CC(=O)O/N=C(\C(=O)Cl)c1nc(N)sc1Cl
Reactant: C=CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC(=O)N[Si](C)(C)C
Solvent: CO
Solvent: ClCCl
Product: C=CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\O)c3nc(N)sc3Cl)[C@H]2SC1
Reaction time: 1 h
Yield: 7.2 %

Procedure:
To a solution of 7β-amino-3-vinyl-3-cephem-4-carboxylic acid (1 g) and N-(trimethylsilyl)acetamide (5.8 g) in dichloromethane (10 ml) was added 2-(2-amino-5-chlorothiazol-4-yl)-2-(Z)-(acetoxyimino) acetyl chloride (1.69 g) under ice-cooling. After being stirred at the same temperature for 1 hour, to this mixture was added methanol (10 ml). After evaporating in vacuo to remove the dichloromethane, the residue was added conc. hydrochloric acid (1.95 ml) at room temperature. After being stirred at the same temperature for 4 hours, the mixture was poured into water (10 ml). The mixture was adjusted to pH 3.5 with 28% ammonium hydroxide in water, and the resulting precipitate was collected by filtration to afford 7β-[2-(2-amino-5-chlorothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (137 mg).
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)C.[F:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.C(I)C>C1COCC1>[CH2:2]([C:15]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[F:9])[CH3:3]
Reactant: CC(C)[N-]C(C)C
Reactant: Fc1cccnc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1ccncc1F
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
To a stirred solution of LDA (200 mmol) in dry THF (400 ml) (prepared by a similar method to that used in Example 1) at -70° C. and under a nitrogen atmosphere was added dropwise 3-fluoropyridine (20 g, 200 mmol). After 30 minutes at this temperature ethyl iodide (60 g, 370 mmol) was added dropwise to the reaction and the mixture was allowed to warm slowly to between -10° and -5° C. whereupon an exotherm occurred and the temperature rose to 15° to 20° C. The mixture was stirred for a further 30 minutes after which time the reaction was quenched by the addition of water (50 ml) and the organic phase separated. The aqueous phase was extracted with ether (3×50 ml) and the combined organic layers were dried over magnesium sulphate and concentrated under reduced pressure. The resulting liquid was distilled at atmospheric pressure to yield the title compound (13 g), b.p. 154°-158° C., which was characterised by 1H-NMR spectroscopy.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH3:17]>CN(C)C=O.CCOC(C)=O>[CH2:16]([N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)[CH3:17]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-nitro-1H-pyrazole (226 mg, 2.0 mmol) in N,N-dimethylformamide (3 mL) were added potassium carbonate (0.33 g, 2.4 mmol) and iodoethane (0.37 g, 2.4 mmol). The resulting mixture was stirred at rt overnight. TLC showed the reaction was complete. The mixture was diluted with EtOAc (40 mL), then washed with water (2×20 mL), brine (20 mL), and dried over anhydrous sodium sulfate. The crude material was purified by chromatography on silica gel, eluting with Hex:EtOAc=70:30 to give the title compound as a white solid. 1H NMR (CDCl3, 400 MHz): δ=1.55 (t, J=7.3 Hz, 3H), 4.22 (q, J=7.3 Hz, 2H), 8.07 (s, 1H), 8.14 (s, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][CH2:20][CH2:21][N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])[CH2:14]1.[CH3:33][C:34]([O:37][C:38]([NH:40][C@@H:41]([C:51](O)=[O:52])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=1[Cl:50])=[O:39])([CH3:36])[CH3:35]>C1C=NC2N(O)N=NC=2C=1.CN(C=O)C>[C:34]([O:37][C:38](=[O:39])[NH:40][CH:41]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=1[Cl:50])[C:51]([N:16]1[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:14][CH:15]1[CH2:19][CH2:20][CH2:21][N:22]1[C:30](=[O:31])[C:29]2=[CH:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]1=[O:32])=[O:52])([CH3:36])([CH3:33])[CH3:35]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1Cl)C(=O)O
Reactant: O=C1c2ccccc2C(=O)N1CCCC1CN(CCc2ccc3ccccc3c2)CCN1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1Cl)C(=O)N1CCN(CCc2ccc3ccccc3c2)CC1CCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6-6 (42 mg, 0.10 mmol) and BOC-D-2,4-dichlorophenylalanine (66 mg, 2 eq) in 0.4 mL of 0.5 M HOAt in DMF and 0.5 mL of anhydrous DMF was added diisopropylcarboimide (24 mg, 2 equivalents). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo and the crude was purified with column chromatography (eluted with hexanes, ethyl acetate 1:2). The purified product, {1-(2,4-Dichloro-benzyl)-2-[2-[3-phthalimido-propyl]-4-(2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (6-7) was obtained as white solid, 30 mg (40%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:14][CH2:13][CH2:12][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([CH3:2])[CH:4]=3)[NH:8][CH:7]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cc1
Reactant: Cc1ccc2[nH]cc(CCN)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2[nH]cc(CCNC(=O)c3ccc(Cc4cccc(F)c4)cc3)c2c1
Yield: 41.9 %

Procedure:
4-(3-Fluorobenzyl)-N-(2-(5-methyl-1H-indol-3-yl)ethyl)benzamide was prepared according to method A with 2-(5-methyl-1H-indol-3-yl)ethanamine hydrochloride (0.060 g; 0.284 mmol), 4-(3-fluorobenzyl)benzoic acid (0.079 g; 0.341 mmol), HATU (0.141 g; 0.370 mmol) and N,N-diisopropylethylamine 0.123 mL; 0.711 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) furnished 0.046 g (42%) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C([O-])(=O)C.[NH4+].N[C:16]1([O:25]O)[CH2:21][CH:20]([CH3:22])[CH2:19][C:18]([CH3:24])([CH3:23])[CH2:17]1>C(O)C>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:22][CH:20]1[CH2:19][C:18]([CH3:24])([CH3:23])[CH2:17][C:16](=[O:25])[CH2:21]1
Reactant: CC1CC(C)(C)CC(N)(OO)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)c1ccccc1
Solvent: CCO
Product: CC1CC(=O)CC(C)(C)C1
Reaction time: 8 h

Procedure:
To a stirred solution of acetophenone (24.3 g.) in ethanol (50 c.c.) containing ammonium acetate (1.6 g.) and kept at or below 0°C, was added 1-amino-3,3,5-trimethylcyclohexyl hydroperoxide (17.3 g.; pure). The solution was kept at 0°C overnight and then worked up as in the previous Examples to give unreacted acetophenone and dihydroisophorone, and a fraction (4.8 g.), b.p. 126° - 130°/0.5 mm. with a peroxide equivalent of 407, shown by mass spectroscopy to contain the peroxide ##SPC26##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].C([O-])(O)=O.[Na+].Cl[CH2:16][C:17](Cl)=[O:18]>CC(C)CC(=O)C.O>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][CH2:16][C:17](=[O:18])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(Br)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=C1COc2ccc(Br)cc2N1
Temperature: 80 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
To a solution of 2-amino-4-bromophenol (25 g, 133.0 mmol), NaHCO3 (22.4 g, 266.0 mmol) in 4-methylpentan-2-one (50 mL) and water (50 mL) at 0° C. was added 2-chloroacetyl chloride (10.0 mL, 200.0 mmol) dropwise. The reaction mixture was stirred at 80° C. for 24 h then cooled to ambient temperature and filtered. The filtrate was washed with water (3×10 mL) and dried over anhydrous Na2SO4. After filtration, the organic phase was evaporated to give 6-bromo-4H-benzo[1,4]oxazin-3-one as a white solid (27 g, 89%). 1H NMR (CDCl3, 400 MHz): δ 8.49 (brs, 1H), 7.08 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 6.93 (d, J=2.0 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 4.61 (s, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:31])=[C:3]([N:8]1[C@H:11](SC)[C@@H:10]([CH:14]([O:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[CH3:15])[C:9]1=[O:30])[C:4]([O:6][CH3:7])=[O:5].[Cl:32]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:32][CH:11]1[N:8]([C:3](=[C:2]([CH3:31])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])[C:9](=[O:30])[C@@H:10]1[CH:14]([O:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18])[CH3:15]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H](C(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@H]1SC
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H](C(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C1Cl
Temperature: 0 °C

Procedure:
To a solution of a mixture (1:3) of methyl 3-methyl-2-[(3S,4R)-4-methylthio-3-{(1RS)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-but-2-enoate (1.30 g) in dichloromethane (13 ml) was added a solution of chlorine (211 mg) in carbon tetrachloride (2.2 ml) at -78° C. The solution was allowed to warm to 0° C. during 45 minutes and concentrated. The residue was dissolved in ethyl acetate (30 ml) and washed with a chilled aqueous sodium bicarbonate (2.5 g), water, and brine. Drying over magnesium sulfate and evaporation left an oil (1.30 g), which showed two spots on silica gel thin layer chromatography (1:1 hexane/ethyl acetate). The residue was chromatographed on silica gel (40 g) eluting with 10-30% ethyl acetate in hexane to afford firstly a mixture (5:6:4) of methyl 2-[(3S)-4-chloro-3-{1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-3-methylbutenoate [a mixture (5:6:4) of (1S,4R) isomer, (1R, 4R) isomer and (1R, 4S) isomer] (550 mg).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[C:6]([N+:13]([O-:15])=[O:14])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])#[N:4].O1CCCC1>C(O)C>[OH:9][CH2:8][C:7]1[C:6]([N+:13]([O-:15])=[O:14])=[C:5]([CH:12]=[CH:11][CH:10]=1)[C:3]#[N:4]
Reactant: N#Cc1cccc(C=O)c1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1cccc(CO)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a solution of NaBH4 (0.2 g) in ethanol (10 ml) at ice bath temperature was added a solution of 3-cyano-2-nitrobenzaldehyde from Example 2c (0.93 g) in ethanol:tetrahydrofuran (15 ml:15 ml). After the addition was completed, the solution was warmed to ambient temperature and stirred for 30 minutes. The volatiles were removed under aspirator vacuum and the residue suspended in water. Dilute (1% aqueous) hydrochloric acid was added slowly until gas evolution had ceased. Ethyl acetate was then added followed by saturation of the aqueous layer with K2CO3. The layers were separated and the ethyl acetate layer was washed with brine, dried (Na2SO4) and concentrated to leave the title product (0.85 g, 90%) as a yellow solid; tlc, Rf =0.25, silica gel, ethyl acetate:hexane (1:1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[N:15]2[CH3:19])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1Cc2ccc(OCc3ccccc3)cc2N1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN1C(=O)Cc2ccc(OCc3ccccc3)cc21
Yield: 31 %

Procedure:
A mixture of 6-benzyloxy-1,3-dihydro-2H-indol-2-one (Example 9) (0.12 g; 0.5 mmol), K2CO3 (0.07 g; 0.5 mmol) and CH3I (0.031 ml) in acetone (5 ml) was refluxed under argon atmosphere for 6 hours. After evaporation to dryness, the residue was purified by flash chromatography eluting with petroleum ether/AcOEt 60/40 to give 6-benzyloxy-N-methyl-1,3-dihydro-2H-indol-2-one.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[O:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:31].[CH3:32][C:33]([CH3:35])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[O:24][CH:25]4[CH2:30][CH2:29][N:28]([CH:33]([CH3:35])[CH3:32])[CH2:27][CH2:26]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:31]
Reactant: CC(C)=O
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OC1CCNCC1)C3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OC1CCN(C(C)C)CC1)C3
Yield: 56 %

Procedure:
A mixture of Example 64 (110 mg; 0.25 mmol; 1 eq.), acetone (109 μL; 1.49 mmol; 6 eq.) and sodium triacetoxyborohydride (210 mg; 0.99 mmol; 4 eq.) in DCM (6 mL) was stirred at room temperature for 60 hours. The reaction mixture was diluted with DCM, washed with sat. aq. NaHCO3, dried over sodium sulfate and concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (68 mg, 56%) as a yellow powder. 1H NMR (CDCl3) δ 7.33 (td, J=8.2, 6.7 Hz, 1H), 6.80-6.63 (m, 2H), 5.05-4.91 (m, 2H), 4.67 (br s, 2H), 4.36 (br s, 1H), 2.91 (s, 2H), 2.86 (s, 1H), 2.78-0.52 (m, 6H), 2.46-2.24 (m, 2H), 2.06-1.88 (m, 2H), 1.88-1.70 (m, 2H), 0.94 (d, J=6.5 Hz, 6H). HPLC (max plot) 94.1%, Rt 3.02 min. UPLC/MS: (MS+) 486.5 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@H:16]1[C@@H:20]([CH2:21][CH3:22])[CH2:19][N:18]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:17]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:9]([NH:15][C@H:16]3[C@@H:20]([CH2:21][CH3:22])[CH2:19][N:18]([C:23]([O:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:24])[CH2:17]3)=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Reactant: NC(=O)c1cnn2cc(Br)nc2c1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.2 %

Procedure:
A solution of 2-bromo-8-chloroimidazo[1,2-b]pyridazine-7-carboxamide (0.940 g, 3.41 mmol), (3S,4S)-benzyl 3-amino-4-ethylpyrrolidine-1-carboxylate (1.017 g, 4.09 mmol) and Hunig's Base (1.788 ml, 10.24 mmol) in DMF (3.0 ml) in a reaction vial was stirred at 90° C. for 2 h. The reaction solution was added slowly to a stirred ice-water resulting in a light tan precipitate. The suspension was stirred for 30 min at 0° C. After filtration, (3S,4S)-benzyl 3-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-4-ethylpyrrolidine-1-carboxylate was collected as a light tan solid (1.716 g, 3.52 mmol, 100% yield). ESI-MS (analytical LCMS Method A): m/z 489.1, 487.1 ([M+H]+).