Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[N:19][OH:20])[C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:5]([F:18])[CH:4]=1.[Cl:21][C:22]1[C:23]([Cl:31])=[N:24][CH:25]=[C:26]([CH:30]=1)[C:27](O)=O>>[Cl:21][C:22]1[CH:30]=[C:26]([C:27]2[O:20][N:19]=[C:2]([C:3]3[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])=[C:5]([F:18])[CH:4]=3)[N:1]=2)[CH:25]=[N:24][C:23]=1[Cl:31]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)COc1ccc(C(N)=NO)cc1F
Product: CC(C)(C)OC(=O)COc1ccc(-c2noc(-c3cnc(Cl)c(Cl)c3)n2)cc1F

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 49 (995.01 mg; 3.50 mmol) and 5,6-dichloronicotinic acid (806.4 mg; 4.2 mmol). The reaction mixture was evaporated. The crude product was dissolved in EtOAc and washed with NH4Cl sat, NaHCO3 sat, brine and dried over MgSO4. After evaporation of the solvents, the resulting solid was suspended in MeCN and filtrated, affording the title compound as an off-white solid. LC/MS (Method B): 420.3 (M−H)−. HPLC (Method A) Rt 5.72 min (Purity: 99.4%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]1([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][C:15]=3[CH:24]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:1]([C:8]1[CH:9]=[CH:10][C:5]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][C:15]=3[CH:24]=2)=[CH:6][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1cc2cc(-c3ccccc3)ccc2o1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCOC(=O)c1cc2cc(-c3ccc(C(C)=O)cc3)ccc2o1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
12.2 g of acetyl chloride was added to a mixture of 10.3 g of 1B, and 120 ml of carbon disulfide, then 21.8 g of anhydrous aluminum chloride was added in portions to the stirred mixture. The mixture then was stirred at room temperature for 2.5 hours, the temperature rising to 32° C. The mixture was poured into 1 liter of ice water, the mixture was stirred for 30 minutes, and the solution was extracted with ether. The extract was dried (MgSO4) and concentrated. The residue was washed with ether and dried. It was dissolved in 100 ml of chloroform, the solution was treated with a decolorizing agent, and 100 ml of hexane was added. The resulting solution was concentrated to about 100 ml and cooled to give ethyl 5-(4-acetylphenyl)benzofuran-2-carboxylate (6A), mp: 105°-107° C.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][C:10]1[CH:25]=[C:13]2[C:14](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1.O>CS(C)=O>[CH3:9][C:10]1[CH:25]=[C:13]2[C:14]([C@@H:18]3[CH2:4][C@H:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1cccn2nc(C)cc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)[C@@H]1C[C@H]1c1cccn2nc(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
Under nitrogen atmosphere, to a suspension of sodium hydride (1.64 g, 41.0 mmol) in dimethyl sulfoxide (30 mi.') was added trimethylsulfoxonium iodide (9.01 g, 41.0 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl (2E)-3-(2-methylpyrazolo[1,5-a]pyridin-4-yl)acrylate (7.86 g, 34.1 mmol) in dimethyl sulfoxide (120 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (5.10 g, yield 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:16]=O)=[CH:4][CH:3]=1.[N:18]1([C:24]2[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH2:16][N:21]2[CH2:20][CH2:19][N:18]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=3)[CH2:23][CH2:22]2)=[CH:6][CH:7]=1
Reactant: CC1(C)CCC(c2ccc(Cl)cc2)=C(C=O)C1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCOC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(C)(C)C3)CC2)cc1

Procedure:
reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde, ethyl 4-piperazin-1-ylbenzoate and sodium triacetoxyborohydride at about 15° C. to about 30° C. and isolating or not isolating the ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate;
Reaction SMILES: Cl.[NH2:2][OH:3].O=[C:5]([C:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7]>CO>[OH:3][N:2]=[C:5]([C:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(=O)c1csc2ccccc12
Reactant: NO
Agent: Cl
Solvent: CO
Product: COC(=O)C(=NO)c1csc2ccccc12
Reaction time: 8 h
Yield: 73.7 %

Procedure:
Hydroxylarnine hydrochloride (503 mg) was added to a stirred solution of methyl 2-oxo-2-(3-benzothienyl)acetate (790 mg) in methanol (30 ml). When all the solid had dissolved the mixture was allowed to stand overnight. The solvent was evaporated and the residue partitioned between ethyl acetace and water. The organic phase was washed with water and brine, dried over magnesium sulphate and evaporated. The title oxime (622 mg) was isolated as a mixture of isomers by column chromatography of the residue (Kieselgel: 3:1 going to 1:1 hexane:ethyl acetate. νmax (CHCl3)/cm-1 3568, 3296, 1737. δH (250 MHz, CDCl3), 3.90 and 4.00 (3H, two s's), 7.37-7.59 (2H, m), 7.61 and 7.77 (1H, two s's), 8.30 and 9.15 (1H, two broad s's), 8.43-8.47 (1H, m); m/z (EI) 235 (M+).
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=[CH:15][N:14]=1)=[S:11])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CCO>O>[CH2:20]([O:19][C:18]1[C:13]([NH:12][C:10]([NH2:9])=[S:11])=[N:14][CH:15]=[CH:16][CH:17]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(NC(=S)Nc1ncccc1OCc1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NC(=S)Nc1ncccc1OCc1ccccc1
Yield: 109.4 %

Procedure:
A 1 L round-bottomed flask was charged with 1-benzoyl-3-(3-(benzyloxy)pyridin-2-yl)thiourea (44.4 g, 122 mmol), potassium carbonate (20.3 g, 147 mmol), and EtOH (400 mL). The reaction mixture was heated to reflux overnight, then cooled, poured into water (900 mL) and filtered to afford 1-(3-(benzyloxy)pyridin-2-yl)thiourea (34.6 g) as a yellow solid. 1H NMR (CDCl3) δ 11.01 (s, 1H), 8.69 (s, 1H), 7.78 (d, 1H), 7.44-7.34 (m, 5H), 7.16 (d, 1H), 7.09 (bs, 1H), 6.91 (dd, 1H), 5.16 (s, 2H). LCMS (25 to 95) Rt=2.06 min (apci) m/z=260 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>C1COCC1.C(OCC)C>[C:11]([Si:8]([CH3:10])([CH3:9])[O:5][CH2:4][CH2:3][CH2:2][NH2:1])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCN
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A solution of 7.4 g (98 mmol) 3-aminopropanol in 10 ml THF was added at room temperature to a suspension of 4.12 sodium hydride (60%; 103.2 mmol) in 140 ml THF. The mixture was stirred for 1 hour and then 16.28 g (108 mmol) tert-butyl-dimethylsilylchloride was added and vigorous stirring was continued for 1 hour. The mixture was diluted with 300 ml diethylether and washed successively with 100 ml of aqueous K2CO3 (10%), 100 ml of water and 100 ml of brine, dried over MgSO4 and evaporated to give 17 g of light yellow crude product. This product was dissolved in ethyl acetate/hexane 1/10 and filtered through a pad of silica gel. The filtrate was concentrated in vacuo to give 13 g (70%) of the desired product as a colorless oil.
Reaction SMILES: [Cl:1][C:2]([CH2:4]Cl)=[CH2:3].[CH2:6]([OH:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1(C)C=CC=CC=1>[Zn].O>[Cl:1][C:2](=[CH2:3])[CH2:4][CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[OH:13]
Reactant: CCCCCCCO
Reactant: C=C(Cl)CCl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(Cl)CC(O)CCCCCC
Yield: 94.1 %

Procedure:
58.30 Grams of 2,3-dichloro-1-propene were added dropwise to a mixture of 30.00 g of heptanol, 90 g of toluene, 120 g of water and 34.35 g of zinc powder at 45° C., and then, the resultant mixture was allowed to react at the same temperature for 10 hours. After the reaction finished, zinc-derived insolubles were filtered off, and the resultant filtrate was subjected to separation. The organic phase was washed with a 7% sodium carbonate aqueous solution and then dried over sodium sulfate. The desiccant was filtered off, and then the toluene was distilled off under reduced pressure to give 47.14 g of 2-chloroallyl-n-hexyl-carbinol. The results were as follows.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH:11]=1)[CH:9]=O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34](Br)(Br)([Br:36])[Br:35].CCCCCC>ClCCl>[Br:35][C:34]([Br:36])=[CH:9][C:8]1[CH:11]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: CCOc1ccc([N+](=O)[O-])c(C=O)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOc1ccc([N+](=O)[O-])c(C=C(Br)Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a solution of 5-ethoxy-2-nitrobenzaldehyde (519 mg) and triphenylphosphine (2.09 g) in dichloromethane (13 mL) was added a solution of carbon tetrabromide (1.32 g) in dichloromethane in three minutes under cooling with ice, and the mixture was stirred overnight at room temperature. Hexane (20 mL) was added to the reaction mixture, and this resulting mixture was stirred for 10 minutes and then filtered through silica gel. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (712 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([O:24][C@H:25]2[C@H:29]([OH:30])[CH2:28][O:27][CH2:26]2)=[C:4]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[CH2:5][N:6]([CH3:17])[C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N+:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1)([O-:33])=[O:32].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:31]([C:34]1[CH:35]=[CH:36][C:37]([C:38]([O:30][C@@H:29]2[C@H:25]([O:24][C:3]3[C:2]([F:1])=[CH:20][C:19]([N+:21]([O-:23])=[O:22])=[CH:18][C:4]=3[CH2:5][N:6]([C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:16])[CH3:17])[CH2:26][O:27][CH2:28]2)=[O:39])=[CH:41][CH:42]=1)([O-:33])=[O:32]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CN(Cc1cc([N+](=O)[O-])cc(F)c1O[C@@H]1COC[C@H]1O)C(=O)OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(Cc1cc([N+](=O)[O-])cc(F)c1O[C@@H]1COC[C@@H]1OC(=O)c1ccc([N+](=O)[O-])cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.2 %

Procedure:
Intermediate 27C (250 mg, 0.595 mmol) was mixed with 4-nitrobenzoic acid (447 mg, 2.68 mmol), PPh3 (741 mg, 2.82 mmol) in THF (1.5 mL) and stirred at rt for 10 min. The reaction was cooled to 0° C., then DIAD (0.589 mL, 2.97 mmol) was added. After stirring at rt for 16 h, the reaction was quenched with H2O and extracted with EtOAc (2×). The organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography to give 27D (268 mg, 0.471 mmol, 79% yield) as a white foam. The relative stereochemistry of hydroxyether is cis however absolute stereochemistry is undetermined MS (ESI) m/z: 570.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:33][CH2:34][CH3:35])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=3)[C:19](=O)[C:18]3[C:17]([C:28]([O:30]CC)=O)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:2].O.[NH2:37][NH2:38]>CO>[CH2:34]([O:33][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:37][NH:38][C:28](=[O:30])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[CH:9][CH:10]=1)[CH3:35]
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccc(C(OCC)OCC)cc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: CCOC(OCC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2nccn2C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A mixture of ethyl 2-(4-(diethoxymethyl)phenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (490 mg, 1.03 mmol), methanol (20 mL) and hydrazine monohydrate (2 mL) was stirred under 25° C. for 3 hr. The resulting mixture was evaporated under reduced pressure to 10 ml and then filtered, 250 mg of 8-(4-(diethoxymethyl)phenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one as a solid was obtained, yield 55%. LC-MS (ESI) m/z: 446 (M+1)+.
Reaction SMILES: Cl[CH:2]([C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[CH3:17])[C:3]([O:5][CH2:6][CH3:7])=[O:4]>CC(O)=O.CCOC(C)=O.[Fe]>[Cl:14][C:12]1[C:11]([O:15][CH3:16])=[CH:10][C:9]([CH3:17])=[C:8]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:13]=1
Reactant: CCOC(=O)C(Cl)c1cc(Cl)c(OC)cc1C
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc(Cl)c(OC)cc1C
Temperature: 60 °C
Reaction time: 17 h
Yield: 45.3 %

Procedure:
Iron powder (193 mg, 3.46 mmol) was added to a stirred solution of ethyl 2-chloro-2-(5-chloro-4-methoxy-2-methylphenyl)acetate (Intermediate 3-5; 480 mg, 1.73 mmol) in AcOH (2 mL) under nitrogen, and the resulting mixture was stirred at 60° C. for 17 hours. The reaction mixture was allowed to cool to ambient temperature, diluted with EtOAc (50 mL), filtered through celite and washed with saturated brine (3×25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford ethyl 2-(5-chloro-4-methoxy-2-methylphenyl)acetate (190 mg, 45.2%) as a colourless gum.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:17][C:18]([OH:20])=[O:19])[CH2:16][CH2:15][O:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=1)=[O:31]>CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:17][C:18]([O:20][CH2:29][C:30](=[O:31])[C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]([F:40])([F:41])[F:42])=[CH:34][CH:33]=2)=[O:19])[CH2:16][CH2:15][O:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC1(NC(=O)OCc2ccccc2)CCOC1
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(CC1(NC(=O)OCc2ccccc2)CCOC1)OCC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 50 °C
Yield: 118 %

Procedure:
(3-{[(Benzyloxy)carbonyl]amino}tetrahydrofuran-3-yl)acetic acid (Preparation 24, 0.311 g, 1.11 mmol) and triethylamine (0.233 mL, 1.67 mmol) were stirred in acetone (4 mL). A solution of 2-bromo-1-[4-(trifluoromethoxy)phenyl]ethanone (0.315 g, 1.11 mmol) in acetone (4 mL) was added and the reaction heated to 50° C. for 1 hour. Rapid formation of a white precipitate was observed. The reaction was partitioned between dichloromethane and water. The organic layer was separated by phase separation cartridge and concentrated in vacuo to afford the title compound as an oil which was used without purification in the next step (0.634 g, 118% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(N(CC)CC)C.C1(C)C(S([N:39]=[N+:40]=[N-])(=O)=O)=CC=CC=1>CC#N>[N+:39](=[C:16]([C:15]([C:3]1[CH:4]=[C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][C:2]=1[F:1])=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N-:40]
Reactant: CCOC(=O)CC(=O)c1cc(CN2CCOCC2)ccc1F
Reactant: Cc1ccccc1S(=O)(=O)N=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C(=[N+]=[N-])C(=O)c1cc(CN2CCOCC2)ccc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.3 %

Procedure:
To a solution of ethyl 3-(2-fluoro-5-(4-morpholinylmethyl)phenyl)-3-oxopropanoate (Preparation 9, 5.00 g) and triethylamine (2.48 mL) in 50 mL CH3CN cooled to 0° C. is added toluenesulfonyl azide (3.51 g, prepared according to Org. Prep. Proc. Intl., 1981, 13, 112) in 10 mL CH3CN. The reaction is stirred at 0° C. for 15 min then at room temperature for 2 h. The reaction is concentrated (below 50° C.). 2N NaOH (25 mL) is added. The aqueous layer is extracted with CHCl3 (3×). The combined organic layers are washed, dried and concentrated to yield 4.68 g (86%) of the desired product as a yellow oil. Physical characteristics are as follows: 1H NMR (CDCl3) δ7.52, 7.44, 7.06, 4.24, 3.75, 3.55, 2.50, 1.24; MS (ESI+) for C16H18FN3O4 m/z 336.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:35]=[CH:34][C:13]([O:14][CH2:15][CH2:16][O:17][C:18](=[O:33])[CH2:19][CH2:20][C@H:21]([NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:22]([OH:24])=[O:23])=[CH:12][CH:11]=2)[C:5]([C:36]#[N:37])=[C:4]([S:38][CH2:39][C:40]2[N:41]=[C:42]([C:45]3[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=3)[S:43][CH:44]=2)[N:3]=1.[OH-].[Na+:53]>C(#N)C.O>[Na+:53].[Na+:53].[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][O:17][C:18](=[O:33])[CH2:19][CH2:20][C@H:21]([NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:22]([O-:24])=[O:23])=[CH:34][CH:35]=2)[C:5]([C:36]#[N:37])=[C:4]([S:38][CH2:39][C:40]2[N:41]=[C:42]([C:45]3[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=3)[S:43][CH:44]=2)[N:3]=1.[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][O:17][C:18](=[O:33])[CH2:19][CH2:20][C@H:21]([NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:22]([O-:24])=[O:23])=[CH:34][CH:35]=2)[C:5]([C:36]#[N:37])=[C:4]([S:38][CH2:39][C:40]2[N:41]=[C:42]([C:45]3[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=3)[S:43][CH:44]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCOC(=O)CC[C@H](NC(=O)CCC(=O)O)C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCOC(=O)CC[C@H](NC(=O)CCC(=O)O)C(=O)[O-])cc1

Procedure:
0.5 g (0.667 mmol) of the compound from example 9 is dissolved in 12.5 ml of acetonitrile and 62.5 ml of water, and 13 ml of 0.1 N sodium hydroxide solution are added. After brief stirring, the mixture is lyophilized. After drying under high vacuum, 0.53 g (quant.) of the title compound remain.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C@@:6]12[CH2:13][CH2:12][C@@H:11]1[CH2:10][CH2:9][C:8](Br)([Br:14])[C:7]2=[O:16])[CH3:2].C(=O)([O-])[O-].[Li+].[Li+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C@@:6]12[CH2:13][CH2:12][C@@H:11]1[CH2:10][CH:9]=[C:8]([Br:14])[C:7]2=[O:16])[CH3:2]
Reactant: CCOC(=O)C[C@@]12CC[C@@H]1CCC(Br)(Br)C2=O
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@@]12CC[C@@H]1CC=C(Br)C2=O
Temperature: 100 °C
Yield: 54.9 %

Procedure:
cis-3,3-Dibromo-2-oxobicyclo[4.2.0]octane-1-acetic acid ethyl ester (14.16 g) lithium bromide (4.88 g, 56.21 mmol), and lithium carbonate (2.98 g, 14.4 mmol) were dissolved in 47.3 mL of DMF under nitrogen and heated to 100° C. for 5 minutes. The reaction mixture was then poured into 500 mL of water and extracted with 4×100 mL of toluene. The organic phase was washed with 4×100 mL of water, dried over MgSO4, and concentrated in vacuo affording 8.86 g (80%) of product.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[N:54]([C:57]1[CH:64]=[CH:63][C:60]([C:61]#[N:62])=[CH:59][CH:58]=1)=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:55]([NH:54][C:57]2[CH:64]=[CH:63][C:60]([C:61]#[N:62])=[CH:59][CH:58]=2)=[O:56])[CH2:48]1
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(NC(=O)N2CC[C@@H](CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)C2)cc1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 4-isocyanatobenzonitrile as the starting materials in 60% yield. LCMS for C31H29ClN9O2 (M+H)+: m/z=594.0.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([OH:17])=[CH:12][C:11]=1[Cl:18])(=[O:3])[CH3:2].[Cl:19][C:20](Cl)([Cl:24])[CH2:21][CH2:22]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([Cl:18])=[CH:12][C:13]([O:17][CH2:22][CH:21]=[C:20]([Cl:24])[Cl:19])=[CH:14][C:15]=1[Cl:16])(=[O:3])[CH3:2]
Reactant: ClCCC(Cl)(Cl)Cl
Reactant: CC(=O)OCCCCOc1c(Cl)cc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 80 °C
Yield: 78.4 %

Procedure:
This compound was prepared in a manner analogous to that set forth in Step E of Example 1, using 25.3 grams (0.086 mole) of 4-(2,6-dichloro-4-hydroxyphenoxy)butyl acetate, 19.5 grams (0.1 mole) of 1,1,1,3-tetrachloropropane, and 18 grams (0.13 mole) of potassium carbonate in 250 mL of DMF was heated at 80° C. during a 16 hour period. The crude reaction product was purified with column chromatography on silica gel using 1:1 methylene chloride:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 27.1 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][O:12][N:13]=[C:14]([C:22](=[O:24])[CH3:23])[C:15]([O:17]C(C)(C)C)=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:25]Br>C(O)(=O)C>[CH2:1]([O:8][C:9]([CH2:11][O:12][N:13]=[C:14]([C:22](=[O:24])[CH2:23][Br:25])[C:15]([OH:17])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: CC(=O)C(=NOCC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: CC(=O)O
Product: O=C(CON=C(C(=O)O)C(=O)CBr)OCc1ccccc1
Reaction time: 0.5 h
Yield: 101.5 %

Procedure:
To a solution of tert-butyl 2-benzyloxycarbonylmethoxyimino-3-oxobutyrate (32.3 g) in acetic acid (32 ml) was slowly added bromine (16 g) at 45° to 48° C. with stirring, and the stirring was continued at the same temperature for 30 minutes. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, followed by washing six times with a saturated aqueous sodium chloride. The solution was evaporated under reduced pressure to give 2-benzyloxycarbonylmethoxyimino-4-bromo-3-oxobutyric acid (35 g).