Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:33])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:68][C:69]([CH3:71])=[O:70])[C:5]([C@@:7]1([CH3:67])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[O:57][C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O)=[O:6].C1(NN)C=CC=CC=1>C(#N)C.O>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([O:68][C:69]([CH3:71])=[O:70])[C:5]([C@@:7]1([CH3:67])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6]
Reactant: CC(=O)O[C@H]1C(=O)[C@]2(C)[C@@H](O[C@@H]3OC[C@@H](O)[C@H](O)[C@H]3O)C[C@H]3OC[C@@]3(OC(C)=O)[C@H]2[C@H](OC(=O)c2ccccc2)[C@]2(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c3ccccc3)c3ccccc3)C(C)=C1C2(C)C
Solvent: CC#N
Solvent: O
Solvent: NNc1ccccc1
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O

Procedure:
In the manner of the procedure of EXAMPLE 1, 0.5 g of taxol-7-xyloside was oxidatively cleaved. The product, after treatment with phenylhydrazine, was taken up in 25% acetonitrile in water and applied to a column of 10 g of C-18 reverse phase silica. The column was eluted with a gradient of acetonitrile in water (30, 35, 40, 45 and 50%).
Reaction SMILES: [Br-].[CH:2]([C:5]1[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[CH:28]=[C:27]([CH:34]([CH3:36])[CH3:35])[C:6]=1[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].[CH2:37]([O:41][C:42](=[O:53])[CH:43]=[C:44]([CH3:52])[CH:45]=[CH:46][CH:47]=[C:48]([CH:50]=O)[CH3:49])[CH2:38][CH2:39][CH3:40]>>[CH2:37]([O:41][C:42](=[O:53])[CH:43]=[C:44]([CH3:52])[CH:45]=[CH:46][CH:47]=[C:48]([CH3:49])[CH:50]=[CH:7][C:6]1[C:5]([CH:2]([CH3:4])[CH3:3])=[CH:30][C:29]([CH:31]([CH3:33])[CH3:32])=[CH:28][C:27]=1[CH:34]([CH3:36])[CH3:35])[CH2:38][CH2:39][CH3:40]
Reactant: CCCCOC(=O)C=C(C)C=CC=C(C)C=O
Reactant: CC(C)c1cc(C(C)C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C(C)C)c1
Agent: [Br-]
Product: CCCCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C(C)C)cc(C(C)C)cc1C(C)C

Procedure:
By the procedure of Example 6: 2,4,6-triisopropyl-benzyl-triphenylphosphonium bromide is condensed with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid butyl ester to form 9-(2,4,6-triisopropyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid butyl ester (oil); which is hydrolyzed by the procedure of Example 7 to form: 9-(2,4,6-triisopropyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid m.p.: 221° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:8]=1[N:21]([CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)[CH3:22])[CH3:2].C(O)C.[BH4-].[Na+]>O1CCCC1.O.O.O.O.O.O.[Ni](Cl)Cl>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][C:8]=1[N:21]([CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)[CH3:22])[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(COc2ccccc2)cc1N(C)CCc1ccc2ccccc2c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCc1ccc(COc2ccccc2)cc1N(C)CCc1ccc2ccccc2c1
Reaction time: 0.25 h

Procedure:
To a solution of the compound prepared in Example 23 (135 mg) in tetrahydrofuran (1.2 ml)-ethanol (0.3 ml) were added portionwise nickel chloride hexahydrate (70 mg) and sodium borohydride (45 mg) at 0° C. The mixture was stirred for 15 minutes. The reaction mixture was extracted with diethyl ether. The organic layer was filtered. The filtrate was extracted with diethyl ether. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the title compound having the following physical data.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([CH2:10][C:11]([OH:13])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[P:14]([OH:17])([OH:16])[OH:15].P(Cl)(Cl)Cl>O1CCOCC1>[CH:7]1[CH:8]=[CH:9][N:4]2[C:3]([CH2:10][C:11]([P:14]([OH:17])([OH:16])=[O:15])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])=[CH:2][N:1]=[C:5]2[CH:6]=1
Reactant: OP(O)O
Reactant: O=C(O)Cc1cnc2ccccn12
Solvent: C1COCCO1
Solvent: ClP(Cl)Cl
Product: O=P(O)(O)C(O)(Cc1cnc2ccccn12)P(=O)(O)O
Temperature: 92.5 °C
Yield: 52.3 %

Procedure:
Imidazo[1,2-a]pyridin-3-yl acetic acid (46 gm), phosphorous acid (75 gm) and 1,4-Dioxane (900 mL) was taken in a four necked round bottom flask fitted with an addition funnel, mechanical stirrer, condenser and thermometer pocket and allowed to stir at 90-95° C. Phosphorus trichloride (130 gm) was then added to reaction mixture and allowed to heat at 90-95° C. The reaction mixture was cooled and distilled water (450 mL) was added to it. The reaction mixture was further heated to 90-95° C. It was then cooled and acetone (1400 mL) was added to it. The solution was further cooled to 0-5° C. and stirred for 4-5 hrs. The precipitated solid was filtered and dried under vacuum to give 44 gm of product.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:15]=[C:14]([S:16][CH3:17])[CH:13]=[C:12]([F:18])[CH:11]=1.IC.[Cl-].[Na+]>C1COCC1.C(C1C=CC=CC=1)C>[Br:9][C:10]1[CH:15]=[C:14]([S:16][CH3:17])[CH:13]=[C:12]([F:18])[C:11]=1[CH3:1]
Reactant: CC(C)[N-]C(C)C
Reactant: CSc1cc(F)cc(Br)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CI
Product: CSc1cc(F)c(C)c(Br)c1
Temperature: -73 °C
Reaction time: 1.5 h

Procedure:
7.5 ml of a 2 M solution of lithium diisopropylamide in THF/HEP/ethylbenzene (Aldrich) were dissolved in 30 ml of anhydrous THF and cooled to −73° C. A solution of 3.0 g of 1-bromo-3-fluoro-5-methylsulfanylbenzene in 10 ml of anhydrous THF added at a temperature between −73° C. and −67° C. Stirring was continued for 90 min at −75° C., then 1.0 ml of iodomethane was added at this temperature. The mixture was then warmed up to room temperature, 100 ml of a saturated aqueous solution of sodium chloride were added and the mixture was extracted twice with 100 ml each of EA. The extracts were dried and concentrated in vacuo to yield 2.0 g of the title compound as a slight yellow oil that was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(O[C:17](=O)[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25](=[O:30])N(OC)C)[CH2:21][CH2:20]1)(C)(C)C.[O:32]=[C:33]1[NH:38][C:37]2[CH:39]=[C:40](C=O)[CH:41]=[CH:42][C:36]=2[O:35][CH2:34]1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:25]([C@H:22]3[CH2:21][CH2:20][C@H:19]([NH:18][CH2:17][C:40]4[CH:41]=[CH:42][C:36]5[O:35][CH2:34][C:33](=[O:32])[NH:38][C:37]=5[CH:39]=4)[CH2:24][CH2:23]3)=[O:30])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Reactant: COc1cccc2scnc12
Product: COc1cccc2sc(C(=O)[C@H]3CC[C@H](NCc4ccc5c(c4)NC(=O)CO5)CC3)nc12

Procedure:
The title compound was prepared according to the same protocol as that described for example 1, steps 1.a to 1.c, using 4-methoxy-benzothiazole (5 mmol), [trans-4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (2.5 mmol) and 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde (0.3 mmol). An orange solid (74 mg) was obtained.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([CH3:7])=[C:3]1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)C(C)C)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(OCC)(=O)C.O>[CH3:7][C:4]1[CH:5]=[CH:6][N:2]([NH:1][C:26](=[O:27])[C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:29])[C:3]=1[C:8](=[O:9])[NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccn(N)c1C(=O)Nc1ccccc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.2 %

Procedure:
1-Amino-3-methyl-N-phenyl-1H-pyrrole-2-carboxamide (5.30 g, 24.62 mmol) was dissolved in 35 mL ethyl acetate and (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (6.50 g, 34.35 mmol) was added. The mixture was cooled in an ice bath and N,N-diisopropylethylamine (19.8 mL, 113.68 mmol) was added dropwise. After 15 min stirring, maintaining the reaction temperature at 0° C., T3P® (50% in ethyl acetate, 14.3 mL, 48.04 mmol) was added dropwise and the reaction was stirred at room temperature for 3 h. Further (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (3.25 g, 17.17 mmol) was added and the mixture was stirred at room temperature overnight. Further N,N-diisopropylethylamine (20 mL, 114 mmol) and T3P® (50% in ethyl acetate, 14.3 mL, 48.04 mmol) were added dropwise at 0° C. and the reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified using Isolera® Purification System (0% to 60% hexane-ethyl acetate) to obtain 7.15 g (75% yield) of the desired product as a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.Cl[CH2:11][C:12]1[C:13]([O:18][CH3:19])=[N:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:19][O:18][C:13]1[C:12]([CH2:11][N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: OCCC1CCNCC1
Reactant: COc1ncccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncccc1CN1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
8.2 g of 4-piperidineethanol, 10.0 g of 3-(chloromethyl)-2-methoxypyridine and 17.5 g of potassium carbonate were suspended in 65 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound as a yellow oil (quantitatively).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.N1C=CC=[CH:13][CH:12]=1.C(B1OB(C=C)OB(C=C)O1)=C.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC.O>[CH3:10][O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([CH:12]=[CH2:13])[N:3]=1
Reactant: COc1nc(Br)cnc1N
Reactant: c1ccncc1
Agent: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C=Cc1cnc(N)c(OC)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-bromo-3-methoxypyrazin-2-amine (800 mg, 3.92 mmol, 1 eq.; Jiang, B. et al. Bioorg. Med. Chem. (2001), 9, 1149-1154.), trivinylboroxine pyridine-complex (944 mg, 3.92 mmol, 1.0 eq), tetrakis(triphenylphosphin)palladium(0) (45 mg, 0.04 mmol, 0.01 eq) and potassium carbonate (542 mg, 3.92 mmol, 1.0 eq) in 40 mL dimethoxyethane/water (3/1) was stirred at room temperature for 10 min and then heated to reflux temperature for 3 hours. The reaction mixture was hydrolysed with 100 mL of water and extracted with ethyl acetate. The resulting organic phase was washed with brine, dried with sodium sulphate and concentrated in vacuo. The crude mixture was purified via MPLC (column: Snap cartridge, eluent: hexane→hexane/ethyl acetate 1/1) to deliver 495 mg (78%) of the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C.[CH:29]([NH:31][NH:32][C:33]([C:35]1([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50][N:51]3[CH2:55][CH2:54][CH2:53][CH2:52]3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)=[O:34])=O>ClCCl>[N:51]1([CH2:50][CH2:49][CH2:48][O:47][C:44]2[CH:43]=[CH:42][C:41]([C:35]3([C:33]4[O:34][CH:29]=[N:31][N:32]=4)[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:46][CH:45]=2)[CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: O=CNNC(=O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1nnc(C2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.1 %

Procedure:
Triphenylphosphine (0.203 g, 0.78 mmol), iodine (0.198 g, 0.78 mmol) and triethylamine (0.217 mL, 1.56 mmol) were dissolved in dichloromethane (5 mL). The mixture was stirred at room temperature for 10 minutes. N′-formyl-4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbohydrazide (0.145 g, 0.39 mmol) in dichloromethane (5 mL) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (25 mL). The organic was dried over sodium sulphate, filtered and concentrated in vacuo to provide a yellow oil. This was purified using preparative HPLC on Fraction-Lynx® eluting with water:acetonitrile:trifluoroacetic acid (95:5:0.1) to provide the title compound (0.028 g, 20%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ1.78-1.85 (m, 4H), 2.05 (m, 2H), 2.30 (m, 2H), 2.56-2.60 (m, 4H), 2.60-2.70 (m, 4H), 3.59 (m, 2H), 3.90-4.05 (m, 4H), 6.90 (d, 2H), 7.20 (d, 2H), 8.30 (s, 1H). HRMS ESI+ m/z 358.2117 [MH]+.
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[N:1]1([C:10]2[N:18]=[C:17]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Reactant: Nc1ccccc1
Solvent: ClCCl
Product: c1ccc(Nc2nc(-n3cnc4ccccc43)c3nc[nH]c3n2)cc1
Temperature: 140 °C
Reaction time: 48 h

Procedure:
300 mg of product obtained in stage 1 above are mixed with 0.52 ml of aniline and the mixture is then heated at 140° C. for approximately 72 hours. The mixture is allowed to return to ambient temperature for 48 hours. A paste is formed in methylene chloride and partial drying is carried out. 48 mg of expected product are obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH2:11][CH3:12])[C:9]#[N:10].CO>CCOCC.C(Cl)Cl>[C:13]1([C:8]([NH2:7])([CH2:11][CH3:12])[CH2:9][NH2:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC(N)(C#N)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: CCC(N)(CN)c1ccccc1
Yield: 81 %

Procedure:
To a stirred suspension of lithium aluminum hydride (LAH, 7.0 g) in 250 mL of ether is added dropwise a solution of the compound of step 1(10.0 g) in 10 mL of ether at −70° C. The reaction mixture is stirred at −60° C. to −70° C. until TLC (10% MeOH in CH2Cl2) shows the disappearance of the starting material. The excess LAH is destroyed by cautious addition of a saturated aqueous Na2SO4 solution. The resulting mixture is filtered and solid is washed with EtOAc. The filtrate is dried over Na2SO4 and concentrated under vacuum to give 8.3 g of the title compound as clear oil.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17](=O)[CH2:18][CH:19]1[CH2:21][CH2:20]1)(=O)OC.O.[NH2:24][NH2:25]>>[CH:19]1([CH2:18][C:17]2[N:24]=[N:25][C:2]3[CH:1]4[CH2:7][CH:4]([C:3]=3[CH:16]=2)[CH2:5][CH2:6]4)[CH2:21][CH2:20]1
Reactant: COP(=O)(CC(=O)CC1CC1)OC
Reactant: O=C1C(=O)C2CCC1C2
Reactant: NN
Solvent: O
Product: c1c(CC2CC2)nnc2c1C1CCC2C1

Procedure:
light brow oil. MS (ESI): 201.1 (MH+). Prepared from bicyclo[2.2.1]heptane-2,3-dione, (3-cyclopropyl-2-oxo-propyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2].Br[C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[C:24]([F:31])[C:23]=1[CH3:32]>>[F:31][C:24]1[C:23]([CH3:32])=[C:22]([NH:11][C:10]2[N:6]([CH2:5][CH:4]([O:18][CH2:19][CH3:20])[O:3][CH2:1][CH3:2])[N:7]=[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:9]=2)[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=1
Reactant: CCOC(Cn1nc(-c2cccnc2)cc1N)OCC
Reactant: Cc1c(F)cc([N+](=O)[O-])cc1Br
Product: CCOC(Cn1nc(-c2cccnc2)cc1Nc1cc([N+](=O)[O-])cc(F)c1C)OCC

Procedure:
Analogously to Example 13A/Step 1, 1.5 g (5.43 mmol) of the compound of Example 4A and 1.4 g (5.97 mmol) of 1-bromo-3-fluoro-2-methyl-5-nitrobenzene gave 1.19 g (50% of theory) of the title compound.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:28][CH:27]2[N:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:24]([CH2:25][CH2:26]2)[CH2:23]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:28][CH:27]2[N:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:24]([CH2:25][CH2:26]2)[CH2:23]1)=[O:19]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(ONC(=O)[C@@H]1CC[C@@H]3CN1C(=O)N3OCc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C2CCC1CC(ONC(=O)[C@@H]1CC[C@@H]3CN1C(=O)N3O)C2
Yield: 65668736 %

Procedure:
To a solution of tert-butyl 3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]-8-azabicyclo[3.2.1]octane-8-carboxylate 46 (0.26 μg, 0.52 mml) in methanol (20 mL) was added 5% Pd/C (0.3 g). The mixture was hydrogenated under 35 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl 3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]-8-azabicyclo[3.2.1]octane-8-carboxylate 47 (0.14 g, 66%) as a white solid.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].C(O)(=O)[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:13].C[O:23][C:24](C(F)(F)F)(C(O)=O)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>>[CH:28]1[CH:27]=[CH:26][C:25]([C:24]([O:3][C@H:2]([C:1]([OH:10])=[O:9])[C@H:4]([O:5][C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:13])[C:6]([OH:8])=[O:7])=[O:23])=[CH:30][CH:29]=1
Reactant: COC(C(=O)O)(c1ccccc1)C(F)(F)F
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: O=C(O)C(O)c1ccccc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Product: O=C(O[C@H](C(=O)O)[C@H](OC(=O)c1ccccc1)C(=O)O)c1ccccc1

Procedure:
producing a chiral salt of III′ by treating the compound of formula (III′) with a chiral resolving agent (e.g., tartaric acid, mandelic acid, Mosher's acid, camphor sulphonic acid, etc., or, preferably, (+)-2,3-dibenzoyl-D-tartaric acid to yield a chiral salt (e.g., (3S,4R)-enantiomer (+)-2,3-dibenzoyl-D-tartrate salt when (+)-2,3-dibenzoyl-D-tartaric acid is the chiral resolving agent)) and isolating the cis isomer of III′ thereby produced;
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br-].[F:13][C:14]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=1[CH2:16][Zn+]>C1COCC1.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>[F:13][C:14]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=1[CH2:16][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Fc1ccc(F)c(C[Zn+])c1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Cc2cc(F)ccc2F)c1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 79.1 %

Procedure:
To a solution of methyl 2-chloroisonicotinate (5.6 g, 32.64 mmol) and Pd(PPh3)4 (0.754 g, 0.65 mmol) in anhydrous THF (100 mL) was added (2,5-difluorobenzyl)zinc(II) bromide (0.5 M in THF) (100 mL, 50.00 mmol) dropwise under nitrogen. The reaction mixture was heated at 60° C. for 15 h. The reaction mixture was quenched by addition of methanol (50 mL) and then filtered. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with satd NH4Cl solution and brine, then dried. The solvent was evaporated under reduced pressure. The residue was suspended in ethanol, filtered and the solid washed with ethanol. The filtrate was concentrated. The residue was dissolved in MTBE (150 mL), then HCl (4 M in dioxane, (8.15 mL) and MeOH (7.5 mL) were added. The resulting suspension was stirred for 20 min, the solid collected, washed with MTBE (×2) and air dried. The solid was dissolved in DCM (200 mL) and washed with satd NaHCO3. The organic phase was dried using a phase separator and evaporated to yield methyl 2-(2,5-difluorobenzyl)isonicotinate (6.8 g, 79%). MS m/z 264 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]([CH3:14])=[CH:10][C:11](Cl)=[O:12]>C(Cl)(Cl)Cl>[CH3:8][C:9]1([CH3:14])[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:1][C:11](=[O:12])[CH2:10]1
Reactant: Nc1ccccc1
Reactant: CC(C)=CC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(=O)Nc2ccccc21
Temperature: 80 °C

Procedure:
Aniline (7.26 g, 45.2 mmol) and 3-methylbut-2-enoyl chloride (53.2 g, 45.2 mmol) were heated in chloroform at reflux for 2 h. After cooling, the mixture was filtered. The filtrate was concentrated to dryness and dried under vacuum. The crude 3-methyl-but-2-enoic acid phenylamide (ca. 10 g) was dissolved in toluene (50 mL). This toluene solution was added to the stirred AlCl3 powder (27 g) portion-wise. After addition, the resulting dark brown solution was heated at 80° C. for 2.5 h. The warm slurry was poured carefully to stirred crashed ice. The resulting mixture was extracted with EtOAc (3×), washed with sat'd NaHCO3, H2O, brine, and dried over MgSO4. The residue was purified by silica gel flash chromatography (CH2Cl2, then EtOAc) to give 2.2 g of pure 1a and about 4-5 g of less pure portion 1a. LC-MS ESI 176 (M+H).