Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[C@H:13]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:12][NH:11][C:10](=[O:24])[CH2:9]1)=[O:7].[H-].[Na+].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].Cl>O1CCCC1.ClCCl.O>[F:29][C:28]([F:31])([F:30])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:27]=1)[C:6]([N:8]1[C@H:13]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:12][N:11]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:10](=[O:24])[CH2:9]1)=[O:7]
Reactant: O=C1CN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)CN1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)CN1C[C@@H](Cc2c[nH]c3ccccc23)N(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice-cooled solution of (5R)-4-[3,5-bis(trifluoromethyl)benzoyl]-5-(1H-indol-3-ylmethyl)piperazin-2-one (2.15 g) in tetrahydrofuran (43 ml) were added successively sodium hydride (60%) (0.37 g) and ethyl bromoacetate (0.56 ml) in a stream of nitrogen. The mixture was stirred for 55 minutes at the same temperature, and water (20 ml) and 0.5N hydrochloric acid (20 ml) were added successively to the mixture. After stirring for 10 minutes, dichloromethane (80 ml) was added into the mixture at room temperature and the organic layer was separated. The organic layer was washed with brine, and dried over magnesium sulfate. After evaporation in vacuo, the residue was purified by column chromatography on silica gel (60 g) eluting with a mixture of dichloromethane-methanol (from 0% to 2% gradient solution) to give (5R)-4-[3,5-bis(trifluoromethyl)benzoyl]-1-(ethoxycarbonylmethyl)-5-(1H-indol-3-ylmethyl)piperazin-2-one (1.20 g) as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:34]([F:37])([F:36])[F:35])[O:13][N:12]([CH3:14])[C:11]([C:15]3[CH:32]=[CH:31][C:18]([CH2:19][N:20]4C(=O)C5C(=CC=CC=5)C4=O)=[C:17]([CH3:33])[CH:16]=3)=[CH:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.NN>C(O)C.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:34]([F:36])([F:35])[F:37])[O:13][N:12]([CH3:14])[C:11]([C:15]3[CH:32]=[CH:31][C:18]([CH2:19][NH2:20])=[C:17]([CH3:33])[CH:16]=3)=[CH:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: Cc1cc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1CN
Yield: 65 %

Procedure:
837 mg of 2-{4-[5-(3,5-Dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazol-3-yl]-2-methyl-benzyl}-isoindole-1,3-dione (Example I14) and 500 mg hydrazine hydrate in 25 ml ethanol were heated at reflux for 2 hours under stirring. The mixture was cooled and diluted with diethyl ether. The solid was filtered off and the filtrate was evaporated. The residue was dissolved in 100 ml of ether and washed with water. The organic phase was dried and evaporated. The residue was purified on silica gel (eluent dichloromethane/methanol 4:1) affording 4-[5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazol-3-yl]-2-methyl-benzylamine as a resin in 65% yield. 1H-NMR (CDCl3, δ in ppm): 7.44 (s, 2H), 7.37 (m, 2H), 7.28 (m, 2H), 5.33 (s, 1H), 3.88 (s, 2H), 2.99 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[N:9][CH:8]=1)C.C1COCC1.CO.O.Cl>CCOC(C)=O.CCOCC>[Cl:13][C:12]1[C:7]([C:6]([OH:15])=[O:5])=[CH:8][N:9]=[C:10]([Cl:14])[CH:11]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCOCC
Product: O=C(O)c1cnc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
Sodium hydroxide (40 mL, 6.25 M solution) was added to a stirred solution of 4,6-dichloronicotinic acid ethyl ester (22) (25.95 g, 118 mmol) in 4:1:1 THF/MeOH/water (600 mL). After 30 minutes, the reaction mixture was acidified to pH 2 with concentrated HCl, diluted with 1:1 EtOAc/Et2O and washed with water and brine. The organic layer was dried (Na2SO4) and concentrated. The resulting off-white solid was twice concentrated from toluene to give the desired product (23) as a white solid (21.73 g, 96%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[N:19]3[C:20]4[C:15]([CH:16]([NH2:21])[CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](Cl)=[O:36].O>ClCCl>[C:1]1([CH2:7][CH2:8][C:9]2[N:19]3[C:20]4[C:15]([CH:16]([NH:21][C:35]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=5)=[O:36])[CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC1CCn2c(CCc3ccccc3)nc3cccc1c32
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(NC1CCn2c(CCc3ccccc3)nc3cccc1c32)c1ccccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.2 %

Procedure:
A portion (0.4 g) of the 5,6-dihydro-2-(2-phenylethyl)-4H-imidazo[4,5,1-ij]quinolin-6-amine obtained in Step 2 of Example 17 was dissolved in anhydrous dichloromethane (5 mL); following the addition of pyridine (0.26 mL), picolinoyl chloride hydrochloride (0.28 g) was added under cooling with ice. After stirring for 4 hrs at room temperature, water (50 mL) and dichloromethane (50 mL) were added to the reaction solution and then two layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to yield the titled compound as pale brown crystals (0.31 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7]Br)([CH3:4])([CH3:3])[CH3:2].[NH2:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][CH:16]=1.CCN(C(C)C)C(C)C>C1COCC1.CCOCC>[C:1]([O:5][C:6](=[O:9])[CH2:7][NH:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NCc1cccs1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNCc1cccs1
Temperature: 25 °C
Yield: 52.8 %

Procedure:
t-Butylbromoacetate (1.45 mL, 10 mmol) was added to 2-aminomethyl thiophene (1.13 g. 10.0 mmol) and DIEA (2.0 ml) in THF (20 mL). The mixture was warmed to room temperature (4 h), diluted with ether (100 mL) and washed with water (20 mL), brine (20 mL), dried (MgSO4), filtered and evaporated in vacuum. The product was purified by column chromatography eluting with 10-25% EtOAc in hexane to give [(thiophen-2-ylmethyl)-amino]-acetic acid tert-butyl ester (1.2 g). LCMS m/z: 229 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Cl)[CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=1[N:12]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:14])=[O:15])[CH2:32][C:28]1[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=1
Reactant: ClCc1cccnc1
Reactant: COC(=O)c1cccc(C=O)c1NS(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(C=O)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 18 h
Yield: 62.6 %

Procedure:
To a solution of 0.20 g (0.573 mmol) of the product of Example 321 in 2.5 mL of DMF was added 0.099 g (0.602 mmol) of 3-picolyl chloride hydrochloride and 0.249 g (1.805 mmol) of potassium carbonate. The reaction was stined for 18 h at room temperature and then the reaction was then diluted with water and extracted with ether. The combined organics were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with ether to give 0.158 g (63%) of the product as tan crystals. Electrospray Mass Spec: 440.9 (M+H)+.
Reaction SMILES: [N:1]([CH:4]1[CH2:8][CH:7]([C:9]2[N:13]3[C:14]4[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:15]=4[N:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH:6]([CH2:29][CH3:30])[CH2:5]1)=[N+]=[N-].C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.CCOC(C)=O>[CH2:29]([CH:6]1[CH:7]([C:9]2[N:13]3[C:14]4[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[C:15]=4[N:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH2:8][CH:4]([NH2:1])[CH2:5]1)[CH3:30]
Reactant: CCC1CC(N=[N+]=[N-])CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC1CC(N)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Temperature: 45 °C
Yield: 80.5 %

Procedure:
A round bottom flask was charged with 1-(-4-azido-2-ethylcyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.650 g, 1.52 mmol, prepared using D from Preparation #25 with NaOH, KK, P with NaBH4, IIII, JJJJ with NaN3), THF (8.0 mL), and water (1.6 mL). To the flask was added triphenylphosphine (0.480 g, 1.83 mmol). The reaction mixture was heated to about 45° C. for about 7 h. The reaction mixture was cooled to room temperature and EtOAc (20 mL) and water (15 mL) were added. The layers were separated and the organic solution was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give an oil that solidified upon standing. The crude material was purified via flash silica gel chromatography eluting with a gradient of 1-10% DCM/MeOH/DEA (900:90:10) in DCM. The product containing fractions were combined and concentrated under reduced pressure to give an oil that was then dried on a vacuum pump overnight to give 3-ethyl-4-(6((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine as a tacky oil (0.49 g, 80%): LC/MS (Table 1, Method b) Rt=1.85 min; MS m/z 401 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[C:22](O)[CH:21]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[N+:26]([C:25]1[CH:20]=[CH:21][C:22]([O:18][C:17](=[O:19])[C@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:23][CH:24]=1)([O-:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 3 h

Procedure:
To a solution of N-tert-butoxycarbonylphenylalanine (53 g, 0.2 mol) and p-nitrophenol (27.8 g, 0.2 mol) in ethyl acetate (200 ml) in an ice-water bath was dropwise added a solution of N,N′-dicyclohexylcarbodiimide (41.2 g, 0.2 mol) in ethyl acetate (100 ml), and the mixture was stirred in an ice-water bath for 3 hours and then at room temperature for 20 hours. The precipitated N,N′-dicyclohexylcarbodiurea was filtered off and the filtrate was concentrated under reduced pressure. The residue thus obtained was recrystallized from ethyl acetate-hexane to give N-tert-butoxycarbonylphenylalanine p-nitrophenyl ester [61.7 g, 80% (% by weight, hereinafter the same)].
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=2)[CH2:3][CH2:2]1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[CH2:23]Br>>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[CH2:23][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:6]=2[N:5]=[C:4]1[CH:1]1[CH2:3][CH2:2]1
Reactant: Fc1cccc(F)c1CBr
Reactant: COc1cccc2nc(C3CC3)[nH]c12
Product: COc1cccc2c1nc(C1CC1)n2Cc1c(F)cccc1F
Yield: 92.1 %

Procedure:
2-(Cyclopropyl)-4-methoxylbenzimidazole (1.00 g, 5.32 mmol) (5014) was reacted with 2,6-difluoro-a-bromo-toluene (1.30 g, 6.28 mmol, 130 M %). The crude product was purified by flash chromatography eluting with 2% methanol/CH2Cl2 and recrystallization from diethylether/hexane (3:1), yielding white crystals of 1-(2,6-Difluorobenzyl)-2-(cyclopropyl)-4-methoxylbenzimidazole (5016) (1.54 g, 4.90 mmol, 92% yield). M.p. 136-139° C. 1H-NMR (200 MHz, CD2Cl2) δ 7.31 (m, 1H, H4′), 7.07 (dd, J=8.0, 7.8 Hz, 1H, H6), 6.94 (m, 3H, H3′,5′,5), 6.61 (dd, J=7.8, 1.0 Hz, H7), 5.46 (s, 2H, CH2PhF2), 3.95 (s, 3H, OCH3), 2.20×2.03 (m, 1H), 1.18-0.97 (m, 4H).
Reaction SMILES: C([Mg]Cl)(C)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[C:9](I)[CH:8]=1.C[O:17][B:18](OC)[O:19]C.Cl>C1COCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[C:9]([B:18]([OH:19])[OH:17])[CH:8]=1
Reactant: CCc1ccc(Cl)cc1I
Reactant: COB(OC)OC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCc1ccc(Cl)cc1B(O)O
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
i-Propylmagnesium chloride (2 M in THF, 8.98 mL, 17.95 mmol) was added dropwise to a cooled (−30° C.) solution of 4-chloro-1-ethyl-2-iodobenzene (4.35 g, 16.3 mmol) in dry THF (40 mL) and the reaction mixture was stirred at the same temperature for 30 min, under argon. After this time, trimethylborate (3.63 mL, 32.6 mmol) was added dropwise and the reaction mixture was stirred at the same temperature for 1.5 h. HCl (1 M, 16 mL) was added and the reaction mixture extracted with AcOEt (3×50 mL). The combined organic layers were dried over sodium sulfate and, after removal of the solvent, a solid was obtained, which was triturated with hexane to obtain the title compound as a white solid (2.15 g, 72%).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]1[CH2:8][C@@H:7]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH2:6][N:5]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[O:18].[BH4-].[Na+].[I-].[Li+]>O1CCCC1.O>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][O:19][C:17]([N:5]2[CH2:6][C@H:7]([O:9][Si:10]([C:13]([CH3:16])([CH3:14])[CH3:15])([CH3:12])[CH3:11])[CH2:8][C@H:4]2[CH2:3][OH:2])=[O:18])=[CH:26][CH:25]=1
Reactant: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc(OC)cc1
Agent: [BH4-]
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(COC(=O)N2C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]2CO)cc1

Procedure:
trans-1-(p-Methoxybenzyloxycarbonyl)-4-t-butyldimethylsilyloxy-L-proline methyl ester (5.64 g) was dissolved in 56.4 ml of dry tetrahydrofuran. Sodium borohydride (1.01 g) and lithium iodide (3.52 g) were added thereto. The resulting mixture was refluxed for 1 hour, diluted with water, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and distilled off to obtain (2S,4R)-1-(p-methoxybenzyloxycarbonyl)-2-hydroxymethyl-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: C[O:2][C:3]1[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5](=O)[CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].S([O-])([O-])(=O)=O.[Mg+2]>CCOCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:9][C:7]1([CH3:10])[CH2:8][C:3](=[O:2])[CH:4]=[CH:5][CH2:6]1
Reactant: COC1=CC(=O)CC(C)(C)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCOCC
Product: CC1(C)CC=CC(=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
Dissolve 3-methoxy-5,5-dimethyl-cyclohex-2-enone (Tetrahedron 57 (2001) 217-225) (10.6 g, 68.7 mmol) in ether (500 ml) cool to 0° C., add dropwise a 1.5M solution of diisobutyl aluminum hydride (68.7 ml, 103 mmol), and stir for 30 minutes. Add saturated aqueous ammonium chloride (25 ml), stir 1 hour, add anhydrous magnesium sulfate (10 g), stir 1 hour. Filter through celite and concentrate. Dissolve the residue in ether (500 ml), add toluene-4-sulfonic acid monohydrate (650 mg, 3.44 mmol) and water (6.2 ml), and stir 1 hour. Wash with saturated aqueous sodium bicarbonate, brine, dry and concentrate to give the title compound as a clear oil (5.0 g, 58%): 1H NMR (CDCl3) δ 6.89-6.84 (m, 1H), 2.28 (s, 2H), 2.26-2.24 (q, 2H), 1.06 (s, 6H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([C:15]1[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:17][C:16]=1[O:30]C(=O)C(C)(C)C)([CH3:14])([CH3:13])[CH3:12]>CCCCCC>[C:11]([C:15]1[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:17][C:16]=1[OH:30])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC1(C)Cc2c(c(C(C)(C)C)cc(OC(=O)C(C)(C)C)c2C(C)(C)C)O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Product: CC1(C)Cc2c(c(C(C)(C)C)cc(O)c2C(C)(C)C)O1
Reaction time: 8 h
Yield: 66.7 %

Procedure:
Under a nitrogen stream, 3.60 ml of diisobutylaluminium hydride (1M in n-hexane) was added dropwise into a solution of 0.43 g of 4,7-di-t-butyl-2,2-dimethyl-5-trimethylacetoxy-2,3-dihydrobenzofuran in 5 ml of n-hexane at room temperature, and the mixture was stirred overnight. After the reaction was quenched with 5% hydrochloric acid, the reaction solution was extracted with water and ethyl acetate. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified on a short column of silica gel (in n-hexane containing 0.2%-1% ethyl acetate) to give 0.22 g of 4,7-di-t-butyl-5-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran as a white solid (yield 67%).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[N+]([O-])(O)=O.C(N1C(C)=CC(C)=N1)(=N)N.[NH2:24][C:25]1[CH:26]=[C:27]([CH:43]=[CH:44][CH:45]=1)[C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])=[O:29].[O:46]=[C:47](Cl)OC(Cl)(Cl)Cl>O1CCOCC1.O>[N:24]([C:25]1[CH:26]=[C:27]([CH:43]=[CH:44][CH:45]=1)[C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])=[O:29])=[C:47]=[O:46]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cccc(C(=O)NCCC(=O)OCc2ccccc2)c1
Agent: Cc1cc(C)n(C(=N)N)n1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=[N+]([O-])O
Product: O=C=Nc1cccc(C(=O)NCCC(=O)OCc2ccccc2)c1
Reaction time: 0.25 h

Procedure:
0.17 ml of ethyldiisopropylamine is added to a solution of 201 mg of 1-amidino-3,5-dimethylpyrazole nitrate in 17 ml of dioxane and 5 ml of water and the mixture is stirred for 15 minutes. 357 mg of 3-(3-(piperazin-1-ylcarboxamido)benzamido)propionic acid hydrochloride (FAB 321; obtainable by reacting benzyl 3-(3-aminobenzamido)propionate with diphosgene to give benzyl 3-(3-isocyanatobenzamido)propionate, adding on 1-BOC-piperazine to give benzyl 3-(3-(4-BOC-piperazin-1-ylcarboxamido)benzamido)propionate, cleaving the BOC group with 4 N HCl in dioxane to give benzyl 3-(3-(piperazin-1-ylcarboxamido)benzamido)propionate hydrochloride (FAB 411) and hydrogenolyzing on 5% Pd/C) and a further 0.17 ml of ethyldiisopropylamine are then added, the mixture is boiled for 45 hours and evaporated, the residue is dissolved in water and the solution is washed with ether and then with ethyl acetate and evaporated again to give 3-(3-(4-amidinopiperazin-1-ylcarboxamido)benzamido)propionic acid, m.p. 234° (decomposition).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]1[C:15]2([CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16]2)[CH2:14][CH2:13][CH2:12]1.[Cl-].[NH4+]>C(N(CC)CC)C.C(Cl)Cl>[CH2:11]1[C:15]2([CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]2)[CH2:14][CH2:13][CH2:12]1
Reactant: OC1CCCC2(CCCC2)C1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C1CCCC2(CCCC2)C1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 95.5 %

Procedure:
With stirring under nitrogen atmosphere at −70° C., 12.0 g of dimethyl sulfoxide was added to a mixture of 14.4 g of oxalyl chloride and 100 ml of methylene chloride. Stirring was continued for 10 minutes. Below −55° C., a mixture of 8.72 g of 7-spiro[4.5]decanol and 20 ml of methylene chloride was added dropwise thereto, followed by stirring for 30 minutes at −70° C. After 50 g of triethylamine was added, the mixture was warmed up to −5° C. while stirring. The reaction mixture was poured into a saturated ammonium chloride aqueous solution, followed by ordinary work-up of extraction, washing and drying, and purification by silica gel chromatography. There was obtained 8.22 g (yield 96%) of 7-spiro[4.5]decanone. This compound was found to have identical spectroscopic characteristics with the former compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].C(=O)([O-])[O-].[K+].[K+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(Cl)Cl>O1CCOCC1.O>[C:18]([O:22][C:23]([N:25]1[CH2:26][CH:27]=[C:28]([C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[F:11])[CH2:29][CH2:30]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc([N+](=O)[O-])ccc2F)CC1
Temperature: 100 °C

Procedure:
Into a 1-neck round-bottom flask were added 2-bromo-1-fluoro-4-nitrobenzene (1760 mg, 8.000 mmol), potassium carbonate (2210 mg, 16.00 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2720 mg, 8.800 mmol), water (8 mL) and 1,4-dioxane (32 mL). The flask was degassed and filled with N2 for 3 times, and then [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with CH2Cl2 (1:1) (330.0 mg, 0.4000 mmol) was added. The mixture was degassed and filled with N2 for 3 times again and was then heated at 100° C. for 16 h. After that time, the mixture was concentrated in vacuo and was then purified by silica gel (240 g) eluting with 1800 mL of 5%, 1000 mL of 10%, 1000 mL of 15% and 1000 mL of 20% EtOAc/hexane to obtain the title compound as a colorless oil. 1H NMR (DMSO-d6, 400 MHz): δ=1.49 (s, 9H), 2.52-2.55 (m, 2H), 3.60 (t, 2H, J=5.6 Hz), 4.09 (brs, 2H), 6.21 (brs, 1H), 7.55-7.60 (m, 1H), 8.21-8.29 (m, 2H). MS (ES+): m/z 223.22 (100) [MH+-Boc]. HPLC: tR=3.83 min (ZQ2000, polar—5 min).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@@H:8]([CH2:11][CH3:12])[CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:22](=[O:27])[C:23]([O:25][CH3:26])=[O:24]>C(Cl)Cl.[Cl-].[Na+].O>[C:1]([O:5][C:6]([NH:7][C@@H:8]([CH2:11][CH3:12])[CH2:9][NH:10][C:22](=[O:27])[C:23]([O:25][CH3:26])=[O:24])=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(=O)Cl
Reactant: CC[C@@H](CN)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](CNC(=O)C(=O)OC)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To an ice cold solution of (S)-tert-butyl(1-aminobutan-2-yl)carbamate (1.0 g, 5.4 mmol) and triethylamine (0.78 mL, 5.6 mmol) in DCM (33 mL) was added methyl chlorooxoacetate (0.52 mL, 5.6 mmol) dropwise. Following the addition, the reaction was allowed to warm to rt and stirred overnight. Brine was added, the layers were separated, and the aqueous layer was washed with DCM. The combined organic extracts were dried (Na2SO4), filtered, and concentrated to provide a yellow oil (1.4 g, 96%), which was used without further purification. 1H NMR (500 MHz, CDCl3) δ 7.78 (s, 1H), 4.59 (d, J=7.6 Hz, 1H), 3.92-3.81 (m, 3H), 3.69 (s, 1H) 3.45 (dt, J=13.5, 4.2 Hz, 1H), 3.39-3.22 (m, 1H), 1.47-1.38 (m, 11H), 0.98 (t, J=7.5 Hz, 3H).