Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:9]=[N+:10]=[N-:11].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:9]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: BrCc1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccccc1
Reaction time: 24 h
Yield: 79.5 %

Procedure:
To a solution of benzylbromide (350 μL, 2.92 mmol) in anhydrous dimethylformamide (7 mL), under argon, was added sodium azide (288 mg, 6.43 mmol). After 24 h at room temperature, the reaction mixture was diluted with ethyl acetate and then washed three times with brine. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was diluted with water and extracted with pentane, dried over sodium sulfate, filtered and evaporated to afford the title compound (309 mg, 80%) as a colorless oil.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S([O-])(O)(=O)=O.[Na+].[CH3:15][C:16](=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O>[CH3:15][C:16]1[NH:7][C:1]2[C:6]([C:17]=1[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:5][CH:4]=[CH:3][CH:2]=2
Reactant: NNc1ccccc1
Reactant: CCCCCC(C)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: CCCCc1c(C)[nH]c2ccccc12
Temperature: 100 °C
Reaction time: 7 h
Yield: 62 %

Procedure:
27 g (0.25 mol) of phenylhydrazine were initially introduced at 90° C. in a solution of 1.12 mol of sodium hydrogen sulphate in 420 ml of water. 30 g (0.263 mol) of heptan-2-one were metered in in the course of 30 min. This mixture was stirred for 7 h at 100° C. After cooling, the batch was neutralised and the organic phase was separated off and distilled. 2-Methyl-3-butylindole was obtained in a yield of 62%.
Reaction SMILES: C([N:8](C(OC(C)(C)C)=O)[C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])C1C=CC=CC=1.C(NCC(O)=O)(OC(C)(C)C)=O>C(Cl)Cl>[NH2:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@@H](CCCCN)C(=O)O
Agent: CC(C)(C)OC(=O)NCC(=O)O
Solvent: ClCCl
Product: NCCCC[C@H](N)C(=O)O
Reaction time: 0.17 h

Procedure:
While maintaining the nitrogen gas atmosphere, three fold molar excess of resin capacity of benzyl-Boc-L-lysine [Lys (Z), Peninsula, supra.] dissolved in methylene chloride is added to the residue of step (B) above. The resulting mixture is shaken and after about 10 minutes, 3 fold molar excess of N,N-dicyclohexylcarbodiimide dissolved in 10-15 ml. of methylene chloride is added with stirring. The resulting mixture is shaken at room temperature for 4.5 to 5 hours. At the end of this period, the reaction mixture is filtered and the residue washed with methylene chloride, ethanol and dried.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][CH3:15])=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([OH:30])=O)[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1.C(N(CC)CC)C>CN(C)C=O>[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([N:14]([C:10]4[CH:11]=[C:12]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:13]5)[CH3:15])=[O:30])[CH2:26][CH2:27]3)=[CH:24][C:19]=2[O:18][CH2:17]1
Reactant: CNc1ccc2[nH]c(C(C)(C)C)cc2c1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C(=O)C1(c2ccc3c(c2)OCO3)CC1)c1ccc2[nH]c(C(C)(C)C)cc2c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
2-tert-Butyl-N-methyl-1H-indol-5-amine (20.2 mg, 0.100 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (20.6 mg, 0.100 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (42.1 μL, 0.300 mmol) and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 16 h at 80° C. The crude product was then purified by preparative HPLC utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)-N-methylcyclopropanecarboxamide. ESI-MS m/z calc. 390.2, found 391.3 (M+1)+. Retention time of 3.41 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-])=O)=[C:6]([NH:8][CH2:9][CH3:10])[CH:7]=1>[Ni].CO.C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([NH2:11])=[CH:4][CH:3]=1
Reactant: CCNc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CCNc1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 9 h
Yield: 85.7 %

Procedure:
A suspension of (5-bromo-2-nitro-phenyl)-ethyl-amine (Step 26.3) (6 g, 24.48 mmol) and Raney nickel (2 g) in MeOH/THF (1:1 v/v, 600 mL) is stirred for 9 h at rt, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated. The residue purified by silica gel column chromatography (Hex/EtOAc, 95:5→85:15) to afford 4.51 g of the title compound as a black oil: ESI-MS: 213.1/215.1 [M−H]−; tR=2.53 min (System 1); TLC: Rf=0.57 (Hex/EtOAc, 1:1).
Reaction SMILES: C([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.C(OC(C1N=C(O)C2C(C=1O)=CC=C(OC1CCCCC1)C=2)=O)CCC.P(Br)(Br)([Br:55])=O>C(#N)C>[Br:55][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([OH:5])=[O:7])[N:9]=1
Reactant: CCCCOC(=O)c1nc(O)c2cc(Sc3ccccc3)ccc2c1O
Reactant: O=P(Br)(Br)Br
Agent: CCCCOC(=O)c1nc(O)c2cc(OC3CCCCC3)ccc2c1O
Solvent: CC#N
Product: O=C(O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
Reaction time: 8 h

Procedure:
1,4-Dihydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (Example A-63 d) Compound A) (29.0 g) and phosphorous oxybromide (67.5 g) in 600 ml anhydrous acetonitrile was stirred at reflux for 4 hours. After cooling the reaction mixture was concentrated and saturated sodium bicarbonate solution and ethyl acetate were added to the residue and stirred overnight. Precipitate that formed between layers was collected and washed with water to give the title compound (10.2 g). MS-(+)-ion M+1=376.0, 378.1.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18]>C(O)C>[CH2:18]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:17][CH2:16][CH:15]=[CH2:14]
Reactant: C=CCCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: C=CCCCC(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 300 ml of ethanol are added 5 g of sodium spheres and after a clear solution is obtained, 32.1 g of diethyl malonate is added in one portion. After 1 h at room temperature, 15 g of 5-bromopent-1-ene is added and the reaction mixture is stirred at room temperature for 16 h. The reaction mixture is evaporated to dryness and the residue is distilled under high vacuum to obtain diethyl pent-4-enylmalonate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[H-].[Na+].Cl[CH2:13][O:14][CH3:15]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][O:14][CH3:15])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Br
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-bromo-3-methylphenol (6-6) (1.0 equiv.) in DMF (0.5 M) at 0° C. was added portionwise 60% wt NaH (1.5 equiv.). The addition was controlled such that internal reaction temperature never went above 10° C. The reaction was stirred at room temperature for 45 minutes, then a solution of chloro(methoxy)methane (1.2 equiv.) in DMF (3 M) was added dropwise via additional funnel. The reaction was stirred at room temperature for 3.5 hours, and then quenched by pouring into ice. The resulting mixture was stirred at room temperature for 1 hour. Ether was added, and the two layers were separated. The aqueous layer was extracted (1×) with ether. The combined organic layers were washed with water (2×), brine, dried over MgSO4, and concentrated to give 1-bromo-4-(methoxymethoxy)-2-methylbenzene (6-7) as a colorless oil. The crude material was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C)C=O.O>[Si:16]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#CCc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.6 %

Procedure:
A solution of (4-hydroxyphenyl)acetonitrile (6.01 g, 45.1 mmol) in N,N-dimethylformamide (60 ml) was treated with imidazole (3.81 g, 58.6 mmol), tert-butyldimethylsilylchloride (7.49 g, 49.6 mmol) and N,N-dimethylaminopyridine (20 mg) and the resulting solution left to stir at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (200 ml×2). The combined organic extracts were washed with sat. aq. sodium chloride (200 ml), dried (sodium sulfate) and the solvent removed in vacuo. Purification by column chromatography on silica gel eluting with ethyl acetate:pentane (0:100 changing to 10:90) gave the title compound as a pale yellow oil (9.44 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][OH:15].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1>[CH3:16][S:17]([O:15][CH2:14][CH2:13][C:3]1[N:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:6][C:2]=1[CH3:1])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Yield: 100 %

Procedure:
2-(5-Methyl-2-phenyl-4-oxazolyl)ethanol (compound [6]; 108.6 g) obtained in Example 3 was dissolved in toluene (600 mL), and methanesulfonyl chloride (45.4 mL) was added, which was followed by stirring under ice-cooling. To this solution was added dropwise triethylamine (81.7 mL) under ice-cooling. After stirring for 1 hr, toluene (1 L) was added and 1N hydrochloric acid (1 L) was added for partitioning. The aqueous layer was extracted again with toluene (0.5 L). The combined organic layers were washed successively with water (1 L), saturated sodium hydrogencarbonate solution (1 L) and saturated brine (1 L), and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (compound [7]; 150 g, yield 100%) as crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:6]([NH:12][C:13](=[O:19])[O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[N:7][CH:8]=[C:9]([CH3:11])[N:10]=1.[Cl:20][C:21]1[C:26]([S:27](Cl)(=[O:29])=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=1.Cl>O.CN(C=O)C>[Cl:20][C:21]1[C:26]([S:27]([N:12]([C:13]([O:14][CH2:15][CH:16]([CH3:17])[CH3:18])=[O:19])[C:6]2[C:5]([O:4][CH3:3])=[N:10][C:9]([CH3:11])=[CH:8][N:7]=2)(=[O:29])=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: COc1nc(C)cnc1NC(=O)OCC(C)C
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1Cl
Temperature: 25 °C
Yield: 43.5 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.083 g) was added to a stirred solution of isobutyl N-(3-methoxy-5-methylpyrazin-2-yl)-carbamate (0.451 g) in dry N,N-dimethylfonmamide (DMF; 8 ml) at 4° C. The mixture was stirred whilst warming to ambient temperature over I hour, was recooled to 4° C. and 2-chloropyridine-3-sulphonyl chloride (0.40 g) was added in portions over 2 minutes. The mixture was allowed to warm to ambient temperature and stirred a further 30 minutes. Water (40 ml) was added, followed by 1M hydrochloric acid to acidify. This mixture was extracted with ethyl acetate (4×15 ml) and the organic extracts were washed with water (10 ml) and saturated sodium chloride solution (10 ml) and then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 0-35% ethyl acetate/hexane through a silica gel Mega Bond Elut column and triturated with ether to give 2-chloro-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)-pyridine-3-sulphonamide (0.34 g) as a solid, m.p. 99°-101° C.; 1H NMR (CDCl3): 0.7 (d, 6 H), 1.7 (m, 1 H), 2.5 (s, 3 H), 3.8 (d, 2 H), 4.0 (s, 3 H), 7.45 (dd, 1 H), 7.9 (s, 1 H), 8.6 (dd, 1 H), 8.7 (dd, 1 H); mass spectrum (+ve ESP): 415 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][C:11]([OH:13])=O)=[C:4]([CH3:15])[CH:3]=1.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(N=C=NC2CCCCC2)CCCCC1.BrC1C=CC(NC(=O)CC(N(C2CCCCC2)C(NC2CCCCC2)=O)=O)=C(C)C=1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[S:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:4]([CH3:15])[CH:3]=1
Reactant: Sc1ccccc1
Reactant: Cc1cc(Br)ccc1NC(=O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1cc(Br)ccc1NC(=O)CC(=O)N(C(=O)NC1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1NC(=O)CC(=O)Sc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a stirred mixture of 5.44 grams (0.02 mole) of 3-[(4-bromo-2-emthylphenyl)amino]-3-oxopropanoic acid prepared in Example V (Compound No. 97) and 2.31 grams (0.02 mole) of thiophenol in approximately 100 milliliters of dry tetrahydrofuran in an oven-dried reaction flask was fed a solution of 4.13 grams (0.02 mole) of 1,3-dicyclohexylcarbodiimide in about 25 milliliters of dry tetrahydrofuran, while cooling the reaction mixture in an ice-water bath. On completing the feed the ice bath was removed and the mixture stirred for about one hour following which the precipitated 1,3-dicyclohexylurea by-product (2.5 grams) was removed by filtration. Vacuum stripping the filtrate gave a solid which was recrystallized from acetone to give a compound, melting point 184° C.-187° C., which proved to be 1-(3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoyl)-1,3-dicyclohexylurea. The filtrate from this was concentrated and flash chromatographed (7:3 hexane:ethylacetate, silica column) to give 2.83 grams (0.008 mole) of S-phenyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanethioate having a melting point of 133° C.-135° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[CH3:12][O-].[Na+].[Cl-]>CO.CN(C=O)C>[CH3:12][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: C[O-]
Reactant: Oc1cccc2cnccc12
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cccc2cnccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of 5-hydroxyisoquinoline (10 g, 69 mmol) in MeOH (100 ml) was added a solution of sodium methoxide in methanol (30% by weight, 13.8 ml, 72.4 mmol) followed by phenyltrimethylanmmonium chloride (12.4 g, 72.4 mmol). The reaction mixture was stirred at room temperature for 2 h, after which time it was filtered and the filtrate evaporated under reduced pressure to afford an oil which was dissolved in DMF (50 ml). The reaction mixture was refluxed for 2 h after which time the reaction mixture was evaporated under reduced pressure. The resulting oil was partitioned between CH2Cl2 and 1N aqueous NaOH, the organic layer was washed twice with 1N aqueous NaOH, dried over MgSO4 and evaporated under reduced pressure. The crude product was purified on silica gel eluting with EtOAc/hexane (1/1, v/v) to afford the subtitle compound as a yellow oil (6.11 g, 56%). 1H NMR (CDCl3) δ: 4.05 (3H, s), 7.00 (1H, d), 7.55 (2H, m), 8.02 (1H, d), 8.55 (1H, d), 9.22 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](F)=[CH:7][C:6]=1[F:15])[CH3:2].[CH3:17][NH2:18]>C1COCC1>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([NH:18][CH3:17])=[CH:7][C:6]=1[F:15])[CH3:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: CN
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(NC)cc1F
Yield: 69 %

Procedure:
Prepared analogously to example 156b from 2,4-difluoro-5-nitro-benzoic acid ethyl ester and 2 M methylamine solution in THF. Yield: 69%.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]#[N:9])[CH2:4][CH2:3]1.[OH:10][NH:11][C:12](=N)[CH:13]([CH3:15])[CH3:14].Cl>C(OCC)(=O)C.C(O)C.[Cl-].[Zn+2].[Cl-]>[CH:13]([C:12]1[N:9]=[C:8]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[O:10][N:11]=1)([CH3:15])[CH3:14]
Reactant: CC(C)C(=N)NO
Reactant: N#CN1CCC(O)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)c1noc(N2CCC(O)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
To a solution of 4-hydroxypiperidine-1-carbonitrile (1 g, 7.93 mmol) and N-hydroxyisobutyrimidamide (0.972 g, 9.51 mmol) in ethyl acetate (40 mL) was added zinc chloride (1 M in Et2O, 9.5 mL, 9.5 mmol) dropwise at rt under argon. Precipitate formed immediately, and the reaction mixture was stirred at rt for 30 min. The solid was collected via filtering, rinsed several times with ether. The solid was dissolved in concentrated HCl (4 mL, 132 mmol), diluted with ethanol (8 mL), and refluxed for 1 h. The reaction mixture was cooled to rt and filtered. The filtrate was concentrated to approximately half of the volume, and diluted with water (15 mL). The solution was basified with solid Na2CO3, followed by extraction with CH2Cl2 (3×30 mL). The combined organic layers were washed with saturated NaHCO3 (60 mL) and brine. It was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (hexanes-EtOAc gradient 0-50% EtOAc) to afford 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-ol (0.59 g, 2.79 mmol, 35% yield) as a clear colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (d, J=7.07 Hz, 6H) 1.55 (d, 1H) 1.60-1.70 (m, J=12.98, 8.61, 8.61, 4.17 Hz, 2H) 1.93-2.02 (m, 2H) 2.89 (spt, J=6.95 Hz, 1H) 3.38 (ddd, J=13.20, 9.03, 3.79 Hz, 2H) 3.88-4.04 (m, 3H). LCMS (m/z)=212 (M+H)+.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH3:6])([O-:3])=[O:2].C(N(CC)CC)C.[Cl-].[Cl-].C([Al+2])C.[CH:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:20]1([CH:19]([OH:26])[CH:4]([N+:1]([O-:3])=[O:2])[CH2:5][CH3:6])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCC[N+](=O)[O-]
Reactant: O=Cc1ccccc1
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C(O)c1ccccc1)[N+](=O)[O-]
Temperature: 25 °C
Yield: 28.7 %

Procedure:
To a solution of nitropropane (0.45 g, 0.005 moles) in dichloromethane (25 mL) at 0° C. was added triethylamine (0.67 mL, 0.005 moles) followed by ethyl aluminum dichloride (1.0 M in hexane, 5 mL, 0.005 moles). After 15 minutes benzaldehyde (0.5 mL 0.005 moles) was added and the solution allowed to warm to room temperature. After a further 3 hours the reaction was cooled in ice to a temperature of 5° C. and quenched with pH 7.0 phosphate buffer. The organic layer was separated, dried and evaporated in vacuo. Flash column chromatography [SiO2, 6:1 hexane, Et2O] gave 1-phenyl-2-nitro-1-butanol (0.28 g, 29%) Erythro:threo ratio 1:1.6.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]([NH:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][OH:18])=[O:14].ClC(Cl)(Cl)C(=N)O[CH2:34][CH:35]=[CH2:36]>C(Cl)Cl.C1CCCCC1.C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:13]([NH:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][O:18][CH2:36][CH:35]=[CH2:34])=[O:14]
Reactant: COC(=O)[C@H](CO)NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Solvent: C1CCCCC1
Solvent: ClCCl
Product: C=CCOC[C@H](NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O)C(=O)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1- oxo-3-phenylpropyl]-L-serine, methyl ester (25 g, 63 mmol) in methylene chloride/cyclohexane (1:1, 600 mL). Add allyl trichloroacetimidate (26 g, 128 mmol) and trifluoromethanesuihfonic acid (5 mL), 56.6 mmol). Stir at room temperature under a nitrogen atmosphere for 5 hours and dilute with methylene chloride. Wash with saturated aqueous sodium hydrogen carbonate, water, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography (gradient 20% ethyl acetate/hexane to 35% ethyl acetate/hexane) to give the title compound; mp 95°-97° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:30]=[CH:29][C:11]([O:12][CH2:13][O:14][C:15]([C:25]([F:28])([F:27])[F:26])([C:21]([F:24])([F:23])[F:22])[C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].CO>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][O:14][C:15]([C:21]([F:22])([F:23])[F:24])([C:25]([F:26])([F:27])[F:28])[C:16]([OH:18])=[O:17])=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(OCOc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(OCOc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Reaction time: 22 h
Yield: 43.3 %

Procedure:
A mixture of ethyl 2-[4-(4-chlorophenyl)phenoxymethoxy]-3,3,3-trifluoro-2-trifluoromethylpropionate (502 mg.) postassium hydroxide (88 mg.), methanol (4 ml.) and water (1 ml.) is stirred at 20° C. for 22 hours, then evaporated in vacuo. The residue is dissolved in water, and the solution is acidified with 3 N-hydrochloric acid. The solid which separates is filtered off. Crystallisation from a mixture of cyclohexane and light petroleum (b.p. 40°-60° C.) gives prisms (204 mg.) of 2-[4-(4-chlorophenyl)phenoxymethoxy]-3,3,3-trifluoro-2-trifluoromethylpropionic acid, m.p. 134°-135° C.
Reaction SMILES: [N+](=[C:3]([C:17](=[O:28])[C@@H:18]([C@@H:20]1[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[NH:21]1)[CH3:19])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-]>ClC(Cl)C.C1C=CC=CC=1.C([O-])(=O)CCCCCCC.[Rh+2].C([O-])(=O)CCCCCCC>[OH:26][C@@H:24]([C@H:23]1[C:22](=[O:27])[N:21]2[C@@H:20]1[C@@H:18]([CH3:19])[C:17](=[O:28])[CH:3]2[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])[CH3:25]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CCCCCCCC(=O)[O-]
Solvent: c1ccccc1
Solvent: CC(Cl)Cl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12

Procedure:
To a solution of 4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (1.0 g) in dichloroethane (10 ml) was added rhodium(II) octanoate (10 mg) under refluxing. After refluxing for 30 minutes, the reaction mixture was cooled and evaporated in vacuo to give a residue. The residue was dissolved in benzene (5 ml) and then evaporated in vacuo to give 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]-heptane-2-carboxylate.