Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1)[CH2:4][CH3:5])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>OS(O)(=O)=O.O=S(=O)=O>[CH2:1]([CH:3]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:9]=2[N:8]=[N:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)n1nnc2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: CCC(CC)n1nnc2c([N+](=O)[O-])cccc21
Temperature: 0 °C
Yield: 45 %

Procedure:
Over a 21/2 hour period, 210 grams of the 1-(1-ethylpropyl)benzotriazole is added to a mixture of 100 milliliters of 90% nitric acid and 400 milliliters of 23% oleum with stirring. The mixed acid solution is cooled in an ice-salt bath and the addition rate is such that a temperature of between 5°-10° C. is maintained. The reaction mixture is maintained at 5°-10° C. for an additional 11/2 hours and then at 25° C. for one more hour. The reaction mixture is then poured over 2500 grams of ice with stirring. After 15 minutes of stirring, the brown precipitate is collected by filtration, washed with additional water and air dried. The crude product is then slurried with 500 milliliters of 95% ethanol and then a second time with an additional 400 milliliter of hot 95% ethanol. The slurry is cooled and the product is collected by filtration and dried to yield 108.5 grams (45%) of brown solid, m.p. 129°-132° C. The analytical sample is recrystallized from chloroform-petroleum ether to give a m.p. 132°-134° C.
Reaction SMILES: [O:1]([C:8]1[C:14]([CH3:15])=[CH:13][C:11]([NH2:12])=[C:10]([CH3:16])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:19](OC)[N:20]([CH2:22][CH3:23])[CH3:21]>C1(C)C=CC=CC=1.CO>[CH2:22]([N:20]([CH3:21])[CH:19]=[N:12][C:11]1[CH:13]=[C:14]([CH3:15])[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][C:10]=1[CH3:16])[CH3:23]
Reactant: Cc1cc(Oc2ccccc2)c(C)cc1N
Reactant: CCN(C)C(OC)OC
Solvent: CO
Solvent: Cc1ccccc1
Product: CCN(C)C=Nc1cc(C)c(Oc2ccccc2)cc1C
Temperature: 50 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
0.18 g (0.8 mmol) of 4-phenoxy-2,5-dimethylaniline was dissolved in 2.5 ml of toluene and this solution was then admixed with 0.18 ml of a solution of N-ethyl-N-methylformamide dimethyl acetal in methanol (60%). After 12 h of stirring of the reaction mixture at 50° C., subsequent filtration and removal of the solvent under reduced pressure, 240 mg (94.8% purity, 96.6% yield) of the product were obtained; log P(HCOOH)=1.87.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:9](Cl)(=[O:11])[CH3:10]>C(Cl)Cl>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:9](=[O:11])[CH3:10])=[CH:3][N:4]=1
Reactant: Nc1cnc(Cl)nc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Nc1cnc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.1 %

Procedure:
5-amino-2-chloro pyrimidine (260 mg, 2 mmol) was dissolved in DCM (5 ml), TEA (0.557 ml, 4 mmol) was added and the reaction mixture was stirred at 0° C. for 15 min. Acetyl chloride (0.213 ml, 3 mmol) was added dropwise at 0° C. and the reaction mixture was stirred for 45 min. The reaction was quenched with an aqueous saturated solution of NaHCO3. The phases were separated and the aqueous phase was basified by adding solid K2CO3 while the pH was allowed to reach ˜9-10 and extracted with dichloromethane. Combined organic phases were dried over Na2SO4 and evaporated in vacuo to afford N-(2-chloropyrimidin-5-yl)acetamide (340 mg) as a crude product.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:16])[CH:12]=2)[CH:7]=1)=[O:5])C.[OH-].[Na+].O>C(O)C>[F:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:15]=[CH:14]2
Reactant: CCOC(=O)c1ccc2cc(F)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6-fluoro-2-naphthoic acid ethyl ester (600 mg, 2.75 mmol) in ethanol (10 mL) at room temperature, is added 1 N NaOH (2.75 mL, 2.75 mmol). After stirring at room temperature for 4 hours, water (10 mL) is added. Acidification (2 N HCl) and filtration gives 6-fluoro-2-naphthoic acid as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[OH:7].[OH-].[Na+].Br[CH2:17]CCCC>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:17][O:7][CH:6]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccco1
Reactant: CCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Product: COC(c1ccccc1)c1ccco1

Procedure:
9 grams of the distilled 1-furyl-1-phenyl-methanol (0.052 mole) is charged to a reactor with 0.39 g (2 mole percent) tetrabutylammonium iodide and 10.4 g of a 50 percent aqueous solution of sodium hydroxide added over a 10 minute period with stirring. This is followed by addition of 17.6 g (0.14 mole) 1-bromopentane over a period of 10 minutes and the reaction mixture allowed to stir for 2 hours. The reaction mixture is then extracted with diethyl ether which, after drying over magnesium sulfate, is evaporated. The resulting crude product is short-path distilled to obtain 2-(methoxy, phenylmethyl)furan in low yield.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH:16]3[CH2:18][CH2:17]3)[C:6]=2[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[C:56]([NH:63][C@H:64]([CH2:69][OH:70])[CH2:65][CH:66]([CH3:68])[CH3:67])([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:16]1([N:7]2[C:6]3[CH:19]=[C:2]([O:70][CH2:69][C@@H:64]([NH:63][C:56](=[O:57])[O:58][C:59]([CH3:60])([CH3:62])[CH3:61])[CH2:65][CH:66]([CH3:68])[CH3:67])[CH:3]=[CH:4][C:5]=3[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8]2=[O:15])[CH2:18][CH2:17]1
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: O=c1c2cnccc2c2ccc(Cl)cc2n1C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(C3CC3)c2c1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 26.4 %

Procedure:
To a solution 8-chloro-6-cyclopropylbenzo[c][2,7]naphthyridin-5(6H)-one (200 mg, 0.739 mmol) in toluene (2 mL) at room temperature was added cesium carbonate (361 mg, 1.108 mmol) and di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (188 mg, 0.443 mmol) and the mixture was degassed with nitrogen for 5 min. The mixture was then treated with N-Boc-L-leucinol (477 mg, 2.216 mmol) followed by palladium(II)acetate (49.8 mg, 0.222 mmol) and degassed for another 10 min. The reaction mixture was sealed and heated at 80° C. After overnight stirring the reaction mixture was cooled to room temperature and filtered through diatomaceous earth (Celite®). The bed was washed with ethyl acetate and the combined filtrate was concentrated under reduced pressure to afford crude product which was purified by combi flash (ethyl acetate and petroleum ether) to afford (S)-tert-butyl (1-((6-cyclopropyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (100 mg, 0.195 mmol, 26% yield) as an off-white solid. LC/MS (ESI) m/e 452.2 [(M+H)+, calcd for C26H34N3O4 452.3]; LC/MS retention time (method C): tR=2.11 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH2:12][NH:13]C(OC(C)(C)C)=O)[CH:5]=1.[ClH:22]>CO>[ClH:22].[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH2:12][NH2:13])[CH:5]=1
Reactant: COC(=O)c1cccc(CCCNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cccc(CCCN)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-(3-tert-butoxycarbonylamino-propyl)-benzoic Acid methyl ester (565 mg) in MeOH (25 mL) was cooled to 0° C. and the solution was saturated with HCl (g). The reaction was stirred at room temperature for 1.5 h and was concentrated in vacuo to provide the title amine (399 mg). MS 194 (M+1).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:24])[CH2:22]Br)[CH:9]=1)(=[O:3])[CH3:2].[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2([OH:38])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:24])[CH2:22][N:35]2[CH2:34][CH2:33][C:32]([C:29]3[CH:30]=[CH:31][C:26]([Br:25])=[CH:27][CH:28]=3)([OH:38])[CH2:37][CH2:36]2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: OC1(c2ccc(Br)cc2)CCNCC1
Reactant: CC(=O)NCCNc1cc(NC(=O)CBr)nc(-c2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCNc1cc(NC(=O)CN2CCC(O)(c3ccc(Br)cc3)CC2)nc(-c2ccccc2)n1
Reaction time: 5 h

Procedure:
N-(6-{[2-(Acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-bromoacetamide (23) (30 μL of a 0.167M solution) was dispensed to a well of a 96 well microtitre plate, followed by [4-(4-bromophenyl)-4-hydroxypiperidine] (30w1 of a 0.167M solution) and N,N-diisopropylethylamine (30 μl of a 0.167M solution). The plate was placed in an oven at 63° C. for 5 hrs. The solvent was removed in vacuo yielding the title compound. LCMS (Method A) RT=2.43 min, m/z (ES+) 569 (MH)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[C:30]([N:34]=[C:35]=[O:36])[CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24]>C1(C)C=CC=CC=1>[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[C:30]([NH:34][C:35]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:36])[CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCOC(=O)c1cccc(N=C=O)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)c1
Yield: 20.6 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (53 mg) was dissolved in toluene (5 ml) with heat, 3-ethoxycarbonylphenyl isocyanate (284 mg) was added, and the admixture was refluxed with heat for 1 hour. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 18 mg of the title compound (yield: 20%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([C:26]([CH3:28])=[CH2:27])=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[OH:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH2:33][NH:34][CH2:35]2.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]([C:26]([CH3:28])=[CH2:27])=[CH:14][C:10]=1[C:11]([N:34]1[CH2:33][C:32]2[C:36](=[CH:37][CH:38]=[CH:39][C:31]=2[OH:30])[CH2:35]1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2c1CNC2
Reactant: C=C(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(C)c1cc(C(=O)N2Cc3cccc(O)c3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.3 %

Procedure:
A mixture of 2,4-bis-benzyloxy-5-isopropenyl-benzoic acid (8.1 g, 21.65 mmol), 4-hydroxyisoindoline hydrobromide (4.91 g, 22.73 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.0 g, 25.98 mmol), 1-hydroxybenzotriazole (3.5 g, 25.98 mmol) and triethylamine (6 ml, 43.3 mmol) in N,N-dimethylformamide (50 ml) was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was treated with a saturated aqueous solution of sodium hydrogen carbonate (200 ml). The mixture was filtered, the solid material was washed copiously with water, sucked dry under reduced pressure and dried in a vacuum oven at 50° C. overnight to afford (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-(4-hydroxy-1,3-dihydro-isoindol-2-yl)-methanone (10.25 g, 96%) as a pale tan solid. 1H NMR (DMSO-d6) (mixture of amide rotamers) 9.68 and 9.60 (1H, 2×br s), 7.45-7.25 (10H, m), 7.20-7.00 (3H, m), 6.82 and 6.72 (1H, 2×d), 6.68 (1H, m), 5.23 and 5.22 (2H, 2×s), 5.18 (2H, s), 5.11 (1H, s), 5.09 (1H, s), 4.77 and 6.67 (2H, 2×s), 4.53 and 4.44 (2H, 2×s), 2.04 (3H, s). MS: [M+H]+ 492.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10]([NH:12][C@H:13]1[C@H:18](OS(C)(=O)=O)[CH2:17][CH2:16][C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O.C(OCC)(=O)C>[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC.CN1CCCC1=O>[N:1]([C@H:18]1[CH2:17][CH2:16][C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14][C@H:13]1[NH:12][C:10]([O:9][C:5]([CH3:6])([CH3:8])[CH3:7])=[O:11])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)[C@H](NC(=O)OC(C)(C)C)C1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)[C@H]1CC[C@H](N=[N+]=[N-])[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 74 h

Procedure:
Sodium azide (357.6 mg) and trioctylmethylammonium chloride (335.5 mg) were added at room temperature to a solution (2 mL) of ethyl (1S,3R,4R)-3-[(t-butoxycarbonyl)amino]-4-methanesulfonyloxycyclohexanecarboxylate (1.01 g) in N-methyl-2-pyrrolidone, followed by stirring at 60° C. for 74 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was washed with aqueous saturated sodium bicarbonate solution and water, followed by drying over magnesium sulfate anhydrate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane ethyl acetate=4:1), to thereby yield 706.2 mg of the title compound. Spectral data of this compound were found to be identical with those of the compound of Example 5.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([C@:25]1([OH:33])[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1)#[CH:24].C(N(CC)CC)C>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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:24]#[C:23][C@:25]2([OH:33])[CH:30]3[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]3)[CH2:26]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Reactant: CO[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CO[C@@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@H]1O
Reaction time: 3 h
Yield: 34.8 %

Procedure:
A mixture of 4.19 g of 2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]pyridine, 1.7 g of (3R)-3-ethynyl-3-quinuclidinol, 500 mg of tetrakis(triphenylphosphine)palladium(0), 10 mg of cuprous iodide, 4.2 ml of triethylamine and 13 ml of N,N-dimethylformamide was heated under stirring in an oil bath kept at 70° C. for 3 hours in a nitrogen atmosphere. After cooling as it was, the mixture was extracted with ethyl acetate-dilute aqueous ammonia. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to NH-silica gel column chromatography and eluted with 20-100% ethyl acetate/hexane and then with 5% methanol/ethyl acetate, to give 1.54 g of the target compound.
Reaction SMILES: [OH:1][C:2]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12]C=O)[CH2:5][CH2:4][CH2:3]1.[OH-].[K+]>CO.O>[NH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:2]1([OH:1])[CH2:5][CH2:4][CH2:3]1
Reactant: O=CNc1ccccc1C1(O)CCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ccccc1C1(O)CCC1

Procedure:
N-(2-(1-hydroxycyclobutyl)phenyl)formamide (103 mg, 0.539 mmol) and potassium hydroxide (0.015 mL, 0.539 mmol) were combined in methanol (3 mL) and the mixture was heated to reflux for 3 hours. The reaction mixture was diluted with H2O (25 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The product was purified by flash chromatography (Analogix, 0 to 40% ethyl acetate in hexanes over 25 minutes, 4 g silica, 18 mL/minutes) to give 1-(2-aminophenyl)cyclobutanol.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:9][C@H:8]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCN(Cc2cccnc2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCCCN(Cc2cccnc2)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 106.8 %

Procedure:
In a round bottomed flask, to a stirred solution of (S)-tert-butyl 2-oxo-1-(pyridin-3-ylmethyl)azepan-3-ylcarbamate (150 mg, 0.470 mmol) in DCM (3 mL) was added 2,2,2-trifluoroacetic acid (0.186 mL, 2.35 mmol) at rt under argon. The reaction mixture was stirred at rt for 4 hr. The reaction mixture was concentrated and the residue was dried under vacuum to give (S)-3-amino-1-(pyridin-3-ylmethyl)azepan-2-one (110 mg, 0.502 mmol, 100% yield). Anal. Calcd. for C12H17N3O m/z 219.3. found: 220.3 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:19]2([O:49][C@H:48]([CH2:50][O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C@@H:39]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@H:30]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:21]2[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[OH:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCCC1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH:19]([OH:20])[C@H:21]([C@H:30]([C@@H:39]([C@@H:48]([CH2:50][O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[OH:49])[O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1c(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc2ccccc21
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1c(C(O)[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H](O)COCc2ccccc2)cc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
First, 7.74 g (9.72 mmol) of 1-C-[1-(phenylsulfonyl)indole-2-yl]-2,3,4,6-tetra-O-benzyl-D-mannopyranose [compound (IV) wherein R1 to R4 are benzyl and R5 is phenylsulfonyl] was dissolved in tetrahydrofuran (240 ml). Then, 1.11 g (29.25 mmol) of lithium aluminum hydride was added to the mixture and stirred at about 0° C. for about 30 minutes. After the reaction was completed, a saturated aqueous solution of Rochelle salt was added to the reaction mixture which was then subjected to extraction with diethylether. The ether solution was washed with saturated saline and then dried on anhydrous sodium sulfate. After removal of the solvent by distillation, the residue was fractionated by column chromatography on silica gel [silica gel: Merck Kieselgel 60 (230-400 mesh ASTM); elution solvent: n-hexane and ethyl acetate (5:2)] to give 5.85 g (yield 75%) of 1-C-[1-(phenylsulfonyl)indole-2-yl]-2,3,4,6-tetra-O-benzyl-D-mannitol [compound (V) wherein R1 to R4 are benzyl and R5 is phenylsulfonyl].
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[NH:11][C:12](=[O:20])[C:13]2[CH2:19][O:18][CH2:17][CH2:16][C:14]=2[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:39]=[CH:38][C:25]([C:26]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:34][C:35](O)=[O:36])[CH2:30][CH2:29]2)=[O:27])=[CH:24][CH:23]=1>>[CH2:1]([N:8]([CH2:9][C:10]1[NH:11][C:12](=[O:20])[C:13]2[CH2:19][O:18][CH2:17][CH2:16][C:14]=2[N:15]=1)[C:35](=[O:36])[CH2:34][N:31]1[CH2:32][CH2:33][CH:28]([C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([F:21])=[CH:39][CH:38]=2)[CH2:29][CH2:30]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(CNCc2ccccc2)nc2c1COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Product: O=C(c1ccc(F)cc1)C1CCN(CC(=O)N(Cc2ccccc2)Cc2nc3c(c(=O)[nH]2)COCC3)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (17.7 mg) from 2-((benzylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C29H31FN4O4 518.58. found 519.4 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.98 (br. s., 2H) 7.28-7.52 (m, 1H) 7.21 (d, J=7.58 Hz, 4H) 4.66 (d, J=8.08 Hz, 2H) 4.60 (br. s., 1H) 4.48 (br. s., 2H) 3.85-4.08 (m, 5H) 3.81 (br. s., 2H) 3.42 (d, J=7.07 Hz, 2H) 3.28 (br. s., 2H) 2.70 (d, J=15.66 Hz, 2H) 2.06-2.36 (m, 3H) 1.17-1.41 (m, 2H)
Reaction SMILES: Cl.Cl[CH:3]([CH2:6][NH2:7])[C:4]#N.[OH-:8].[Ca+2:9].[OH-:10]>O>[NH:7]1[CH2:6][CH:3]1[C:4]([O-:10])=[O:8].[Ca+2:9].[NH:7]1[CH2:6][CH:3]1[C:4]([O-:10])=[O:8]
Reactant: N#CC(Cl)CN
Reactant: [OH-]
Agent: Cl
Agent: [Ca+2]
Solvent: O
Product: O=C([O-])C1CN1
Temperature: 60 °C

Procedure:
14.1 g of alpha-chloro-beta-aminopropionitrile hydrochloride was dissolved in 160 g of water, and with stirring, 12 g of calcium hydroxide was gradually added. Then, the reaction mixture was heated to 60° C., and reacted at 60° to 65° C. for 8 hours. After the reaction, the excess of calcium hydroxide was removed by filtration. The residue was analyzed by high-speed liquid chromatography in the same way as in Example 1. The yield of calcium aziridine-2-carboxylate formed was 92.5%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[C:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25]([CH3:32])([CH3:31])[CH:24]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[C:15]([C:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25]([CH3:32])([CH3:31])[CH:24]=2)[CH:16]=1)([O-:22])=[O:21]
Reactant: CC1(C)C=C(c2cc([N+](=O)[O-])ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)C=C(c2cc([N+](=O)[O-])ccc2N2CCNCC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.5 %

Procedure:
A solution of 4-[4-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (300 mg, 0.676 mmol) produced in Example (88b) in dichloromethane (3 mL) was stirred at an external temperature of 0° C. Trifluoroacetic acid (1 mL) was gradually added dropwise thereto over a period of 15 minutes. The reaction mixture was allowed to warm to room temperature while stirring for 90 minutes. While cooled in an ice bath, saturated aqueous solution of sodium hydrogencarbonate to the mixture to make the mixture basic. Extraction was performed with ethyl acetate, and the separated organic layer was washed with water and then dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 180 mg of the title compound as a light yellow solid.