Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[CH3:13][CH:14]1[NH:19][CH2:18][CH2:17][NH:16][C:15]1=[O:20].C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:19]1[CH2:18][CH2:17][NH:16][C:15](=[O:20])[CH:14]1[CH3:13])=[N:7][N:6]=[CH:5]2
Reactant: CC1NCCNC1=O
Reactant: Clc1nncc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1C(=O)NCCN1c1nncc2cc(Br)ccc12
Temperature: 190 °C
Yield: 60.5 %

Procedure:
In three separate sealed tubes were placed a mixture of 6-bromo-1-chlorophthalazine (0.250 g, 1.03 mmol), 3-methylpiperazin-2-one (0.239 g, 2.09 mmol), K2CO3 (0.155 g, 1.12 mmol) and 5 mL of CH3CN. The three reactions were heated at 190° C. for 15 min in a microwave oven. The reaction mixtures were combined, concentrated onto silica gel and purified using flash chromatography eluting with 2M NH3 in MeOH/CH2Cl2 (0:1→1:19) to give 200 mg (60%) of an orange oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]2[C:7](O[C:10](=O)[C:3]=2[CH:2]=1)=O.N[C:13]1C=CC=CC=1>>[NH:1]1[C:2]2[C:4](=[CH:7][CH:13]=[CH:10][CH:3]=2)[CH:5]=[CH:6]1
Reactant: O=C1OC(=O)c2cnccc21
Reactant: Nc1ccccc1
Product: c1ccc2[nH]ccc2c1

Procedure:
In like fashion, reaction of 3,4-pyridinedicarboxylic anhydride (Formula Vb hereinbelow) with an aniline of Formula VI or an indole of Formula VII (Z--H hereinbelow) produces a mixture of 3-(Z--CO)-4-pyridinecarboxylic acid (Formula IIc) and 4-(Z--CO)-3-pyridinecarboxylic acid (Formula IId). The mixture is in turn reacted with a diarylamine of Formula III to produce an isomeric mixture of furo[3,4-c]pyridine-1(3H)-one (Formula Ic) and furo[3,4-c]pyridine-3(1H)-one (Formula Id). ##STR22##
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CN(C)C(N(C)C)=O>>[C:5]1([O:11][C:1]([Cl:4])=[O:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Cl
Reactant: Oc1ccccc1
Solvent: CN(C)C(=O)N(C)C
Product: O=C(Cl)Oc1ccccc1
Temperature: 120 °C
Yield: 99 %

Procedure:
In a reaction vessel provided with stirrer, thermometer and introduction tube for phosgene, a mixture of 94 g of phenol and 4.4 g of N,N,N',N'-tetramethyl urea were heated at 120° C and phosgene was led through at a speed of 100 g per hour. The introduction of phosgene was interrupted after 5 hours and the reaction mixture was distilled. 144 g (=92% of the theoretical amount) of a 99% chloroformic acid phenyl ester were obtained.
Reaction SMILES: [H-].[Na+].[C:3]1(=O)C2[C:7]([S:8][C:9]3[C:14](N=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:6][CH:5]=[CH:4]1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[N:26]=[C:27]=[O:28].Cl.[CH3:30][N:31]([CH:33]=[O:34])[CH3:32]>>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[NH:26][C:27]([CH:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[S:8][C:7]4[CH:6]=[CH:5][CH:4]=[CH:3][C:32]=4[N:31]([C:30]=23)[C:33]1=[O:34])=[O:28]
Reactant: CN(C)C=O
Reactant: O=c1cccc2sc3ccccc3nc1-2
Reactant: O=C=Nc1ccc(F)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: O=C(Nc1ccc(F)cc1F)C1C(=O)N2c3ccccc3Sc3cccc1c32
Reaction time: 12 h

Procedure:
To a suspension of sodium hydride (0.14 g) in DMF (10 ml) was added pyrrolo[3,2, -1kl]phenothiazine-1-one (0.48 g) and to the resulting solution was slowly added 2,4-difluorophenyl isocyanate (0.31 g). The reaction mixture was stirred for 12 hours and then poured onto ice water (50 ml). The resulting mixture was acidified to pH 2.0 with 6N HCl and the precipitated solid was collected and then air dried to yield the title compound (2.84 g). A sample recrystallized from methylene chloride had a m.p. of 208°-209° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](N)([NH:11][CH3:12])[CH:6]([CH:10]=1)[C:7]([O-:9])=[O:8].C(NC1C=CC(C(O)=O)=C(N[CH2:28][C:29]2[O:30][CH:31]=[CH:32][CH:33]=2)C=1)(=O)C.CC1OC(C=O)=CC=1>ClCCCl.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH2:12][C:31]2[O:30][C:29]([CH3:28])=[CH:33][CH:32]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: CNC1(N)C=CC(Cl)=CC1C(=O)[O-]
Reactant: CC(=O)Nc1ccc(C(=O)O)c(NCc2ccco2)c1
Agent: Cc1ccc(C=O)o1
Solvent: C1CCOC1
Solvent: ClCCCl
Product: Cc1ccc(CNc2ccc(Cl)cc2C(=O)O)o1

Procedure:
Reductive amination of 5-chloro-2-amino-methylanthranilate carried out as described for compound 1 using 5-methyl furaldehyde in DCE for 4 hrs. After workup, the product was isolated by FC using 10-30% acetone/hexanes to afford a light yellow solid. The ester was subsequently taken up in THF and saponified using 1N at 60° C. for 12 hrs. The solution was cooled, acidified and the product collected as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([Li])[C:4]2[C:12]([C:13]=1[CH3:14])=[CH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6]=1[CH:5]=2.[Si:16]([CH3:20])([CH3:19])(Cl)[Cl:17]>C1COCC1>[Cl:17][Si:16]([CH3:20])([CH3:19])[CH:3]1[C:4]2[C:12](=[CH:11][C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[CH:5]=2)[C:13]([CH3:14])=[C:2]1[CH3:1]
Reactant: [Li]C1C(C)=C(C)c2cc3c(cc21)CCC3
Reactant: C[Si](C)(Cl)Cl
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)Cl)c2cc3c(cc21)CCC3
Temperature: 22.5 °C
Yield: 76.7 %

Procedure:
(1,5,6,7-tetrahydro-2,3-dimethyl-s-indacen-1-yl)lithium (9.27 g, 0.04874 moles) in THF (90 mL) was added dropwise to a solution of Me2SiCl2 (18.90 g, 0.1463 moles) in THF (50 mL). This mixture was then allowed to stir at 20-25° C. 16 hours. After the reaction period the volatiles were removed and the residue extracted and filtered using hexane. The removal of the hexane resulted in the isolation of the desired product as an orange/brown oil (10.35 g, 76.7 percent).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[CH2:6]([O:13][C:14](ON1C(=O)CCC1=O)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCCCCCC.CCOC(C)=O>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:1][N:2]([CH2:3][C:4]#[CH:5])[C:14](=[O:15])[O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: C#CCNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: C#CCN(C)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of N-methylprop-2-yn-1-amine (3.05 ml, 36.2 mmol) in THF (50 ml) and NaHCO3 sat. aqueous solution (50.0 ml), N-(benzyloxycarbonyloxy)succinimide (11.31 ml, 39.8 mmol) was added and the reaction was stirred overnight. Then, organic layers were extracted with ethyl acetate (2×100 mL). Organic phases were collected, dried, filtered and solvent was removed under reduced pressure. The product was purified by Biotage Si 10 g with a gradient of heptane and EtOAc affording the title compound (5 g, 24.60 mmol, 68.0% yield) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[CH2:13]1[CH:21]2[N:16]([CH2:17][CH2:18][C:19](=O)[CH2:20]2)[CH2:15][CH2:14]1>[OH-].[K+].O>[CH2:13]1[CH:21]2[N:16]([CH2:17][CH:18]=[C:19]([C:7]3[C:6]4[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[NH:9][CH:8]=3)[CH2:20]2)[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: O=C1CCN2CCCC2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1
Yield: 38.2 %

Procedure:
A mixture of 5-nitro-1H-indole (4.48 g, 27.6 mmol) and and 7-octahydroindolizinone (5.0 g, 35.9 mmol) in methanolic potassium hydroxide (10% potassium hydroxide in 50 mL of methanol) was heated to reflux for 3.5 hours. The reaction was diluted with water and the precipitate was collected by filtration. The filter cake was triturated with hot diethyl ether and filtered. The filter cake was recrystallized from methanol and dried to give 2.99 g of the title compound. (38.5%). Calculated for C16H17N3O2: Theory: C, 67.83; H, 6.05; N, 14.83. Found: C, 68.07; H, 6.27; N, 14.82. MS(FD) (m/e): 283.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([O:16][CH3:17])=[CH:11][CH:10]=2)=[O:6])[CH3:3].[Sn].C(=O)=O>C(O)C>[CH2:2]([O:4][C:5]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:16][CH3:17])[CH:13]=2)[NH:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cc2cc(OC)ccc2[nH]1
Agent: Cl
Agent: O=C=O
Agent: [Sn]
Solvent: CCO
Product: CCOC(=O)C1Cc2cc(OC)ccc2N1
Reaction time: 1 h

Procedure:
A three neck 3-liter round bottom flask equipped with a mechanical stirrer, water condenser, and a gas inlet tube was charged with 500 ml. of absolute ethanol and chilled in a dry ice-acetone bath. Dry hydrogen chloride gas was added at a rapid rate for 0.5 hours. Fifty grams of 5-methoxyindole-2-carboxylic acid ethyl ester (B. Heath-Brown and P. G. Philpott, J. Chem. Soc. 1965, 7185) followed by 100 g. of tin metal (30 mesh) were added to the solution with stirring. With the dry ice bath in place, but with no additional cooling the reaction mixture was stirred gently for 6 hours. The crystalline solid that separated was removed by filtration. The mother liquor was evaporated under reduced pressure to give an oil. The oil dissolved in 500 ml. of absolute ethanol, was placed in a 3-liter round bottom flask equipped with a stirrer and thermometer, and chilled to 10°. Gaseous ammonia was bubbled into the mixture until the pH was 9 (by wet pH paper) and the mixture was allowed to stand at 10° for one hour. The white precipitate was filtered and the filtrate was evaporated on a rotary evaporator to dryness. The initial white precipitate and the residue from the evaporation were combined and triturated repeatedly with warm ether. The combined ether triturates were washed with a sodium chloride solution (a water: saturated salt solution, 1:1) with vigorous shaking; whereupon most of the basic tin salts were suspended and separated in the aqueous phase. Both phases were filtered through Celite and separated. The ether solution was dried over magnesium sulfate and evaporated under reduced pressure on the rotary evaporator. The oily residue was dried in vacuo to give 22 g. of d,l-2,3-dihydro-5-methoxy-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:13][NH2:14].[H][H]>[Pd].CO>[CH3:13][NH:14][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: CN
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)N1CCC(NC)CC1

Procedure:
A mixture of 102 parts of ethyl 4-oxo-1-piperidinecarboxylate, 50 parts of methanamine and 400 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off over Hyflo and the filtrate is evaporated, yielding 111 parts of ethyl 4-(methylamino)-1-piperidinecarboxylate as a residue.
Reaction SMILES: [C:1](=[O:14])([O-])[O:2][C:3]1[CH:8]=CC=C[C:4]=1C(C)(C)C.[C:15]1([CH2:23][NH2:24])[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=1.[CH2:25](O)C>>[C:1]([NH:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:23][NH2:24])=[CH:16][CH:17]=1)([O:2][C:3]([CH3:4])([CH3:8])[CH3:25])=[O:14]
Reactant: CCO
Reactant: NCc1ccc(CN)cc1
Reactant: CC(C)(C)c1ccccc1OC(=O)[O-]
Product: CC(C)(C)OC(=O)NCc1ccc(CN)cc1
Temperature: 25 °C

Procedure:
Tert-butylphenyl carbonate (2.7 mL, 14.7 mmol) was added dropwise to a solution of p-xylylenediamine (2 g, 14.7 mmol) in ethanol (20 mL) at 80° C. The reaction mixture was refluxed overnight. The solution was then cooled to room temperature and any solids were removed, which leaves a yellow solution. The solution was then concentrated to 10 mL and diluted with water (60 mL). The solution pH was adjusted to 3 with 2M HCl followed by an extraction with dichloromethane (3×75 mL). The water solution pH was then adjusted to pH 12 followed by extraction with dichloromethane (3×75 mL). The organic solutions were combined and washed with sodium bicarbonate (2×75 mL), dried with sodium sulfate, and concentrated down to a white solid. Characterization matches previously published literature (M. A. Ghanem, et al., “Covalent modification of glassy carbon surface with organic redox probes through diamine linkers using electrochemical and solid-phase synthesis methodologies”, Journal of Materials Chemistry, (2008), 18(41), pg 4917-4927).
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[C:15]([O:18][C:19]3[CH:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:34])[C:8]1=[O:35])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:35])[N:9]([CH3:34])[C:10]=3[N:17]=[CH:16][C:15]=2[O:18][C:19]2[CH:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[CH:32][CH:31]=1
Reactant: Cc1ccc(Oc2cnc3c(c2Cc2ccc(Cl)cc2)c(=O)n(CCCOC=O)c(=O)n3C)cn1
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Oc2cnc3c(c2Cc2ccc(Cl)cc2)c(=O)n(CCCO)c(=O)n3C)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-1-methyl-6-((6-methylpyridin-3-yl)oxy)-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (10 mg, 0.020 mmol) in THF (5 mL) and water (5 mL) was added LiOH.H2O (1.70 mg, 0.040 mmol). The reaction was stirred at RT for 30 min then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4, and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-3-(3-hydroxypropyl)-1-methyl-6-((6-methylpyridin-3-yl)oxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2 mg, 21.2% yield) as a white solid. 1H NMR (CDCl3) δ: 8.29 (s, 1H), 8.20 (d, J=2.4 Hz, 1H), 7.16-7.18 (m, 4H), 7.10 (d, J=8.6 Hz, 1H), 7.03 (s, 1H), 4.76 (s, 2H), 4.24 (t, J=6.2 Hz, 2H), 3.70 (s, 3H), 3.53-3.57 (m, 2H), 3.04 (t, J=7.0 Hz, 1H), 2.54 (s, 3H), 1.92-1.96 (m, 2H). LCMS: MH+ 467 and TR=1.903 min.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.[C:17]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:20](C(Cl)=O)=[CH:19][CH:18]=1.[CH2:32]([N:34]1[C:46]2[CH:45]=[CH:44][C:43]([NH2:47])=[CH:42][C:41]=2[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH3:33]>>[C:26]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:27]=[CH:28][C:29]([C:6]([N:8]2[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]2[C:10]([NH:47][C:43]2[CH:44]=[CH:45][C:46]3[N:34]([CH2:32][CH3:33])[C:35]4[C:40]([C:41]=3[CH:42]=2)=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:12])=[O:7])=[CH:30][CH:31]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: C=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-methyleneproline, [1,1′-biphenyl]-4-carbonyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 46% purity by LC/MS. MS(ESI+): m/z=500.4.
Reaction SMILES: [C:1](=[O:4])(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)O[C:17](=O)[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2)=O.Cl[CH2:29]Cl>>[CH3:29][C:16]1([CH3:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH:1]=[O:4]
Reactant: O=C([O-])O
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: ClCCl
Agent: [Na+]
Product: CC1(C)CCCCC1C=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a stirred mixture of the product of Example 46d (700 mg, 5.0 mmol) and sodium bicarbonate (420 mg, 5.0 mmol) in dichloromethane (10 mL) at 0° C. under argon was added Dess-Martin periodinane (3.14 g, 7.4 mmol). The reaction mixture was stirred at 0° C. for 2 hours and then slowly warmed to room temperature. The mixture was concentrated under reduced pressure and the residue purified by column silica gel chromatography to give the title compound as a colorless oil (600 mg, Yield: 85% yield). Rf=0.8 (10:1) petroleum ether/:ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 9.81 (d, J=2.4 Hz, 1H), 2.10-2.05 (m, 1H), 1.50-1.24 (m, 8H), 1.13 (s, 3H), 0.99 (s, 3H) ppm.
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:16][C@@H:15]2[C@@H:13]([CH2:14]2)[N:12]1[C:17](=[O:31])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28](=[O:30])[NH2:29])=[N:20]1)=[O:10])C1C=CC=CC=1>C1COCC1.CCOC(C)=O>[C:28]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]([CH2:18][C:17]([N:12]2[C@H:11]([C:9]([OH:10])=[O:8])[CH2:16][C@@H:15]3[C@H:13]2[CH2:14]3)=[O:31])[N:20]=1)(=[O:30])[NH2:29]
Reactant: NC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)OCc2ccccc2)c2ccccc12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(1R,3S,5R)-2-[2-(3-carbamoyl-indazol-1-yl)-acetyl]-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester (3.9 g, 8.85 mmol) was dissolved in THF (120 mL) and EtOAc (120 mL). Air was removed from the flask and replaced with nitrogen three times. Pd/C 10% (390 mg) was added to the solution which was again degassed, placed under a hydrogen atmosphere, and stirred at RT for 4 h. The catalyst was removed through a pad of Celite and washed with EtOAc. Solvents were removed under reduced pressure and the foam thus obtained was used without further purification in the next step. MS (LCMS): 346.2 [M+NH4]+, 327.1 [M−H]−; tR (HPLC conditions f): 1.12 min.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].CN(C=O)C.[H-].[Na+].[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29])[CH2:23]Cl>C(OCC)(=O)C>[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29])[CH2:23][N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3](=[O:4])[C:2]([F:1])([F:10])[F:11]
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Reactant: O=C(c1ccc[nH]1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Cn2cccc2C(=O)C(F)(F)F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
2-(Trifluoroacetyl)-1H-pyrrole (0.97 g) was added to DMF solution (10 ml) of 60% sodium hydride (0.16 g) and the mixture was stirred at room temperature for 30 minutes. 3-Methyl-4-nitrobenzyl chloride (1.0 g) was added thereto and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitrobenzyl)-2-(trifluoroacetyl)-1H-pyrrole (1.53 g).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1)#[N:2].O.[OH-].[Na+]>C(OCC)C>[NH2:2][CH2:1][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(CO)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: NCc1ccc(CO)cc1
Temperature: 25 °C
Yield: 29.5 %

Procedure:
To a stirred suspension of LiAH4 (285 mg, 7.52 mmol) in diethylether (10 mL) at 0° C. was added a solution of 4-cyanobenzyl alcohol (0.5 g, 3.76 mmol) in diethylether (5 mL) over 15 min. The grey reaction mixture was heated to reflux for 3 h. After cooling to r.t., the mixture was treated successively with water (1 mL), 2M NaOH (2 mL) and water (2 mL) under vigorous stirring. The resulting white slurry was filtered and washed with CH2Cl2 (20 mL). Extraction with additional CH2Cl2 (20 mL) and n-butanol (20 mL) and evaporation yielded an oil, which upon flash chromatography (0-15% MeOH in CH2Cl2) gave 152 mg (29%) of 4-(aminomethyl)benzylalcohol (57 MBT52B) as a white solid. Rf=0.51 (30% MeOH in CH2Cl2+3.5% NH4OH).
Reaction SMILES: [NH2:1][C@H:2]([C@@H:10]([OH:22])[C@H:11]([OH:21])[C@@H:12]([NH2:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+](C1C=CC(O[C:33](=[O:50])[C@H:34]([C@H:46]([CH2:48][CH3:49])[CH3:47])[NH:35][C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])=CC=1)([O-])=O.[OH-:51].[Na+]>O1CCCC1>[C:36]([NH:35][C@H:34]([C:33]([NH:1][CH:2]([CH:10]([OH:22])[CH:11]([OH:21])[CH:12]([NH:20][C:33](=[O:50])[C@H:34]([C@H:46]([CH2:48][CH3:49])[CH3:47])[NH:35][C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:37])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:50])[C@H:46]([CH2:48][CH3:49])[CH3:47])([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:51]
Reactant: N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)CC
Temperature: 25 °C
Reaction time: 21 h
Yield: 86 %

Procedure:
A mixture of 10 mg (0.033 mmol) of the resultant compound of Example 171 and 38.6 mg (0.10 mmol) of Cbz-isoleucine p-nitrophenyl ester in 0.2 ml of tetrahydrofuran was stirred at ambient temperature for 21 h. The resulting misture was diluted with 1 ml of tetrahydrofuran, treated with 0.5 ml of 3N NaOH, stirred for 45 min, extracted with chloroform, washed sequentially with 3N NaOH and saturated brine, dried over MgSO4, and concentrated. The residue was purified on silica gel by eluting with 2% methanol in chloroform to provide 23 mg (86%) of the desired compound. Mass spectrum: (M+H)+ =795.
Reaction SMILES: [NH2:1][CH:2]([CH:20]([CH3:22])[CH3:21])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=[O:4].[CH2:23](Br)[C:24]#[CH:25]>>[CH2:25]([NH:1][CH:2]([CH:20]([CH3:22])[CH3:21])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=[O:4])[C:24]#[CH:23]
Reactant: CC(C)C(N)C(=O)OCc1cccc(Oc2ccccc2)n1
Reactant: C#CCBr
Product: C#CCNC(C(=O)OCc1cccc(Oc2ccccc2)n1)C(C)C

Procedure:
Following the procedure of Example 2, (6-phenoxy-2-pyridyl)methyl 2-amino-3-methylbutanoate and 2-propyn-1-yl bromide are reacted, resulting in a mixture of two end products, which are separated to give (6-phenoxy-2-pyridyl)methyl 2-[N-(2-propynyl)amino]-3-methylbutanoate and (6-phenoxy-2-pyridyl)methyl 2-[N,N-(di-2-propynyl)amino]-3-methylbutanoate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.O.NN>C(O)C.[Ni]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([NH2:9])[CH:3]=1
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.4 %

Procedure:
To a stirred solution of 4-bromo-2-nitrotoluene (2.04 g, 9.44 mmol) (Aldrich Chemical Company) in ethanol (25 mL) was added hydrazine hydrate (1.14 mL, 23.60 mmol) drop-wise. After being stirred for 5 min, a suspension of Raney nickel (˜100 mg) in ethanol (5 mL) was added slowly and carefully. Gas evolution was observed. After gas evolution subsided, the reaction mixture was heated to reflux for 1 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated on a rotary evaporator, diluted with water (25 mL) and extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered and concentrated to produce 1.57 g (89.4%) of a colorless oil.