Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:13]2[S:12][C:11](=[O:14])[NH:10][C:9]=2[C:8]([OH:15])=[CH:7][CH:6]=1)=[O:4].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O>[N:16]([CH2:2][C:3]([C:5]1[C:13]2[S:12][C:11](=[O:14])[NH:10][C:9]=2[C:8]([OH:15])=[CH:7][CH:6]=1)=[O:4])=[N+:17]=[N-:18]
Reactant: O=C(CCl)c1ccc(O)c2[nH]c(=O)sc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(=O)c1ccc(O)c2[nH]c(=O)sc12
Reaction time: 0.17 h

Procedure:
7-(2-Chloro-acetyl)-4-hydroxy-3H-benzothiazol-2-one (example 1, step a) (331 g) was dissolved in N,N-dimethylformamide (1800 mL) and stirred in an ice bath for 10 minutes. Sodium azide (88.3 g) was added portionwise over 15 minutes. The reaction was stirred for 72 hours and then the reaction mixture was divided into 3 equal portions and each quenched separately into ice and water (2.5 L). The solid was filtered off and washed with water (1 L) and re-suspended in acetonitrile (1.5 L). The solvent was evaporated and a further portion of acetonitrile (1 L) added and solvent evaporated again to dry the product. Diethyl ether (1.5 L) was added and the mixture stirred to achieve an homogeneous suspension. The solid was collected and dried in vacuo at 35° C. for 24 hours to give the subtitled compound. Yield 285 g.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)(=O)=O.[CH3:26][O-:27].[Na+]>>[CH3:26][O:27][C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1
Reactant: C[O-]
Reactant: CCCOc1ccccc1-c1nc2nc(S(C)(=O)=O)ncc2c(=O)[nH]1
Agent: [Na+]
Product: CCCOc1ccccc1-c1nc2nc(OC)ncc2c(=O)[nH]1

Procedure:
In a similar manner to Example 61 reaction of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.50 g) and sodium methoxide solution (from sodium, 0.16 g, and methanol, 20 ml) yielded the title compound, 0.29 g, m.p. 231-2° C. (recrystallized from methanol).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([CH3:10])=[N:6][S:7][C:8]=1N.[NH2:11][C:12]1[C:21]([C:22]([O:24]N2C3C=C(Cl)C=CC=3N=N2)=[O:23])=[C:15]2[N:16]=[CH:17][C:18]([F:20])=[CH:19][N:14]2[N:13]=1.O>CN1C(=O)CCC1>[NH2:11][C:12]1[C:21]([C:22]([O:24][C:8]2[S:7][N:6]=[C:5]([CH3:10])[C:4]=2[Br:3])=[O:23])=[C:15]2[N:16]=[CH:17][C:18]([F:20])=[CH:19][N:14]2[N:13]=1
Reactant: Cc1nsc(N)c1Br
Reactant: Nc1nn2cc(F)cnc2c1C(=O)On1nnc2ccc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nsc(OC(=O)c2c(N)nn3cc(F)cnc23)c1Br
Reaction time: 0.17 h

Procedure:
NaH (210.3 mg, 5.259 mmol) was added to a solution of 4-bromo-3-methyl-isothiazol-5-amine (533 mg, 2.761 mmol) in dry NMP (21.95 mL) at RT. The solution was stirred at RT for 5 min before (6-chlorobenzotriazol-1-yl) 2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate 6a* (914.4 mg, 2.630 mmol) was added. After 10 min, the reaction mixture was treated with water (120 mL) and stirred for 15 mins. The pale brown solid was filtered off and dried in vacuo to afford 4-bromo-3-methylisothiazol-5-yl 2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylate. (801 mg, 82%). MS (ES+) 370.5.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].[CH:14]1([NH2:17])[CH2:16]C1.[C:18]12[C:24](=CC=CC=1)[NH:23]C(=O)OC2=O>>[CH:7]1([NH:6][C:4](=[O:5])[C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]=2[NH:1][CH2:16][C:14]2[NH:17][CH2:18][CH2:24][N:23]=2)[CH2:8][CH2:9]1
Reactant: Nc1ccccc1C(=O)NC1CC1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccccc1NCC1=NCCN1

Procedure:
2-Amino-N-cyclopropylbenzamide (prepared from cyclopropylamine and isatoic anhydride, using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give N-cyclopropyl-2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]benzamide, isolated as the hydrochloride salt.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[C:10]([C:21]([OH:23])=[O:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CO.[H][H]>COC(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C@H:10]([C:21]([OH:23])=[O:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: Cc1ccccc1C1=C(C(=O)O)CN(C(=O)OC(C)(C)C)CC1
Solvent: CO
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: Cc1ccccc1[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O
Temperature: 25 °C

Procedure:
In a glove box an autoclave was charged with 4-o-tolyl-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester (2.5 g), [Ru(OAc)2 ((R)-(2-furyl)-MeOBIPHEP)] (24 mg), triethylamine (1.1 mL) and methanol (25 mL). The asymmetric hydrogenation was run for 60 h at 80° C. under 40 bar of hydrogen. After cooling to room temperature the pressure was released from the autoclave, the methanol solution was diluted with tert-butyl methyl ether (320 mL) and extracted with 1 M aqueous sodium hydroxide solution (2×, 320 mL). The aqueous layer was poured on ice, acidified with ice-cold 2 M aqueous hydrochloric acid solution to pH 1 and extracted with ethyl acetate (3×). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo and triturated from n-heptane to give (3S,4S)-4-o-tolyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester as a white solid, MS: 318.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:14]=3[CH:20]=2)=O)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23].C(O)(=O)C>C(O)C>[CH3:18][C:16]1([CH3:19])[CH2:15][C:14]2[CH:20]=[C:10]([C:8](=[N:22][NH2:23])[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:11]=[CH:12][C:13]=2[O:17]1
Reactant: CC1(C)Cc2cc(C(=O)c3ccc(Cl)cc3)ccc2O1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC1(C)Cc2cc(C(=NN)c3ccc(Cl)cc3)ccc2O1

Procedure:
This compound was prepared in a manner analogous to that of Example 1, Step D, using 1.4 grams (0.005 mole) of (4-chlorophenyl) (2,3-dihydro-2,2-dimethylbenzofuran-5-yl)ketone, 0.4 mL (0.008 mole) of hydrazine hydrate, and 0.3 mL of acetic acid in 50 mL of ethanol. The yield of (4-chlorophenyl) (2,3-dihydro-2,2-(dimethyl- benzofuran-5-yl) ketone hydrazone was 1.23 grams. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]2[C:17]([O:19][CH3:20])=[O:18])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34]Br>CN(C=O)C.O>[CH3:16][C:11]1[N:12]([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[C:31]([O:30][CH3:29])[CH:32]=2)[C:13](=[O:15])[CH2:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:8][CH:7]=2)[C:10]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C1=C(C)NC(=O)CC1c1ccc(C(F)(F)F)cc1
Reactant: COc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)N(Cc2cccc(OC)c2)C(=O)CC1c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Yield: 0.1 %

Procedure:
The product from Example 5, Step 1 (0.627 g, 2.00 mmol, 1.00 equiv) and cesium carbonate (0.975 g, 3.00 mmol, 1.50 equiv) were combined in DMF (9 mL) for 15 minutes at rt. 3-Methoxybenzyl bromide (0.436 mL, 3.12 mmol, 1.56 equiv) was added and the reaction was heated to 100° C. for 6 hours. The reaction was diluted with H2O and extracted with Et2O. The organic phase was washed with H2O and satd. NaCl, dried over MgSO4 and concentrated en vacuo to provide 0.762 mg (88%) of the title compound as an oil. MS (ES+) m/e 434 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)=[CH:16][C:9]=23)[CH:5]=[N:4][CH:3]=1.[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[N:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55]>C(Cl)Cl.C(O)(=O)C.ClCCCl>[NH:20]1[CH2:19][CH2:18][CH:17]([C:15]2[NH:14][C:10]3=[N:11][CH:12]=[CH:13][C:8]([C:6]4[N:7]=[C:2]([NH:1][CH2:30][C:31]5[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=5)[CH:3]=[N:4][CH:5]=4)=[C:9]3[CH:16]=2)[CH2:22][CH2:21]1.[F:52][C:53]([F:58])([F:57])[C:54]([O-:56])=[O:55]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3c(-c4cncc(N)n4)ccnc3[nH]2)CC1
Reactant: O=Cc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C([O-])C(F)(F)F
Product: c1cncc(CNc2cncc(-c3ccnc4[nH]c(C5CCNCC5)cc34)n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Example 319A (50 mg, 0.13 mmol) in a mixed solvent of 1,2-dichloroethane (1 ml) and acetic acid (0.5 ml) was added nicotinaldehyde (20 mg, 0.19 mmol). The mixture was stirred at room temperature for 2 hours and sodium triacetoxyborohydride (40 mg, 0.19 mmol) was added. The mixture was stirred overnight. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was concentrated and purified by flash chromatography on silica gel using an ISCO Companion eluting with heptanes/ethyl acetate (30%) to give Boc-protected intermediate which was dissolved in CH2Cl2 (10 mL) then treated with trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 5 hours and concentrated. The residue was purified by reverse-phase HPLC on Zorbax XDB C-18 using a gradient of 5-40% acetonitrile/water (containing 0.1% trifluoroacetic acid) to afford the title compound as a trifluoroacetate salt. 1H NMR (400 MHz, DMSO-d6) δ 1.64-1.86 (m, 2H), 2.02-2.25 (m, 2H), 3.05 (dd, J=13.0, 8.4 Hz, 3H), 3.38 (d, J=12.4 Hz, 2H), 4.77 (d, J=4.5 Hz, 2H), 6.57 (s, 1H), 7.51 (d, J=5.1 Hz, 1H), 7.77 (dd, J=8.0, 5.3 Hz, 1H), 8.12 (s, 1H), 8.24 (t, J=6.3 Hz, 2H), 8.45 (s, 1H), 8.68 (d, J=5.3 Hz, 1H), 8.82 (s, 1H). MS (ESI+) m/z 386 (M+H)+.
Reaction SMILES: [S-2:1].[Na+].[Na+].[S].Cl[C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=O.Cl[CH2:15][C:16](=[O:18])[CH3:17].[OH-].[Na+]>O.C(OCC)C.CN1CCCC1=O>[C:16]([C:15]1[S:1][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH:8]=1)(=[O:18])[CH3:17]
Reactant: [S-2]
Reactant: O=Cc1ccccc1Cl
Reactant: CC(=O)CCl
Agent: [Na+]
Agent: [OH-]
Agent: [S]
Solvent: CCOCC
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a 200 ml four-necked flask, equipped with a stirrer, a thermometer and a reflux condenser, were added 11.7 g (150 m moles) of anhydrous sodium sulfide, 3.2 g (100 m moles) of sulfur and 100 ml of N-methylpyrrolidone, and the mixture was stirred at room temperature for one hour. To the reaction mixture was dropwise added 14.1 g (100 m moles) of 2-chlorobenzaldehyde, and the mixture was stirred at room temperature for 12 hours. To the reaction mixture, was dropwise added 11.1 g (120 m moles) of chloroacetone with cooling, and the reaction mixture was stirred at room temperature for 6 hours. After finishing the reaction, 100 ml of diethyl ether and 100 ml of water were added to the reaction mixture, and pH value of the aqueous layer was adjusted to higher than 11 with a sodium hydroxide aqueous solution, and extracted with diethyl ether. The diethyl ether extract was washed twice with water, and the diethyl ether layer was concentrated under a reduced pressure to obtain 13.0 g of 2-acetylbenzo[b]thiophene (yield 74%). Purity of the product was 95% as determined by gas chromatography.
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][OH:4].[CH2:7]([OH:12])[CH:8]([OH:11])[CH2:9][OH:10].[CH2:13]([OH:18])[CH:14]([OH:17])[CH2:15][OH:16].[CH2:19]([OH:24])[CH:20]([OH:23])[CH2:21][OH:22].[C:25]([OH:34])(=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].ON1C(=O)CCC1=O.CC(N=C=NC(C)C)C>C1COCC1>[CH2:27]([CH:26]([CH2:1][CH2:2][CH2:3][CH2:7][CH2:8][CH3:9])[C:25]([OH:34])=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[OH:18][CH2:13][CH:14]([CH2:15][OH:16])[OH:17].[OH:24][CH2:19][CH:20]([CH2:21][OH:22])[OH:23].[OH:6][CH2:1][CH:2]([CH2:3][OH:4])[OH:5].[OH:12][CH2:7][CH:8]([CH2:9][OH:10])[OH:11]
Reactant: CCCCCCCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: O=C1CCC(=O)N1O
Solvent: OCC(O)CO
Solvent: C1CCOC1
Product: CCCCCCC(CCCCCC)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 250 mL vessel, tetraglycerol (5.0 g, 15.91 mmol) was added and dissolved into anhydrous THF (50 mL). Octanoic acid (15.12 mL, 95.44 mmol) was also dissolved into the reaction mixture which was stirred magnetically at room temperature for one hour to fully dissolve the reagents. N,N-dimethylaminopyridine (0.194 g, 1.59 mmol) and N-hydroxysuccinimide (0.183 g, 1.59 mmol) were both dissolved in the solution. When the catalysts were fully dissolved, N,N-diisopropylcarbodiimide (15.0 mL, 97.03 mmol) was pipetted into the vessel and was sealed to keep the reaction dry. The reaction proceeded overnight at 55° C. The solution was stripped of THF via rotoevaporation and redissolved into chloroform. The organic layer was washed 2× with sodium bicarbonate buffer and 2× with deionized water to remove unreacted starting materials. The chloroform was removed to yield a clear viscous liquid. NMR analysis supported full conversion of hydroxyl groups to the octanoic esters.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(C)C.Br[CH2:27][CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1>C1C=CC=CC=1>[Br:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:9][CH2:10][N:11]([CH2:27][CH2:28][C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][CH:30]=3)[CH2:12][CH2:13]2)=[CH:5][CH:4]=1
Reactant: Brc1ccc(OC2CCNCC2)cc1
Reactant: BrCCc1c[nH]c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CC(C)O
Product: Brc1ccc(OC2CCN(CCc3c[nH]c4ccccc34)CC2)cc1
Reaction time: 22 h

Procedure:
A mixture of 8.1 g of 4-(p-bromophenoxy)piperidine hydrochloride, 12.6 g of potassium carbonate and 60 ml. of isopropanol is stirred and refluxed for one hour. A solution of 6.5 g of 3-(2-bromoethyl)indole in 15 ml. of isopropanol is then added. Stirring and refluxing is continued for 22 hours, and the reaction mixture is filtered hot. A yellow oil separates in the cooled filtrate and the supernatant isopropanol is decanted from the oil. The isopropanol is diluted with ether, causing the unreacted 4-(p-bromophenoxy)piperidine to separate. After filtration, the isopropanol is removed under reduced pressure to give a yellow oil. The oil is permitted to stand for 3 weeks during which time it solidifies to a soft brown solid. Trituration of the solid with benzene affords yellow crystals, which are recrystallized from acetonitrite to give slightly yellow cubes of 3-{2-[4-(p-bromophenoxy)piperidyl]ethyl]-indole, m.p. 132°-134° C.
Reaction SMILES: CO[C:3](=[O:20])[C:4]([OH:19])=[CH:5][C:6](=[O:18])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[O:8][CH3:9].C=O.[NH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.Cl[C:33]1C=C(C=CC=1Cl)CN(C)C(C1CN(CCN2CCOCC2)C(=O)C=1O)=O>>[F:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]2[CH2:33][N:23]([CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:3](=[O:20])[C:4]=2[OH:19])=[O:18])=[CH:16][CH:15]=1
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCOCC2)C1
Reactant: NCCN1CCNCC1
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)cc1)OC
Agent: C=O
Product: CON(Cc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(CCN2CCNCC2)C1
Yield: 4.3 %

Procedure:
3-[(4-Fluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 44-D) was treated with paraformaldehyde and N-(2-aminoethyl)piperazine as described in the preparation of Compound 13. The mixture was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white powder (0.0110 g, 4.3% yield). 1H NMR (500 MHz, CDCl3) δ: 2.55 (t, J=6.2 Hz, 2H), 2.71 (s, 4H), 2.98 (s, 4H), 3.47 (t, J=5.5 Hz, 2H), 3.57 (s, 3H), 4.03 (s, 2H), 4.68 (s, 2H), 6.87 (s, 2H), 7.17 (m, 2H), 9.72 (bs, 1H), 11.45 (bs, 1H). HRMS (M+H) calcd for C19H25FN4O4: 391.17816. found: 391.1786.
Reaction SMILES: [Na].C(O)C.Cl.[CH3:6][CH:7]([CH3:12])[CH2:8][C:9](=[NH:11])[NH2:10].[C:13](OCC)(=[O:20])[CH2:14][C:15](OCC)=[O:16]>O.C(O)(=O)C>[CH2:8]([C:9]1[N:10]=[C:15]([OH:16])[CH:14]=[C:13]([OH:20])[N:11]=1)[CH:7]([CH3:12])[CH3:6]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)CC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(C)Cc1nc(O)cc(O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.2 %

Procedure:
Sodium (0.75 g, 32.94 mmol) and ethanol (20 mL) were introduced in a flask. Once all the sodium had dissolved, 3-methylbutanimidamide hydrochloride (1.5 g, 10.98 mmol) and diethyl malonate (1.67 mL, 10.98 mmol) were added. It was stirred for 1 hour at room temperature and for 5 hours under reflux. The reaction crude was cooled at room temperature and concentrated to dryness. The solid obtained was dissolved in water and the pH was adjusted to 5 with acetic acid. The precipitate formed was filtered providing 1.5 g of the title compound (yield: 81%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:8][C:9]([OH:11])=[O:10])[C:5](O)=[O:6].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[NH2:16].C(N(CC)CC)C.O>C1(C)C(C)=CC=CC=1>[Cl:12][C:13]1[CH:14]=[C:15]([N:16]=[C:5]([OH:6])[CH:4]([CH2:3][O:2][CH3:1])[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: COCC(CC(=O)O)C(=O)O
Reactant: Nc1cc(Cl)cc(Cl)c1
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Product: COCC(CC(=O)O)C(O)=Nc1cc(Cl)cc(Cl)c1

Procedure:
150 g of 2-methoxymethylsuccinic acid, 150g of 3,5-dichloroaniline and 0.5 g of triethylamine are heated under reflux, for four hours, in 1.5 liters of xylene, and the water formed is separated off by means of a water separator. The solvent is then drawn off. 250 g of end product are obtained in crystalline form.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](I)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[N:18]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[N:19]1>>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:22]2[N:18]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[N:19]=[CH:20][CH:21]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC1(C)OB(c2ccn(C3CCCCO3)n2)OC1(C)C
Reactant: Cc1c(I)ccc(C#N)c1Cl
Product: Cc1c(-c2ccnn2C2CCCCO2)ccc(C#N)c1Cl
Yield: 68.5 %

Procedure:
The title compound was prepared from 2-chloro-4-iodo-3-methylbenzonitrile (3.52 g, 12.68 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.88 g, 13.95 mmol) using the method of Example 34(a) affording 2.62 g of the title compound.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:37]([O:39][CH3:40])=[O:38])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C@@H:16](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1COCC1.[N:46]([Si](C)(C)C)=[N+:47]=[N-:48]>>[N:46]([C@@H:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:37]([O:39][CH3:40])=[O:38])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:21]2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1)=[N+:47]=[N-:48]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](OS(=O)(=O)c1ccc(C)cc1)COc1ccccc1-3
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N=[N+]=[N-])COc1ccccc1-3
Temperature: 65 °C
Reaction time: 20 h
Yield: 84 %

Procedure:
To a solution of the foregoing product from step 1 in dry THF (0.06 M) azidotrimethylsilane (3.5 eq.) and tetrabutylammonium triphenyldifluorosilicate (3.5 eq.) were added. The reaction was stirred for 20 h at 65° C. then 1 more eq. of azidotrimethylsilane was added and the mixture stirred at 65° C. for 36 h. The volatiles were evaporated in vacuo and the crude dissolved in EtOAc was washed with hydrochloric acid (1 N), sodium hydrogen carbonate (saturated solutions) and brine. Drying over Na2SO4, filtration and concentration in vacuo gave the crude product, which was purified by flash chromatography on silica gel (5:95 EtOAc/PE) to afford the title compound as white foam (84%); MS (ES+) m/z 431 (M+H)+.
Reaction SMILES: [N+]([O-])(O)=[O:2].C([O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:19])=[CH:13][C:14](=[O:18])[O:15]2)=[CH:10][CH:9]=1)C>C(Cl)(Cl)Cl>[OH2:2].[OH:19][C:12]1[C:11]2[C:16](=[CH:17][C:8]([OH:7])=[CH:9][CH:10]=2)[O:15][C:14](=[O:18])[CH:13]=1
Reactant: O=[N+]([O-])O
Reactant: CCOc1ccc2c(O)cc(=O)oc2c1
Solvent: ClC(Cl)Cl
Product: O
Product: O=c1cc(O)c2ccc(O)cc2o1
Reaction time: 2 h

Procedure:
Fuming nitric acid (25 ml) was added to a stirred suspension of 7-ethoxy-4-hydroxycoumarin (m.p. 267°-8°; 5.0g) in chloroform (500 ml) at room temperature over 1.5 hours. After a further two hours, the solvent was removed in vacuo and 6N hydrochloric acid (100 ml) added to the residue. Filtration and recrystallisation from ethanol gave the product, m.p. 153°-4°(d); (C11H9NO6 requires C, 52.59; H, 3.61; N, 5.58. Found: C, 52.48; H, 3.36; N, 5.29).
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]1([C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10])[OH:8].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.Cl>CC(N(C)C)=O>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:8][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[OH:10])=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccccc1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(Oc2ccccc2O)cc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 53 %

Procedure:
Anhydrous DMA (50 ml) was added to t-BuOK (5.46 g, 48.7 mmol) and catechol (5.00 g, 45.4 mmol) at 0° C. under argon, the mixture was heated to 120° C. over 10 min. A solution of 1-fluoro-4-nitro-benzene (6.40 g, 45.4 mmol) in anhydrous DMA (10 ml) was added dropwise over 20 min. The reaction mixture was then stirred at 130° C. for 1.5 h, cooled, and poured into 1N HCl (200 ml), extracted with EtOAc (2×50 ml). The combined extract was washed H2O (3×150 ml), brine (150 ml), dried with Na2SO4, concentrated and purified by silica gel flash column chromatography to give desired product 388A (5.56 g, 53%) as a faintly yellow solid (0%-1% ethyl acetate-CH2Cl2).
Reaction SMILES: C([O:8][C:9](=[O:30])[CH2:10][C@H:11]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:12][N:13]1[C:18](=[O:19])[CH2:17][CH2:16][CH:15]([CH3:20])[C:14]1=[O:21])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:26]([O:25][C:23]([NH:22][C@H:11]([CH2:12][N:13]1[C:18](=[O:19])[CH2:17][CH2:16][CH:15]([CH3:20])[C:14]1=[O:21])[CH2:10][C:9]([OH:30])=[O:8])=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: [H][H]
Reactant: CC1CCC(=O)N(C[C@H](CC(=O)OCc2ccccc2)NC(=O)OC(C)(C)C)C1=O
Agent: [Pd]
Solvent: CO
Product: CC1CCC(=O)N(C[C@H](CC(=O)O)NC(=O)OC(C)(C)C)C1=O
Yield: 34.6 %

Procedure:
(S)-3-t-butoxycarbonylamino-4-(3-methyl-2,6-dioxo-piperidin-1-yl)-butyric acid benzyl ester (218 mg, 0.52 mmol) synthesized in Section (1) was dissolved in methanol and 10% Pd/C (22 mg, 0.1 eq) was added thereto, followed by stirring for 1 hour under 1 atm hydrogen gas. After the reaction was complete, Pd on charcoal was removed by celite filtration. The residue was purified by prep-TLC to afford 59 mg (yield: 35%) of the title compound.
Reaction SMILES: [N:1]([CH:4]([C:9]([CH3:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:5]([O:7][CH3:8])=[O:6])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O.C1COCC1>[CH3:10][C:9]([CH3:17])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C@@H:4]([C:5]([O:7][CH3:8])=[O:6])[NH2:1]
Reactant: COC(=O)C(N=[N+]=[N-])C(C)(C)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@@H](N)C(C)(C)c1ccccc1
Reaction time: 12 h
Yield: 60.3 %

Procedure:
A solution of methyl 2-azido-3-methyl-3-phenylbutanoate (2.6 g, 11.2 mmol) and PPh3 (4.4 g, 16.7 mmol) in H2O (400 uL) and THF (100 mL) was stirred at 25° C. over 2d then at 50° C. for 12 h. The solution was concentrated and purified via column chromatography (silica, 5% MeOH in DCM (1% NH4OH)) yielding the title compound (1.4 g, quant.): LCMS (ES) m/e 208 (M+H)+.