Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:10])[N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[C-:11]#[N:12].[K+].C(=O)([O-])O.[Na+]>ClCCl.O>[CH3:1][N:2]([CH3:10])[N:3]1[CH2:8][CH2:7][C:6]([OH:9])([C:11]#[N:12])[CH2:5][CH2:4]1
Reactant: [C-]#N
Reactant: CN(C)N1CCC(=O)CC1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CN(C)N1CCC(O)(C#N)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
A solution of 6.0 g 1-dimethylamino-piperidin-4-one (prepared as described in Journal of Medicinal & Pharmaceutical Chemistry, 4, 423-36; 1961) in 30 ml of dichloromethane is added to a mixture of 4.1 g potassium cyanide and 10.6 g sodium hydrogencarbonate in 30 ml of water. The resulting mixture is stirred at room temperature for 3 hours, then extracted with ethyl acetate, the organic layer dried over sodium sulfate, and the solvent evaporated. 4.8 g 1-Dimethylamino-4-hydroxy-piperidine-4-carbonitrile is obtained. 1H-NMR (CDCl3): 3.95 ppm (s, broad, 1H), 2.90 ppm (m, 2H), 2.68 ppm (m, 2H), 2.40 ppm (s, 6H), 2.15 ppm (m, 2H), 1.95 ppm (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]#[N:26])[CH:23]=3)[N:18]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[N:17]=2)[CH:13]=[CH:14][CH:15]=1.[OH-:33].[Na+].OO>CCO>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([NH2:26])=[O:33])[CH:23]=3)[N:18]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[N:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: [OH-]
Reactant: N#Cc1ccc2c(c1)c(-c1cccc(OCCC3CCCCN3)c1)nn2C1CCCCO1
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ccc2c(c1)c(-c1cccc(OCCC3CCCCN3)c1)nn2C1CCCCO1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
3-[3-(2-Piperidylethoxy)phenyl]-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.67 g, 1.6 mmol) was dissolved in 2 mL EtOH and the solution was cooled to 0° C. Aqueous 6 N NaOH solution (1.04 mL, 0.25 g, 6.2 mmol) and aqueous 30% H2O2 (0.7 mL, 0.21 g, 6.2 mmol) were added to the reaction mixture. The reaction mixture was warmed to room temperature and stirred for 1.5 h. The reaction was quenched by addition of 6 N HCl. The resultant solution was neutralized by addition of saturated aqueous solution of sodium bicarbonate. The solution was extracted with EtOAc, the organic layer was washed with water, brine, dried (Na2SO4) and filtered. The filtrate was concentrated to 0.61 g (87%) of the title compound obtained as a yellow solid. ES-MS (m/z) 449 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([OH:17])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19]OS(OC)(=O)=O.[OH-].[Na+].O1CCOCC1>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([O:17][CH3:19])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1c(OCc2ccccc2)ccc(C=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C=O)ccc(OCc2ccccc2)c1C
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A mixture of 4-benzyloxy-2-hydroxy-3-methyl-benzaldehyde (1.57 g, 6.49 mmol), dimethylsulfate (1.04 ml, 10.9 mmol), NaOH (1.02 g, 25.5 mmol), 1,4-dioxane (20 mL) and water (10 mL) was stirred at 90° C. for 6 h. The reaction mixture was cooled to RT, water (100 mL) was added, extracted with EtOAc (150 mL). The extract was washed with brine (100 mL), dried over Na2SO4 and evaporated. The residue was purified on SiO2 (25 g) column, hexane to toluene. Yield 1.20 g (4.68 mmol, 72%), white solid. 1H NMR (300 MHz, DMSO): δ 10.11 (s, 1H), 7.64 (d, J=8.9 Hz, 1H), 7.49-7.32 (m, 5H), 7.05 (d, J=8.9 Hz, 1H), 5.24 (s, 2H), 3.81 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][O:10][C:11](=[O:19])[C:12](=[O:18])[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.[Cl-].[NH4+]>C(OCC)C.C1COCC1>[CH3:9][O:10][C:11](=[O:19])[C:12]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([OH:18])[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)C(=O)c1cccs1
Reactant: Cl[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C(O)(c1cccs1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
98.6 ml (0.197 mol) of a 2M solution of Cyclohexylmagnesium chloride in diethyl ether, were added to a solution of 27.97 g (0.164 mol) of 2-oxo-2-thien-2-ylacetic acid methyl ester dissolved in 370 ml of THF, at −78° C. under a N2atmosphere. The mixture was stirred at this temperature for 10 minutes, and then warmed to room temperature. After 1 h, the reaction mixture was treated with a saturated solution of ammonium chloride and extracted three times with ethyl acetate. The organic phases were combined, washed with water, and dried over MgSO4. After removal of the solvent, the oil obtained was purified by column chromatography (silica gel) using hexane/AcOEt 90:10 as eluent. The yield was 16.2 g (39.5%) of a pure product, whose structure was confirmed by 1H-NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12](OCC3C=CC([N+]([O-])=O)=CC=3)[C@H:11]([C:25]([OH:27])=O)[CH2:10]2)=[CH:5][CH:4]=1.[N+:30]([C:33]1[CH:51]=[CH:50][C:36]([CH2:37][O:38][C:39]([NH:41][C:42]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[NH:43])=[O:40])=[CH:35][CH:34]=1)([O-:32])=[O:31]>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:39]([O:38][CH2:37][C:36]3[CH:35]=[CH:34][C:33]([N+:30]([O-:32])=[O:31])=[CH:51][CH:50]=3)=[O:40])[C@H:11]([C:25]([N:47]3[CH2:46][CH2:45][N:44]([C:42](=[NH:43])[NH:41][C:39]([O:38][CH2:37][C:36]4[CH:35]=[CH:34][C:33]([N+:30]([O-:32])=[O:31])=[CH:51][CH:50]=4)=[O:40])[CH2:49][CH2:48]3)=[O:27])[CH2:10]2)=[CH:28][CH:29]=1
Reactant: N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCNCC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(=N)NC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 141.6 %

Procedure:
740 mg of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxy)pyrrolidine-2-carboxylic acid was dissolved in 7.4 ml of dry acetonitrile, and 330 mg of N,N'-carbonyldiimidazole were added to the resulting solution, after which the mixture was stirred at room temperature for 30 minutes. At the end of this time, a solution of 525 mg of 1-(4-nitrobenzyloxycarbonylamidino)piperazine [prepared as described in step (c) above] dissolved in 10 ml of acetonitrile was added to the resulting mixture, and the mixture was left to stand overnight under the same conditions. The reaction mixture was then diluted with ethyl acetate, after which it was washed with an aqueous solution of sodium hydrogencarbonate, with water and with an aqueous solution of sodium chloride, in that order, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography, eluted first with ethyl acetate alone and then with a 4:1 by volume mixture of ethyl acetate and acetonitrile, in that order. The fractions containing the desired compound were concentrated by evaporation under reduced pressure, to obtain 890 mg of the title compound, as a powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[CH3:21][C:20]1[C:14]2[C:15](=[N:16][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:13]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: C#CCCn1nc2cccc(C)c2n1
Reactant: Brc1ccccn1
Product: Cc1cccc2nn(CCC#Cc3ccccn3)nc12
Yield: 50 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (66 mg, 0.42 mmol) and 2-but-3-ynyl-4-methyl-2H-benzo[d][1,2,3]triazole (70 mg, 0.38 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 50 mg (0.19 mmol, 50%) of 4-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow semi-solid.
Reaction SMILES: [NH2:1][CH:2]([PH:9](=[O:11])[OH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>>[C:17]1([CH2:16][O:15][C:13]([NH:1][CH:2]([PH:9](=[O:10])[OH:11])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:14])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(c1ccccc1)[PH](=O)O
Product: O=C(NC(c1ccccc1)[PH](=O)O)OCc1ccccc1
Yield: 90 %

Procedure:
The process is performed according to the operating conditions described in 1.4., starting with 1 g (5.85 mmol) of (aminophenylmethyl)phosphinic acid and 1.17 g (6.86 mmol) of benzyl chloroformate. 1.6 g of product are recovered (yield=90%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:11])[C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[CH3:10][O:9][C:7]([C:6]1[C:5]([CH3:11])=[CH:4][S:3][C:2]=1[NH:1][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:8]
Reactant: COC(=O)c1c(C)csc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1scc(C)c1C(=O)OC)C(=O)OCC

Procedure:
Reaction of methyl 2-amino-4-methylthiophene-3-carboxylate with diethyl ethoxymethylenemalonate in a manner similar to that used in Reference Example 10 yields diethyl (3-methoxycarbonyl-4-methylthienyl)aminomethylenemalonate as crystals melting at 105.5°-106°C.
Reaction SMILES: II.[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([S:14][CH3:15])[NH:8][C:7]2=O.[N+:17]([C:20]1[N:24]=[CH:23][NH:22][N:21]=1)([O-:19])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([S:14][CH3:15])[N:8]=[C:7]2[N:22]1[CH:23]=[N:24][C:20]([N+:17]([O-:19])=[O:18])=[N:21]1
Reactant: CSc1nc2ccc(Br)cc2c(=O)[nH]1
Reactant: O=[N+]([O-])c1nc[nH]n1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CSc1nc(-n2cnc([N+](=O)[O-])n2)c2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 89 %

Procedure:
Iodine (16.5 g, 65.1 mmol) was added to a suspension of compound 5a (8.03 g, 29.6 mmol), 3-nitro-1H-1,2,4-triazole (11.8 g, 103.6 mmol), triphenylphosphine (18.1 g, 69.1 mmol) in 630 mL of toluene. The reaction mixture was rapidly heated to 95° C. for 15 minutes after which 25 mL of N,N-diisopropylethylamine was added and the mixture was stirred for another 50 minutes. The reaction was cooled to room temperature and concentrated under reduced pressure. The crude product was precipitated from ethanol, to give 6 as a yellow solid (9.67 g, 89%). mp: 204° C.,
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[C:6]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:33])[CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:22][C:21]=2[F:34])[CH2:16][CH2:15]1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:31]([CH:28]([CH2:29][CH3:30])[C:27]([NH:26][C:23]1[CH:24]=[CH:25][C:20]([N:17]2[CH2:16][CH2:15][CH:14]([C:6]([OH:13])([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:2][CH2:3][CH2:4][CH3:5])[CH2:19][CH2:18]2)=[C:21]([F:34])[CH:22]=1)=[O:33])[CH3:32]
Reactant: CCC(CC)C(=O)Nc1ccc(N2CCC(C(=O)c3ccccc3)CC2)c(F)c1
Reactant: [Li]CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(O)(c1ccccc1)C1CCN(c2ccc(NC(=O)C(CC)CC)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
To a solution of n-BuLi (1 mL, 2.5 M in hexanes) in THF (10 mL) at −78° C., N-[4-(4-benzoyl-piperidin-1-yl)-3-fluoro-phenyl]-2-ethyl-butyramide (200 mg, 0.50 mmol) in THF (10 mL) was added. After 10 min, the mixture was warmed to 25° C. and diluted with satd. aq. NaHCO3 (10 mL). The mixture was extracted with EtOAc, and the organic layer was concentrated and purified by PTLC to provide the title compound (130 mg, 57%). MS: 455.4. 1H NMR (CDCl3): 7.42-7.15 (m, 7H), 6.84 (t, J=9.1, 1H), 3.42 (d, J=11.7, 1H), 3.32 (d, J=11.7, 1H), 2.61-2.45 (m, 2H), 2.01-1.82 (m, 4H), 1.78-1.62 (m, 3H), 1.61-1.41 (m, 6H), 1.32-1.15 (m, 4H), 0.98-0.80 (m, 9H).
Reaction SMILES: N12CCCN=C1CCCCC2.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[N:24][OH:25])[NH:20][CH:21]2[CH2:23][CH2:22]2)=[C:15](F)[CH:14]=1>O1CCCC1>[Br:12][C:13]1[CH:18]=[CH:17][C:16]2[C:19]([NH:20][CH:21]3[CH2:23][CH2:22]3)=[N:24][O:25][C:15]=2[CH:14]=1
Reactant: ON=C(NC1CC1)c1ccc(Br)cc1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Brc1ccc2c(NC3CC3)noc2c1
Yield: 70.1 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.12 ml) was added to 4-bromo-N-cyclopropyl-2-fluoro-N′-hydroxybenzenecarboximidamide (Intermediate 52) (0.2 g) in tetrahydrofuran (2 ml) then heated at 150° in a microwave for 70 min. The mixture was applied to a Varian Bond-Elut SPE cartridge (silica, 20 g) then eluted with cyclohexane:ethyl acetate (100:0 to 80:20) to give the title compound as a white solid (0.13 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:29]=[O:30]>O1CCCC1>[C:16]1([C@H:14]([N:10]2[CH2:11][CH2:12][O:13][C@@H:8]([C:5]3[CH:6]=[CH:7][C:2]([CH:29]=[O:30])=[CH:3][CH:4]=3)[CH2:9]2)[CH3:15])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)C=O
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(Br)cc2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(C=O)cc2)C1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 101.9 %

Procedure:
To a solution of (2S)-2-(4-bromophenyl)-4-((1R)-1-phenylethyl)morpholine (intermediate 13, 63.3 g, 183 mmol) in tetrahydrofuran (450 ml) was added n-butyllithium (1.57 M in hexane solution, 175 ml, 275 mmol) at −78° C. and the mixture was stirred for 20 minutes. N,N-dimethylformamide (28.3 ml 365 mmol) was added and the mixture was stirred for 2 hours at −78° C. and then allowed to be warmed to −10° C. The reaction was quenched with aqueous ammonium chloride, and the resulting solution was partitioned between water and ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford crude 4-((2S)-4((1R)-1-phenylethyl) morpholin-2-yl)benzaldehyde (intermediate 14, 55.1 g). This compound was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][S:5][C:6]1[C:7](=[O:14])[O:8][C:9]([CH3:13])=[CH:10][C:11]=1[OH:12].[OH:19]O>C(O)(=O)C>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][S:5]([C:6]1[C:7](=[O:14])[O:8][C:9]([CH3:13])=[CH:10][C:11]=1[OH:12])=[O:19]
Reactant: OO
Reactant: Cc1cc(O)c(SCc2ccccc2F)c(=O)o1
Solvent: CC(=O)O
Product: Cc1cc(O)c(S(=O)Cc2ccccc2F)c(=O)o1

Procedure:
3-(o-Fluorobenzylthio)-4-hydroxy-6-methyl-2-pyrone (13.8 g., 0.0519 mole) and 30% hydrogen peroxide (5.9 g., 0.0519 mole) were mixed with glacial acetic acid (100 ml.) with stirring. After ten days the peroxide had been consumed, and the solution was diluted with water. The resulting mixture was extracted with methylene chloride. The extract was dried (MgSO4) and evaporated to dryness, leaving 13.3 g. (91 percent) of a colored solid. Recrystallization from a mixed hexane-benzene solution gave the pure product as a white solid, m.p. 115°-116°C.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])[CH:22]=[CH:23][CH:24]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: COc1cccc(N=C=O)c1
Solvent: ClCCl
Product: COc1cccc(NC(=O)Nc2ccc(OC)c(-c3c(Br)cnn3C)c2)c1
Yield: 91.7 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.032 g, 0.12 mmol) was treated with 3-methoxyphenyl isocyanate (0.018 g, 16.0 μL, 0.14 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.10 to afford Compound 72 (0.047 g, 0.11 mmol, 94%) as a solid film. LCMS m/z (%)=431 (M+H79Br, 100), 433 (M+H81Br, 93). 1H NMR (400 MHz, acetone-d6) δ: 8.13 (s, 2H), 7.68 (d, J=8.9 Hz, 1H), 7.49 (s, 1H), 7.43 (s, 1H), 7.30 (s, 1H), 7.16 (d, J=8.1 Hz, 1H), 7.12 (d, J=7.3 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H). 3.68 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:21][C@@H:20]([C:22]3[CH:33]=[CH:32][C:25]4[O:26][C:27]([CH3:31])([CH3:30])[O:28][CH2:29][C:24]=4[CH:23]=3)[O:19][C:18]2=[O:34])=[CH:4][CH:3]=1.[C:37]1([N:43]=[C:44]=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(O)(C)C>ClCCl>[CH3:31][C:27]1([CH3:30])[O:26][C:25]2[CH:32]=[CH:33][C:22]([C@H:20]3[O:19][C:18](=[O:34])[N:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:44]([NH:43][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[O:45])=[CH:36][CH:35]=4)[CH2:21]3)=[CH:23][C:24]=2[CH2:29][O:28]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4ccc(N)cc4)C(=O)O3)ccc2O1
Reactant: O=C=Nc1ccccc1
Solvent: CC(C)O
Solvent: ClCCl
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4ccc(NC(=O)Nc5ccccc5)cc4)C(=O)O3)ccc2O1
Reaction time: 5 h

Procedure:
A solution of (5R)-3-(6-{2-[(4-aminobenzyl)oxy]ethoxy}hexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (150 mg) in dichloromethane (5 ml) under nitrogen was treated with phenyl isocyanate (0.07 ml) and the mixture stirred at 20° for 5 h. Isopropyl alcohol (5 ml) was added and the solution was stirred for a further 18 h. The solvent was evaporated in vacuo and the residue purified by SPE (silica, 10 g). Elution with EtOAc-cyclohexane (3:7) then EtOAc gave the title compound (159 mg). LCMS RT=3.68 min.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(C(C)C)C(C)C)C.[CH:14]([S:17][C:18](=[O:31])[CH2:19][C@H:20]([NH:24][C:25](=[O:30])[CH2:26][CH2:27][CH:28]=[CH2:29])[C:21]([OH:23])=[O:22])([CH3:16])[CH3:15].[Cl-].[NH4+]>CN(C=O)C>[CH:14]([S:17][C:18](=[O:31])[CH2:19][C@H:20]([NH:24][C:25](=[O:30])[CH2:26][CH2:27][CH:28]=[CH2:29])[C:21]([O:23][CH2:2][C:3]#[N:4])=[O:22])([CH3:16])[CH3:15]
Reactant: N#CCBr
Reactant: C=CCCC(=O)N[C@@H](CC(=O)SC(C)C)C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCC(=O)N[C@@H](CC(=O)SC(C)C)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
2-Bromoacetonitrile (0.510 ml, 7.32 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.153 ml, 0.878 mmol) were added to a solution of (S)-4-(isopropylthio)-4-oxo-2-(pent-4-enamido)butanoic acid (Compound 1f-IB) (200 mg, 0.732 mmol) in DMF (1 ml), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution (1 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→60/40) to afford (S)-cyanomethyl 4-(isopropylthio)-4-oxo-2-(pent-4-enamido)butanoate (Compound 1g-IB) (161 mg, 70%).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14](=O)([O:21]C1C=CC([N+]([O-])=O)=CC=1)[O:15][CH2:16][C:17]([NH:19][CH3:20])=[O:18]>ClCCCl>[N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][N:4]([C:14]([O:15][CH2:16][C:17]([NH:19][CH3:20])=[O:18])=[O:21])[CH2:3][CH2:2]1
Reactant: CNC(=O)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCCl
Product: CNC(=O)COC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution of 0.53 g (2.85 mmol) of 1,1-dimethylethyl 1-piperazinecarboxylate in 5 ml of 1,2-dichloroethane is added dropwise at about 0° C. to a solution, cooled to 0° C., of 1.1 g (3 mmol) of 2-(methylamino)-2-oxoethyl 4-nitrophenyl carbonate, prepared in step 2.2. of Example 2, in 10 ml of 1,2-dichloroethane. Stirring is continued at 0° C. for 1 hour, and then at room temperature for 3 hours. The reaction mixture is concentrated under reduced pressure and the residue thus obtained is purified by chromatography on silica gel, eluting with a 20/80 mixture of ethyl acetate and cyclohexane. The gradient is gradually increased to complete the elution with ethyl acetate. An oily residue that crystallizes from diisopropyl ether is obtained. 0.61 g of product is obtained in the form of a white solid, and is used without further purification in the following step.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:6][C@@H:5]1[CH3:21])(=[O:3])[CH3:2].O.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)OB([C:35]2[CH:36]=[N:37][N:38]([CH2:40][C:41]3[CH:46]=[N:45][CH:44]=[CH:43][N:42]=3)[CH:39]=2)OC1(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:35]3[CH:36]=[N:37][N:38]([CH2:40][C:41]4[CH:46]=[N:45][CH:44]=[CH:43][N:42]=4)[CH:39]=3)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:6][C@@H:5]1[CH3:21])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Reactant: CC1(C)OB(c2cnn(Cc3cnccn3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1c2ccc(-c3cnn(Cc4cnccn4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
A 100-mL round-bottom flask was charged with isopropyl (3S)-4-acetyl-7-bromo-3-methyl-1,2,3,4-tetrahydroquinoxaline-1-carboxylate (60 mg, 0.17 mmol), bis(triphenylphosphine)palladium(II) dichloride (12 mg, 0.02 mmol), water (8 mL), 1,4-dioxane (20 mL), cesium carbonate (165 mg, 0.50 mmol), and 2-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]methylpyrazine (60 mg, 0.21 mmol). The resulting mixture stirred overnight at 70° C. After cooling to room temperature, the reaction mixture was passed through a short pad of celite and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (1#waters2767): Column, Xbridge Phenyl 19×150 mm; mobile phase, Phase A: water (0.05% NH4HCO3), Phase B: CH3CN (15% CH3CN up to 60% in 8 min); Detector, UV220&254 nm to afford (S)-isopropyl 4-acetyl-3-methyl-7-(1-(pyrazin-2-ylmethyl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (27.7 mg, 38%) as a white solid. 1H NMR (300 MHz, CD3OD) δ ppm 1.10 (d, J=6.60 Hz, 3H), 1.27-1.37 (m, 6H), 2.22 (s, 3H), 3.35-3.50 (m, 1H), 4.05-4.17 (m, 1H), 4.95-5.10 (m, 2H), 5.58 (s, 2H), 7.39 (br s, 2H), 7.91 (s, 1H), 8.03 (s, 1H), 8.21 (s, 1H), 8.49 (s, 1H), 8.56 (d, J=2.70 Hz, 1H), 8.59-8.62 (m, 1H). MS (ESI, pos. ion) m/z 435 [M+H]+.