Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](O)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][C:8]=2[CH3:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.[CH2:34]([O:36][C:37](=[O:48])[C@H:38]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1)[NH2:39])[CH3:35].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH2:34]([O:36][C:37](=[O:48])[C@@H:38]([NH:39][C:27]([C:24]1[N:16]2[C:15]([CH2:14][N:13]([C:11](=[O:12])[C:10]3[CH:30]=[CH:31][C:7]([C:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=4)=[C:8]([CH3:32])[CH:9]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17]2)=[CH:26][CH:25]=1)=[O:28])[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([OH:47])=[CH:45][CH:46]=1)[CH3:35]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1C1=CCCCC1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3=CCCCC3)c(C)c1)C2
Temperature: 25 °C
Reaction time: 36 h
Yield: 59.5 %

Procedure:
10-(4-Cyclohex-1-en-1-yl-3-methyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 5, Step E (0.240 g, 0.563 mmol), L-tyrosine ethyl ester hydrochloride (0.157 g, 0.676 mmol), 1-hydroxy benzotriazole (0.084 g, 0.619 mmol) and 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.119 g, 0.619 mmol) were combined in amine-free N,N-dimethylformamide (2.25 mL), followed by the addition of N,N-diisopropylethylamine (0.294 mL, 1.69 mmol). The reaction was stirred at room temperature for 36 hours, then diluted with ethyl acetate and washed with water, 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The combined aqueous washings were saturated with sodium chloride and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 50% ethyl acetate in hexane, followed by precipitation from diethyl ether with petroleum ether, to afford 0.207 g of the title compound as a white solid.
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12].P(Cl)(Cl)(Cl)=O.[BH4-].[Na+]>O>[Cl:12][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: OCc1ccc(Cl)nc1
Temperature: 95 °C
Reaction time: 5 h

Procedure:
69.5 g (0.5 mol) of 6-hydroxynicotinic acid are introduced into a mixture of 200 g (1 mol) of phosphorus pentachloride and 233 g (1.5 mol) of phosphorus oxychloride at room temperature, the mixture is stirred at 95° C. for 5 hours and excess phosphorus chlorides are then removed in vacuo. The crystalline residue is introduced into a solution of 75 g (1.98 mol) of sodium borohydride in 1,000 ml of water, the temperature being maintained at 30° C. at most. The mixture is then stirred at room temperature until the completion of gas evolution and is filtered with suction from solid material, and the filtrate is extracted using ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][CH3:10].[Li]CCCC.CN(C)[CH:18]=[O:19].Cl>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:18]=[O:19])=[C:4]([F:8])[C:3]=1[O:9][CH3:10]
Reactant: CN(C)C=O
Reactant: COc1c(F)cccc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1c(Cl)ccc(C=O)c1F
Temperature: -49 °C
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
To a solution of 2-chloro-6-fluoroanisole (321.2 g) in 2 L of dry tetrahydrofuran (THF), cooled to −70° C., was added 890 mL of 2.5 M n-BuLi in hexane over 30 min with good mechanical stirring. During the addition the reaction warmed to −48 to −50° C. and was held there for 15 min after addition was complete. The solution was cooled to −75° C. before a solution of 177 g of dimethylformamide (DMF) in 100 mL of THF was added keeping the temperature below −50° C. The reaction was warmed to room temperature and 260 g of 37% aqueous HCl was slowly added and stirring was continued for 2 hours. The phases were separated and the organic phase concentrated and taken into 2 L of ether. The solution was washed twice with 500 mL of aqueous 10% HCl. The organic phase was dried over MgSO4, filtered and concentrated to 372 g of a light gold oil (93% pure by GC). This oil was distilled bulb to bulb to give 282 g (75% yield) of a light gold oil that solidified upon standing. A small sample was crystallized from pentane to give fine white needles; MP 44-45° C.; 1H NMR (CDCl3, 300 MHz) δ 10.3 (s, 1H); 7.5 (dd, 1H, J=6.6, 8.5 Hz); 7.3 (m, 1H); 4.0 (s, 3H).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12.C([Sn](CCCC)(CCCC)[C:24]1[N:25]=[CH:26][S:27][CH:28]=1)CCC>O1CCOCC1.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>[S:27]1[CH:28]=[C:24]([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][N:6]2[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]23)[N:25]=[CH:26]1
Reactant: O=C1C=C2c3cccc(I)c3CCN2C(=O)CN1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C1C=C2c3cccc(-c4cscn4)c3CCN2C(=O)CN1
Temperature: 150 °C
Yield: 86.6 %

Procedure:
To a degassed solution of 9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (1 g, 2.82 mmol) and 4-(tributylstannyl)thiazole (1.48 g, 3.95 mmol) in dioxane (16 mL) was added Pd(PPh3)4 (130 mg, 0.11 mmol) and the mixture was heated in the microwave at 150° C. for 2 h. The solvent was removed under reduced pressure. The crude product was crystallized from DCM to yield the title compound (760 mg). UPLC-MS: MS 312.1 (M+H+); UPLC rt 0.66 min.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C:9]1[C:17]2[N:16]=[C:15]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:14]([CH2:27][CH2:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)[C:13]=2[CH:12]=[CH:11][CH:10]=1.[H-].[Na+].[CH:45]1(Br)[CH2:47][CH2:46]1>CN(C)C=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:3]1([O:8][C:9]2[C:17]3[N:16]=[C:15]([CH2:18][O:19][C:20]4[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=4)[N:14]([CH2:27][CH2:28][CH2:29][CH:30]4[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]4)[C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:47][CH2:45][CH2:46]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(O)cccc32)CC1
Reactant: BrC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OC4CCCC4)cccc32)CC1
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of 4-hydroxy-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole trifluoroacetate (300 mg, 0.6 mmol, 1 eq) in anhydrous N,N-dimethylformamide (3 m) was treated with sodium hydride (60% in mineral oil, 26 mg, 0.66 mmol, 1.1 eq). The resulting mixture was stirred for thirty minutes at room temperature. Cyclopropyl bromide (0.66 mmol, 1 eq) was added to the reaction and the resulting mixture was stirred for two hours at room temperature. The reaction was quenched with the addition of water (5 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (2×10 ml), then brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by flash column chromatography to yield the title product as a crystalline product in 50% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[N:11]3[N:16]=[CH:17][C:18](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=1)#[CH:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[N:11]3[N:16]=[CH:17][C:18]([C:21]#[C:20][C:22]4[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCc1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Reactant: C#Cc1ccc(N)nc1
Product: CCc1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3ccc(N)nc3)cnn12

Procedure:
The title compound was prepared 5-(4-chloro-phenyl)-7-ethyl-3-iodo-pyrazolo[1,5-a]pyrimidine (96 mg, 0.25 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (30 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (41 mg, 44%). MS (ISP) 374.3 [(M+H)+]; mp 205-206° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10])#[CH:2].Br[C:12]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:13]=1[CH:14]=[O:15].C(N(CC)CC)C>CN(C)C=O>[CH3:10][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:12]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:13]=1[CH:14]=[O:15]
Reactant: COc1ccc(Br)c(C=O)c1
Reactant: C#Cc1ccccc1OC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C#Cc2ccccc2OC)c(C=O)c1
Yield: 67.3 %

Procedure:
The resulting 2-ethynylanisole (0.79 g) and 2-bromo-5-methoxybenzaldehyde (1.14 g) were reacted in dimethylformamide (50 ml) in the presence of dichloro-bis-triphenylphosphine palladium (1.0 g), cuprous iodide (0.5 g) and triethylamine (15 ml), in nitrogen atmosphere at 50° C. for 6 hr. The resulting reaction solution was evaporated, and to the resulting residue were added ethyl acetate and water. The resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give 0.95 g of the title compound as a pale yellow oil.
Reaction SMILES: C[NH:2]C.BrC[C:6]1[N:11]=[C:10]([N:12]2[C:16](=O)C3=CC=CC=C3[C:13]2=O)[CH:9]=[CH:8][CH:7]=1>C(O)C>[CH3:13][N:12]([CH3:16])[C:10]1[N:11]=[C:6]([NH2:2])[CH:7]=[CH:8][CH:9]=1
Reactant: CNC
Reactant: O=C1c2ccccc2C(=O)N1c1cccc(CBr)n1
Solvent: CCO
Product: CN(C)c1cccc(N)n1
Reaction time: 2 h

Procedure:
To ethanol (140 ml) saturated with dimethylamine gas at ice bath temperature is added 6-bromomethyl-2-phthalimido-pyridine (13.6 gm, 43 mmol). After stirring for 2 hours, the solution is concentrated to half volume to remove any excess dimethylamine. Hydrazine hydrate (2.4 ml) is added and refluxed for 2 hours. The reaction is cooled, filtered to remove precipitated byproduct and evaporated to dryness. The residue is dissolved in chloroform, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to give 3.8 gm of 6-dimethylamino-2-amino pyridine as an oil.
Reaction SMILES: FC1C=C(CN)C=NC=1.[CH3:10][N:11]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[N:12]1.[CH2:18]([N:22]1[CH2:26][CH2:25][N:24]([C:27]2[S:28][C:29]([C:33](O)=[O:34])=[C:30]([CH3:32])[N:31]=2)[C:23]1=[O:36])[CH:19]([CH3:21])[CH3:20]>>[CH2:18]([N:22]1[CH2:26][CH2:25][N:24]([C:27]2[S:28][C:29]([C:33]([NH:17][CH2:16][C:13]3[CH:14]=[CH:15][N:11]([CH3:10])[N:12]=3)=[O:34])=[C:30]([CH3:32])[N:31]=2)[C:23]1=[O:36])[CH:19]([CH3:21])[CH3:20]
Reactant: Cc1nc(N2CCN(CC(C)C)C2=O)sc1C(=O)O
Reactant: Cn1ccc(CN)n1
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CC(C)C)C2=O)sc1C(=O)NCc1ccn(C)n1
Yield: 58 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with (1-methyl-1H-pyrazol-3-yl)methanamine to react with 2-(3-isobutyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid in place of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 58% yield: mp 158-161° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.43 (s, 1H), 7.37 (s, 1H), 5.80-5.78 (m, 1H), 4.39 (d, J=5.3 Hz, 2H), 4.12-4.07 (m, 2H), 3.86 (s, 3H), 3.60-3.55 (m, 2H), 3.11 (d, J=7.4 Hz, 2H), 2.59 (s, 3H), 1.96-1.87 (m, 1H), 0.93 (d, J=7.4 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 162.4, 157.4, 155.6, 152.9 152.6, 138.6, 129.5, 118.3, 117.0, 51.5, 42.8, 41.9, 38.8, 34.3, 26.7, 19.9, 17.1; MS (ES+) m/z 376.8 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]([C:14]([NH2:16])=O)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.P(Cl)(Cl)(Cl)(Cl)[Cl:26]>P(Cl)(Cl)(Cl)=O>[Cl:26][C:4]1[C:5]([C:14]#[N:16])=[N:6][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:2]([CH3:1])[N:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1[nH]c(=O)c(C(N)=O)nc1-c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c(C#N)nc1-c1ccccc1

Procedure:
In analogy to the procedure described in example 12 1-phenyl-1,2-propanedione and 2-aminomalonamide were heated in an aqueous solution to give 5-methyl-3-oxo-6-phenyl-3,4 -dihydro-pyrazine-2-carboxylic acid amide. Then, the 5-methyl-3-oxo-6-phenyl-3,4-dihydro-pyrazine-2-carboxylic acid amide was treated with triethylamine and phosphorus pentachloride in phosphorus oxychloride at reflux to give the 3-chloro-5-methyl-6-phenyl-pyrazine-2-carbonitrile. The 3-chloro-5-methyl-6-phenyl-pyrazine-2-carbonitrile was finally treated with 2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride (J. Heterocycl. Chem. 1971, 8(5), 779-83) and N-ethyldiisopropylamine in N,N-dimethylformamide at room temperature to yield the 5-methyl-6-phenyl-3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-pyrazine-2-carbonitrile as yellow amorphous solid; MS: 341 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[Si:20](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl.CN(C)C1C=CN=CC=1>[Si:20]([O:1][CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH2:5][CH2:4]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCC1CCNc2ccccc21
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC1CCNc2ccccc21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
To a solution of 4-(hydroxymethyl)-1,2,3,4-tetrahydroquinoline (16.07 g, 0.098 mol) in dichloromethane (100 mL) at 0° C. were added sequentially triethylamine (16.3 mL, 0.12 mol), tert-butyldiphenylsilylchloride (28.4 g, 0.103 mol) and 4-(dimethylamino)pyridine (0.6 g, 4.9 mmol). After 30 minutes, the solution was warmed to room temperature and stirred for another 2 hours. The reaction mixture was diluted with dichlormethane (200 mL), washed with water (50 mL) and saturated aqueous sodium chloride solution (50 mL). The organic layers were collected, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to provide 22.1 g (56%) of the desired compound.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[O:9]=[C:10]([CH3:20])[CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>CS(C)=O>[CH3:20][C:10]1([CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][O:9]1
Reactant: C[S+](C)(C)=O
Reactant: CC(=O)CCC(=O)OC(C)(C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CCC1(C)CO1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 67.2 %

Procedure:
Trimethylsulfoxonium iodide (19.54 g, 88.78 mmol) was added to a suspension of sodium hydride (3.71 g, 92.82 mmol) in DMSO (50 ml) while cooling in an ice-bath, and the mixture was stirred for 2.5 hours. To which a solution of tert-butyl 4-oxopentanoate (13.90 g, 80.71 mmol) in DMSO (20 ml) was added, and the mixture was stirred at room temperature for 15 hours. The mixture was poured into ice water, extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to afford tert-butyl 3-(2-methyl-2-oxiranyl)propionate (10.1 g, yield 67%) as a pale yellow oil.
Reaction SMILES: [O:1]1[C:6]2=[C:7]3[C:11](=[CH:12][CH:13]=[C:5]2[O:4][CH2:3][C@@H:2]1[CH2:14][OH:15])[NH:10][CH:9]=[CH:8]3.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>ClCCl.CN(C)C1C=CN=CC=1>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:15][CH2:14][C@H:2]2[O:1][C:6]3=[C:7]4[C:11](=[CH:12][CH:13]=[C:5]3[O:4][CH2:3]2)[NH:10][CH:9]=[CH:8]4)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1COc2ccc3[nH]ccc3c2O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2COc3ccc4[nH]ccc4c3O2)cc1

Procedure:
A solution of (S)-2,3-dihydro-7H-1,4-dioxino[2,3-e]indol-2-ylmethanol (0.75 g; prepared by the method described above) in dichloromethane (50 ml) was stirred with cooling in an ice bath. 4-(Dimethylamino)pyridine (0.59 g) and 4-toluenesulphonyl chloride (0.84 g) were then added and the solution stirred at ambient temperature overnight. The mixture was diluted with dichloromethane (200 ml), washed sucessively with water (50 ml), saturated aqueous copper(II) sulphate solution (2×50 ml) and water (50 ml), then dried over sodium sulphate and the solvent evaporated to give (S)-2,3-dihydro-7H-1,4-dioxino[2,3-e]indol-2-ylmethyl 4-toluenesulphonate (1.04 g) as a pale brown oil which solidified on standing.
Reaction SMILES: O[C:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[C:6]2[C:7]([CH3:21])=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:23])[CH3:22]>C(OCC)(=O)C.CCCCCC>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([CH:2]2[C:6]3[C:7]([CH3:21])=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:17])([CH3:18])[CH3:19])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=3[O:4][C:3]2([CH3:23])[CH3:22])[CH:29]=[CH:28][CH:27]=1
Reactant: COc1cccc(C2(O)c3c(C)c(NC(=O)CC(C)(C)C)c(C)c(C)c3OC2(C)C)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cccc(C2c3c(C)c(NC(=O)CC(C)(C)C)c(C)c(C)c3OC2(C)C)c1
Yield: 77 %

Procedure:
Using N-(3-hydroxy-3-(3-methoxyphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 259, the title compound was synthesized in the same manner as in Example 271. Yield: 77%. Melting point: 166-167° C. (ethyl acetate-hexane).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH:6]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4].[K+].[Br-].[N:25]([C:28]1[CH:29]=[C:30]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:31]=[CH:32][CH:33]=1)=[C:26]=[O:27]>O1CCCC1>[C:10]([O:9][C:7]([CH:6]1[CH2:14][CH2:15][CH:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:5]1[C:3](=[O:4])[CH2:2][NH:1][C:26](=[O:27])[NH:25][C:28]1[CH:29]=[C:30]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:31]=[CH:32][CH:33]=1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CN
Reactant: COC(=O)Cc1cccc(N=C=O)c1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CCC2c2ccccc2)c1
Yield: 59.4 %

Procedure:
By proceeding in a fashion similar to that described in Example 2, but starting from 6.2 g of tert-butyl (2RS,5SR)-1-(2-aminoacetyl)-5-phenylprolinate in solution in 150 cm3 of anhydrous tetrahydrofuran and 4.2 g of methyl 3-isocyanatophenylacetate, 6 g of methyl (2RS,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenylacetate are obtained [proton NMR (200 MHz, DMSO D6, δ in ppm), 2 rotamers at room temperature, peak coalescence at 120° C.: 1.5 (s, 9H, (CH3)3); 3.6 (s, 2H, CH2CO); 3.65 (s, 3H, OCH3); 6.8 to 7.7 (m, 9H, aromatic). Infrared spectrum (KBr), characteristic bands in cm-1 : 3365, 3155, 3110, 3090, 3060, 3030, 2975, 2950, 2930, 2875, 1738, 1700, 1650, 1610, 1595, 1560, 1495, 1435, 1395, 1365, 1315, 1250, 1220, 1155, 1015, 905, 890, 860, 845, 780, 760, 700].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8](O)[C:9]1[S:13][C:12]([NH:14][C:15]([C:17]2([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[N:11][CH:10]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:42]1[CH2:46][CH2:45][C@@H:44]([OH:47])[CH2:43]1>ClCCl>[O:24]1[C:23]2[CH:27]=[CH:28][C:20]([C:17]3([C:15]([NH:14][C:12]4[S:13][C:9]([CH:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[N:42]5[CH2:46][CH2:45][C@@H:44]([OH:47])[CH2:43]5)=[CH:10][N:11]=4)=[O:16])[CH2:18][CH2:19]3)=[CH:21][C:22]=2[O:26][CH2:25]1
Reactant: O=C(Nc1ncc(C(O)c2ccccc2Cl)s1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: O[C@@H]1CCNC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ncc(C(c2ccccc2Cl)N2CC[C@@H](O)C2)s1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33333.3 %

Procedure:
1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid [5-[(2-chloro-phenyl)-hydroxy-methyl]-thiazol-2-yl]-amide (0.500 g, 1.17 mmol) was placed in 10 mL of anhydrous dichloromethane containing trieihylamine (984 μL, 7.02 mmol). The mixture was cooled to 0° C. and methanesulfonyl chloride (364 μL, 4.68 mmol) was added, immediately followed by (R)-pyrrolidin-3-ol (945 μL, 11.7 mmol) and the solution was allowed to stir for 10 minutes at room temperature. The crude product was washed three times with an equal volume of a saturated aqueous solution of sodium bicarbonate, followed by a saturated aqueous solution of sodium chloride. The organic layer was then dried over sodium sulfate and evaporated to dryness. The crude mixture was purified by column, chromatography (20-90% ethyl acetate in hexanes on silica gel) to yield the product as a white solid (194.2 mg, 0.390 mol, 33.3%). 1H NMR (400 MHz, DMSO-d6) δ 1.09-1.15 (m, 2H), 1.41-1.44 (m, 2H), 1.54-1.63 (m, 1H), 1.93-2.77 (m, 5H), 4.20 (S, 1H), 4.72-4.77 (m, 1H), 4.96 (d, J=7.0 Hz, 1H), 6.00 (s, 2H), 6.85 (d, J=0.9 Hz, 2H), 6.95 (s, 1H), 7.24-7.29 (m, 1H), 7.37-7.43 (m, 3H), 7.76-7.80 (m, 1H), 11.03 (s, 1H. ESI-MS m/z calc. 497.1, found; 498.1 (M+1)+; Retention time 2.36 minutes.
Reaction SMILES: [NH:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:8])=[CH:5][N:4]=1)[NH2:2].[C:19]([C:21]1[CH:22]=[N:23][N:24]([C:26](=[CH:32]N(C)C)[C:27](OCC)=[O:28])[CH:25]=1)#[N:20].Cl.CCN(C(C)C)C(C)C>CC(O)C>[C:19]([C:21]1[CH:22]=[N:23][N:24]([C:26]2[CH:32]=[N:2][N:1]([C:3]3[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[O:8])=[CH:5][N:4]=3)[C:27]=2[OH:28])[CH:25]=1)#[N:20]
Reactant: NNc1ccc(C(=O)NCC2CCOCC2)cn1
Reactant: CCOC(=O)C(=CN(C)C)n1cc(C#N)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: N#Cc1cnn(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)c1
Reaction time: 15 h
Yield: 34.2 %

Procedure:
Combined 6-hydrazinyl-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (107 mg, 0.427 mmol) and ethyl 2-(4-cyano-1H-pyrazol-1-yl)-3-(dimethylamino)acrylate (100 mg, 0.427 mmol) in 2-propanol (1423 μl) and treated with 1.85N HCl (841 mg, 0.427 mmol). The resulting clear mixture was stirred overnight (15 h) and then Hunig's base (297 μl, 1.708 mmol) was added and the reaction was stirred at ambient temperature for 2.5 h. The reaction mixture was then concentrated in vacuo and purified using HPLC (20-95% ACN in water, TFA-buffered). Product-containing fractions were concentrated in vacuo to give a solid (volume ˜20 mL). The solid was filtered and dried in vacuum to give the title compound (57.4 mg, 34.2% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (qd, J=12.21, 4.29 Hz, 2H) 1.62 (d, J=12.88 Hz, 2H) 1.81 (m, J=10.96, 7.29, 3.76, 3.76 Hz, 1H) 3.20 (t, 2H) 3.27 (t, J=10.86 Hz, 2H) 3.86 (dd, J=11.24, 2.65 Hz, 2H) 8.29 (s, 1H) 8.42 (br. s., 3H) 8.74 (t, J=5.68 Hz, 1H) 8.93 (s, 2H) 13.41 (br. s., 1H). MS m/z [M+H]+394.