Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=3)([OH:16])[C:10]3[N:11]=[C:12]([CH3:14])[O:13][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:25]=1.[H-].[Na+].[CH3:28]I>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[N:21]([CH3:28])[CH:22]=3)([OH:16])[C:10]3[N:11]=[C:12]([CH3:14])[O:13][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:25]=1
Reactant: CI
Reactant: Cc1nc2c(o1)CCc1cc(Cl)ccc1C2(O)c1c[nH]c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2c(o1)CCc1cc(Cl)ccc1C2(O)c1cn(C)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of the product from step (vii) (2.0 g) in tetrahydrofuran (20 ml) at 0° C. was added sodium hydride (60% dispersion by wt, 0.22 g). The mixture was stirred at 0° C. for 40 min and treated with methyl iodide (0.35 ml). The mixture was further stirred at 0° C. for 2 hours and room temperature for 24 hours then partitioned between ethyl acetate and water. The organic phase was washed with water and saturated brine, dried (MgSO4) and solvent evaporated. Purification was by chromatography eluting with 10% ethanol in dichloromethane to give the product as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][CH2:11][CH2:12]O)[CH2:7][N:6]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:4].C[CH2:23][N:24](CC)CC.CS(Cl)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:23]([CH2:12][CH2:11][O:10][C@H:8]1[CH2:7][N:6]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C@H:5]([C:3]([N:2]([CH3:1])[CH3:21])=[O:4])[CH2:9]1)#[N:24]
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](OCCO)CN1C(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)[C@@H]1C[C@@H](OCCC#N)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
To a solution of 3.00 g of the compound obtained in Step 143-2 and 2.01 g of Et3N in CHCl3 (30 ml) was added 1.36 g of methane sulfonyl chloride under ice cooling and the reaction mixture was stirred at room temperature for one hour. To the solution was added a saturated aqueous solution of NaHCO3 and the resulting mixture was extracted with EtOAc; the organic layer was washed with saturated brine and dried over Na2SO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in MeCN (40 ml) was added 2.58 g potassium cyanide and 260 mg of 18-crown-6-ether, and the reaction mixture was refluxed for two hours. To the solution was added water and the resulting mixture was extracted with EtOAc; the organic layer was washed with saturated brine and dried over Na2SO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60N; mobile phase: EtOAc) obtained 1.22 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([NH2:16])[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:10]=1)=[O:5])[CH3:2].CO[CH:19]([N:22]([CH3:24])[CH3:23])OC>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([N:16]=[CH:19][N:22]([CH3:24])[CH3:23])[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C(=O)OCC)n1N
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C(=O)OCC)n1N=CN(C)C
Temperature: 105 °C

Procedure:
A mixture of 406C (482 mg, 2.13 mmol) and dimethoxymethyl-dimethyl-amine (1.5 ml) in anhydrous DMF (5 ml) was heated at 105° C. overnight. After the solvent was removed, the residue was purified by silica gel flash column chromatography to give 406D (546 mg, 91%) as pink crystals (25% EtOAc—hexanes). MS Found: (M+H)+=282.1
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:32][C:31]4[CH2:30][CH2:29][NH:28][CH2:27][C:26]=4[CH:25]=3)=[O:23])[CH:18]([C:33]([O:35]CC)=[O:34])[CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.C(O)C.[OH-].[Na+].Cl>O1CCCC1>[ClH:2].[C:33]([CH:18]1[CH2:17][N:16]([S:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([Cl:2])[CH:4]=3)[CH:9]=2)(=[O:15])=[O:14])[CH2:21][CH2:20][N:19]1[C:22]([C:24]1[S:32][C:31]2[CH2:30][CH2:29][NH:28][CH2:27][C:26]=2[CH:25]=1)=[O:23])([OH:35])=[O:34]
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1cc2c(s1)CCNC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1cc2c(s1)CCNC2

Procedure:
In tetrahydrofuran (1 ml), 4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonyl-1-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]piperazine hydrochloride (95 mg) was dissolved, followed by the addition of ethanol (2 ml) and 1N sodium hydroxide (3 ml). The resulting mixture was heated under reflux for 30 minutes. To the reaction mixture, 4N hydrochloric acid (2 ml) was added and the precipitate thus obtained was collected by filtration, whereby the title compound (83 mg, 90%) was obtained as a colorless foam.
Reaction SMILES: [H-].[Na+].[NH2:3][CH:4]1[CH:11]2[CH2:12][C:7]3([OH:14])[CH2:8][CH:9]([CH2:13][CH:5]1[CH2:6]3)[CH2:10]2.[CH2:15]([O:22][C:23]1[C:32]2[C:27](=[CH:28][C:29](F)=[C:30]([Cl:33])[CH:31]=2)[CH:26]=[CH:25][N:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(N(C)C)=O>[CH2:15]([O:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:14][C:7]34[CH2:12][CH:11]5[CH2:10][CH:9]([CH2:13][CH:5]([CH:4]5[NH2:3])[CH2:6]3)[CH2:8]4)=[C:30]([Cl:33])[CH:31]=2)[CH:26]=[CH:25][N:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Reactant: Fc1cc2ccnc(OCc3ccccc3)c2cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: NC1C2CC3CC1CC(Oc1cc4ccnc(OCc5ccccc5)c4cc1Cl)(C3)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 417 mg, 10.4 mmol, 3 eq.) in dimethyl acetamide (7 mL) was added a solution of 4-amino-adamantan-1-ol (640 mg, 3.82 mmol, 1.1 eq.) in dimethyl acetamide (7 mL). After stirring for 60 min at room temperature, a solution of 1-benzyloxy-7-chloro-6-fluoro-isoquinoline (1, 1.0 g, 3.48 mmol) in dimethyl acetamide (7 mL) was added and stirring was continued at room temperature until the reaction went to completion. The reaction was quenched by addition of water (15 mL) and the reaction mixture was extracted twice with a mixture of dichloromethane and 2-propanol (3:1). The combined organic layers were evaporated, water was added and the mixture was subjected to lyophilization to remove remainders of dimethyl acetamide. The obtained crude product was purified by flash chromatography (SiO2, 0%→30% methanol in dichloromethane) to yield 473 mg of the title compound as diastereomeric mixture. Rt=1.35 min, 1.55 min (Method 3). Detected mass: 435.2 (M+H+).
Reaction SMILES: [O:1]([CH2:9][CH2:10][C:11]1[CH:22]=[CH:21][C:14]([CH:15]=[CH:16][C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[CH2:23](O)C>[Pd]>[O:1]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][CH:16]([C:17]([O:19][CH3:20])=[O:18])[CH3:23])=[CH:21][CH:22]=1)[Si:2]([C:5]([CH3:7])([CH3:6])[CH3:8])([CH3:4])[CH3:3]
Reactant: COC(=O)C=Cc1ccc(CCO[Si](C)(C)C(C)(C)C)cc1
Reactant: CCO
Agent: [Pd]
Product: COC(=O)C(C)Cc1ccc(CCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-(2-t-butyldimethylsiloxyethyl)cinnamate (1.53 g) in ethanol (25 ml) was added a 10% palladium on activated carbon (0.15 g), and the mixture was stirred at room temperature for 2 hours under an atmosphere of hydrogen. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. To a solution of the residue in tetrahydrofuran (35 ml) was added lithium bis(trimethylsilyl)amide (1.0 mol/l solution in tetrahydrofuran, 3.9 ml) at -78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a solution of iodomethane (0.533 g) in tetrahydrofuran (2 ml), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The extract was washed with water, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of n-hexane and methylene chloride (3:1) as eluent to give 1-(2-t-butyldimethylsiloxyethyl)-4-(2-methoxycarbonylpropyl)benzene (0.724 g) as a colorless oily liquid.
Reaction SMILES: [CH2:1]([C:3]([C:21]1[S:25][C:24]([C:26]([NH:28][NH2:29])=[O:27])=[C:23]([CH3:30])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[C:31](N1C=CN=C1)(N1C=CN=C1)=[O:32]>C1COCC1.CCOC(C)=O>[CH2:1]([C:3]([C:21]1[S:25][C:24]([C:26]2[O:27][C:31](=[O:32])[NH:29][N:28]=2)=[C:23]([CH3:30])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:17])([CH3:18])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)NN)s1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(-c2n[nH]c(=O)o2)s1
Yield: 63.2 %

Procedure:
A mixture of 5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid hydrazide (432 mg, 1 mmol), 1,1′-carbonyldiimidazole (405 mg, 2.5 mmol) and triethylame (0.28 ml, 2 mmol) in THF (10 ml) is stirred at reflux overnight. It is diluted with EtOAc, washed with 1N HCl solution. The organic phase is concentrated and chromatographed (Hex to 20% EtOAc/Hex to give the title compound (290 mg, 63%).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:19](Cl)=[O:20].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[N+](C)([O-])=O>[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:19]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1)=[O:20]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: COc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(=O)c2ccc3ccccc3c2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
To commercially available nitromethane (10 ml) were added commercially available anisole (1.081 g), commercially available 2-naphthoyl chloride (1.906 g) and commercially available ytterbium(III) trifluoromethanesulfonate (620 mg), and the admixture was stirred at 60° C. for 8 hours. The reaction mixture was partitioned between water and chloroform, and the chloroform layer was then dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate to obtain 817 mg of the title compound (yield: 31%).
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([C:10]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)[CH:7]=[CH:6][N:5]=1)=O.CCOC(C)=O.Cl.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[N+:25]([C:21]1[CH:20]=[C:19]([C:11]2[C:10]([C:8]3[CH:7]=[CH:6][N:5]=[C:4]([NH:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:9]=3)=[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]3[N:12]=2)[CH:24]=[CH:23][CH:22]=1)([O-:27])=[O:26]
Reactant: Nc1ccccc1
Reactant: CS(=O)c1nccc(-c2c(-c3cccc([N+](=O)[O-])c3)nn3ccccc23)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccccc3)n2)c1
Temperature: 100 °C
Yield: 52 %

Procedure:
3-[2-(Methylsulfinyl)-4-pyrimidinyl]-2-(3-nitrophenyl)pyrazolo[1,5-a]pyridine (1.5 g, 3.9 mmol) was dissolved in aniline (5 mL). The dark mixture was heated at 100° C. for 5 h. The mixture was cooled and EtOAc (20 mL) and 1N HCl (10 mL) was added. The aqueous layer was extracted with EtOAc (20 mL) and the organic extracts combined, washed with 1N HCl, (15 mL), brine (10 mL), dried over MgSO4 and filtered. The organic solvent was removed in vacuo. The crude material was purified by silica gel chromatography (30-50% EtOAc/hexanes) to give the titled product (830 mg, 52% yield). 1H NMR (400 MHz, d6-DMSO) δ 6.58 (d, 1H, J=5.3 Hz), 6.98 (m, 1H), 7.05 (m, 1H), 7.19 (brs, 1H), 7.28-7.36 (m, 3H), 7.57-7.63 (m, 3H), 8.00 (m, 1H), 8.25-8.31 (m, 3H), 8.54 (m, 1H), 8.69 (m, 1H); ES-LC/MS: m/z (M+H)=409.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.C([Li])CCC.CN(C)[CH:17]=[O:18]>O1CCCC1>[Br:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[CH:5]=1)[CH:17]=[O:18]
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc(F)cc(Br)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 55.3 %

Procedure:
Add dropwise a solution of 1,3-dibromo-5-fluorobenzene (12.39 mL, 98.5 mmol) in tetrahydrofuran (20 mL) to a solution of n-butyllithium (64.61 mL, 103.4 mmol, 1.6 M in hexanes) in tetrahydrofuran (55 mL) at −78° C. Stir at −78° C. for 45 minutes, add dimethylformamide (7.62 mL, 98.5 mmol), stir at −78° C. for 1.5 hours, remove cooling bath and stir 10 minutes. Add saturated aqueous ammonium chloride (150 mL) and extract with diethyl ether (2×700 mL). Wash combined organic layers sequentially with water (1×300 mL) and saturated aqueous sodium chloride (1×300 mL). Dry over magnesium sulfate and concentrate under reduced pressure. Subject residue to silica gel chromatography, eluting with 0-10% ethyl acetate in hexanes to provide the desired compound (11.05 g, 55.3%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:23]
Reactant: O=C(Cl)c1ccccc1F
Reactant: NC(=O)c1c(N)ncn1CCOc1ccccc1
Product: NC(=O)c1c(NC(=O)c2ccccc2F)ncn1CCOc1ccccc1
Yield: 93 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 22, using 1.00 g (4.06 mmol) of 4-amino-1-(2-phenoxyethyl)-5-imidazolecarboxamide prepared in the same manner as in Example 155 and 2-fluorobenzoyl chloride instead of benzoyl chloride to obtain 1.39 g of 4-(2-fluorobenzoylamino)-1-(2-phenoxyethyl)-5-imidazolecarboxamide (yield 93%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:12][CH:13]2[CH2:15][CH2:14]2)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH2:29]([O:36][NH2:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C1COCC1>[CH2:29]([O:36][NH:37][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([F:11])[C:2]([Cl:1])=[CH:3][C:4]=1[NH:12][CH:13]1[CH2:15][CH2:14]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)c1cc(F)c(Cl)cc1NC1CC1
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NOCc1ccccc1)c1cc(F)c(Cl)cc1NC1CC1
Yield: 100.3 %

Procedure:
Following the procedure of Example A, 4-chloro-2-cyclopropylamino-5-fluoro-benzoic acid (Example C-3, 2.0 g, 8.7 mmol) was reacted with carbonyldiimidazole (1.7 g, 10.5 mmol), O-benzylhydroxylamine hydrochloride (1.67 g, 10.5 mmol), and triethylamine (1.5 mL, 10.5 mmol) in THF (50 mL) to give 2.92 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH:7]=[C:8]([C:13]([CH3:15])=O)[C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2].[NH2:19]/[C:20](/[CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1)=[CH:21]\[C:22]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[O:23]>C(O)C>[CH3:12][O:11][C:9]([C:8]1[CH:7]([C:6]2[CH:16]=[CH:17][CH:18]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:21]([C:22]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[O:23])=[C:20]([CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[NH:19][C:13]=1[CH3:15])=[O:10]
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: COCCOC(=O)/C=C(\N)Cn1ccnc1
Solvent: CCO
Product: COCCOC(=O)C1=C(Cn2ccnc2)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1

Procedure:
A mixture of methyl 2-(3-nitrobenzylidene)-acetoacetate (2.5 g, 0.01 mol), ethanol (20 ml) and 2-methoxyethyl 3-amino-4-(imidazol-1-yl)crotonate (3 g) is heated at reflux for 5 hours to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][NH2:22])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]1(=O)[O:32][C:30](=[O:31])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][N:22]1[C:30](=[O:31])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]2[C:27]1=[O:32])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)C[C@@H](C(=O)NN)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H](C(=O)NN1C(=O)c2ccccc2C1=O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Yield: 44.2 %

Procedure:
A solution of 1.0 g of (E)-2(R)-[1(S)-(tertbutoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerohydrazide and 0.41 g of phthalic anhydride in 50 ml of toluene was heated at reflux for 2 hours. The mixture was cooled and the solvent was evaporated and replaced with ethyl acetate. The ethyl acetate solution was washed with 2M aqueous hydrochloric acid, 5% aqueous sodium hydrogen carbonate and then with brine. The ethyl acetate phase was dried over anhydrous magnesium sulphate and the solvent was evaporated. The residue was trituated with diethyl ether to give 0.60 g of (E)-2(R)-[1(S)-(tertbutoxycarbonyl)-4-phenyl-3-butenyl]-4-methyl-N-phthalimidovaleramide in the form of a white solid.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][S:10][CH2:11][CH:12]([OH:24])[CH2:13][S:14][CH2:15][CH2:16][S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25](Cl)(=[O:28])[CH:26]=[CH2:27].CN(C1C=CC=CN=1)C>>[C:25]([O:24][CH:12]([CH2:13][S:14][CH2:15][CH2:16][S:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:11][S:10][CH2:9][CH2:8][S:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:28])[CH:26]=[CH2:27]
Reactant: C=CC(=O)Cl
Reactant: OC(CSCCSc1ccccc1)CSCCSc1ccccc1
Agent: CN(C)c1ccccn1
Product: C=CC(=O)OC(CSCCSc1ccccc1)CSCCSc1ccccc1

Procedure:
An excess of 2-(phenylthio)ethanethiol is reacted with epichlorohydrin to form 1,3-bis(2-(phenylthio)ethylthio)propan-2-ol. In the final step, the 1,3-bis(2-(phenylthio)ethylthio)propan-2-ol is reacted with a acryloyl chloride in the presence of a tertiary alkyl amine and dimethylaminopyridine to form 1,3-bis(2-(phenylthio)ethylthio)propan-2-yl acrylate.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].[OH2:13]>>[CH2:2]([OH:1])[C@H:3]1[O:4][C@H:11]([O:12][C@:9]2([CH2:11][OH:12])[O:13][C@H:3]([CH2:2][OH:1])[C@@H:5]([OH:6])[C@@H:7]2[OH:8])[C@H:9]([OH:10])[C@@H:7]([OH:8])[C@@H:5]1[OH:6]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O
Product: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O

Procedure:
To a Hobart mixer is added 23% fructose, 57% non dairy creamer, 15% instant soluble coffee, 3.5% carboxymethyl cellulose and 1.5% mocha flavor system. The ingredients are blended into a uniform mixture. An agglomerating solution formed from a 60/40 mixture of sucrose and water (6.5%) is added and the mixture is agitated until the desired agglomerated particles are formed. The resulting agglomerated particles are placed in a vacuum oven at 90° F. (33° C.) and 4.5 TORR (mm HG) to reduce the moisture below 3.5%. The dried agglomerated particles are then sized so as to pass through a 12 mesh screen.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][NH2:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]1([CH2:7][O:8][C:9]([NH:11][NH:12][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.5 %

Procedure:
Into a stirred solution of 6.65 g (0.040 mol) of N-[(phenylmethoxy)carbonyl]hydrazine in 40 ml of dimethylformamide was dropped a solution of 8.58 g (0.044 mol) of t-butyl bromoacetate in 20 ml of dimethylformamide followed by a solution of 8.2 ml (0.048 mol) of N,N-diisopropylethylamine in 8 ml of dimethylformamide. After the mixture had been stirred at room temperature for one day, the solvent was distilled off in vacuo and the residue was taken up in ether and water. The organic layer was washed three times with water, dried (magnesium sulfate) and evaporated in vacuo to leave an oil (10.6 g), which was purified by column chromatography on silica gel eluting with ethyl acetate/toluene (1:1). The appropriate fractions were evaporated in vacuo and the residue was stirred with petroleum ether yielding 6.0 g of the title compound, melting point 61°-62° C.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CCCCO)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
To a solution of benzyl 5-hydroxypentanoate (2.01 g, 9.65 mmol) in anhydrous dichloromethane (30 mL) under nitrogen at −15° C. was added triethylamine (2.7 mL, 19.3 mmol) followed by a solution of methanesulfonyl chloride (1.5 mL, 19.3 mmol) dropwise over 20 minutes. The reaction was stirred at room temperature overnight and then diluted to 75 mL using dichloromethane. The organic layer was washed three times with saturated NaHCO3 and the combined aqueous layers backextracted with dichloromethane. The combined organic phases were dried over MgSO4, filtered, and concentrated. The resulting dark orange oil was purified by column chromatography (column 5″L×1″W; eluted with a gradient of 100% hexanes→10%→20%→25% diethyl ether in hexanes) to afford the product as a pale yellow oil (1.39 g, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:38]=[CH:37][C:32]3[NH:33][C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]5[CH:38]=[CH:37][C:32]6[NH:33][C:34](=[O:36])[O:35][C:31]=6[CH:30]=5)[CH:23]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: O=c1[nH]c2ccc(Oc3cc(Cl)ncn3)cc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4ccc5[nH]c(=O)oc5c4)ncn3)CC1)C(=O)N2

Procedure:
100 mg (0.36 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 90 mg (0.34 mmol) 6-(6-chloropyrimidin-4-yloxy)benzo[d]oxazol-2(3H)-one and 0.07 mL (0.41 mmol) DIPEA in 2.0 mL DMF were stirred overnight at RT and for 4 h at 40° C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. The precipitate formed was suction filtered, washed and dried.