Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[C:29]([N:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:47]=[CH:46][C:45](B3OC(C)(C)C(C)(C)O3)=[CH:44][N:43]=2)[CH2:38][CH2:37]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([CH2:11][O:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:45]3[CH:46]=[CH:47][C:42]([N:39]4[CH2:40][CH2:41][N:36]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:37][CH2:38]4)=[N:43][CH:44]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: Brc1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(COc5ccc6ccccc6n5)cn34)cn2)CC1

Procedure:
Compound 15a (130 mg. 0.29 mmol) was subjected to Suzuki coupling conditions with 2-(4-BOC-piperazin-1-yl)pyridine-5-boronic acid pinacol ester using the methods described in Example 1, Step G to obtain compound 47a. Mass Spectrum (LCMS, ESI pos.) Calcd. for C34H38N8O4: 623.2 (M+H). Found 623.3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH2:7]([O:14][C:15](Cl)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[OH-].[Na+].C1(C)C=CC=CC=1>[NH:1]([C:15]([O:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16])[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(O)CCNC(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
6.0 g of β-alanine are taken up in 33.7 ml of 2N NaOH and cooled to +5°. At this temperature there are then added dropwise, simultaneously, 22.5 ml of a 50% solution of chloroformic acid benzyl ester in toluene and 16.8 ml of 4N NaOH. The emulsion is subsequently stirred in an ice bath for 3 hours. After separating off the organic phase, the aqueous phase is extracted once more with ether and then, while cooling with an ice bath, the pH is adjusted to 1 with 44 ml of 2N HCl. By filterirg off the precipitate and drying in a high vacuum at 50°, Z-β-Ala-OH is obtained in the form of a white powder; Rf (CH2Cl2 /MeOH/concentrated aqueous ammonia solution [5:3:1])=0.37.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O>CC(O)=O>[Cl:1][CH2:2][C:3]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=2[N:5]=1
Reactant: O=C(CCl)Nc1ccc(F)cc1Nc1ccccc1
Solvent: CC(=O)O
Product: Fc1ccc2nc(CCl)n(-c3ccccc3)c2c1
Temperature: 70 °C

Procedure:
A mixture of 2-chloro-N-(4-fluoro-2-phenylaminophenyl)acetamide (740 mg, 2.62 mmol) in AcOH (20 mL) was heated at 70° C. for 5 h under a nitrogen atmosphere. The volatiles were removed in vacuo and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with DCM (×3) and the combined organic fractions washed with water, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) to afford the title compound as a brown oil which crystallised on standing (570 mg, 84%). LCMS (Method C): RT 3.40 min [M+H]+ 261.2.
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][C:5]1([CH2:11][CH2:12][N:13]2[C:17](=[O:18])[CH2:16][S:15][CH:14]2[CH2:19][CH2:20][CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(O)(=O)C>CCOCC>[OH:4][C:5]1([CH2:11][CH2:12][N:13]2[C:17](=[O:18])[CH2:16][S:15][CH:14]2[CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:3])=[O:27])=[CH:29][CH:30]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Reaction time: 6 h

Procedure:
A solution of diazomethane (approximately 2.5 g., 0.06 mole) in ether (100 ml.) is mixed with a solution of 4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid (11.7 g., 0.03 mole) in ether (100 ml.). The resulting solution is allowed to stand at room temperature for 6 hours. Acetic acid is then added to destroy the excess diazomethane, and the solution is washed with dilute sodium bicarbonate solution and dried over sodium sulfate. Evaporation of volatile materials in vacuo yields the title compound as a nearly colorless, viscous oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[C:27]([F:30])([F:29])[F:28])[C:21](O)=[O:22]>CCCCCCC.CCOC(C)=O>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:26]([C:27]([F:28])([F:29])[F:30])=[C:18]([C:17]([F:16])([F:31])[F:32])[CH:19]=1
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(O)c1ccc(C(F)(F)F)c(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1ccc(C(F)(F)F)c(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3,4-bis(trifluoromethyl)benzoic acid (CAS RN 133804-66-7) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Yellow solid (43%). MS (ESI): m/z=439.12 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][CH2:26][NH:27][C:28](=[O:42])[C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][N:38]=[C:37](Cl)[N:36]=4)=[CH:31][CH:30]=3)[CH:23]=2)[NH:18][CH:17]=1)#[N:15]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:37]2[N:36]=[C:35]([C:32]3[CH:33]=[CH:34][C:29]([C:28](=[O:42])[NH:27][CH2:26][CH2:25][C:22]4[CH:23]=[C:24]5[C:19](=[CH:20][CH:21]=4)[NH:18][CH:17]=[C:16]5[C:14]#[N:15])=[CH:30][CH:31]=3)[CH:40]=[CH:39][N:38]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: CC(C)(C)OC(=O)N1CCN(c2nccc(-c3ccc(C(=O)NCCc4ccc5[nH]cc(C#N)c5c4)cc3)n2)CC1

Procedure:
Using piperazine-1-carboxylic acid tert-butyl ester and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. 1H NMR (DMSO) δ 1.44 (s, 9H); 2.98 (t, 2H, J=7 Hz); 3.45 (bs, 4H); 3.56 (m, 2H); 3.83 (bs, 4H); 7.18 (d, 1H, J=8 Hz); 7.31 (d, 1H, J=5 Hz); 7.48 (d, 1H, J=8 Hz); 7.51 (s, 1H); 7.94 (d, 2H, J=8 Hz); 8.22 (m, 3H); 8.49 (d, 1H, J=5 Hz); 8.70 (bt, 1H); 12.12 (bs, 1H). MS (ion spray) m/z 552 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.C([Li])CCC.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28](=C=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].[Cl-].[NH4+].[O:35]1CCCC1>>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28]([OH:35])([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:12])([F:11])[F:1])=[CH:5][CH:6]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=C=O)CC1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(OC(F)(F)F)cc2)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 40 %

Procedure:
4-trifluoromethoxy bromobenzene (2.41 g, 10 mmol) was dissolved in dry tetrahydrofuran (30 mL), cooled to −78° C., to which slowly added dropwise n-butyllithium (1.6M n-hexane solution, 6.5 mL), kept the temperature below −70° C. during the dropwise adding procedure, after adding, kept stirring this system for 20 min, added 4-carbonyl piperidine-1-formic acid tert-butyl ester (1.99 g, 10 mmol) in tetrahydrofuran solution, kept the temperature below −70° C. during the dropwise adding procedure, after adding, the temperature can be increased to room temperature while stirring for 15 h. After the reaction was finished, added saturated ammonium chloride aqueous solution to quench reaction, partitioned, organic phases were washed by saturated saline, followed by anhydrous sodium sulphate drying, concentration, column chromatography (PE: EA=15:1) to give 1.6 g light yellow gel-like substance, yield: 40%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]([NH:10][C:11](=[O:15])[CH2:12][CH2:13][CH3:14])([CH3:9])[CH3:8].[S:21](Cl)(=[O:24])(=[O:23])[NH2:22]>>[S:21]([NH:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]([NH:10][C:11](=[O:15])[CH2:12][CH2:13][CH3:14])([CH3:9])[CH3:8])(=[O:24])(=[O:23])[NH2:22]
Reactant: NS(=O)(=O)Cl
Reactant: CCCC(=O)NC(C)(C)COc1cccc(N)c1C#N
Product: CCCC(=O)NC(C)(C)COc1cccc(NS(N)(=O)=O)c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 215a from N-(1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-yl)butyramide (Example 229b) and sulfamoyl chloride in 100% yield. MS 355 (MH+).
Reaction SMILES: [N:1](OCCCC)=[O:2].[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[CH3:18])([O-:10])=[O:9].CC(C)([O-])C.[K+].O>CN(C)C=O.C(O)(=O)C>[CH3:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]=1[CH:18]=[N:1][OH:2]
Reactant: Cc1cccc([N+](=O)[O-])c1C
Reactant: CCCCON=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1cccc([N+](=O)[O-])c1C=NO
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A solution of 274 g (2.6 mol) of n-butyl nitrite (97%) and 300 g (2.0 mol) of 3-nitro-o-xylene (97%) in 750 ml of dimethylformamide is cooled to from −55 to −60° C., and a solution of 522 g (4.56 mol) of potassium tert-butoxide in 750 ml of dimethylformamide is added dropwise at this temperature over a period of 2.5 hours. During the addition, the color of the solution changes from yellow to deep red and the solution becomes viscous. The reaction is monitored by HPLC. For work-up, initially 300 ml of water are added and then about 300 ml of glacial acetic acid, until the pH has reached 5-6. During the addition, the temperature increases to −10° C., and a yellow suspension is formed. The reaction mixture is then poured onto 6 kg of ice-water and the residue that has formed is filtered off with suction, washed with 5 l of water and dried in a drying cabinet at 30° C. overnight. This gives 339 g of a light-beige crude product which is freed from the impurities by suspension in about 3 l of toluene at 80-90° C. for 2 hours. After cooling, the product is filtered off with suction and dried. This gives 276 g of 2-nitro-6-methyl-benzaldoxime.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]3[C:12](=[O:13])[CH2:11][CH:10]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:9][C:7]3=[N:8][C:4]=2[CH:3]=1.ClC1C=CC2N=C3CC(C4C=CC=CC=4)CC(=O)N3C=2C=1.[NH2:43][OH:44].[ClH:45].C([O-])C.[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([CH2:9][CH:10]([C:14]3[CH:19]=[CH:18][C:17]([Cl:45])=[CH:16][CH:15]=3)[CH2:11][C:12]([NH:43][OH:44])=[O:13])[NH:8][C:4]=2[CH:3]=1
Reactant: O=C1CC(c2ccccc2)Cc2nc3cc(Cl)ccc3n21
Reactant: NO
Reactant: Cl
Agent: CC[O-]
Agent: O=C1CC(c2ccccc2)Cc2nc3ccc(Cl)cc3n21
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(CC(Cc1nc2ccc(Cl)cc2[nH]1)c1ccc(Cl)cc1)NO
Reaction time: 1 h

Procedure:
The above mentioned regioisomeric mixture of 7-chloro-3-phenyl-3,4-dihydropyrido[1,2-a]benzimidazol-1(2H)-one and 8-chloro-3-phenyl-3,4-dihydropyrido[1,2-a]benzimidazol-1(2H)-one (331 mg) and hydroxylamine•HCl (83 mg) in ethanol (2 ml) was heated to reflux with stirring. Sodium ethanolate (82 mg) was added to give a clear solution. Refluxing was continued for 1 h whereupon a new precipitate is formed. Water (2 ml) was added and the mixture was kept at rt overnight. The solid was isolated by suction filtration and washed with water. After drying in vacuo 4-(5-chloro-2-benzimidazolyl)-3-(4-chlorophenyl)butyrohydroxamic acid (242 mg) is obtained as light red solid.
Reaction SMILES: [C:1](=[NH:8])([S:6][CH3:7])[NH:2][C:3]([NH2:5])=[O:4].[CH3:9][N:10]=[C:11]=[O:12]>C(Cl)Cl>[C:3]([N:2]=[C:1]([S:6][CH3:7])[NH:8][C:11]([NH:10][CH3:9])=[O:12])(=[O:4])[NH2:5]
Reactant: CN=C=O
Reactant: CSC(=N)NC(N)=O
Solvent: ClCCl
Product: CNC(=O)NC(=NC(N)=O)SC
Reaction time: 8 h

Procedure:
A mixture of 13 parts of methyl thioallophanimidate 74 parts of methylene chloride and 6 parts of methylisocyanate is refluxed for 2 hours. After standing overnight at room temperature, the solution is evaporated under vacuum to give crude methyl N-carbamoyl-4-methylthioallophanimidate (a compound of formula I).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][N:14]([C:18]([CH3:20])=[O:19])C(=O)C.[B-](F)(F)(F)F.[CH3:26][CH2:27][O+:28](CC)CC>ClCCl.CO>[C:27]([C:7]1[NH:8][C:9]2[C:5]([C:6]=1[CH2:12][CH2:13][NH:14][C:18](=[O:19])[CH3:20])=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)(=[O:28])[CH3:26]
Reactant: COc1ccc2[nH]cc(CCN(C(C)=O)C(C)=O)c2c1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2[nH]c(C(C)=O)c(CCNC(C)=O)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To N-[2-(5-methoxyindol-3-yl)ethyl]diacetamide (4) (35 mg) dissolved in dichloromethane (3 ml), at 0° C., is added Meerwein's reagent (0.15 mmol, 0.15 ml). The mixture is maintained at room temperature for 12 h. The solution is filtered. A red precipitate is obtained. The precipitate is dissolved in methanol (1 ml). After reacting for 15 min, the methanol is evaporated off and the ethyl acetate is extracted out. N-[2-(2-Acetyl-5-methoxyindol-3-yl)ethyl]acetamide (2) is thus obtained, Yield=75%.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])[CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:23].O>ClCCl>[CH3:14][C:13]([C:7]1[CH:8]=[C:9]([S:11]([CH3:12])=[O:23])[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:6]=1[OH:17])([CH3:16])[CH3:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: ClCCl
Solvent: O
Product: CS(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2,6-bis(1,1-dimethylethyl)-4-(methylthio)phenol (2.0 g, 3.9 mmole) and meta-chloroperoxybenzoic acid (0.86 g, 4.1 mmole) in dichloromethane (25 ml) was stirred at room temperature for 20 hours. Water was added and the phases were separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to dryness. Chromatography on silica gel gave the title compound, m.p. 171°-173°.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=O)=[CH:4][C:3]=1[CH3:16].[O-:17][C:18]#[N:19].[Na+].C(=O)([O-])O.[Na+].[OH-].[Na+]>ClCCl.C(O)(=O)C>[Br:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]([N:9]2[C:10]([CH3:15])([CH3:14])[C:11](=[O:13])[NH:19][C:18]2=[O:17])=[CH:6][C:7]=1[CH3:8]
Reactant: N#C[O-]
Reactant: Cc1cc(NC(C)(C)C(=O)O)cc(C)c1Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(N2C(=O)NC(=O)C2(C)C)cc(C)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a mixture of 2-((4-bromo-3,5-dimethylphenyl)amino)-2-methyl propanoic acid (5.79 g of the compound obtained from Reaction 1-1) in dichloromethane (62 mL) and acetic acid (62 mL), sodium cyanate (5.03 g, 59.8 mmol) was added at room temperature. The mixture was stirred at room temperature for three hours. A saturated solution of sodium hydrogen carbonate (400 mL) was added to adjust the pH to 7-8 using a 5 N aqueous sodium hydroxide, and this mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained solid was washed sequentially with ethyl acetate-hexane and then with dichloromethane-hexane to obtain 1-(4-bromo-3,5-dimethylphenyl)-5,5-dimethylimidazolidine-2,4-dione (3.80 g, 66%).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@@H:9]1[CH2:13][C:12]([CH3:19])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C@H:11]([CH2:20][CH3:21])[CH2:10]1)C1C=CC=CC=1.C([N:36](CC1C=CC=CC=1)[C@H:37]1[CH2:41][C:40]([CH3:47])([C:42]([O:44][CH2:45][CH3:46])=[O:43])[C@@H:39]([CH2:48][CH3:49])[CH2:38]1)C1C=CC=CC=1>>[NH2:8][C@@H:9]1[CH2:13][C:12]([CH3:19])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C@H:11]([CH2:20][CH3:21])[CH2:10]1.[NH2:36][C@H:37]1[CH2:41][C:40]([CH3:47])([C:42]([O:44][CH2:45][CH3:46])=[O:43])[C@@H:39]([CH2:48][CH3:49])[CH2:38]1
Reactant: CCOC(=O)C1(C)C[C@H](N(Cc2ccccc2)Cc2ccccc2)C[C@@H]1CC
Reactant: CCOC(=O)C1(C)C[C@@H](N(Cc2ccccc2)Cc2ccccc2)C[C@H]1CC
Product: CCOC(=O)C1(C)C[C@@H](N)C[C@H]1CC
Product: CCOC(=O)C1(C)C[C@H](N)C[C@@H]1CC
Yield: 100 %

Procedure:
A mixture of (2R,4S)-ethyl 4-(dibenzylamino)-2-ethyl-1-methylcyclopentanecarboxylate and (2S,4R)-ethyl 4-(dibenzylamino)-2-ethyl-1-methylcyclopentanecarboxylate (0.864 g, 2.28 mmol) was debenzylated using General Procedure FF to give (2R,4S)-ethyl 4-amino-2-ethyl-1-methylcyclopentanecarboxylate and (2S,4R)-ethyl 4-amino-2-ethyl-1-methylcyclopentanecarboxylate (0.45 g, 100%). LC/MS (Table 2, Method a) Rt=1.55 min; MS m/z: 200 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH:3]([CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)=[CH2:4].[C:11]([C:15]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[CH:17][C:16]=1[O:25][C@H:26]([CH3:30])[C:27](Cl)=[O:28])([CH3:14])([CH3:13])[CH3:12].O>C1(C)C=CC=CC=1>[C:11]([C:15]1[CH:20]=[C:19]([C:21]([CH3:23])([CH3:22])[CH3:24])[CH:18]=[CH:17][C:16]=1[O:25][C@H:26]([CH3:30])[C:27]([N:9]1[C@H:5]([CH:3]=[CH2:4])[CH2:6][CH2:7][C:8]1=[O:10])=[O:28])([CH3:12])([CH3:13])[CH3:14]
Reactant: C[C@@H](Oc1ccc(C(C)(C)C)cc1C(C)(C)C)C(=O)Cl
Reactant: C=CC1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C[C@@H]1CCC(=O)N1C(=O)[C@@H](C)Oc1ccc(C(C)(C)C)cc1C(C)(C)C
Temperature: 25 °C
Yield: 48.5 %

Procedure:
To 60% sodium hydride (74 mg, 2.2 mmol) in toluene (10 mL) at 0° C. was added dropwise a solution of 5-vinylpyrrolidin-2-one (222 mg, 2.0 mmol) in toluene (5 mL) over a 5 min period. The cooling bath was removed and the solution was allowed to warm to 25° C. to ensure complete generation of the anion. To the anion at 25° C. was added dropwise a solution of (2R)-2-(2,4-di-t-butylphenyloxy)propanoyl chloride (16, 716 mg, 2.2 mmol) in toluene (5 mL) over a 5 min period. TLC indicated that the reaction was complete upon addition of the acid chloride (silica gel plates; hexane and ethyl acetate, 4:1). Water (30 mL) was added to the reaction mixture and the phases were separated. The aqueous phase was extracted with methylene chloride (1×25 mL). The combined organic phases were washed with a saturated aqeous sodium bicarbonate solution (1×50 mL) and dried (MgSO4). Concentration and purification by flash chromatography on silica gel (EM silica gel 60, 0.040-0.063 partical size, 230-400 Mesh, column size: 4.5 cm diameter×15 cm length) using hexane and ethyl acetate (19:1) afforded 360 mg (45%) of (5S)-N-((2R)-2-(2,4-di-t-butylphenyloxy)propanoyl)-5 -ethenylpyrrolidin-2-one (19a) as a thick oil: 1H NMR (CDCl3) δ1.28 (s, 9 H), 1.42 (s, 9 H), 1.77-1.80 (d, 3 H), 1.95-2.10 (m, 1 H), 2.23-2.33 (m, 1 H), 2.52-2.82 (m, 2 H), 4.91-4.97 (q, 1 H), 5.10-5.19 (m, 2 H), 5.80-5.90 (m, 1 H), 5.97-6.03 (m, 1 H), 6.49-6.53 (d, 1 H), 7.12-7.16 (d, 1 H), 7.35 (s, 1 H); 13C NMR (CDCl3) δ175.4, 172.9, 157.3, 153.4, 143.1, 137.2, 135.6, 124.3, 123.2, 115.8, 71.6, 57.9, 35.2, 34.2, 31.9, 31.4, 29.9, 24.3, 18.2; IR (neat) 2965 (vs), 1741 (vs), 1715 (vs), 1590 (s), 1230 (vs), 710 (w) cm-1.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[CH2:5]([O:12][C:13](Cl)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>N1C=CC=CC=1.C(Cl)Cl>[CH2:5]([O:12][C:13](=[O:14])[NH:4][CH2:1][C:2]#[CH:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#CCN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#CCNC(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 32.9 %

Procedure:
To a solution of propargylamine (6.4 g, 71.2 mmol) in pyridine (100 mL) was added benzylchloroformate (13.37 g, 78.2 mmol) in 10 mL CH2Cl2 over 0.5 h. The reaction was stirred for 16 h and the volatiles were removed in vacuo. The residue was dissolved in EtOAc and the organic solution was washed with water (2×). The organic solution was washed with dilute aqueous HCl followed by saturated NaHCO3. The organic solution was dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound of Step A (4.43 g).
Reaction SMILES: [N+]([O-])(O)=O.[NH2:5][NH:6][C:7]([NH2:9])=N.CN([CH:13]=[C:14]([C:17](=[O:23])[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)C#N)C.[OH-].[Na+]>C(O)C>[NH2:9][C:7]1[C:14]([C:17]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[O:23])=[CH:13][NH:5][N:6]=1
Reactant: CN(C)C=C(C#N)C(=O)c1cccs1
Reactant: N=C(N)NN
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: Nc1n[nH]cc1C(=O)c1cccs1
Yield: 17.7 %

Procedure:
To a mixture of aminoguanidine nitrate (17.1, 125 mmol) and α-[(dimethylamino)methylene]-β-oxo-2-thiophenepropanenitrile (3) (20.6 g, 100 mmol) in commercial absolute ethanol (120 mL) is added 10N NaOH (5 g of solid NaOH in 12.5 mL of water). The reaction mixture is refluxed for 6 hrs and the solvents removed at reduced pressure on a rotary evaporator. Water (250 mL) is added and an initial precipitate forms and is filtered (13.3 g, 68.8 mmol, 69%). On further standing the aqueous layer deposits an additional quantity of the titled compound (3.42 g, 17.7 mmol, 18%), yielding product (4) as a tan solid (total 16.72 g, 86.5 mmol, 87%).
Reaction SMILES: [CH2:1](B(O)O)[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[C:15]1[CH:33]=[CH:32][C:18]2[N:19]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]3[C:28]([O:30][CH3:31])=[O:29])[O:21][C:17]=2[CH:16]=1.O1CCCC1>C1(C)C=CC=CC=1>[CH2:1]([C:15]1[CH:33]=[CH:32][C:18]2[N:19]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]3[C:28]([O:30][CH3:31])=[O:29])[O:21][C:17]=2[CH:16]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)[C@@H]1CCCCN1c1nc2ccc(Br)cc2o1
Reactant: CC(C)CB(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CCCCN1c1nc2ccc(CC(C)C)cc2o1
Temperature: 80 °C
Yield: 13.6 %

Procedure:
Isobutyl boronic acid (475 mg), potassium carbonate (644 mg) and tetrakis triphenylphosphine palladium (269 mg) were added sequentially to a solution of methyl (2S)-1-(6-bromo-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate (790 mg) [see Preparation 40] in toluene:tetrahydrofuran, 60:40 by volume, (20 ml) under nitrogen. The reaction mixture was then heated to 80° C. for 20 hours, after which time the solvent was removed under reduced pressure and the residue partitioned between water and dichloromethane. The organic layer was separated and washed with water, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 80:20, by volume, hexane:ethyl acetate to afford methyl (2S)-1-(6-isobutyl-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate (100 mg) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:14]S(C)(=O)=C>>[CH3:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][C:6]=1[C:10]([F:11])([F:12])[F:13]
Reactant: C=S(C)(C)=O
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1
Product: Cc1c([N+](=O)[O-])cccc1C(F)(F)F

Procedure:
reacting 3-nitrobenzotrifluoride with dimethyloxosulfonium methylide to produce 2-methyl-3-nitro-benzotrifluoride; and