Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:5]1[C:22](=[O:23])[CH:21]=[CH:20][C@@:19]2([CH3:24])[C:6]=1[CH:7]=[CH:8][C@@H:9]1[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]1[CH2:11][CH2:12][C:13]2=[O:25])[C:2]([CH3:4])=[O:3].[OH:26]O.[OH-].[Na+]>CO.C(Cl)Cl>[NH:1]([C:5]1[C:22](=[O:23])[C@@H:21]2[O:26][CH:20]2[C@@:19]2([CH3:24])[C:6]=1[CH:7]=[CH:8][C@@H:9]1[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]1[CH2:11][CH2:12][C:13]2=[O:25])[C:2]([CH3:4])=[O:3]
Reactant: OO
Reactant: CC(=O)NC1=C2C=C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)C=CC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)NC1=C2C=C[C@H]3[C@@H]4CCC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)C2O[C@H]2C1=O
Temperature: 0 °C
Reaction time: 120 h
Yield: 80 %

Procedure:
To an ice cold solution of 4-acetamino-androsta-1,4,6-triene-3,17-dione (3.384 g, 10 mmol) in methanol (50 ml) and CH2Cl2 (25 ml) are added gradually 35% H2O2 (4.5 ml) and 2N NaOH (1 ml). The mixture was allowed to stand at 0°-5° C. for 5 days. Then ice water was added, the mixture concentrated under vacuum to a small volume and the precipitate filtered off. Thus almost pure title compound was obtained (1.99 g). From the mother liquor 1.020 g of starting product was recovered. Therefore the yield is about 80% considering the recovery.
Reaction SMILES: [Na].C(O)C.Cl.[CH:6]1([NH:11][C:12]([NH2:14])=[NH:13])[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:15][C:16]1[N:21]2[N:22]=[C:23]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:24]([C:25](=O)[C:26]#[C:27][CH3:28])=[C:20]2[CH:19]=[CH:18][CH:17]=1>O>[Cl:15][C:16]1[N:21]2[N:22]=[C:23]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[C:24]([C:25]3[CH:26]=[C:27]([CH3:28])[N:14]=[C:12]([NH:11][CH:6]4[CH2:10][CH2:9][CH2:8][CH2:7]4)[N:13]=3)=[C:20]2[CH:19]=[CH:18][CH:17]=1
Reactant: CC#CC(=O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Reactant: N=C(N)NC1CCCC1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: Cc1cc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)nc(NC2CCCC2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.8 %

Procedure:
To a dry round bottom flask was added sodium metal (81 mg, 3.5 mmol). Ethanol (20 mL) was added and allowed to react with sodium at room temperature until completely dissolved. N-Cyclopentylguanidine hydrochloride (572 mg, 3.5 mmol) was added and the mixture was allowed to stir at room temperature for 10 minutes. To the resultant mixture was added 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-butyn-1-one (842 mg, 2.69 mmol) and the reaction mixture was allowed to stir at room temperature for 72 hours, then heated to 70° C. for 12 hours. The reaction mixture was cooled to room temperature and diluted with water. The mixture was extracted with ethyl acetate, and the combined extracts were washed with water and brine. The organic layer was dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (4:1 hexanes:ether to 3:2 hexanes:ether) provided 4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-6-methyl-2-pyrimidinamine (1.11 g, 98%) as a yellow foam. Rf 0.45 (3:1 hexanes:ethyl acetate). 1H NMR (CDCl3) δ 8.35 (d, 1H), 7.64 (m, 2H), 7.24 (m, 1H), 7.13 (m, 2H), 7.03 (d, 1H), 6.22 (s, 1H), 5.10 (m, 1H), 4.35 (m, 1H), 2.19 (s, 3H), 2.03 (m, 2H), 1.60 (m, 6H); MS m/z 422 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[F:31][C:32]([F:42])([F:41])[C:33]([NH:35][CH:36]1[CH2:40][CH2:39][NH:38][CH2:37]1)=[O:34]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:38]5[CH2:39][CH2:40][CH:36]([NH:35][C:33](=[O:34])[C:32]([F:42])([F:41])[F:31])[CH2:37]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:29])[F:30])[CH:3]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: O=C(NC1CCNC1)C(F)(F)F
Product: O=C1N=C(N2CCC(NC(=O)C(F)(F)F)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
N-(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidin-3-yl)-2,2,2-trifluoro-acetamide was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 2,2,2-Trifluoro-N-pyrrolidin-3-yl-acetamide following General Procedure B.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9](=O)[CH3:10])[CH:5]=[CH:4][N:3]=[CH:2]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:18].[Na+].Cl>CO>[CH3:10][CH:9]([NH2:18])[CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: [BH3-]C#N
Reactant: CC(=O)CCCn1ccnc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: CC(N)CCCn1ccnc1
Yield: 55 %

Procedure:
A solution of 8.3 g of 5-(1H-imidazol-1-yl)-2-pentanone, 44.0 g of ammonium acetate, and 3.5 g of sodium cyanoborohydride in 200 ml of methanol was stirred at room temperature for 2.5 days. The reaction mixture was acidified with hydrochloric acid and concentrated to dryness. The residue was taken up in potassium carbonate solution and extracted with dichloromethane. The combined extracts were dried over potassium carbonate and evaporated and the residue was distilled to give 4.6 g (55%) of alphamethyl-1H-imidazole-1-butanamine, bp 110°-117° C./0.25 mm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C1CC[C@@H](c2ccc(Br)cc2)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Solvent: ClCCl
Product: OC1CC[C@H](c2ccc(Br)cc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
To a solution of (3R)-3-(4-Bromophenyl)cyclopentanone (1.14 g, 4.77 mmol, CARBOXYLIC ACID 4, Step A) in 10 mL of CH2Cl2 at −78° C. was added diisobutylaluminum hydride (7.2 mL, 1.0 M in CH2Cl2). The mixture was stirred at −78° C. for 1 hr and then 5.0 mL of sat'd Rochelle's salt aqueous solution was added. The mixture was poured into diluted HCl solution and extracted with CH2Cl2 (3×10 mL). Organic layers were combined, washed with sat'd NaHCO3 and brine. The organic layer was dried over MgSO4 and concentrated to give 1.16 g (100%) of the title compound as a 1:1 ratio diastereomeric mixture, which cannot be separated by chromatography.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][N:12]([CH3:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>>[CH3:11][N:12]([CH3:19])[C:13]1[CH:18]=[CH:17][C:16]([CH:8]=[O:9])=[CH:15][CH:14]=1
Reactant: CN(C)c1ccccc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)c1ccc(C=O)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
83.0 g (0.54 mole) of phosphorus oxychloride was slowly added, drop by drop, to 33.3 g (0.45 mole) of dimethylformamide under cooling with ice. After stirring for a while, 55 g (0.45 mole) of dimethylaniline was added dropwise thereto and the resulting reaction mixture was stirred at 90° C. for 2 hours. The catalyst was slowly decomposed by the addition of 200 ml of ice water and the resulting mixture was made weakly alkaline by the addition of 350 g of a 20% aqueous sodium hydroxide solution. After the mixture was cooled by allowing it to stand for a while, the precipitated 4-dimethylaminobenzaldehyde was separated by filtration, washed thoroughly with water to remove any salts and impurities, and then dried at 50° C. Thus, there was obtained 59.8 g of 4-dimethylaminobenzaldehyde (in an 89% yield based on the dimethylaniline).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:24]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: O=C(Nc1ccc2[nH]cc(C3CCNCC3)c2n1)c1ccccc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.062 mMol) benzoyl chloride, the title compound was prepared.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][S:9][CH2:10][CH2:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[N:3]=1.[F:23][C:24]([F:30])([F:29])[CH2:25][N:26]=[C:27]=[S:28]>C(#N)C>[F:23][C:24]([F:30])([F:29])[CH2:25][NH:26][C:27](=[S:28])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][S:9][CH2:10][CH2:11][N:12]2[C:13](=[O:22])[C:14]3=[CH:21][CH:20]=[CH:19][CH:18]=[C:15]3[C:16]2=[O:17])[N:3]=1
Reactant: Nc1ccnc(CSCCN2C(=O)c3ccccc3C2=O)n1
Reactant: FC(F)(F)CN=C=S
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCSCc1nccc(NC(=S)NCC(F)(F)F)n1
Reaction time: 72 h
Yield: 62.6 %

Procedure:
A mixture of 4-amino-2-[(2-phthalimidoethyl)thiomethyl]pyrimidine (5.9 g.), 2,2,2-trifluoroethylisothiocyanate (3.9 g.) and acetonitrile (20 ml.) was stirred at 70° for 72 hours. The reaction mixture was cooled and the crystalline precipitate collected to give 4-[3-(2,2,2-trifluoroethyl)thioureido]-2-[(2-phthalimidoethyl)thiomethyl]pyrimidine (5.35 g.), m.p. 178°-179°.
Reaction SMILES: [CH2:1]([CH:3]([CH2:12][CH3:13])[CH2:4][CH:5]1[CH2:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6]1)[CH3:2]>O1CCCC1.[Pd]>[CH2:12]([CH:3]([CH2:1][CH3:2])[CH2:4][CH:5]1[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[CH2:8]1)[CH3:13]
Reactant: CCC(CC)CC1C=C(C(=O)O)C1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCC(CC)CC1CC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
3-(2-Ethylbutyl)-1-cyclobutenecarboxylic acid (39.0 g) was dissolved in tetrahydrofuran (200 mL). To the solution was added 5 w/w % palladium on activated carbon (5.5 g). The mixture was stirred at RT overnight under hydrogen atmosphere (1 atm). The 5 w/w % palladium on activated carbon was filtered off using Celite and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/4→1/2) to give the title compound (25.2 g).
Reaction SMILES: O1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1.[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19]>>[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][N:19]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[NH:10][CH:11]=[N:12][C:8]=2[CH:7]=1
Reactant: c1nc2ccc(-c3nnco3)cc2[nH]1
Reactant: NCc1ccccc1F
Product: Fc1ccccc1Cn1cnnc1-c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 5-(1,3,4-oxadiazol-2-yl)benzimidazole (186 mg, 1 mmol) and 2-fluorobenzylamine (0.5 ml) as described above; yield: 0.044 g (15.0%);
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:23][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:40]([NH2:42])[CH3:41]>O.C(Cl)Cl>[CH2:40]([NH:42][C:20]([C@@H:17]1[CH2:16][CH2:15][C@H:14]([N:13]2[C:12]3[CH:23]=[C:24]([CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[CH:25]=[CH:26][C:11]=3[NH:10]/[C:9]/2=[N:8]\[C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:35][CH:34]=2)[CH2:19][CH2:18]1)=[O:22])[CH3:41]
Reactant: O=C(/N=c1\[nH]c2ccc(CN3CCCCC3)cc2n1[C@H]1CC[C@@H](C(=O)O)CC1)c1ccc(F)cc1
Reactant: CCN
Solvent: O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCNC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCCCC4)cc32)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.1 %

Procedure:
cis-4-((E)-2-(4-Fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylic acid (0.025 g, 0.052 mmol) was cooled to 0° C. under nitrogen. To this mixture was added thionyl chloride (0.381 mL, 5.22 mmol), and the resulting reaction mixture was stirred for 10 minutes. The mixture was concentrated under reduced pressure and dried under high vacuum. The residue was suspended in THF (0.5 mL) and cooled to 0° C. under a nitrogen atmosphere. To this mixture was added ethanamine (2M in THF) (0.059 mL, 1.045 mmol) dropwise, and the reaction was stirred at 0° C. for 30 minutes. The reaction mixture was diluted with water (10 mL) and DCM (20 mL), and the layers were separated. The organic phase was dried over sodium sulfate, filtered, and solvent was concentrated under reduced pressure to afford (E)-N-(1-(cis-4-(ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide (0.025 g, 95% yield). MS m/z=506.2 [M+H]. Calc'd for C29H36FN5O2: 505.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, J=7.19 Hz, 3H) 1.42-1.50 (m, 2H) 1.50-1.63 (m, 4H) 1.63-1.89 (m, 4H) 2.14-2.28 (m, 2H) 2.32-2.47 (m, 4H) 2.57-2.66 (m, 1H) 2.67-2.89 (m, 2H) 3.21-3.32 (m, 2H) 3.56 (s, 2H) 4.77-5.03 (m, 1H) 7.17-7.23 (m, 1H) 7.25-7.35 (m, 2H) 7.53 (d, J=8.12 Hz, 1H) 7.63 (s, 1H) 7.83-7.94 (m, 1H) 8.29-8.43 (m, 2H) 12.79 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([C@H:18]1[C:21](=[O:22])[NH:20][C@@H:19]1[CH2:23][C:24](=[O:39])[CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)=[O:27])([O:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6])[CH3:3].C1(C)C=CC(S([N:49]=[N+:50]=[N-])(=O)=O)=CC=1.C(N(CC)CC)C>C(#N)C>[N+:49](=[C:25]([C:24](=[O:39])[CH2:23][C@@H:19]1[C@@H:18]([C:2]([CH3:1])([O:4][C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[O:6])[CH3:3])[C:21](=[O:22])[NH:20]1)[C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=1)=[O:27])=[N-:50]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.6 %

Procedure:
To a solution of 4-nitrobenzyl 4-[(2R,3S)-3-{1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl}-4-oxoazetidin-2-yl]-3-oxobutanoate (58.3 mg) in acetonitrile (1.17 ml) was added a solution of p-toluenesulfonyl azide (25.3 mg) in acetonitrile (0.228 ml) at 0° C. After stirring for 5 minutes at 0° C., a solution of triethylamine (53.7 μl) in acetonitrile (0.483 ml) was added dropwise. The stirring mixture was allowed to warm to ambient temperature during 15 minutes and kept at the same temperature for 20 minutes. The solvent was distilled off and the residue (85.9 mg) was flash-chromatographed on silica gel (1 g) eluting with a mixture of methylene chloride and ethyl acetate (50:1 to 3:1) to give 4-nitrobenzyl 2-diazo-4-[(2R,3S)-3-{1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl}-4-oxoazetidin-2-yl]-3-oxobutanoate (58.4 mg) as an amorphous solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:15]=[CH:14][C:10]([N:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=1.CN(OC)[C:18](=[O:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1COCC1>[CH3:12][N:11]([CH3:13])[C:10]1[CH:14]=[CH:15][C:7]([C:18](=[O:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:8][CH:9]=1
Reactant: CCCCCCC(=O)N(C)OC
Reactant: CN(C)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCC(=O)c1ccc(N(C)C)cc1
Reaction time: 1 h
Yield: 48.2 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 51 mL, 127 mmol) was added dropwise to 4-bromo-N,N-dimethylaniline (23.1 g, 115 mmol, Aldrich Chemical Co.) in anhydrous THF at -78° C. After 10 min. a solution of N-methyl-N-methoxyheptanamide (10.0 g, 57.7 mmol) in 20 mL THF was added dropwise via canula. The reaction was allowed to proceed 1 hr., then quenched with 1 N aq. HCl and carefully poured into sat. NaHCO3. The aqueous layer was extracted with ethyl ether, and the combined organic fraction was washed with water, brine, dried (MgSO4), and concentrated in vacuo. Flash chromatography (15% EtOAc/hexanes) yielded 1-(4-dimethylaminophenyl)heptan-1-one as a yellow solid (6.49 g, 48%). MS 234 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH2:12][CH:13]=C)[C:8](=[O:11])[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:22].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:8](=[O:11])[CH2:9][CH3:10])[CH2:12][CH:13]=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCC(C(=O)CC)(c1ccccc1)c1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCC(=O)C(CC=O)(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 17.2 %

Procedure:
4,4-diphenyl-6-hepten-3-one (144 mg) was dissolved in a mixture of dioxane and water (3:1, 11 ml). A 10% aqueous osmium tetroxide solution (0.5 ml) was added. The resultant solution was stirred at room temperature for 5 min. A solution of sodium periodate (550 mg) in water was then added dropwise. The reaction mixture was allowed to stir for 16 hours. Water was added, and the aqueous mixture was extracted with ethyl acetate (3×). The combined extracts were washed with water (once) and dried (MgSO4). Rotary evaporation of the solution gave a crude product which was purified by preparative thin layer chromatography (PTLC) on silica gel. Development with hexane/ethyl acetate (2:1) produced three bands. The lowest band (Rf 0.66) was scraped off the plate and eluted with methanol to yield 25 mg of 3,3-diphenyl-4-oxo-hexanal.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([CH2:11][CH3:12])[C:7]=1[CH2:13]Br)=[O:5])[CH3:2].[CH2:15]([O:17][C:18](=[O:32])[CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[O:30][CH3:31])[CH3:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH3:31][O:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[CH2:21][N:20]([CH2:13][C:7]1[C:8]([CH2:11][CH3:12])=[N:9][O:10][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:32]
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Reactant: CCOC(=O)c1onc(CC)c1CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(CC)noc1C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.5 %

Procedure:
4-Bromomethyl-3-ethyl-isoxazole-5-carboxylic acid ethyl ester (1.03 g, 3.93 mmol) was dissolved in 40 mL of acetonitrile. N-(2,4-dimethoxybenzyl)glycine ethyl ester (1.09 g, 4.32 mmol), potassium carbonate (1.63 g, 11.8 mmol) and potassium iodide (0.98 g, 5.90 mmol) were added, and the mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was partitioned between CH2Cl2 and water. The aqueous layer was extracted with additional CH2Cl2 and the combined organic layer was dried over MgSO4 and concentrated. The crude oil was purified by flash chromatography (0-30% EtOAc/hexanes) to give 0.88 g of the title compound. MS: (+) m/z 435.53 (M+1).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9]([C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[N:15][CH:16]=1)[CH3:10].[S]>>[CH2:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:8]=2)=[N:15][CH:16]=1)[CH3:10]
Reactant: Nc1ccccc1N
Reactant: CCc1ccc(C)nc1
Agent: [S]
Product: CCc1ccc(-c2nc3ccccc3[nH]2)nc1

Procedure:
130 g. of o-phenylenediamine, 121 g. of 5-ethyl-2-methylpyridine and 96 g. of sulfur were heated at 160°-170° C. for 20 hours. The reaction mixture was dissolved in 2,000 ml. of chloroform and the solution was washed with water and 6 N hydrochloric acid successively. Chloroform was removed by evaporation in vacuo. The residue was subjected to silica gel column chromatography and recrystallized from ethyl acetate. The product showed no melting point depression upon mixing with the product of the preceding example. Yield, 137 g (61% of theory).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][C:14](O)([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)cc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(C2=CCN(C(=O)OCc3ccccc3)CC2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-hydroxy-4-[4-[[(phenylmethoxy)carbonyl]amino]phenyl]-1-piperdinecarboxylic acid phenylmethyl ester (EXAMPLE 17, Step 1, 2.50 g) in dry methylene chloride under N2 is treated with trifluoroacetic acid (0.84 mL), stirred at ambient temperature for three hours, diluted with saturated aqueous potassium carbonate (25 mL) to neutralize excess trifluoroacetic acid, and the layers are separated. The organic phase is washed with water (20 mL) and saline (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is chromatographed on silica gel (230-400 mesh, 300 g), eluting with a gradient of ethyl acetate/hexane (20/80-50/50). Pooling of fractions with an Rf =0.69 by TLC (ethyl acetate/hexane, 50/50) and removal of solvent under reduced pressure gives the title compound, mp 146-148° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]Cl)=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S(=O)(=O)(O)O.P(=O)(O)(O)O>O>[CH2:8]([C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccccc1CCl
Reactant: c1ccccc1
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccccc1Cc1ccccc1
Yield: 88.9 %

Procedure:
A solution of 70 parts of o-xylyl chloride and 240 parts of benzene is added to a mixture of 135 parts of 80 per cent strength by weight sulfuric acid and 135 parts of 85 per cent strength by weight phosphoric acid at from 75° to 77° C, whilst stirring thoroughly. After a further 5 hours at from 75° to 77° C, 200 parts of water are added, the organic phase is separated off and 80 parts (88.9% of theory) of o-benzyltoluene boiling at 98°C at 0.2 mm Hg are isolated by distillation.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.C([O-])([O-])=O.[K+].[K+].Br[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([N+:37]([O-:39])=[O:38])[CH:31]=1>CN(C=O)C>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=2)=[CH:31][C:32]=1[N+:37]([O-:39])=[O:38]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)c([N+](=O)[O-])c2)CC1
Temperature: 80 °C
Yield: 64.7 %

Procedure:
To a 150-mL RB-flask containing tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (5.58 g, 16.5 mmol), K2CO3 (5.60 g, 40.5 mmol) and PdCl2dppf (1.48 mmol, 1.21 g) was added a solution of 4-bromo-1-fluoro-2-nitrobenzene (3.30 g, 15.0 mmol) in DMF (50.0 mL) at room temperature under argon. The mixture was heated to 80° C. under argon for 12 hours. After cooling to room temperature, the mixture was filtered through Celite and the Celite was washed with EtOAc (3×100 mL). The filtrates were washed with H2O (3×200 mL), brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (EtOAc/hexanes 1:9) to afford tert-butyl 4-(4-fluoro-3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (3.13 g, 65.1%): 1H NMR (400 MHz, CDCl3) δ 8.06-7.89 (m, 1H), 7.66-7.49 (m, 1H), 7.30-7.10 (m, 1H), 6.19-5.95 (br, 1H), 4.10-3.95 (m, 2H), 3.58 (t, 2H, J=5.6 Hz), 2.49-2.34 (m, 2H), 1.42 (s, 9H).