Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH2:4][CH2:5][CH:6]([N+:15]([O-:17])=[O:16])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH2:1]([C:3]1[CH2:4][CH2:5][C@H:6]([N+:15]([O-:17])=[O:16])[C@H:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:8]=1)[CH3:2]
Reactant: CCC1=NC(c2ccccc2)C([N+](=O)[O-])CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1=N[C@@H](c2ccccc2)[C@@H]([N+](=O)[O-])CC1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a flame dried round bottomed flask under nitrogen was added 250 mg (1.07 mmol) 6-Ethyl-3-nitro-2-phenyl-2,3,4,5-tetrahydro-pyridine as a mixture of cis and trans isomers and 5 ml of anhydrous THF (TLC rf.=Trans 0.6; Cis 0.4; eluting solvent hexane:ethylacetate/50:50). The reaction mixture was cooled to −78° C. and 1.07 ml (1.07 mmol) of 1N lithium bis(trimethylsilyl)amide solution in THF was introduced. The reaction mixture was stirred for 20 min, and then quenched directly into a well stirred solution of 2 gm Baker Silica Gel (40 uM Flash Chromatography Packing). The solids were filtered and the filtrate was concentrated in vacuo to afford an orange red oil, 0.23 gm (92%) as the desired cis isomer, Cis-6-Ethyl-3-nitro-2-phenyl-2,3,4,5-tetrahydro-pyridine (TLC rf.=0.4, hexane:ethylacetate/50:50). Mass spectrum APCI (m/z) 233 (p+1).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]([C:28]([F:31])([F:30])[F:29])([F:27])[C:7]([F:26])([F:25])[C:8]([F:24])([F:23])[C:9]([F:22])([F:21])[C:10]([F:20])([F:19])[C:11]([F:18])([F:17])[CH2:12][CH2:13][N:14]=[N+]=[N-])=[N+]=[N-].NN>[OH-].[OH-].[Pd+2].CO>[NH2:1][CH2:4][CH2:5][C:6]([C:28]([F:29])([F:30])[F:31])([F:27])[C:7]([F:25])([F:26])[C:8]([F:23])([F:24])[C:9]([F:21])([F:22])[C:10]([F:19])([F:20])[C:11]([F:18])([F:17])[CH2:12][CH2:13][NH2:14]
Reactant: [N-]=[N+]=NCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(CCN=[N+]=[N-])C(F)(F)F
Agent: [Pd+2]
Agent: NN
Agent: [OH-]
Solvent: CO
Product: NCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(CCN)C(F)(F)F
Yield: 38.8 %

Procedure:
A mixture of 1,10-diazido-3-trifluoromethyl-3,4,4,5,5,6,6,7,7,8,8-undecafluorodecane (7.2 g, 14.7 mmol), methanol (40 mL), Pearlman's catalyst (0.6 g) and a solution of hydrazine (1.1 g, 36 mmol) in methanol (5 mL) was heated under reflux for 21 hours. The mixture was diluted with methanol and filtered through a pad of celite. Methanol was evaporated and the residue was distilled to give 2.5 g (39%) of 1,10-diamino-3-trifluoromethyl-3,4,4,5,5,6,6,7,7,8,8-undecafluorodecane, a colorless oil; bp 0.2 mm, 85°-95° C./0.2 mm; Glc (OV-17, 110° C. to 260° C. at 16° C./min) RT 5.4 min; IR (neat) 3350, 3050, 2975 and 1050-1380 cm-1 ; 1H NMR (CDCl3) δ 3.0 (t, J=6 Hz, 4H), 2.20 (m, 4H) and 1.23 (s, 4H). Anal Calcd for C11H12F 14 N2 : C, 30.15; H, 2.76; F, 60-70. Found: C, 29.85; H, 2.36; F, 60.32.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][CH2:6][CH2:7][S:8][CH2:9][C:10]([OH:12])=[O:11].[CH3:13]O>>[CH3:13][O:11][C:10](=[O:12])[CH2:9][S:8][CH2:7][CH2:6][Cl:5]
Reactant: CO
Reactant: O=C(O)CSCCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)CSCCCl
Temperature: 5 °C
Reaction time: 2.5 h

Procedure:
Thionyl chloride (10 ml) was added to a solution of the title compound of Example 9 (9.7 g, 0.06 mole) in methyl alcohol (100 ml) cooled to 5° C. via an ice bath. The ice bath was removed and the reaction stirred for 2.5 hours at room temperature. The methyl alcohol and excess thionyl chloride were removed using a rotary evaporator to give 9.8 g, of an oil which was identified by NMR as the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([NH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][O:1][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:18][CH:17]=1)=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCc1ccc(CO)cc1)c1ccccn1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(CNC(=O)c2ccccn2)cc1
Yield: 80.5 %

Procedure:
Using General Procedure G: Reaction of pyridine-2-carboxylic acid 4-hydroxymethyl-benzylamide (200 mg, 0.83 mmol), Et3N (144 uL, 0.99 mmol), and MsCl (71 uL, 0.91 mmol) for 10 minutes at 0° C. gave the title compound (214 mg, 81%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.92 (s, 3H), 4.69 (d, 2H, J=3.3 Hz), 5.23 (s, 2H), 7.41-7.47 (m, 5H), 7.85-7.87 (m, 1H), 8.24 (d, 1H, J=7.8 Hz), 8.50 (br s, 1H), 5.84 (d, 1H, J=3.9 Hz).
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:15][C:16]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>>[CH3:15][C:16]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][C:12](=[O:13])[CH2:11][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Cc1cccc(N)c1C
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: Cc1cccc(NC(=O)CC23CC4CC(CC(C4)C2)C3)c1C
Yield: 12.6 %

Procedure:
Prepared according to the method of Example 1b) from 1-adamantaneacetyl chloride (0.2 g) and 2,3-dimethylaniline (0.11 g) to give the title compound as a white solid (0.034 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:5]=2[N:4]([CH2:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22](O)=[O:23])[CH2:18][CH2:17]2)[C:3]1=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.C(N(CC)CC)C.[Cl-].[NH4+]>CS(C)=O.C(Cl)Cl>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([F:12])([F:14])[F:13])=[CH:10][C:5]=2[N:4]([CH2:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)=[O:23])[CH2:18][CH2:17]2)[C:3]1=[O:25]
Reactant: C1COCCN1
Reactant: Cn1c(=O)n(C[C@H]2CC[C@H](C(=O)O)CC2)c2cc(C(F)(F)F)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cn1c(=O)n(C[C@H]2CC[C@H](C(=O)N3CCOCC3)CC2)c2cc(C(F)(F)F)ccc21
Reaction time: 8 h

Procedure:
trans-4-(3-Methyl-2-oxo-6-trifluoromethyl-2,3-dihydro-benzoimidazol-1-ylmethyl)cyclohexanecarboxylic acid (78 mg, 0.22 mmol), HATU (100 mg, 0.26 mmol), morpholine (23 mg, 0.26 mmol) and triethyl amine (0.04 ml, 0.26 mmol) were dissolved in DMSO and the mixture were shaken overnight. 3 ml of a saturated solution of ammonium chloride and 2 ml of DCM were added and the organic layer was separated and washed with water. The organic solvent was evaporated and the crude was purified by silica column using ethyl acetate as eluent. 25 mg (yield 27%) of the titled compound were isolated.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[F:31][C:32]1[CH:46]=[CH:45][C:35]([CH:36]([NH2:44])[C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)=[CH:34][CH:33]=1>>[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH:36]([NH:44][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])[C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)=[CH:45][CH:46]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Reactant: NC(c1ccc(F)cc1)c1ccc(F)cc1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 91 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 4,4'-di-fluorobenzhydrylamine (prepared as described in Preparation 12) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 91%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[C:8]#[N:9])=[CH:3][CH:2]=1.N.O>CO.[Ni]>[N:1]1[CH:2]=[CH:3][C:4]([CH:7]([C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=2)[CH2:8][NH2:9])=[CH:5][CH:6]=1
Reactant: N#CC(c1ccncc1)c1ccc(C(F)(F)F)nc1
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CO
Product: NCC(c1ccncc1)c1ccc(C(F)(F)F)nc1
Yield: 82.5 %

Procedure:
A mixture of 2-(pyridin-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile (360 mg, 1.36 mmol) and NH3.H2O (2 mL) in MeOH (30 mL) was hydrogenated with Raney Ni (700 mg) under H2 (50 Psi) for 5 h. The reaction mixture was filtered and concentrated to give 2-(pyridin-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine (300 mg), which was used in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:17])[CH2:14][CH:15]=[CH2:16])[CH2:9]1)=O)(C)(C)C.CN(C=O)C.[H-].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](F)[C:27]=1[CH3:33].Cl.CCO>>[Cl:25][C:26]1[C:27]([CH3:33])=[C:28]([CH:29]=[CH:30][CH:31]=1)[O:17][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][CH:15]=[CH2:16]
Reactant: Cc1c(F)cccc1Cl
Reactant: C=CC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: C=CC[C@H](Oc1cccc(Cl)c1C)[C@H]1CCNC1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((S)-1-Hydroxy-but-3-enyl)pyrrolidine-1-carboxylic acid t-butyl ester (31 mg, 130 μmol) was dissolved in DMF (470 μL, 6.1 mmol). 60% Sodium hydride in oil (0.4:0.6, sodium hydride:mineral oil, 10.1 mg, 169 μmol) was carefully added, and the mixture allowed to stand for 15 minutes. 2-Chloro-6-fluorotoluene (47.0 μL, 390 μmol) was added. The mixture was stirred at 70° C. for 3 hours. The reaction was quenched with MeOH, and the solvent was removed. 1.2M HCl in EtOH (630 μL, 760 μmol) was added, and the mixture was stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (1 mg, 100% purity). MS m/z: [M+H]+ calcd for C15H20C1NO, 266.12. found 266.0.
Reaction SMILES: [OH-].[Ba+2].[OH-].[C:4]([CH:7]([C:13]([CH3:22])([CH3:21])[CH:14](Cl)[CH2:15][C:16]([Cl:19])([Cl:18])[Cl:17])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:6])[CH3:5].Cl>C(O)C>[C:4]([C:7]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([CH3:22])([CH3:21])[CH:14]1[CH2:15][C:16]([Cl:19])([Cl:18])[Cl:17])(=[O:6])[CH3:5]
Reactant: CCOC(=O)C(C(C)=O)C(C)(C)C(Cl)CC(Cl)(Cl)Cl
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1(C(C)=O)C(CC(Cl)(Cl)Cl)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
Anhydrous barium hydroxide (0.86 g) was added to 10 ml of absolute ethanol, and 1.76 g of ethyl 2-acetyl-4,6,6,6-tetrachloro-3,3-dimethylhexanoate was then added thereto, while the reaction mixture was cooled with ice. After stirring at room temperature for 2 hours, the mixture was rendered neutral with an ethereal hydrogen chloride, while cooled with ice, the solvent was distilled off. The resulting residue was dissolved in diethyl ether, and the solution was washed successively with water, aqueous sodium bicarbonate, and aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent ws distilled off, and the residue was purified by column chromatography (silica gel-benzene) to give 1.3 g (82% yield) of ethyl 1-acetyl-2-(2,2,2-trichloroethyl)-3,3-dimethylcyclopropanecarboxylate.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][N+:13]([O-])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C[Si]([C:21]#[N:22])(C)C>C(N(CC)CC)C>[C:21]([C:14]1[CH:15]=[C:10]([CH2:9][P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=[CH:12][N:13]=1)#[N:22]
Reactant: CCOP(=O)(Cc1cc[n+]([O-])cc1)OCC
Reactant: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Product: CCOP(=O)(Cc1ccnc(C#N)c1)OCC

Procedure:
A mixture of 1.2 g of 4-(diethylphosphonomethyl)pyridine-N-oxide, 1.35 ml of triethylamine and 2.6 ml of trimethylsilylcyanide is heated at 90° for 1 hour. The volatiles are removed in vacuo and the residue is dissolved in ethyl acetate and washed with a small volume of aqueous sodium bicarbonate. After drying over magnesium sulfate the solvent is removed in vacuo to afford 2-cyano-4-(diethylphosphonomethyl)pyridine as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)(=[O:15])[CH3:14]
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)Cc1ccc(OC(C)=O)cc1
Reaction time: 2 h

Procedure:
10 g (0.06 mol) of methyl 4-hydroxyphenylacetate are treated with 18.36 g (0.18 mol) of acetic anhydride (17 ml) and 1 ml of pyridine and the mixture is heated to boiling for 2 hours. The solvents are largely evaporated in vacuo, the residue is taken up in water and the solution is extracted with ethyl acetate. After drying using sodium sulphate, the solvent is distilled off in vacuo and a pale yellow, thin oil is obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CN([C:29]([O:33][N:34]1N=NC2C=CC=C[C:35]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CONC>C(#N)C>[CH3:29][O:33][N:34]([CH3:35])[C:14]([C:11]1[N:10]=[CH:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:12]=1[CH3:13])=[O:16]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1c(C(=O)O)ncn1Cc1ccccc1
Agent: CNOC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ncn(Cc2ccccc2)c1C
Yield: 134 %

Procedure:
Part B: To a magnetically stirred solution of N-benzyl-5-methyl-1H-imidazole-4-carboxylic acid (6.77 gram, 0.031 mol) in anhydrous acetonitrile (35 ml) was successively added diisopropylethylamine (DIPEA) (17.2 ml, 0.0992 mol), HBTU (14.098 gram, 0.0372 mol) and methoxy-methylamine (3.63 gram, 0.0372 mol). The resulting mixture was reacted at 20° C. for 16 hours and subsequently concentrated in vacuo. The resulting residue was taken up in ethylacetate and successively washed with 5% aqueous NaHCO3 solution and water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting oily residue (18.45 gram) was purified by flash chromatography (ethyl acetate/acetone=7/3 (v/v)) to give N-methoxy-N-methyl-5-methyl-1-benzyl-1H-imidazole-4-carboxamide (10.77 gram, 82% yield). MH+=260. 1H-NMR (400 MHz, CDCl3): 2.34 (s, 3H), 3.47 (s, 3H), 3.77 (s, 3H), (s, 2H), 7.05-7.10 (m, 2H), 7.18-7.28 (m, 3H), 7.48 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:7](=[O:8])[CH:6]=[CH:5][CH2:4][CH2:3]1.[OH:16][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]1[C@@H:31]2[C@@H:26]([NH:27][C:28]([NH:30]2)=[O:29])[CH2:25][S:24]1)=O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:17]([NH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:7](=[O:8])[CH:6]=[CH:5][CH2:4][CH2:3]1)(=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]1[C@@H:31]2[C@@H:26]([NH:27][C:28]([NH:30]2)=[O:29])[CH2:25][S:24]1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: NC1(c2ccccc2Cl)CCC=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NC1(c2ccccc2Cl)CCC=CC1=O
Yield: 31.7 %

Procedure:
A solution of 6-amino-6-(2-chlorophenyl)-2-cyclohexen-1-one (50 mg, 0.23 mmol), (+)-biotin (56 mg, 0.23 mmol), hydroxybenzotriazole (31 mg, 0.23 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (66 mg, 0.35 mmol) in dimethylformamide (1 ml) was stirred at room temperature for 42 h. The reaction was partitioned between water and ethyl acetate, the organic phase was washed with water, brine, dried (Na2SO4), and the solvent removed by evaporation. Flash chromatography on silica gel eluted with 17:3 ethyl acetate/hexane afforded 6-biotinoylamino-6-(2-chlorophenyl)-2-cyclohexen-1-one (32.7 mg, 32%).
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9]O.S(Cl)([Cl:13])=O>CN(C)C=O>[CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][Cl:13]
Reactant: O=S(Cl)Cl
Reactant: O=c1cc(CO)occ1O
Solvent: CN(C)C=O
Product: O=c1cc(CCl)occ1O
Temperature: 10 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
50 g(351.8 mmol) of kojic acid was dissolved in 250 ml of N,N-dimethylformamide. The resulting solution was cooled in an ice bath of 10° C. and 30 ml(411.3 mmol) of thionyl chloride was added dropwise thereto. The mixture was stirred at room temperature for 2 hours and 2000 ml of ice water was added. The precipitate was filtered and dissolved into 1000 ml of ethyl acetate. The reaction product was dried over magnesium sulfate, decolored with active charcoal and filtered. The filtrate was concentrated and hexane was added to give crystals, which were then dried under vacuum to give 37.5 g(66.83%) of the desired chlorokojic acid as a yellow solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12]>O>[N+:1]([C:7]1[C:6]([CH3:12])=[CH:5][C:10]([OH:11])=[CH:9][CH:8]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(O)c1
Solvent: O
Product: Cc1cc(O)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A reaction apparatus with a stirrer was charged with 84 ml of 99% nitric acid and 540 ml water, and the mixture was cooled to 0° C. Thereafter, at one and the same time, 54 g of m-cresol and 53 g of liquid N2O3 were added. The temperature was kept through cooling the whole time below 5° C. After the addition of m-cresol and N2O3 had been completed, the stirring was continued for 1 hour, the temperature then being kept at approx. 0° C. Thereafter the temperature was allowed to rise to approx. 30° C., and at that temperature the stirring was continued for 2 hours. The reaction mixture was thereafter cooled to 0° C. and a solid product was then precipitated. This solid product was then filtered off, washed with water and dried. In this way, 70 g of raw p-nitro-m-cresol with a melting point of 118°-122° C. was obtained.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH:14]=[C:13]([NH2:17])[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2].CC1(C)[O:27][C:26](=O)[CH:25]=[C:24]([CH3:29])O1>C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:26](=[O:27])[CH:25]=[C:24]([CH3:29])[NH:17][C:13]=2[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)cc(N)n(C)c1=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(=O)cc(C)[nH]c2n(C)c1=O
Temperature: 160 °C
Reaction time: 0.33 h

Procedure:
Alternatively, (R)-3-(5-acetoxyhexyl)-1,7-dimethylpyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione was prepared as follows: To a mixture of (R)-3-(5-acetoxyhexyl)-6-amino-1-methyluracil (2.1 g, 7.41 mmol) in xylenes (70 ml) heated to 160° C. was added over 30 minutes a solution of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (2.0 ml, 15.3 mmol) in xylenes (30 ml). After stirring at 160° C. for 20 minutes, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 20% ethyl acetate-toluene to afford(R)-3-(5-acetoxyhexyl)-1,7-dimethylpyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (1.37 g, 53% yield) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.20 (d, 3H), 1.25-1.71 (m, 6H), 2.00 (s, 3H), 2.46 (s, 3H), 3.62 (s, 3H), 4.00 (t, 2H), 4.86 (sextet, 1H), 6.49 (s, 1H), 12.15 (s, 1H).13C NMR (75 MHz, CDCl3) δ 19.64, 20.96, 22.46, 25.02, 27.19, 29.15, 35.19, 40.67, 70.29, 94.48, 105.71, 150.09, 150.73, 164.92, 165.18, 167.82, 170.15.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:21]/[CH:22]=[C:23](/[CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])\[CH3:24])[C:10](=[O:20])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)=[CH:5][CH:4]=1.Cl>C(O)C.[Fe]>[CH3:1][N:2]([CH3:31])[C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:21]/[CH:22]=[C:23](/[CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])\[CH3:24])[C:10](=[O:20])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])=[CH:7][CH:8]=1
Reactant: CC(C)=CCC/C(C)=C/CN(C(=O)c1ccccc1[N+](=O)[O-])c1ccc(N(C)C)cc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CC(C)=CCC/C(C)=C/CN(C(=O)c1ccccc1N)c1ccc(N(C)C)cc1
Yield: 56 %

Procedure:
N-(4-dimethylaminophenyl)-N-geranyl-2-nitrobenzamide (2.5 g) was dissolved in ethanol (35 ml), to the solution was added 1N-aqueous HCl (6.5 ml) and iron powder (1.3 g), and the mixture was stirred under heat for 2 hrs. After filtering the insolubles, distilling off the solvent, and neutralizing with 10% sodium hydroxide solution, the mixture was extracted with ethyl acetate, washed with water and saturated saline and dried over anhydrous MgSO4. The solvent was distilled off. The residue was purified by a silica gel column chromatography (hexane:ethyl acetate=3:1) to give N-(4-dimethylaminophenyl)-N-geranyl-2-aminobenzamide 1.3 g (58%) as an oily product.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([Cl:21])[CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[C:7]=2[O:6]1)=[N+]=[N-]>[Pt]>[Cl:21][C:11]1[CH:12]=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:7]2[O:6][CH:5]([CH2:4][NH2:1])[CH2:9][C:8]=2[CH:10]=1
Reactant: [N-]=[N+]=NCC1Cc2cc(Cl)cc(-c3cccc(Cl)c3)c2O1
Agent: [Pt]
Product: NCC1Cc2cc(Cl)cc(-c3cccc(Cl)c3)c2O1
Yield: 50 %

Procedure:
Treatment of (±)-[5-chloro-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.00 g, 2.24 mmol) with sodium azide (0.93 g, 14.3 mmol) generally according to the procedure described for Intermediate 98 provided 0.41 g of (±)-2-(azidomethyl)-5-chloro-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (100 mg, 5 wt. %) generally according to the procedure described for Example 1 provided 0.31 g (50%) of (±)-1-[5-chloro-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 195° C. (dec); Anal. calcd for C15H13Cl2NOHCl: C, 54.49; H, 4.27; N, 4.24. Found: C, 51.59; H, 4.21; N, 4.02.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[CH2:2]1.Cl.[NH2:15][C@@H:16]([C:18]1[C:23]([F:24])=[CH:22][C:21]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[C:20]([CH3:30])[CH:19]=1)[CH3:17].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O1CCCC1>[F:24][C:23]1[CH:22]=[C:21]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:20]([CH3:30])=[CH:19][C:18]=1[C@H:16]([NH:15][C:11]([C:3]1[CH2:2][O:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:13])[CH3:17]
Reactant: Cc1cc([C@@H](C)N)c(F)cc1NS(C)(=O)=O
Reactant: O=C(O)C1=Cc2ccccc2OC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc([C@@H](C)NC(=O)C2=Cc3ccccc3OC2)c(F)cc1NS(C)(=O)=O
Reaction time: 8 h
Yield: 38.1 %

Procedure:
To a solution of 2H-chromene-3-carboxylic acid (0.015 g, 0.085 mmol), N-[4-((R)-1-aminoethyl)-5-fluoro-2-methylphenyl]methanesulfonamide hydrochloride (20.00 mg, 0.07 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.032 g, 0.085 mmol) in N,N-dimethylformamide (0.39 g) was added N,N-diisopropylethylamine (0.046 g, 0.35 mmol). Tetrahydrofuran (0.38 g) was added to dilute solution. The reaction was stirred overnight. It was then concentrated and purified by HPLC to obtain the product (10.8 mg, 37%) a solid. m/z=405.1 (M+1). 1H-NMR (400 MHz, DMSO-d) δ 9.19 (s, 1H), 8.61 (d, 1H, J=7.66 Hz), 7.37 (s, 1H), 7.30-7.21 (m, 3H), 7.07 (d, 1H, J=11.41 Hz), 6.96 (dt, 1H, J=7.54 Hz), 6.84 (d, 1H, J=7.81 Hz), 5.25-5.18 (m, 1H), 4.88 (s, 2H), 3.02 (s, 3H), 2.25 (s, 3H), 1.41 (d, 3H, J=7.07 Hz).