Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:29])=[C:5]([N:16]2[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=O)[CH2:18][CH2:17]2)[S:6][C:7]=1[NH:8][C:9](=[O:15])[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])#[N:2].FC(F)(F)C(O)=O.C(=O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.ClC(Cl)C>[CH2:22]([N:19]1[CH2:18][CH2:17][N:16]([C:5]2[S:6][C:7]([NH:8][C:9](=[O:15])[CH:10]([CH2:11][CH3:12])[CH2:13][CH3:14])=[C:3]([C:1]#[N:2])[C:4]=2[CH3:29])[CH2:21][CH2:20]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCC(CC)C(=O)Nc1sc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1C#N
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)C(=O)Nc1sc(N2CCN(Cc3ccccc3)CC2)c(C)c1C#N

Procedure:
To a solution of 1.06 g (2.52 mmol) of the title compound from Example 30 in 10 mL of CH2Cl2 was added 10 mL of trifluoroacetic acid. After 2 h at ambient temperature the reaction was concentrated in vacuo. To 0.040 g (0.092 mmol) of this intermediate in 1 mL of dichloroethane was added 0.032 mL (0.20 mmol) of benzaldehyde, followed by 0.066 g (0.31 mmol) of sodium triacetoxyborohydride. After 16 h at ambient temperature the reaction was quenched by the addition of 10 mL of saturated aqueous NaHCO3. The reaction was extracted with CH2Cl2 and the organic layer was dried (Na2SO4) and concentrated in vacuo. Purification by preparative thin layer chromatography (15% EtOAc in hexane) afforded the title compound as a white solid. 1H NMR (500 MHz, CDCl3) 8.69 (s, 1H), 7.35 (m, 5H), 3.72 (s, 1H), 3.57 (s, 1H), 2.94 (t, J=5.0 Hz, 4H), 2.58 (s, 4H), 2.26 (m, 1H), 2.16 (s, 3H), 1.73 (m, 2H), 1.61 (m, 2H), 0.95 (t, J=7.5 Hz, 6H); mass spectrum (ES) m/e=411.2 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:3]=1.O.[NH2:23][NH2:24].C(O)CO>O>[NH2:9][C:8]1[C:7]2[C:2](=[N:3][C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:5][C:6]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:24][N:23]=1
Reactant: N#Cc1c(-c2ccccc2)cc(N2CCOCC2)nc1Cl
Reactant: NN
Solvent: O
Solvent: OCCO
Product: Nc1n[nH]c2nc(N3CCOCC3)cc(-c3ccccc3)c12
Temperature: 130 °C

Procedure:
A mixture consisting of 15.0 gm (0.05 mol) of 2-chloro-6-morpholino-4-phenyl-3-cyano-pyridine (see Example C), 20 ml of 80% hydrazine hydrate and 100 ml of ethylene glycol was heated for 3 hours at 130° C. Thereafter, the resulting solution was poured into about 1 liter of water, whereupon a virtually colorless precipitate formed which was collected by suction filtration, washed with water and then immediately reprecipitated from 700 ml of 0.1 N hydrochloric acid with concentrated ammonia. The reprecipitated product was collected by suction filtration, washed and dried, yielding 13.7 gm (93% of theory) of practically pure 3-amino-6-morpholino-4-phenyl-1H-pyrazolo[3,4-b]pyridine, m.p. 178°-180° C., of the formula ##STR6## After recrystallization from ethanol it had a melting point of 180°-182° C.
Reaction SMILES: C(P(C1CCCCC1)C1CCCCC1)C.C1(C)C=CC=CC=1.II.[CH2:25]([N:27]1[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29][C:28]1=[O:34])[CH3:26]>[Ir+].ClC1CCC=CCCC=1.CO>[CH2:25]([N:27]1[CH2:32][C@H:31]([CH3:33])[NH:30][CH2:29][C:28]1=[O:34])[CH3:26]
Reactant: CCn1cc(C)ncc1=O
Agent: [Ir+]
Agent: CCP(C1CCCCC1)C1CCCCC1
Agent: ClC1=CCCC=CCC1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCN1C[C@H](C)NCC1=O

Procedure:
A mixture of chloro-1,5-cyclooctadiene iridium (I) dimer (34 mg, 51 μmol) and (S)-1-[(R)-2-di-(3,5-bis(trifluoromethyl)phenyl)phosphino)ferrocenyl]ethyldicyclohexylphosphine (44 mg, 51 μmol; Solvias AG, SL-J006-2) in a mixture of 1:2 toluene and methanol (100 mL; purged with nitrogen for 15 minutes) was sonicated under an atmosphere of nitrogen for 15 minutes. To the resultant mixture, iodine (0.39 g, 1.52 mmol) and 1-ethyl-5-methylpyrazin-2(1H)-one (7.0 g, 50.66 mmol) was added. The resultant mixture was heated in an oil bath at 50° C. under an atmosphere of hydrogen gas at 800 psi for 48 hours. The product mixture was filtered through a pad of Celite. The filtrate was concentrated under vacuum. The residue was treated with chloroform saturated with ammonia gas (100 mL). The resultant suspension was filtered through a pad of Celite, which was the rinsed with chloroform saturated with ammonia gas. The combined filtrate was concentrated under vacuum. The residue was concentrated as a solution in toluene for subsequent reaction.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:30][Si](C)(C)C.CO>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:8]([NH2:30])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=C(O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 109.8 %

Procedure:
A solution 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid (304 mg, 1.0 mmol) in methylene chloride (10 mL) and N,N-dimethylformamide (1 drop) was cooled to 0° C. and then treated with a 2.0M solution of oxalyl chloride in methylene chloride (1.5 mL, 3.0 mmol). The reaction was stirred for 30 min at 0° C. At this time, 1,1,1,3,3,3-hexamethyldisilazane (2.0 mL, 9.5 mmol) was added to the reaction mixture. The reaction was allowed to slowly warm to 25° C. and then stirred at 25° C. for 16 h. The reaction mixture was then treated with methanol (3 mL) and diluted with methylene chloride (35 mL). The resulting mixture was washed with a 5% aqueous sulfuric acid solution (2×10 mL), water (1×25 mL), and a saturated aqueous sodium chloride solution (3×25 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionamide (333 mg, 92.5%) as a pale yellow oil: EI-HRMS m/e calcd for C15H17F4NO (M+) 303.1246, found 303.1252.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6]C(=O)C)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH2:15]Cl.[O-]CC.[Na+].[OH-].[K+]>C(O)C>[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:6])=[CH:10][CH:11]=1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: CC[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(OCc2ccc(Cl)cc2Cl)cc1

Procedure:
In ethanol, p-hydroxyacetoanilide is reacted with 2,4-dichlorobenzyl chloride in the presence of sodium ethoxide and the resultant 4-(2,4-dichlorobenzyloxy)-acetoanilide is treated with potassium hydroxide in ethanol, whereby 4-(2,4-dichlorobenzyloxy)-aniline is obtained as crystals melting at 70°-71° C. In a similar manner, the following compounds can be prepared from the corresponding substituted benzyl halide derivatives.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([F:20])=[CH:15][N:14]=1.O>CN(C=O)C>[Cl:12][C:13]1[N:18]=[C:17]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[C:16]([F:20])=[CH:15][N:14]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cnc(Cl)nc1-n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Indole (1.0 g, 8.54 mmol) was added in portions to a suspension of NaH (0.358 g, 8.96 mmol) in DMF (10 mL) at 0° C. under N2 and stirred for 15 minutes at RT. 2,4-Dichloro-5-fluoro-pyrimidine (1.49 g, 8.96 mmol) was then added in portions and allowed to stir at RT overnight. The reaction mixture was poured into cold water, extracted into DCM, washed in brine, dried with Na2SO4, filtered, and dried in vacuo to obtain an oil. The residue was purified using flash chromatography on a silica column eluting with hexane:EtOAc (1000:25) to (1000:50), to yield 1-(2-chloro-5-fluoro-pyrimidin-4-yl)-1H-indole after drying the collected fraction (0.11 g, 5%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[I:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1.CO>N1C=CC=CC=1>[I:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])=[N:17][CH:18]=1
Reactant: Nc1ccc(I)cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(I)cn2)cc1
Temperature: 25 °C

Procedure:
p-Toluenesulfonyl chloride (2.00 g, 10.4 mmol) was added to a solution of 5-iodo-2-aminopyridine (2.50 g, 11.4 mmol) in 6 mL of pyridine, and the resultant solution was warmed at 90° C. for 18 h. After cooling to room temperature, the solution was added portionwise to 75 mL of ice-water with stirring. The resultant precipitate was collected, washed with water, and dried in vacuo to afford a pale yellow powder, which was stirred with 20 mL of methanol for several minutes. The solid product was then collected, washed with methanol, and dried in vacuo to provide the title compound as an off-white powder. LC/MS 374.8 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]([OH:28])[CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:29]3[CH:34]=[CH:33][C:32]([O:35]C)=[CH:31][CH:30]=3)[S:8][C:7]=2[CH:37]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(OCC)(=O)C.CO>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]([OH:28])[CH2:22][N:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:17][CH:18]=3)=[O:12])=[C:9]([C:29]3[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=3)[S:8][C:7]=2[CH:37]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCC(O)CN3CCCC3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: CCS
Solvent: CCOC(C)=O
Product: O=C(c1ccc(OCC(O)CN2CCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Yield: 67 %

Procedure:
[6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl][4-(2-hydroxy-3-pyrrolidinylpropoxy)phenyl]methanone (250 mg, 0.50 mmol) was converted to 164 mg of the title compound by the procedure of Example 32 using 0.18 mL (2.48 mmol) of ethanethiol (0.18 mL, 2.48 mol) and 398 mg (2.98 mmol) of aluminum chloride except that 6:4 ethyl acetate/methanol gradient was used as the chromatography eluent.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CC(C)([O-])C.[Na+].[NH:15]1[CH2:19][CH2:18][C@H:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16]1.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:8][C:6]1[CH:7]=[C:2]([N:15]2[CH2:19][CH2:18][C@H:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:16]2)[CH:3]=[N:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: Cc1cncc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: Cc1cncc(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
A solution of 3-bromo-5-methylpyridine (138 mg, 0.892 mmol), sodium tert-butoxide (154 mg, 1.604 mmol), tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate (224 mg, 1.203 mmol) and 2-(dicyclohexylphosphino)-2′,6′-isopropoxybiphenyl (RuPhos, 37.4 mmol) in anhydrous 1,4-dioxane (7 ml) was purged with argon. Tris(dibenzylideneacetone)dipalladium (0) (Pd2(DBA)3, 73.5 mg, 0.08 mmol) was added and the mixture was stirred at 70° C. for two hours in a closed vial. After cooling to room temperature the mixture was filtered through kieselguhr and concentrated under reduced pressure. The residue was purified by column chromatography (silica, gradient from 0.5 to 7% methanol containing 7N NH3 in dichloromethane (DCM)) to afford 163 mg of a yellow solid (0.588 mmol, 73%) MS (ESI) 278.2 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=1[Cl:35])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)=[O:23].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1[O:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:22](=[O:23])[C:21]2[CH:32]=[CH:33][C:34]([Cl:35])=[C:19]([Cl:18])[CH:20]=2)=[CH:26][CH:27]=1)#[N:2]
Reactant: O=C(Nc1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(C#N)c1
Temperature: 125 °C
Reaction time: 12 h
Yield: 59.1 %

Procedure:
tert-Butyl 2-(3-cyano-4-fluorophenyl)acetate (2.0 g, 8.5 mmol) and the product of step A (2.9 g, 10 mmol) were diluted with DMSO (22 mL) followed by the addition of potassium carbonate (1.4 g, 10 mmol). The reaction was heated to 125° C. and stirred for 12 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and 10% aqueous sodium carbonate. The layers were separated and the organic layer was washed with 10% aqueous sodium carbonate two more times followed by water and brine. The organic material was dried over MgSO4, filtered and concentrated. The material was purified using a biotage 40M column eluting with hexanes:ethyl acetate (8:2) to yield tert-butyl 2-(3-cyano-4-(4-(3,4-dichlorobenzamido)phenoxy)phenyl)acetate (2.5 g, 59% yield) as a white solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:12][C@H:11]([CH:13]([CH3:15])[CH3:14])[N:10]([CH2:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[O:18])[C:9]2=[O:30])=[CH:4][CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:73][N:74](C)CCN(C)C>CN(C=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:73]([C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:12][C@H:11]([CH:13]([CH3:14])[CH3:15])[N:10]([CH2:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:29])[F:28])[CH:21]=3)=[O:18])[C:9]2=[O:30])=[CH:4][CH:3]=1)#[N:74]
Reactant: CC(C)[C@H]1CN(c2ccc(Br)nc2)C(=O)N1CC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: CN(C)CCN(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)[C@H]1CN(c2ccc(C#N)nc2)C(=O)N1CC(=O)Nc1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
A solution of 2-[(5S)-3-(6-bromopyridin-3-yl)-2-oxo-5-(propan-2-yl)imidazolidin-1-yl]-N-[3-(trifluoromethyl)phenyl]acetamide (150 mg), zinc cyanide (91 mg), Pd2(dba)3 (8.5 mg), Xantphos (11 mg), and N,N,N′,N′-tetramethylethylenediamine (14 μL) in DMF (2 mL) was stirred under irradiation with microwave at 180° C. for 30 min. Additional zinc cyanide (91 mg) was added thereto, and the resulting mixture was stirred under the same condition for 30 min. NH silica gel was added thereto, the mixture was stirred, followed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford the title compound (47 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:27])[CH2:17][N:18]([CH2:23][C:24]([OH:26])=O)[CH2:19][C:20]([OH:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.CCN(CC)CC.[NH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][C:55]([NH:57][CH2:58][CH2:59][O:60][C@@H:61]1[O:69][C@@H:68]([CH3:70])[C@@H:66]([OH:67])[C@@H:64]([OH:65])[C@@H:62]1[OH:63])=[O:56]>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:27])[CH2:17][N:18]([CH2:19][C:20]([OH:22])=[O:21])[CH2:23][C:24]([NH:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][C:55]([NH:57][CH2:58][CH2:59][O:60][C@@H:61]1[O:69][C@@H:68]([CH3:70])[C@@H:66]([OH:67])[C@@H:64]([OH:65])[C@@H:62]1[OH:63])=[O:56])=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CN(CC(=O)O)CC(=O)NCCCCCC(=O)OCc1ccccc1
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)CCCCCN)[C@@H](O)[C@H](O)[C@@H]1O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C[C@@H]1O[C@@H](OCCNC(=O)CCCCCNC(=O)CN(CC(=O)O)CC(=O)NCCCCCC(=O)OCc2ccccc2)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of 2,2′-[(2-{[6-(benzyloxy)-6-oxohexyl]amino}-2-oxoethyl)azanediyl]diacetic acid (1.0 g, 2.54 mmol) in CH2Cl2 (30 mL) at 0° C. was added trifluoroacetic anhydride (448 μL, 3.17 mmol). After stirring at 0° C. for 3 hr, the mixture was cooled to −30° C., to which a solution of Et3N (848 μL, 6.08 mmol) in DMF (20 mL) was added dropwise over 30 mins After stirring at −30° C. for 30 min, a mixture of 6-amino-N-{2-[(α-L-fucopyranosyl)oxy]ethyl}hexanamide (812 mg, 2.54 mmol) in DMF (30 mL) was added and the resulting mixture was allowed to stir at rt. After stirring for 16 hr, the mixture was concentrated and the residue was purified by flash chromatography on C18 reverse phase silica gel (42 g), eluting with 0-40% AcCN in water to produce the title compound. UPLC Method B: m/e=697.3876 [M+1]; Rt=3.398 min. 1H NMR (CD3OD) δ 1.23 (3 H, d, J=6.59), 1.39-1.36 (4 H, m), 1.56 (6 H, s), 1.67 (6 H, d, J=10.32), 2.23 (2 H, t, J=7.50), 2.41 (2 H, t, J=7.37), 3.24 (6 H, m), 3.42 (4 H, s), 3.49 (2 H, s), 3.57-3.52 (3 H, m), 3.68 (1 H, s), 3.77 (3 H, t, J=1.65), 3.98-3.94 (1 H, m), 4.77 (1 H, s), 5.14 (2 H, s), 7.38 (5 H, d, J=4.43).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][N+:4]=1[O-])[CH3:2]>CCO.[NH4+].[Cl-].C(Cl)Cl.CO.[Fe]>[CH2:1]([C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CCc1cc(N)ccn1

Procedure:
A solution of 388.0 g (2.3 mol) 2-ethyl-4-nitro-pyridine-1-oxide in 3.0 L EtOH and 1.0 L saturated NH4Cl solution (1.0 L) is stirred with 647.5 g (11.6 mol) iron powder. This mixture is refluxed for 3 h. The iron powder is filtered off with Celite®, and the solvent is removed from the filtrate in vaccuo to afford a crude oil. This oil is diluted with DCM/MeOH (1.0 L, 10:1) and the undissolved NH4Cl is removed by filtration, the filtrate is dried in vaccuo to afford the title compound. Yield: 200.0 g (71%).
Reaction SMILES: [Sn](Cl)Cl.[NH2:4][C:5]1[C:13]2[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=3)=[N:11][C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:9][C:8]=2[S:7][C:6]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30].Cl.[Na+].[Cl-]>O1CCOCC1.CCO>[NH2:4][C:5]1[C:13]2[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=3)=[N:11][C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:9][C:8]=2[S:7][C:6]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc([N+](=O)[O-])c3)c2c1N
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc(N)c3)c2c1N
Temperature: 90 °C

Procedure:
A solution of tin (II) chloride (23.0 g) in abs. EtOH (250 ml) was added to a solution of ethyl 5-amino-4-(3-nitrophenyl)-2-phenyl-thieno[2,3-d]pyrimidine-6-carboxylate (example 31(d), 16.6 g) in 1,4-dioxane p.a. (250 ml). 37% aq. HCl (6.9 ml) was added and the mixture was heated under reflux (90° C.) for 16 h. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was suspended in EtOAc (500 ml). 4N aq. NaOH was added to obtain a pH of 10–11. The mixture was diluted by adding sat. aq. NaCl. The organic layer was separated, dried (MgSO4) and concentrated under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:27].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+].[I-].[K+]>CC(C)=O>[CH2:28]([O:27][C:3]1[CH:4]=[CH:5][C:6]([C:8]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)([C:13]([F:14])([F:15])[F:16])[C:9]([F:11])([F:12])[F:10])=[CH:7][C:2]=1[Cl:1])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1ccc(COC(c2ccc(O)c(Cl)c2)(C(F)(F)F)C(F)(F)F)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: COc1ccc(COC(c2ccc(OCc3ccccc3)c(Cl)c2)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
100 mg (0.2 mmol) of 2-chloro-4-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenol (example 3) in 4 ml of acetone were treated with 47 mg (0.3 mmol) of benzyl bromide, 157 mg (0.5 mmol) of Cs2CO3 and 4 mg (0.025 mmol) of potassium iodide. The reaction mixture was stirred at 50° C. overnight, cooled to room temperature, filtered and the solvent was evaporated. The residue was dissolved in EtOAc and water, the phases were separated and the inorganic one was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4) and evaporated to give 82 mg (67%) of crude 1-benzyloxy-2-chloro-4-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-benzene.