Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][C@@H:3]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[NH:2]2.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][CH2:30][CH2:31][C:32](O)=[O:33].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][CH2:30][CH2:31][C:32]([N:2]1[C@H:3]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:4][C@H:5]2[C@@H:1]1[CH2:8][CH2:7][CH2:6]2)=[O:33]
Reactant: O=C(O)CCCc1ccc2ccccc2c1
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCC[C@@H]2N1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCC[C@@H]2N1C(=O)CCCc1ccc2ccccc2c1
Temperature: -5 °C
Reaction time: 48 h

Procedure:
2 5 g of benzyl (lS,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylate and 2.2 g of 4-(2-naphthyl)butyric acid are dissolved in 40 ml of DMF and cooled to -5° C. 7.7 ml of triethylamine and then 10 ml of n-propylphosphonic anhydride (50 % strength solution in dichloromethane) were pipetted into this solution under a nitrogen atmosphere. This mixture was stirred at room temperature for 48 hours, to effect complete conversion. The solution was diluted with 100 ml of ethyl acetate and successively extracted two times each with saturated NaHCO3 solution, 10 % strength citric acid solution and saturated NaCl solution. After drying over MgSO4 and concentration of the organic phase, the crude product obtained was separated by column chromatography over silica gel (cyclohexane/ethyl acetate). This gave 2.52 g of the desired product.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl.[CH3:21][N:22]([CH2:24][CH2:25]Cl)[CH3:23]>CC(N(C)C)=O>[CH3:21][N:22]([CH2:24][CH2:25][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:23]
Reactant: CN(C)CCCl
Reactant: Oc1ccccc1CCCCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN(C)CCOc1ccccc1CCCCc1ccccc1
Yield: 77.4 %

Procedure:
Following a procedure similar to that described in Example 2, 226 mg of 2-(4-phenylbutyl)phenol (prepared as described in Preparation 3), 96 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) and 173 mg of dimethylaminoethyl chloride hydrochloride were reacted in dimethylacetamide. The crude product extracted was purified by column chromatography through silica gel, using a 20:1 by volume mixture of methylene chloride and methanol as the eluent, to give 230 mg (yield 77%) of the title compound as an oil.
Reaction SMILES: COC1C=CC([CH2:7][N:8](C)[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:21]4[CH:26]=[C:25]([NH2:27])[C:24]([F:28])=[CH:23][C:22]=4[F:29])[C:15](=[O:20])[N:16]3[CH3:19])=[CH:11][N:10]=2)=CC=1.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[NH2:27][C:25]1[C:24]([F:28])=[CH:23][C:22]([F:29])=[C:21]([C:14]2[C:15](=[O:20])[N:16]([CH3:19])[C:17]3[C:12]([CH:13]=2)=[CH:11][N:10]=[C:9]([NH:8][CH3:7])[CH:18]=3)[CH:26]=1
Reactant: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2cc(N)c(F)cc2F)c(=O)n3C)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cc2c(cn1)cc(-c1cc(N)c(F)cc1F)c(=O)n2C
Temperature: 25 °C
Reaction time: 6 h
Yield: 30.7 %

Procedure:
To a solution of 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2,4-difluorophenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (3 g, 6.8 mmol) in DCM (100 mL) was added CF3COOH (20 mL) and the resulting mixture was stirred at 25° C. for 6 h. Water was added and the mixture was extracted with water. The combined aqueous layers were neutralized with NH3H2O to pH 7. The precipitate was collected by filtration and dried to give 3-(5-amino-2,4-difluorophenyl)-1-methyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (661 mg, 30% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.39 (s, 1 H), 7.78 (s, 1 H), 7.08-6.93 (m, 2 H), 6.80 (dd, J=10.2, 8.1 Hz, 1H), 6.16 (s, 1 H), 5.00 (s, 2 H), 3.50 (s, 3 H), 2.84 (d, J=4.8 Hz, 3 H); MS (ESI) m/z: 317.0[M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=2[N+:16]([O-])=O)[C:3]1=[O:19]>CO.[Pd]>[NH2:16][C:7]1[CH:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=[CH:11][C:6]=1[N:4]1[CH2:5][C:2]([CH3:1])([CH3:20])[C:3]1=[O:19]
Reactant: CC1(C)CN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1=O
Agent: [Pd]
Solvent: CO
Product: CC1(C)CN(c2ccc(C(F)(F)F)cc2N)C1=O

Procedure:
A mixture of 3,3-dimethyl-1-(2-nitro-4-(trifluoromethyl)phenyl)azetidin-2-one (1.67 g, 5.8 mmol, 1.0 equiv) and 10% Pd/C (300 mg) in MeOH (30 mL) was exposed to an atmosphere of H2. After consumption of the starting material, the mixture was filtered and concentrated to afford 1-(2-amino-4-(trifluoromethyl)phenyl-3,3-dimethylazetidin-2-one, which was advanced without further purification. MS (MH+) 259.1; Calculated 259.1 for C12H14F3N2O.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:30](=[O:31])[N:11]3[N:12]=[CH:13][C:14]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[C:10]3=[N:9]2)=[CH:5][CH:4]=1.[CH3:36][Mg]Br.CO>C1COCC1>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:30](=[O:31])[N:11]3[NH:12][CH:13]([CH3:36])[C:14]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:15]([C:16]4[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=4)[C:10]3=[N:9]2)=[CH:5][CH:4]=1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CO
Product: CC1Nn2c(nn(Cc3ccc(C(F)(F)F)cc3)c2=O)C(c2ccc(Cl)cc2)=C1c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a solution of 2-(4-(trifluoromethyl)benzyl)-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (250 mg, 0.485 mmol), prepared as described in Example 17, in THF (4 mL) at −20° C. was added methyl magnesium bromide (0.81 mL, 2.43 mmol, 3.0 M in Et2O). The reaction was stirred at −20° C. for 30 min. LC-MS showed that the reaction was complete. To the reaction mixture was added 20 mL of MeOH to quench the reaction. The reaction was allowed to warm to RT and the solvent was evaporated. The residue was diluted with EtOAc (100 mL), washed with H2O (10 mL) and saturated aqueous NaCl (5 mL×2). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using an automated system, eluting with a gradient of (0% to 80% EtOAc for 40 min. and holds at 80% for 10 min.) to give the title compound, 2-(4-(Trifluoromethyl)benzyl)-7,8-bis(4-chlorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (254 mg), as a beige solid in 98% yield. HPLC retention time: 4.23 min; MS [M+H]+: found 531. 1HNMR (CDCl3, 400 MHz) 67.52 (d, 2H), 7.38 (d, 2H), 7.17-7.11 (m, 4H), 7.05 (dd, 2H), 6.94 (dd, 2H), 4.94 (s, 2H), 4.16 (q, 1H), 1.24 (d, 3H).
Reaction SMILES: [C:1]1([CH:7]([CH3:12])[CH2:8][SiH:9]([Cl:11])[Cl:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Cl:10][Si:9]([Cl:11])([CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:12])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C[SiH](Cl)Cl)c1ccccc1
Reactant: C=Cc1ccccc1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CC(C[Si](Cl)(Cl)CCc1ccccc1)c1ccccc1
Yield: 74 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1, 10.0 g (0.046 mole) of 3-phenyl-1,1-dichloro-1-silabutane, 7.2 g (0.07 mole) of styrene, and 20 μl of 1% chloroplatinic acid in isopropanol were placed and reacted for 3 hours under the dry nitrogen atmosphere at 60° C. Vacuum distillation of the reaction products gave 11.0 g (bp, 133°-5° C./0.6 mmHg) of 3,3-dichloro-1,5-diphenyl-3-silahexane.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=2[CH:5]=[CH:4]1.Br[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH3:15][O:14][C:12]([C:7]1[C:6]2[CH:5]=[CH:4][N:3]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:13]
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: BrCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1ccn2CCOc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
NaH (60% dispersion in mineral oil, 68.5 mg, 1.71 mmol) is added to solution of methyl indole-4-carboxylate (200 mg, 1.142 mmol) in DMF (5 ml) and the resulting suspension is stirred at room temperature for 20 minutes. After this time (2-bromoethoxy)benzene (298 mg, 1.484 mmol) is added and the reaction is stirred at room temperature for 18 hours. Dilution with EtOAc (50 ml) and washing with water (25 ml×2), saturated NaHCO3 (25 ml) and brine (25 ml), drying over MgSO4, concentration in vacuo and purification by chromatography (SiO2, EtOAc/iso-hexane) affords 1-(2-Phenoxy-ethyl)-1H-indole-4-carboxylic acid methyl ester; [M+H]+ 296
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([NH2:20])=[CH:8][C:9]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)=[CH:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27])=O.OOS([O-])=O.[K+]>CN(C=O)C.O>[C:1]([N:5]1[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([O:18][CH3:19])[CH:17]=3)=[CH:8][C:7]=2[N:20]=[C:21]1[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1cccc(C=O)c1
Reactant: COc1cncc(-c2ccc(NC(C)(C)C)c(N)c2)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cncc(-c2ccc3c(c2)nc(-c2cccc(C#N)c2)n3C(C)(C)C)c1
Yield: 64.8 %

Procedure:
N1-tert-Butyl-4-(5-methoxy-pyridin-3-yl)-benzene-1,2-diamine (0.630 g, 2.32 mmol) is dissolved in DMF (5 mL) and water (1 mL). To this solution is added 3-formyl-benzonitrile (0.315 g, 2.40 mmol), followed by Oxone (1.54 g, 2.50 mmol). This reaction mixture is sonicated at room temperature for 1 hour. The solvent is removed in vacuum. The residue is partitioned between EtOAc (3×10 mL) and saturated sodium bicarbonate solution (10 mL). The organic layer is washed with brine, dried over sodium sulfate and is filtered. The filtrate is concentrated and the residue is purified by flash chromatography (40 g silica gel, eluted with 0-100% EtOAc in hexane) to give 3-[1-tert-butyl-5-(5-methoxy-pyridin-3-yl)-1H-benzimidazol-2-yl]-benzonitrile (0.575 g, 65%) as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](=[O:22])[CH2:18][C:19](=[O:21])[CH3:20])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].ClCCl>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17](=[O:22])[CH2:18][C:19](=[O:21])[CH3:20])=[CH:13][CH:14]=1
Reactant: CC(=O)CC(=O)CCc1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Product: CC(=O)CC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 77.3 %

Procedure:
That is, 1.5 g of Pd-activated carbon (10%) was weighed in a nitrogen atmosphere and 20 ml of dichloromethane and 1.31 g (4.4 mmol) of 6-(4-benzyloxyphenyl)-2,4-hexanedione were added thereto. The atmosphere in the reaction system was exchanged with hydrogen at 1 atm and stirred at room temperature for 11 hours. The obtained reaction mixture was filtered to remove insoluble matter and the solvent was distilled off under reduced pressure. The residue was charged in a silica gel column and developed first with dichloromethane to remove byproducts. Subsequently, a solution containing a compound eluted from the column with a mixed solvent of 1:1 (by volume ratio) acetone/hexane was concentrated to dryness under reduced pressure to obtain 0.70 g (3.4 mmol) of the objective 6-(4-hydroxyphenyl)-2,4-hexanedione as pale yellow solid. Yield: 77%. Identification was performed by elementary analysis of C and H, and 1H-NMR.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]1[CH:44]=[C:43]([CH:45]=[O:46])[CH:42]=[CH:41][C:38]=1[C:39]#[N:40]>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([CH:45]([OH:46])[C:43]2[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[C:37]([F:36])[CH:44]=2)[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Reactant: N#Cc1ccc(C=O)cc1F
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(C(O)c3ccc(C#N)c(F)c3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and 2-fluoro-4-formylbenzonitrile.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:8][C:9](=[O:20])[C:10]([NH:12][CH2:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=O)[CH3:7].O>C1(C)C=CC=CC=1>[CH2:6]([O:8][C:9]([C:10]1[O:19][C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][N:12]=1)=[O:20])[CH3:7]
Reactant: CCOC(=O)C(=O)NCC(=O)C(C)(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ncc(C(C)(C)C)o1
Yield: 57.6 %

Procedure:
Phosphorus oxychloride (16.3 ml, 0.178 mol) is added to a stirred solution of N-(3.3-dimethyl-2-oxo-butyl) oxalamic acid ethyl ester (38.4 g, 0.178 mol) in toluene (p150 ml). The mixture is heated gradually to reflux, and then refluxed for 16 h. After cooling, the mixture is added portionwise to water (500 ml) and stirred vigorously. The organic phase is separated and washed thoroughly with saturated sodium hydrogen carbonate solution (500 ml) and then twice with water (500 ml). The organic phase is then dried over sodium sulfate and evaporated in vacuo. The residue is purified by flash column chromatography (silica gel, petroleum ether/ethyl acetate 7:3 v/v) to give 5-tert-butyl-oxazole-2-carboxylic acid ethyl ester (20.23 g, 58%) as an oil.
Reaction SMILES: [CH3:1]OP(OC1C=CC(C#N)=CC=1)(OC)=S.C(C1C=C(C)C([CH2:24][N:25]2[C:30](=O)N(CC3C(C)=CC(C(C)(C)C)=C(O)C=3C)C(=O)N(CC3C(C)=CC(C(C)(C)C)=C(O)C=3C)[C:26]2=[O:61])=C(C)C=1O)(C)(C)C>>[CH3:1][C:26]([N:25]([CH3:30])[CH3:24])=[O:61].[CH3:24][N:25]([CH3:30])[C:26](=[O:61])[CH3:1]
Reactant: COP(=S)(OC)Oc1ccc(C#N)cc1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1Cn1c(=O)n(Cc2c(C)cc(C(C)(C)C)c(O)c2C)c(=O)n(Cc2c(C)cc(C(C)(C)C)c(O)c2C)c1=O
Product: CC(=O)N(C)C

Procedure:
CYANOX® 1790 1,3,5-tris(4-t-butyl-3-hydroxy-2,6-dimethyl-benzyl)-1,3,5-triazine-2,4,6(1H,3H,5H)trione antioxidant, sold by Cytec Industries.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[OH:9][CH2:10][C:11]1[N:12]=[CH:13][NH:14][CH:15]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I.CCOC(C)=O.O>[OH:9][CH2:10][C:11]1[N:12]=[CH:13][N:14]([C:2]2[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=2)[CH:15]=1
Reactant: OCc1c[nH]cn1
Reactant: Ic1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: OCc1cn(-c2ccc(I)cc2)cn1
Temperature: 130 °C

Procedure:
A mixture of 1,4-diiodobenzene 1-1 (4.00 g, 12.1 mmol), 4-(hydroxymethyl)imidazole II-1 (1.20 g, 12.2 mmol), 8-hydroxyquinoline (0.176 g, 1.21 mmol) and K2CO3 (1.69 g, 12.2 mmol) in DMSO (12 mL) was degassed before being charged with CuI (0.230 g, 1.21 mmol). The mixture in a sealed tube was heated at 130° C. overnight. Water and EtOAc were added. The mixture was filtered. The organic layer was separated, then applied to a silica gel column, which was eluted with 0-5% MeOH in CH2Cl2 to give 4-hydroxymethyl 1-(4-iodophenyl)imidazole I-1 (0.810 g). MS 301.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:30]3[N:31]=[N:32][NH:33][CH:34]=3)=[C:27]([CH3:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Cc1nc(Cl)ccc1-c1c[nH]nn1
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1-c1c[nH]nn1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (60 mg, 0.19 mmol) and 6-chloro-2-methyl-3-(1H-1,2,3-triazol-4-yl)pyridine (Example 433, Step 3) (59 mg, 0.19 mmol) as starting materials.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[NH:7]1[CH2:10][CH2:9][CH2:8]1>C(Cl)Cl>[N:7]1([CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH2:10][CH2:9][CH2:8]1
Reactant: C1CNC1
Reactant: C=CC(=O)OC
Solvent: ClCCl
Product: COC(=O)CCN1CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.5 %

Procedure:
Methyl acrylate (2.082 mL, 23.12 mmol) was added to a solution of azetidine (1.2 g, 21.02 mmol) in DCM and the resulting solution stirred at ambient temperature, under an inert atmosphere for 16 h. The reaction mixture was evaporated and the crude product purified by FCC, eluted with 25% EtOAc in DCM, to afford the desired material (2.0 g, 66.5%) as a colourless oil. NMR Spectrum: 1H NMR (400 MHz, CDCl3) δ 1.97-2.1 (2H, m), 2.33 (2H, d), 2.67 (2H, d), 3.18 (4H, t), 3.67 (3H, s).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([CH2:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[N:9]=2)[CH2:4][CH2:3]1.C(O)C>[Pd].C1COCC1>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:9]=[C:10]([CH2:17][S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:20])=[O:19])[C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(CS(=O)(=O)c3ccccc3)n2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCN(c2ccc(N)c(CS(=O)(=O)c3ccccc3)n2)CC1
Yield: 99 %

Procedure:
A mixture of 1-methyl-4-{5-nitro-6-[(phenylsulfonyl)methyl]pyridin-2-yl}-piperazine (1.60 g, 4.35 mmol) and 10% Pd/C (200 mg) in a 1:1 mixture of ethanol:THF is hydrogenated at 45 psi for 4 h at ambient temperatures. The catalyst is filtered off and the filtrate is concentrated in vacuo to afford the title compound as a yellow solid, 1.45 g (99% yield), identified by NMR analysis.
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[C:27]2[CH:32]=[CH:31][C:30]([C:33]([O:35]C)=[O:34])=[CH:29][C:28]=2[CH3:37])[CH:12]=[CH:11][C:10]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=1[CH3:45]>CO>[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[C:27]2[CH:32]=[CH:31][C:30]([C:33]([OH:35])=[O:34])=[CH:29][C:28]=2[CH3:37])[CH:12]=[CH:11][C:10]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=1[CH3:45]
Reactant: COC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(-c3ccc(Cl)cc3C)c(Cl)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1-c1ccc(NCc2ccc(C(F)(F)F)cc2-c2ccc(C(=O)O)cc2C)cc1Cl
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.26 mL, 0.79 mmol) was added to a THF (2 mL) and MeOH (1 mL) solution of methyl 2′-(((2,4′-dichloro-2′-methyl-[1,1′-biphenyl]-4-yl)amino)methyl)-2-methyl-5′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate (340 mg, 0.61 mmol) and the resulting homogeneous mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off, dried in vacuo, and the resulting residue was used in the next step without further purification.
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1)C.[CH:14]([C:26]([O:28]CC)=[O:27])([C:21]([O:23]CC)=[O:22])[CH2:15][C:16]([O:18]CC)=[O:17].[Na]>C1(C)C=CC=CC=1>[C:21]([C:14]([C:26]([OH:28])=[O:27])([CH2:4][C:5]1[C:9]2[C:8](=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:7][CH:6]=1)[CH2:15][C:16]([OH:18])=[O:17])([OH:23])=[O:22]
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Reactant: CN(C)Cc1c[nH]c2ccccc12
Agent: [Na]
Solvent: Cc1ccccc1
Product: O=C(O)CC(Cc1c[nH]c2ccccc12)(C(=O)O)C(=O)O

Procedure:
Gramine (17.4 g) and triethyl 1,1,2-ethanetricarboxylate (24.6 g) were suspended in dry toluene. Sodium (0.05 g) was added and the stirred reaction was heated at reflux for six hours. The reaction mixture was cooled, washed with 2N hydrochloric acid (100 ml) and the organic layer was dried (MgSO4) and evaporated. The resulting brown oil was dissolved in ethanol (400 ml) and potassium hydroxide (56 g) was added. The reaction was heated to reflux for six hours, cooled, poured onto ice and acidified to pH1 with 5N hydrochloric acid. The mixture was saturated with sodium sulphate and extracted with ethyl acetate, dried (Na2SO4), filtered and evaporated. The resulting oil was crystallised from 1,2-dichloroethane (400 ml) to yield the title compound, mp 184°-185° C.; found: C, 55.33; H, 4.67; N, 4.32; C14H13NO6. 0.75(H2O) requires C, 55.17; H, 4.80; N, 4.60%.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]2[N:13]([C:29](=[O:42])[CH2:30][NH:31][C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:14][CH:15]([C:16](=[O:28])[NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[CH:9]12)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:35]([O:34][C:32](=[O:33])[NH:31][CH2:30][C:29]([N:13]1[CH2:14][CH:15]([C:16](=[O:28])[NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[CH:9]2[NH:8][CH2:12][CH2:11][CH:10]12)=[O:42])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCC2C1C(C(=O)Nc1cccc3ccccc13)CN2C(=O)CNC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCC(=O)N1CC(C(=O)Nc2cccc3ccccc23)C2NCCC21)OCc1ccccc1
Reaction time: 1 h
Yield: 110.4 %

Procedure:
A solution of 55 (400 mg, 0.69 mmol) in DCM (10 mL) was treated with TFA (3 mL) at ambient temperature. After 1 h, the solution was concentrated, diluted with EtOAc, and washed with saturated NaHCO3. The aqueous phase was back extracted with DCM and the combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 56 (360 mg) which was used without further purification. Mass spectrum, m/z [473.2] (M+H)+.