Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:17]([O-:21])(=[O:20])[CH2:18][CH3:19].[Na+]>C(OC(=O)CC)(=O)CC>[ClH:1].[CH3:19][C:18](=[CH:13][C:12]1[CH:15]=[CH:16][C:9]([S:8][C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)=[CH:10][CH:11]=1)[C:17]([OH:21])=[O:20]
Reactant: O=Cc1ccc(Sc2ccncc2)cc1
Reactant: CCC(=O)[O-]
Agent: CCC(=O)OC(=O)CC
Agent: Cl
Agent: [Na+]
Product: CC(=Cc1ccc(Sc2ccncc2)cc1)C(=O)O
Reaction time: 5 h
Yield: 55.6 %

Procedure:
A mixture of 5 g of 4-(4-pyridylthio)benzaldehyde hydrochloride, 4 g of sodium propionate and 50 ml of propionic anhydride was stirred for 5 hours at a temperature of 150° to 155° C. and concentrated under reduced pressure. Water was added to the mixture which was then heated to precipitate crystals. The resulting crystals were separated by filtration, washed with water and converted into the corresponding hydrochloride by treatment with methanolic hydrogen chloride. The resulting hydrochloride was recrystallized from a mixture of methanol and diethyl ether to obtain 3.4 g (56% yield) of 2-methyl-3-[4-(4-pyridylthio)phenyl]propenoic acid hydrochloride as colorless needles having a melting point of 213°-218° C.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=2)[C:5]([CH3:15])=[N:4][C:3]=1I.C([SnH](CCCC)CCCC)CCC.[F-].[K+].C1C[O:35][CH2:34]C1>>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=2)[C:5]([CH3:15])=[N:4][C:3]=1[CH:34]=[O:35]
Reactant: Cc1nc(I)c(Cl)n1-c1ccc(C#N)cc1
Reactant: C1CCOC1
Agent: CCCC[SnH](CCCC)CCCC
Agent: [F-]
Agent: [K+]
Product: Cc1nc(C=O)c(Cl)n1-c1ccc(C#N)cc1
Temperature: 50 °C

Procedure:
A solution of the product from (b) (1.03 g, 3 mmol) and tetrakis (triphenylphosphine)palladium (0.3 g) in THF (70 ml) was installed under an atmosphere of carbon monoxide and heated to 50° C. Tributyltin hydride (0.96 g, 3.3 mmol) in THF (40 ml) was instilled by motor-driven syringe over 4.5 hours. After an additional 0.5 hours the mixture was stirred with 100 ml of 10% potassium fluoride solution for 15 minutes, then extracted twice with dichloromethane. The organic layers were dried over magnesium sulphate and evaporated to an orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[CH:17]=[C:16]([OH:19])[CH:15]=[CH:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+].C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:20]([O:19][C:16]1[CH:17]=[C:18]2[C:13]([CH:12]=[CH:11][CH:10]=[C:9]2[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:14][CH:15]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc2ccc(O)cc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cccc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 8-(tert-butoxycarbonylamino)-2-naphthol, as described above in Step H, (93 mg, 0.36 mmol), benzyl bromide (64 mg, 0.37 mmol), and Cs2CO3 (146 mg, 0.45 mmol) in dry DMF (3 mL) was stirred, under argon, at ambient temperature for 18 hrs. The reaction mixture was poured into saturated aqueous NaHCO3 (15 mL) and EtOAc (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of hexane −5 to 15% diethyl ether to yield the desired product as a pale solid.
Reaction SMILES: [CH3:1][C:2]([CH2:16]OS(C)(=O)=O)([C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=O)[C:3]([O:5][CH3:6])=[O:4].C(O)(=O)C.C([O-])(=O)C.[Na+].O.[NH2:32][NH2:33].[OH-].[Na+]>C(OCC)C.O.CO>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[C:2]([C:3]([O:5][CH3:6])=[O:4])([CH3:1])[CH2:16][NH:33][N:32]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)C(C)(COS(C)(=O)=O)C(=O)c1ccc(Cl)cc1
Reactant: NN
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COC(=O)C1(C)CNN=C1c1ccc(Cl)cc1
Reaction time: 0.75 h

Procedure:
Into a 5 liter RBF was added 700 g (2.07) mole) of methyl 2-methyl-2-mesyloxymethyl-3-(4-chlorophenyl)-3-keto-propanoate and 1700 ml of methanol. The slurry is warmed to 50° C. whereon, 248 g (4.14 mole) of acetic acid and 186 g (2.28 mole) of sodium acetate are added. Without further heating, 207 g (4.14 mole) of hydrazine hydrate is added over 20 minutes and the temperature is allowed to rise to reflux. After the addition, the mixture is allowed to stir for 45 minutes whereon the temperature has fallen 50° C. The mixture is worked up with 2 kgs of ice, 2 kgs of cold water and 5 liters of ethyl ether and neutralized using approximately 300 g of 50% NaOH to achieve pH 8. After separating the organic layer and washing it with brine the organic layer is thoroughly dried with MgSO4. The resulting solution of 3-(4-chlorophenyl)-4-carbomethoxy-4-methyl-4,5-dihydro-1H-pyrazole is used as is in the next reaction. NMR data was consistent with the structure.
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C@@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][S@:9]2=[O:14])[CH:3]=1.[CH3:15][N:16]=[C:17]=[S:18].[Cl-].[NH4+]>O1CCCC1.[N+]([O-])([O-])=O.[Fe+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C@@:8]2([C:17](=[S:18])[NH:16][CH3:15])[CH2:13][CH2:12][CH2:11][CH2:10][S@:9]2=[O:14])[CH:3]=1
Reactant: O=[S@@]1CCCC[C@H]1c1cccnc1
Reactant: CN=C=S
Agent: [Fe+3]
Agent: O=[N+]([O-])[O-]
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=S)[C@]1(c2cccnc2)CCCC[S@]1=O
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 485.1 %

Procedure:
Ammonia gas is condensed at -50° C. to obtain 2 ml of liquid ammonia, which is treated with iron (III) nitrate (0.0015 g), followed by sodium metal (0.02 g). The solution turns blue and then dark grey after 20 minutes. It is then treated with a solution of (1R,2S)-2-(3-pyridyl)tetrahydro-2H-thiopyran 1-oxide (0.06 g) in tetrahydrofuran (8 ml) during 2 minutes, at -40° C. The mixture is stirred for 2 minutes and is then treated with a solution of methyl isothiocyanate (0.033 g) in tetrahydrofuran (2 ml), by syringe. The reaction mixture is stirred for 5 minutes at -35° C. and then treated with ammonium chloride (0.05 g) and warmed to 20° C. The mixture is treated with methanol (0.3 ml) and evaporated under reduced pressure. The residue is partitioned between brine (10 ml) and dichloromethane (3×30 ml). The organic phases are combined and dried with magnesium sulphate, filtered and evaporated under reduced pressure, to give (1R,2R)-2-(3-pyridyl)-N-methyltetrahydro-2H-thiopyran-2-carbothioamide 1-oxide (0.4 g; 99% ee) in the form of a white solid, m.p. 215° C. [NMR (CDCl3): 8.7(s,1H); 8.5(s,2H); 8.1(d,1H); 7.3(s,1H); 3.8(s,1H); 3.1(d,3H); 2.8(s,1H); 2.4-1.5(m,6H)].
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[O:12][C:13]([CH:16]=[CH:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[CH2:1]([O:8][C:9]([C:11]1[O:12][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C(=O)OCc2ccccc2)o1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1ccc(C(=O)OCc2ccccc2)o1
Reaction time: 0.5 h

Procedure:
To 5-(2-tert-butoxycarbonylethenyl)furan-2-carboxylic acid benzyl ester (0.15 g, 0.46 mmol) obtained in Example 41, step 2 was added trifluoroacetic acid (3 mL), and the mixture was stirred for 30 minutes. The solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:32][O:33][CH3:34])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:23]([O:25]C(C)(C)C)=[O:24])=[C:17]([CH2:20][O:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>C(Cl)Cl>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:32][O:33][CH3:34])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:23]([OH:25])=[O:24])=[C:17]([CH2:20][O:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: COCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
To a cold suspension of tert-butyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate (syn isomer) (1.0 g) in methylene chloride (20 ml) were added trifluoroacetic acid (4.4 g) and anisole (0.2 ml), and the mixture was gradually warmed at 40° C., followed by stirring at 10° C. for 3 hours. After evaporation of the reaction mixture, to the residue was added ethyl acetate (20 ml), followed by extracting with an aqueous solution of sodium bicarbonate. The resultant aqueous solution was adjusted to pH 2.0 with diluted hydrochloric acid and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate, water and an aqueous solution of sodium chloride in turn, dried and then evaporated to dryness under reduced pressure. The residue was stirred for 30 minutes in diethyl ether, and the remained substance was collected by filtration to give 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.56 g).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:18]=2)[C:10](=[O:27])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][CH2:30]Br>>[CH2:1]([N:8]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:18]=2)[C:10](=[O:27])[N:9]1[CH2:28][O:29][CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]n(Cc3ccccc3)c2=O)cn1
Reactant: COCBr
Product: COCn1c(=O)n(-c2cnn(Cc3c(C)noc3C)c2)c(=O)n1Cc1ccccc1
Yield: 18 %

Procedure:
Prepared as in example 10-91 from 1-benzyl-4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1,2,4-triazolidine-3,5-dione (example 10-91a) and bromomethyl methyl ether. Yield: 18%. MS M+H calculated 411.17. Found 411.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.02 μM.
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]1[C@H:14]([C:15]([F:18])([F:17])[F:16])[CH2:13][NH:12][CH2:11]1)=O)(C)(C)C.FC(F)(F)C(O)=O.Cl>ClCCl>[NH2:8][CH2:9][C@H:10]1[C@H:14]([C:15]([F:18])([F:16])[F:17])[CH2:13][NH:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CNC[C@H]1C(F)(F)F
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC[C@@H]1CNC[C@H]1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
In 1 ml of dichloromethane, is dissolved 202 mg (0.754 mmol) of trans-3-(tert-butoxycarbonylaminomethyl)-4-trifluoromethylpyrrolidine. To the above solution, is added 1 ml of trifluoroacetic acid on cooling with ice, and the mixture is stirred at 0° C. for 1 hour. To the reaction mixture, is added 0.19 ml of conc-hydrochloride, and the mixture was concentrated under reduced pressure to give 161 mg of the objective substance as a slightly yellow powder (yield 88.6%).
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[O:14][C:13]([CH3:20])([CH3:19])[CH2:12]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:19][C:13]1([CH3:20])[O:14][C:15]([CH3:17])([CH3:18])[CH2:16][N:11]([CH2:10][CH2:9][OH:8])[CH2:12]1
Reactant: CC1(C)CN(CCOCc2ccccc2)CC(C)(C)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)CN(CCO)CC(C)(C)O1
Reaction time: 48 h

Procedure:
Dissolve 4-(2-benzyloxy-ethyl)-2,2,6,6-tetramethyl-morpholine (490 mg, 1.77 mmol) MeOH (40 mL). Add to a pressure vessel containing a slurry of 10% Pd/C (100 mg) in MeOH (20 mL). Pressurize with 45 psi hydrogen gas. Monitor the reaction by MS. After 48 h, add another portion of 10% Pd/C (100 mg) and re-pressurize to 45 psi hydrogen. Stir an additional 3 days. Filter the reaction mixture through Celite® eluting with MeOH. Concentrate to give the desired product in quantitative yield. MS (ES+) 188.3 (M+1)+.
Reaction SMILES: [I:1][C:2]1[CH:11]=[N:10][C:5]2[NH:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[F:12][C:13]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:14]=1[C:15](Cl)=[O:16]>>[F:12][C:13]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:14]=1[C:15]([N:9]1[CH2:8][CH2:7][NH:6][C:5]2[N:10]=[CH:11][C:2]([I:1])=[CH:3][C:4]1=2)=[O:16]
Reactant: Ic1cnc2c(c1)NCCN2
Reactant: O=C(Cl)c1cc(F)ccc1F
Product: O=C(c1cc(F)ccc1F)N1CCNc2ncc(I)cc21
Yield: 47 %

Procedure:
7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (614 mg) was reacted with 2,5-difluorobenzoyl chloride as in General Procedure 2 to give the title compound as an off-white foam (47% yield). M.p. foam, LCMS: m/z=402.20 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.70-1.90 (m, 2H), 3.50-3.65 (m, 2H), 5.29 (bs, 1H), 6.99 (s, 1H), 7.10-7.18 (m, 2H), 7.20-7.25 (m, 1H), 7.99 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][C:10]([CH:20]([CH3:22])[CH3:21])=[N:9]2)=[CH:4][C:3]=1[N+:23]([O-])=O>C(OCC)(=O)C.CO.[Pd]>[NH2:23][C:3]1[CH:4]=[C:5]([N:8]2[C:12]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])=[CH:11][C:10]([CH:20]([CH3:22])[CH3:21])=[N:9]2)[CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: CC(C)c1cc(C(=O)OC(C)(C)C)n(-c2ccc(O)c([N+](=O)[O-])c2)n1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)c1cc(C(=O)OC(C)(C)C)n(-c2ccc(O)c(N)c2)n1

Procedure:
To a solution of tert-butyl 1-(4-hydroxy-3-nitrophenyl)-3-isopropyl-1H-pyrazole-5-carboxylate (0.27 g, 0.78 mmol) in ethyl acetate/methanol (1:1, 10 mL) was added palladium on carbon (30 mg) and the mixture was hydrogenated (50 psi) overnight under Parr. The solution was filtered and washed with methanol. The combined filtrate was concentrated to afford tert-butyl 1-(3-amino-4-hydroxyphenyl)-3-isopropyl-1H-pyrazole-5-carboxylate. The crude tert-butyl 1-(3-amino-4-hydroxyphenyl)-3-isopropyl-1H-pyrazole-5-carboxylate was treated with 25% TFA in CH2Cl2 (2 mL) and stirred overnight at RT. The solvent was evaporated to obtain 1-(benzo[d]oxazol-5-yl)-3-tert-butyl-1H-pyrazole-5-carboxylic acid. To a solution of 1-(benzo[d]oxazol-5-yl)-3-tert-butyl-1H-pyrazole-5-carboxylic acid in xylenes (3 mL) was added triethyl orthoformate (0.16 mL, 0.96 mmol) and a catalytic amount of PPTS. The reaction mixture was heated at 140° C. for 4 hours. The solvent was evaporated and the residue was treated with methylene chloride with stirring for 1 hour. The resulting solid was filtered and washed with methylene chloride to obtain 1-(benzo[d]oxazol-5-yl)-3-isopropyl-1H-pyrazole-5-carboxylic acid (0.1 g, 45% yield: for three steps). MS (ESI) m/z: 272.0 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([CH3:30])([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][CH:8]=1)[CH3:2].[H-].[Na+].[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39]Br>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:3][C:4](=[O:31])[C:5]([CH3:30])([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:39][C:38]3[CH:41]=[CH:42][CH:43]=[C:36]([O:35][CH3:34])[CH:37]=3)[C:18](=[O:21])[N:17]2[CH3:22])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccccc1
Reactant: COc1cccc(CBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3cccc(OC)c3)C(=O)N2C)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
A solution of 2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester (0.40 g, 0.94 mmol) in DMF (10 mL) is treated with NaH (60% oil suspension, 0.094 g, 2.35 mmol) and stirred at room temperature under N2 for 30 minutes. The reaction is cooled to 0° C. and treated with tetrabutylammonium iodide (0.040 g, 0.11 mmol) and 3-methoxybenzyl bromide (0.29 g, 1.43 mmol) and then warmed to room temperature and stirred for 1.5 h. The reaction is quenched with 1 N HCl (15 mL) and worked up extractively with Et2O and water. The organic layer is dried (MgSO4) and the solvent removed in vacuo to afford crude product that is purified by flash chromatography using 2:1 hexanes:acetone to afford 0.28 g (55%) 3-(4-{2-[1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester. 1H NMR. Rf=0.41 (1:1 acetone:hexanes). MS (ES+) Calc'd for C32H39N2O6 (M+1) 547. Found m/z 547 (100%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([CH3:15])[NH:7][C:6]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([CH3:15])[N:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)OCC)c1CCOC
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(CCOC)c(C(=O)OCC)n(-c2ccccc2)c1C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
A mixture of diethyl 3-(2-methoxyethyl)-5-methyl-1H-pyrrole-2,4-dicarboxylate (100 mg, 0.35 mmol), phenyl boronic acid (130 mg, 1.06 mmol), copper acetate (130 mg, 0.71 mmol), dry pyridine (110 mg, 1.40 mmol), molecular sieves (400 mg) and dichloromethane (10 mL) was purged with argon gas for 30 min and stirred overnight. The mixture was filtered through a celite bed, washed with dichloromethane (15 mL) and concentrated under reduced pressure. The crude compound was purified by column chromatography over silica gel (100-200 mesh) using 20% ethyl acetate/pet ether as eluent to afford diethyl 3-(2-methoxyethyl)-5-methyl-1-phenyl-pyrrole-2,4-dicarboxylate (50 mg, 40%) as a colourless oil.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][C:13]([CH:15]1[CH2:19][C:18](=[O:20])[N:17]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])[CH2:16]1)=[O:14].[NH4+].[Cl-].C1C[O:34][CH2:33]C1>>[CH3:11][O:12][C:13]([C:15]1([CH2:33][OH:34])[CH2:19][C:18](=[O:20])[N:17]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])[CH2:16]1)=[O:14]
Reactant: COC(=O)C1CC(=O)N(c2c(C)cccc2C)C1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Product: COC(=O)C1(CO)CC(=O)N(c2c(C)cccc2C)C1
Temperature: -50 °C
Reaction time: 0.08 h
Yield: 34 %

Procedure:
LHMDS (1 M solution in THF, 9.72 mL, 9.72 mmol) was added slowly to a cooled (−50° C.) solution of 1-(2,6-dimethyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (2 g, 8.1 mmol) in THF (50 mL). Stirred at −50° C. for 5 min then warmed to 0° C. and stirred further for 5 min. After cooling back to −50° C., (CH2O)n (1.2 g, 40.5 mmol) was added and the resulting reaction mixture was warmed to room temperature and stirred for 2 h. Saturated aqueous NH4Cl solution (25 mL) was added, extracted with EtOAc (3×75 mL). The combined organic layer was washed with water (100 mL), brine (100 mL), dried (Na2SO4) and evaporated. The residue was purified by automated flash chromatography (SiO2, 20→50% EtOAc/hexanes) to give 1-(2,6-dimethyl-phenyl)-3-hydroxymethyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (762 mg, 34% yield). LC-MS: R, (retention time): 0.9 min, MS: (ES) m/z 278.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:4]=1[NH2:5].[C:14](Cl)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:4]=1[NH:5][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc(C(F)(F)F)cc1N
Solvent: ClCCl
Product: COc1ccc(C(F)(F)F)cc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 2-methoxy-5-(trifluoromethyl) aniline (1 eq) in DCM at 0° C. was added TEA (1 eq) followed by dropwise addition of pivaloyl chloride (1 eq). The reaction mixture was warmed to room temperature and left stirred overnight. Diluted with DCM and washed with satd. sodium bicarbonate, water, brine and dried over sodium sulfate. Filtered, evaporated and dried under vacuum to provide pure product as an off white solid in 95% yield. ES/MS m/z 276.1 (MH+).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([S:11][CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[F:13][C:14]1([F:26])[O:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:22](B(O)O)[C:16]=2[O:15]1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:26][C:14]1([F:13])[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[C:19]([C:2]3[N:10]4[C:5]([CH:6]=[N:7][C:8]([S:11][CH3:12])=[N:9]4)=[CH:4][CH:3]=3)[C:17]=2[O:18]1
Reactant: OB(O)c1cccc2c1OC(F)(F)O2
Reactant: CSc1ncc2ccc(Br)n2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CSc1ncc2ccc(-c3cccc4c3OC(F)(F)O4)n2n1
Temperature: 80 °C
Yield: 62.8 %

Procedure:
7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.531 g, 2.18 mmol), 2,2-Difluorobenzo[1,3]dioxole-4-boronic acid (0.624 g, 3.09 mmol), Tetrakis(triphenylphosphine)palladium(0) (125 mg, 0.108 mmol), 2.00 M of Sodium carbonate in Water (2.70 mL), and 1,4-Dioxane (6.6 mL) were combined in a vial, degassed (freeze-pump-thaw) and was heated under an atmosphere of Nitrogen at 80° C. overnight. Conversion was ˜75%. Further heating for a second night lead to little additional product relative to bromide. The mixture was diluted with water (20 mL) then extracted with EtOAc (3×30 mL). The org. was washed with brine, dried, filtered through 7 mL silica gel, washing with EtOAc, then conc. in vacuo onto 7 g silica gel. Purification on an ISCO (80 g, 0-10% EtOAc:Hex) afforded first an impurity, then the product 7-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.440 g; Yield=63.0%). LCMS (HPLC): 1.46 min, 322 (M+H); 1H-NMR (DMSO-d6): 9.12 (s, 1H), 8.16 (d, 1H, J=8.1 Hz), 7.48 (d, 1H, J=7.9 Hz), 7.40 (m, 1H), 7.33 (d, 1H, J=4.8 Hz), 7.16 (d, 1H, J=4.8 Hz), 2.55 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][N:38]([CH3:48])[C:39](=[O:47])[CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:44]3[CH2:43][CH2:42][N:41]([CH2:40][C:39]([N:38]([CH3:48])[CH3:37])=[O:47])[CH2:46][CH2:45]3)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:30])[CH3:31])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)CN1CCNCC1
Reactant: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N,N-dimethyl-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12e) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 675.3 [(M+H)+]