Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][O:7]2.CN(CCN(CCN(C)C)C)C.C([Li])CCC.[CH:31](N1CCOCC1)=[O:32].Cl>C1COCC1>[F:1][C:2]1[C:11]([CH:31]=[O:32])=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][O:7]2
Reactant: COc1ccc(F)c2c1OCCC2
Reactant: O=CN1CCOCC1
Agent: CN(C)CCN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C=O)c(F)c2c1OCCC2
Temperature: -74 °C
Reaction time: 1 h

Procedure:
To a 130 ml THF solution containing 3.6 g of 5-fluoro-8-methoxychromane and 4.2 ml of N,N,N′,N′,N″-pentamethyldiethylenetriamine there was added dropwise 8 ml of n-butyllithium (2.55 M, hexane solution) at −74° C. After stirring at −74° C. for 1 hour, N-formylmorpholine was added. Stirring was continued for 1 hour at room temperature, and then 1N hydrochloric acid was added to the reaction mixture while cooling on ice, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The desiccant was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane system) to obtain the target compound (1.50 g) as a colorless solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([C:8]1[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[N:10][C:11]([S:15][CH3:16])=[N:12][C:13]=1O)#[N:7].CN(C)C1C=CC=CC=1.O>O1CCOCC1>[Cl:3][C:13]1[N:12]=[C:11]([S:15][CH3:16])[N:10]=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[C:8]=1[C:6]#[N:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc(-c2nc(SC)nc(O)c2C#N)c1
Solvent: CN(C)c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2nc(SC)nc(Cl)c2C#N)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Phosphorus oxychloride (0.75 ml) was added to a stirred solution of 5-cyano-4-(3-methoxyphenyl)-2-methylthio-6-hydroxy-pyrimidine (example 1a, 305 mg) in dry 1,4-dioxane (1 ml). A drop of N,N-dimethylaniline was added. After 3 h at 80° C., the mixture was cooled to 0° C. in an ice bath and crushed ice was slowly added. After cessation of the exothermic reaction, H2O (3 ml) was added. The solids were collected by filtration and dried in vacuo.
Reaction SMILES: [CH2:1]([S:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[C:14]([OH:16])=[O:15])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].OO.C(O)(=[O:28])C>O>[CH2:1]([S:10]([C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=1)[C:14]([OH:16])=[O:15])=[O:28])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: O=C(O)c1cc(SCC(=O)c2ccccc2)cc(C(F)(F)F)c1
Reactant: CC(=O)O
Agent: OO
Solvent: O
Product: O=C(O)c1cc(S(=O)CC(=O)c2ccccc2)cc(C(F)(F)F)c1

Procedure:
A solution of 2.6 g. (7.5 m moles) of 3-phenacylthio-5-trifluoromethylbenzoic acid and .75 ml. of 30% hydrogen peroxide in 15 ml. of acetic acid is heated on a steam bath for 1 hour, after which the reaction mixture is cooled and diluted with water to the turbidity point. The crystalline product which forms on standing is filtered, 1.0 g., m.p. 148°-151° C., and finally recrystallized from acetone-isopropyl ether, 850 mg., m.p. 154°-155° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:13]([OH:17])[CH2:14][CH2:15][CH3:16])=[C:9]([CH2:11][CH3:12])[N:10]=2)[CH:5]=[CH:6][N:7]=1>C(OCC)(=O)C.C(Cl)Cl.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])=[C:9]([CH2:11][CH3:12])[N:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CCCC(O)c1c(CC)nc2c(Cl)nccn12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCC(=O)c1c(CC)nc2c(Cl)nccn12
Temperature: 60 °C
Reaction time: 5 h

Procedure:
The resulting 1-(8-chloro-2-ethylimidazo[1,2-a]pyrazin-3-yl)-1-butanol was dissolved in ethyl acetate (4 mL) and methylene chloride (1 mL), then activated manganese (IV) oxide (3 g) was added thereto, and the mixture was heated under stirring at 60° C. for 5 hours. After being allowed to cool, the reaction mixture was filtered and washed with ethyl acetate, and then the filtrates were combined and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (226 mg) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:3]=1.[CH2:18](OCC)[CH3:19].Cl>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:18][CH3:19])=[O:9])[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:3]=1
Reactant: CCOCC
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Temperature: 20 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
To a solution of 2-chloro-6-(4-chloro-phenyl)-pyrimidine-4-carboxylic acid (1.35 g, 5.0 mmol) in ethanol (50 mL) was added diethyl ether (10 mL) which had been saturated previously with hydrochloric acid gas. The reaction mixture was stirred for 24 h at 20° C. The solution was evaporated under reduced pressure and the residual oil was dissolved in ethyl acetate. The solution was washed with saturated sodium hydrogencarbonate solution and with brine, dried over sodium sulfate, and evaporated under reduced pressure. The residual material was crystallized from ethyl acetate/heptane to give the title compound (1.17 g, 78%) as light yellow solid. MS ISN (m/e): 297.1 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.31 (s, 1H), 8.13 and 7.53 (2 d, 2×2H), 4.53 (q, 2H), 1.47 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[O:12][C:5]2=[C:6]([NH2:11])[N:7]=[CH:8][C:9](I)=[C:4]2[C:3]=1[CH3:13].CC1(C)C(C)(C)OB([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[CH:26]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:11][C:6]1[N:7]=[CH:8][C:9]([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]3)[CH:26]=2)=[C:4]2[C:3]([CH3:13])=[C:2]([Cl:1])[O:12][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Cc1c(Cl)oc2c(N)ncc(I)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: COCCOC
Product: Cc1c(Cl)oc2c(N)ncc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c12
Temperature: 100 °C
Yield: 61.5 %

Procedure:
A vial was charged with 2-chloro-4-iodo-3-methylfuro[2,3-c]pyridin-7-amine (100 mg, 0.32 mmol), tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (140 mg, 0.39 mmol), Cs2CO3(150 mg, 0.48 mmol), Pd(dppf)Cl2 (20 mg, 0.027 mmol, 8 mole %), and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (40 mg, 0.080 mmol, 26 mole %) in DME (5 mL) and H2O (0.5 mL). The vial was purged with N2 and heated at 100° C. in a microwave reactor for 1 h. Water (20 mL) was added, and the mixture was extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (EtOAc) to afford 85 mg (62%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 7.67 (s, 1H), 7.48 (s, 1H), 7.39 (s, 1H), 4.66 (s, 2H), 4.23 (m, 4H), 2.85 (m, 1H), 2.14 (m, 2H), 2.10 (m, 1H), 1.94 (s, 3H), 1.87 (m, 1H), 1.41 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.NC(N)=[S:15]>C(O)C>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][SH:15]
Reactant: BrCc1ccc2ccccc2c1
Reactant: NC(N)=S
Solvent: CCO
Product: SCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.4 %

Procedure:
To a stirred solution of 2-(bromomethyl)naphthalene (10 g) in ethanol (40 ml) was added thiourea (3.79 g) and the reaction heated to reflux. After 6 h, the reaction was cooled in an ice bath, the precipitate was filtered off and washed with ice-cold ethanol. This was then added to NaOH solution (25%, 30 ml) and heated to reflux. After 2 h, the reaction was cooled to room temperature and water (200 ml) was added. The mixture was extracted with diethylether 3 times, the organic phase was separated, dried and concentrated to afford 5 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.[CH2:37]([C:40]1([CH2:50][CH:51]=[CH2:52])[CH2:49][N:43]2S(=O)(=O)O[CH2:46][C@H:42]2[CH2:41]1)[CH:38]=[CH2:39]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH2:46][C@H:42]1[CH2:41][C:40]([CH2:37][CH:38]=[CH2:39])([CH2:50][CH:51]=[CH2:52])[CH2:49][NH:43]1
Reactant: C=CCC1(CC=C)C[C@@H]2COS(=O)(=O)N2C1
Reactant: Clc1cncc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: C=CCC1(CC=C)CN[C@@H](Cc2c(Cl)cncc2Cl)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
To a solution of 3,5-dichloropyridine (1.069 g, 7.22 mmol) in THF (12.04 ml) at −78° C. was added lithium diisopropylamide, 2.0 M heptane/THF/ethylbenzene (4.57 ml, 9.15 mmol) dropwise. After stirring for 1 h, a solution of (R)-5,5-diallyltetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (1.172 g, 4.82 mmol) in THF (10 mL) was added dropwise at −78° C. and the mixture was allowed to warm to room temperature with stirring for 6 h. After evaporating of the solvent, the resulting beige foam was treated with hot 2 N HCl (12 ml) and EtOH (12 ml) overnight. The mixture was cooled to room temperature and basified with 1 N NaOH and extracted with EtOAc. The extracts were dried, evaporated and purified by chromatography through a REDISEP™ pre-packed silica gel column (40 g), eluting with a gradient of 1% to 6% MeOH in DCM, to provide (R)-3,5-dichloro-4-((4,4-diallylpyrrolidin-2-yl)methyl)pyridine (0.70 g, 2.249 mmol, 46.7% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 2H), 5.66-5.86 (m, 2H), 5.03-5.18 (m, 4H), 3.59-3.72 (m, 1H), 3.25 (d, J=7.15 Hz, 1H), 2.97 (d, J=11.51 Hz, 1H), 2.82 (d, J=11.51 Hz, 1H), 2.10-2.28 (m, 4H), 1.78 (dd, J=13.06, 6.95 Hz, 1H), 1.51-1.61 (m, 1H); LCMS (ESI) m/z 311.0 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([SH:12])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([NH:30][CH:31]([CH2:36][CH:37]3[O:39][CH2:38]3)[C:32]([O:34]C)=[O:33])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([NH:30][CH:31]([CH2:36][CH:37]([OH:39])[CH2:38][S:12][C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[NH:11][N:10]=3)[C:32]([OH:34])=[O:33])(=[O:28])=[O:29])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1
Reactant: Sc1n[nH]c(-c2ccccc2)n1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3n[nH]c(-c4ccccc4)n3)C(=O)O)cc2)cc1

Procedure:
Example 42 is prepared from 5-phenyl-1H-1,2,4-triazole-3-thiol and 1d using the procedure described for compound 20.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:12](=O)[NH:11][C:10]([CH:14]2[CH2:16][CH2:15]2)=[N:9][C:8]=1[C:17]([OH:19])=[O:18]>>[Cl:6][C:7]1[C:8]([C:17]([OH:19])=[O:18])=[N:9][C:10]([CH:14]2[CH2:16][CH2:15]2)=[N:11][C:12]=1[Cl:3]
Reactant: O=C(O)c1nc(C2CC2)[nH]c(=O)c1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: O=C(O)c1nc(C2CC2)nc(Cl)c1Cl
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Phosphorus oxychloride (200 mL, 328 g, 2.14 mol) and 5-chloro-2-cyclopropyl-1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acid (i.e. the product of Step B1 or B2) (96.8 g, 451 mmol) were combined and heated at 90° C. for 5 h. The reaction mixture was cooled to 50-60° C. and concentrated at reduced pressure to half volume. After cooling to 30° C. the reaction mixture was added over 60 minutes to a mixture of t-butanol (200 mL) and water (300 mL), with the temperature maintained at 8-10° C. The mixture was seeded, water (300 mL) was added gradually at 10-15° C. and the mixture was stirred for 1 h. After cooling to 5° C. the precipitated product was isolated by filtration and washed with water (3×50 mL). The solid was dried in a vacuum oven to afford the title compound (93 g).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]4[CH:19]([CH3:25])[CH2:20][C:21](=[O:24])[NH:22][N:23]=4)=[CH:17][C:11]=3[N:10]=2)C(=O)C2=CC=CC=C12.O.NN.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([C:18]3[CH:19]([CH3:25])[CH2:20][C:21](=[O:24])[NH:22][N:23]=3)=[CH:17][C:11]=2[N:10]=1
Reactant: CC1CC(=O)NN=C1c1ccc2[nH]c(CCCN3C(=O)c4ccccc4C3=O)nc2c1
Agent: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc2[nH]c(CCCN)nc2c1
Yield: 50.9 %

Procedure:
25.9 g (62 mmol) of 6-[2-(3-phthalimidopropyl)-1H-benzimidazol -5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone and 16.0 ml (330 mmol) of hydrazine hydrate are boiled under reflux in 300 ml of ethanol for 1 5 hours. The thick suspension obtained is concentrated by evaporation under vacuum and the residue is taken up with 500 ml of 2N hydrochloric acid and the solution is filtered. The filtrate is concentrated by evaporation under vacuum and after the addition of 100 ml of ethanol it is again concentrated by evaporation. The solid obtained as residue is taken up with 200 ml of saturated potassium carbonate solution and the mixture is extracted with 3×100 ml of isopropanol. The combined organic phases are dried and concentrated by evaporation under vacuum. 13·9 g (79%) of a colorless solid are obtained after recrystallization from ethanol/water.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:15][CH2:14][CH2:13][O:12][C:5]2=[C:6]([C:9](=[O:11])[CH3:10])[C:7]=1[Cl:8].[N+:16]([O-])([OH:18])=[O:17]>>[Cl:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]2[O:15][CH2:14][CH2:13][O:12][C:5]2=[C:6]([C:9](=[O:11])[CH3:10])[C:7]=1[Cl:8]
Reactant: CC(=O)c1c(Cl)c(Cl)cc2c1OCCO2
Reactant: O=[N+]([O-])O
Product: CC(=O)c1c(Cl)c(Cl)c([N+](=O)[O-])c2c1OCCO2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
5',6'-Dichloro-2',3'-ethylenedioxyacetophenone (8.5 g, 0.0344 miol) was added in portions to 34.5 mL of stirring fuming nitric acid at a rate such that the temperature of the reaction mixture remained below 10° C. The mixture was stirred for an additional 10 minutes at 5 C. and then poured onto 250 g of crushed ice giving yellow precipitate. The precipitate was isolated by filtration and washed with water. Drying gave 5',6'-dichloro-2',3'-ethylenedioxy-4'-nitroacetophenone (8.9 g, 0.0341 mol), m.p. 181°-182° C.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]([CH3:27])[C:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15][C:14]([C:18]#[C:19][CH3:20])([OH:17])[CH2:13][CH2:12]1.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH3:27][N:10]([CH3:9])[C:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15][C:14]([C:18]2[NH:1][C:2]3=[N:3][CH:4]=[CH:5][CH:6]=[C:7]3[C:19]=2[CH3:20])([OH:17])[CH2:13][CH2:12]1
Reactant: Nc1ncccc1I
Reactant: CC#CC1(O)CCC(c2ccccc2)(N(C)C)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: Cc1c(C2(O)CCC(c3ccccc3)(N(C)C)CC2)[nH]c2ncccc12
Temperature: 79 °C
Reaction time: 2 h

Procedure:
2-Amino-3-iodopyridine (3,108 mg, 14.13 mmol), 4-(dimethylamino)-4-phenyl-1-(prop-1-ynyl)cyclohexanol (4,000 mg, 15.54 mmol), lithium chloride (630 mg, 14.83 mmol) and sodium carbonate (4.49 g, 42.38 mmol) were combined in dimethylformamide (absolute, 60 ml) in an argon atmosphere. The catalyst ([Pd(dppf)Cl2×CH2Cl2], 1,154 mg, 1.41 mmol) was then added. The red solution was heated at 79° C. (oil bath temperature) for 5 h. To bring the reaction to completion, a further 0.3 equivalent of 2-amino-3-iodopyridine (932 mg, 4.24 mmol) and 0.05 equivalent of catalyst (577 mg, 0.71 mmol) were added. Thereafter, the mixture was stirred at 99° C. (oil bath temperature) for a further 2 h. The black reaction mixture was cooled to room temperature and water (50 ml; stirring for 10 min) and methylene chloride (50 ml) were added in succession. The phases were separated (the mixture was filtered over kieselguhr) and the aqueous phase was extracted with methylene chloride (3×20 ml). The combined organic phases were washed with saturated NaCl solution (3×20 ml) and dried over sodium sulfate. After filtration, the volatile constituents were removed completely in vacuo. The residue was absorbed on kieselguhr and separated by chromatography (silica gel [200 g]; chloroform/ethanol [9:1 1,000 ml]). 1,200 mg (3.43 mmol; 22% of the non-polar diastereomer were isolated as a colourless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.C([Li])(C)(C)C.[CH:19](N1CCOCC1)=[O:20]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:19]=[O:20])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: O=CN1CCOCC1
Reactant: FC(F)(F)Oc1cc(Br)ccc1I
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=Cc1ccc(Br)cc1OC(F)(F)F
Temperature: -74 °C
Reaction time: 1.5 h
Yield: 51.1 %

Procedure:
Add 4-bromo-1-iodo-2-(trifluoromethoxy)benzene (22.04 g, 60 mmol) to a 1000 mL 3-neck flask equipped with a magnetic stir bar, thermocouple, addition funnel, and N2 inlet and replace the atmosphere in the flask with nitrogen. After adding anhydrous THF (300 mL), cool the mixture to −74° C. and treat dropwise with a solution of t-butyllithium (70 mL of 1.7 M solution, 120 mmol). Stir the resulting solution for 90 minutes and then treated dropwise with a solution of N-formyl morpholine (14.52 g, 126 mmol) in THF (15 mL). Stir the mixture an additional 15 minutes at −74° C. and then allow to warm to 0° C. over 1 hour. Quench the reaction by the adding 0.25 M citric acid (200 mL) and extract with ethyl acetate (1×300 mL). Wash the organic layer with saturated sodium chloride solution (1×200 mL), dry over anhydrous magnesium sulfate, filter through Celite®, and concentrate to an oil. Purify the crude product via silica gel chromatography eluting with hexanes to afford 8.24 g (51%) of the product as white crystals: 1H NMR (300 MHz, CDCl3) δ 10.32 (s, 1H), 7.85 (d, J=8.3 Hz, 1H), 7.63-7.53 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([O:15][CH3:16])[C:10]=1[CH:17]=[O:18].[F:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[C:22]([CH3:28])[CH:21]=1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([O:15][CH3:16])[C:10]=1[CH:17]([C:23]1[CH:24]=[CH:25][C:20]([F:19])=[CH:21][C:22]=1[CH3:28])[OH:18]
Reactant: COc1nn(C)c(-c2c(F)cccc2F)c1C=O
Reactant: Cc1cc(F)ccc1[Mg]Br
Solvent: C1CCOC1
Product: COc1nn(C)c(-c2c(F)cccc2F)c1C(O)c1ccc(F)cc1C
Temperature: 0 °C
Yield: 83.6 %

Procedure:
To a mixture of 5-(2,6-difluorophenyl)-3-methoxy-1-methyl-1H-pyrazole-4-carboxaldehyde (0.25 g, 0.99 mmol) (i.e. the product of Step D) in tetrahydrofuran (5 mL) at −30° C. was added 4-fluoro-2-methylphenylmagnesium bromide (0.5 M in hexanes, 2.0 mL, 1.0 mmol). The reaction mixture was allowed to warm to 0° C., quenched with saturated ammonium chloride solution and concentrated under reduced pressure. The resulting material was diluted with dichloromethane and water, poured onto a solid phase extraction tube (Varian Chem Elute®, prepacked with diatomaceous earth) and eluted with dichloromethane. The dichloromethane eluant was concentrated under reduced pressure and the resulting material purified by silica gel chromatography (0 to 100% gradient of ethyl acetate in dichloromethane as eluant) to provide the title compound (0.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH:14]1([CH2:17][O:18][C:19]2[CH:20]=[C:21]([C:27](=[O:37])[CH2:28][C:29]3[C:34]([Cl:35])=[CH:33][N:32]=[CH:31][C:30]=3[Cl:36])[CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][O:18][C:19]2[CH:20]=[C:21](/[C:27](/[O:37][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:28]/[C:29]3[C:30]([Cl:36])=[CH:31][N:32]=[CH:33][C:34]=3[Cl:35])[CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[CH2:16][CH2:15]1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OCC1CC1
Product: COc1ccc(C(=O)O/C(=C\c2c(Cl)cncc2Cl)c2ccc(OC)c(OCC3CC3)c2)cc1OC

Procedure:
The compound was obtained starting from 3,4-dimethoxy-benzoyl chloride and 1-(3-cyclopropylmethoxy-4-methoxy-phenyl)-2-(3,5-dichloro -pyridin-4-yl)-ethanone, following the procedure of Example 7.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.S(Cl)(Cl)=O.[NH2:19][C:20]1[C:26]([O:29][CH3:30])([O:27][CH3:28])[CH:25]2[CH:23]([O:24]2)[C:22](=[O:31])[CH:21]=1.CC(C)([O-])C.[Li+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C.CO.O>[CH3:28][O:27][C:26]1([O:29][CH3:30])[C:20]([NH:19][C:12]([C:11]2[C:2]([OH:1])=[N:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[O:14])=[CH:21][C:22](=[O:31])[CH:23]2[CH:25]1[O:24]2
Reactant: COC1(OC)C(N)=CC(=O)C2OC21
Reactant: O=C(O)c1cc2ccccc2nc1O
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COC1(OC)C(NC(=O)c2cc3ccccc3nc2O)=CC(=O)C2OC21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 64.7 %

Procedure:
In a dry round bottom flask charged with 2-hydroxyquinoline-3-carboxylic acid (528 mg, 2.8 mmol) was added thionyl chloride (4 mL, 57 mmol). The mixture was then heated to reflux for 20 minutes before rotary evaporation of the thionyl chloride. In a separate flask amine 5 (430 mg, 2.3 mmol) was dissolved in anhydrous tetrahydrofuran (17 mL) and cooled to −78° C. under an inert nitrogen atmosphere. To the cooled amine solution was slowly added lithium tert-butoxide (in 1 M tetrahydrofuran; 3 mL, 3 mmol) followed by stirring for 15 minutes. The acid chloride was then suspended in tetrahydrofuran (12 mL) and directly added to the cooled amine solution. The reaction mixture was stirred overnight, during which time it came to room temperature. The reaction was then diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to afford 550 mg crude material that contained 10% of the O-aroylated product (as determined by LC-MS). The solid was stirred in 8/1 methanol/water (9 mL) containing 25 mg potassium carbonate for an hour after which it was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, and brine. The ethyl acetate was dried over anhydrous magnesium sulfate, filtered and concentrated give a solid containing a small amount of the ester. The product was then purified over a small plug of silica, eluting with 95/5 dichloromethane/ethyl acetate to give 530 mg of a pale yellow solid (64% yield). The product structure was confirmed by 1H NMR. NMR (CDCl3): δ12.30 (br.s, 1H), 10.60 (br.s, 1H), 9.00 (m, 1H), 7.80 (m, 1H), 7.65 (m, 1H), 7.40 (m, 2H), 5.60 (m, 1H), 3.85 (m, 1H), 3.70 (s, 3H), 3.50 (m, 1H), 3.40 (s, 3H) ppm.