Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]([CH3:22])([OH:21])[CH3:20]>>[OH:21][C:19]([CH3:22])([CH3:20])[CH2:18][N:3]1[C:4]2[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1]
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: CC(C)(O)CCl
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(C)(C)O

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 1-chloro-2-methyl-2-propanol: 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.5 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 6.60 (s, 1H), 4.12 (s, 2H), 2.52 (s, 3H), 1.30 (s, 6H); MS (ES) m/z 297 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[C:8]([CH:11]=1)[C:9]#[N:10])([O-:3])=[O:2].[OH:19][CH2:20][CH2:21][NH2:22].C([BH3-])#N.[Na+].Cl>O1CCCC1.CO>[OH:19][CH2:20][CH2:21][NH:22][CH:15]1[CH2:16][CH2:17][N:12]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]=2[C:9]#[N:10])[CH2:13][CH2:14]1
Reactant: NCCO
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(=O)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(NCCO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Nitro-2-(4-oxopiperidin-1-yl)benzonitrile (5.0 g), 2-hydroxyethylamine (1.5 g) and sodium cyanoborohydride (1.3 g) were added to a mixed solvent of methanol (100 ml) and tetrahydrofuran (50 ml) and the mixture was stirred at room temperature for 1 h. An aqueous hydrochloric acid solution was added to keep the reaction mixture acidic. The solvent was evaporated under reduced pressure. Aqueous sodium hydroxide solution was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow precipitation, whereby the title compound (3.6 g) was obtained, melting point: 115° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:5][C:6]=1[C:7](=O)[CH3:8].Cl.[NH2:17][OH:18]>N1C=CC=CC=1.CO>[Cl:1][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:5][C:6]=1[C:7](=[N:17][OH:18])[CH3:8]
Reactant: NO
Reactant: CC(=O)c1sc(-c2cccnc2)nc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(=NO)c1sc(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 1-[4-chloro-2-(3-pyridyl)thiazol-5-yl]ethanone (0.5 g, 2.1 mmol) in a mixture of pyridine (2 ml) and methanol (15 ml) was added hydroxylamine hydrochloride (0.29 g, 4.2 mmol). The resluting solution was stirred at ambient temperature for 18 hours. The precipitated white solid was filtered and dried at vacuum to afford the desired 1-[4-chloro-2-(3-pyridyl)thiazol-5-yl]ethanone oxime. 1H NMR (300 Mz, DMSO-d6): δ:12.2 (s, 0.29H), 11.89 (s, 0.69H), 9.10 (s, 1H), 8.70 (d, 1H, J=4.8 Hz), 8.30 (m, 1H), 7.55 (m, 1H), 2.41 (s, 1H), 2.29 (s, 2H).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:16])=[CH:10][CH:9]=1.[CH3:26][C:27]1[CH:28]=[C:29](O)[CH:30]=[CH:31][C:32]=1[CH3:33].[OH-].[Na+]>>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[O:16][C:30]3[CH:31]=[C:32]([CH3:33])[C:27]([CH3:26])=[CH:28][C:29]=3[C:14]=2[C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(O)cc1C
Reactant: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2oc3cc(C)c(C)cc3c2-c2ccc(OC)cc2)cc1

Procedure:
160 g of 73% strength aqueous sulphuric acid are added dropwise to a mixture of 54.5 g of 1,2-di-(4-methoxyphenyl)-2-oxo-ethanol (p-anisoin) and 73 g of 3,4-dimethylphenol and the mixture is heated at 130°-135° for 20 minutes and then cooled to 20°. The reaction mixture is rendered alkaline by adding an aqueous solution of sodium hydroxide and is heated under reflux and then cooled. It is extracted twice with ethyl acetate; the combined organic extracts are washed with a 2 N aqueous solution of sodium hydroxide and with water, dried over sodium sulphate and filtered and the filtrate is concentrated to half its volume and cooled. The crystalline precipitate is filtered off and recrystallised from ethyl acetate and gives 2,3-di-(4-methoxyphenyl)-5,6-dimethylbenzofurane, melting point 153°.
Reaction SMILES: CC(OC([NH:8][C:9]1[S:13][C:12]2[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:11]=2[N:10]=1)=O)(C)C.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.O>N1C=CC=CC=1>[NH2:8][C:9]1[S:13][C:12]2[CH:14]=[C:15]([NH:18][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:23][CH:24]=3)[CH:16]=[CH:17][C:11]=2[N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(N)cc2s1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: O
Product: Nc1nc2ccc(NC(=O)c3ccc(OC(F)(F)F)cc3)cc2s1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 6-aminobenzothiazol-2-yl tert-butyl carbamate (Intermediate 4, 0.900 g, 3.39 mmol) in pyridine (8 mL), 4-trifluoromethoxybenzoyl chloride (0.535 mL, 3.39 mmol) was added. After stirring for 2 h at 60° C., the solution was poured into water (100 mL). The resulting precipitate was filtered off, washed with water and dried. The so obtained solid was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (20 mL) was added. After stirring for 3 h at r.t., the volatiles were removed in vacuo and dimethyl-formamide (100 mL) was added to the residue. The solution was neutralised by adding saturated sodium hydrogencarbonate solution. Water (400 mL) was added and the mixture was stirred overnight. The precipitated N-(2-aminobenzothiazol-6-yl)-4-trifluoromethoxy-benzamide was filtered off, washed with water and dried (grey solid, 1.16 g, 3.27 mmol, 84%). LC/ESI-MS: m/z=354 [M+H]+; m/z=352 [M−H]−; Rt=3.20 min.
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1([C:17]([NH:19][C@H:20]([C:28]([O:30]C)=[O:29])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:18])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>CO>[C:1]([S:5][CH2:6][C:7]1([C:17]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:18])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)C1(CSC(C)(C)C)CCc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)SCC1(C(=O)N[C@@H](Cc2ccccc2)C(=O)O)CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
Dissolve N-[[1,2,3,4-tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-L-phenylalanine, methyl ester (158 mg, 0.36 mmol) in methanol (3 mL). Add a solution of lithium hydroxide hydrate (1 mL in water, 1 mmol) and stir at room temperature under argon overnight. Partition between 1N hydrochloric acid and methylene chloride. Separate the organic phase and extract the acidic phase with methylene chloride (2×10 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo to give the title compound (149 mg, 97%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][OH:12].[O-:13][Mn](=O)(=O)=O.[K+].OS([O-])=O.[Na+].[NH4+].[OH-]>CC(C)=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1cc(C)c(Br)c(CO)c1
Agent: O=S([O-])O
Agent: [K+]
Agent: [NH4+]
Solvent: CC(C)=O
Product: COc1cc(C)c(Br)c(C(=O)O)c1
Temperature: 60 °C
Yield: 49.8 %

Procedure:
A solution of (2-bromo-5-methoxy-3-methyl-phenyl)-methanol ((Example 192: step c) 7.85 g, 34.0 mmol) in acetone (300 mL) was heated to 60° C. and treated over 25 min. with KMnO4 (12.6 g, 79.8 mmol) as an aqueous solution (175 mL). The mixture was heated to 60° C. for an additional 35 min. A saturated aqueous solution of NaHSO3 was added until the solution turned beige in color. Concentrated NH4OH was added to pH 10 and the solids were filtered through a medium porosity fritted funnel. The filtrate was acidified to pH 4 with concentrated HCl, and the solution was extracted with ether (2×200 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the product 2-bromo-5-methoxy-3-methyl-benzoic acid (4.15 g, 50%) as a white solid. 1H NMR (MeOD): δ 6.968 (d, 1H, J=2.8 Hz), 6.775 (d, 1H, J=3.2 Hz), 3.776 (s, 3H), 2.352 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:18]=2[C@@H:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([N:25]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:20]2)=[O:11])=[N:4][C:5](Br)=[C:6]([F:8])[CH:7]=1.[F:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][C:42]=1B(O)O.C(N(CC)CC)C>CCO.C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:42]2[CH:41]=[CH:40][N:39]=[CH:38][C:37]=2[F:36])=[N:4][C:3]=1[C:10]([NH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C@@H:19]1[CH2:24][CH2:23][CH2:22][C@H:21]([NH2:25])[CH2:20]1)=[O:11]
Reactant: OB(O)c1ccncc1F
Reactant: Nc1cc(F)c(Br)nc1C(=O)Nc1cnccc1[C@@H]1CCC[C@H](N2C(=O)c3ccccc3C2=O)C1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1cc(F)c(-c2ccncc2F)nc1C(=O)Nc1cnccc1[C@@H]1CCC[C@H](N)C1

Procedure:
A solution of 3-amino-6-bromo-N-(4-((1R,3S)-3-(1,3-dioxoisoindolin-2-yl)cyclohexyl)pyridin-3-yl)-5-fluoropicolinamide (1.0 equiv), 3-fluoropyridin-4-yl-boronic acid (3.0 equiv.), tetrakistriphenylphosphine (0.2 equiv.) and triethylamine (3.0 equiv.) in 1:1 EtOH/toluene (0.1 M) was heated at 120° C. with microwave irradiation for 1200 seconds. Upon cooling, removal of the volatiles in vacuo, the Suzuki product was directly purified by reverse phase HPLC. The product fraction was lyophilized and the resulting phthalimide group was deprotected as described in Method 9 yielding, after RP HPLC purification and lyophilization, 5-amino-N-(4-((1R,3S)-3-aminocyclohexyl)-pyridin-3-yl)-3,3′-difluoro-2,4′-bipyridine-6-carboxamide as the TFA salt. LCMS (m/z): 425.1 (MH+); LC Rt=2.08 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:15]1[NH:19][N:18]=[C:17]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([Cl:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)[N:16]=1)[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[CH:8]=1.[I-].[Na+]>CC(C)=O>[Cl:32][C:30]1[N:29]=[CH:28][N:27]([C:24]2[CH:25]=[CH:26][C:21]([NH:20][C:17]3[N:16]=[C:15]4[CH:6]([C:7]5[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[CH:8]=5)[CH2:5][CH2:4][CH2:3][CH2:2][N:19]4[N:18]=3)=[CH:22][C:23]=2[O:33][CH3:34])[CH:31]=1
Reactant: COc1cc(Nc2n[nH]c(C(CCCCCl)c3cc(F)cc(F)c3)n2)ccc1-n1cnc(Cl)c1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(Nc2nc3n(n2)CCCCC3c2cc(F)cc(F)c2)ccc1-n1cnc(Cl)c1
Yield: 4.3 %

Procedure:
A solution of 5-(5-chloro-1-(3,5-difluorophenyl)pentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine (855 mg, 1.685 mmol), sodium iodide (1.26 g, 8.43 mmol), and diisoproplylethylamine (0.589 mL, 3.37 mmol) in acetone (20 mL) was heated in a sealed vessel at 100° C. for 4 h. The reaction was concentrated in vacuo. The crude product was purified using reverse phase preparatory-HPLC (MeOH/water/TFA). The purified material was crystallized from methanol to afford 34 mg (4% yield) of the titled compound as a white solid. LC-MS (M+H)+ 471.3. 1H NMR (500 MHz, chloroform-d) δ ppm 7.52 (d, J=1.53 Hz, 1 H) 7.42 (d, J=2.44 Hz, 1 H) 7.10 (d, J=8.55 Hz, 1 H) 7.03 (d, J=1.53 Hz, 1 H) 6.84 (dd, J=8.55, 2.44 Hz, 1 H) 6.70-6.80 (m, 3 H) 6.65 (s, 1 H) 4.18-4.32 (m, 3 H) 3.81 (s, 3 H) 2.06-2.25 (m, 2 H) 1.84-2.03 (m, 4 H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[C:34](B(O)O)=[N:35][CH:36]=[CH:37][CH:38]=1>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:34]3[C:33]([F:32])=[CH:38][CH:37]=[CH:36][N:35]=3)[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: OB(O)c1ncccc1F
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2csc(-c3ncccc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3-fluoropyridin-2-yl)boronic acid gave 237. LCMS (ES+) m/z 435 (M+1).
Reaction SMILES: [CH:1]1([NH:6][C:7](=[O:23])[NH:8][C@H:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([O:12]C(C)(C)C)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH:1]1([NH:6][C:7](=[O:23])[NH:8][C@H:9]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]([OH:12])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)[C@H](NC(=O)NC1CCCC1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCCC1)N[C@@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.2 %

Procedure:
To a stirred solution of (R)-tert-butyl 2-(3-cyclopentylureido)-2-phenylacetate (1.31 g, 4.10 mmol) in CH2Cl2 (25 mL) was added TFA (4 mL) and triethylsilane (1.64 mL; 10.3 mmol) dropwise, and the resulting solution was stirred at room temperature for 6 hours. The volatile components were removed under reduced pressure and the crude product was recrystallized in ethyl acetate/pentanes to yield (R)-2-(3-cyclopentylureido)-2-phenylacetic acid as a white solid (0.69 g, 64%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17-1.35 (m, 2H) 1.42-1.52 (m, 2H) 1.53-1.64 (m, 2H) 1.67-1.80 (m, 2H) 3.75-3.89 (m, 1H) 5.17 (d, J=7.93 Hz, 1H) 6.12 (d, J=7.32 Hz, 1H) 6.48 (d, J=7.93 Hz, 1H) 7.24-7.40 (m, 5H) 12.73 (s, 1H). LC-MS: Anal. Calcd. for C14H18N2O3: 262.31; found: 263.15 (M+H)+. HPLC XTERRA® C-18 3.0×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.2% H3PO4, B=10% water, 90% methanol, 0.2% H3PO4, RT=1.24 min, 100% homogeneity index.
Reaction SMILES: [OH2:1].[ClH:2].Cl.[Cl:4][C:5]1[CH:32]=[CH:31][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)=[O:21])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1.Cl.[OH-].[K+]>C(O)(=O)C>[ClH:4].[ClH:2].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:29](=[O:1])[NH2:30])=[CH:27][CH:28]=3)=[O:21])[CH2:14][CH2:15]2)=[CH:31][CH:32]=1
Reactant: O
Reactant: N#Cc1ccc(NC(=O)NCCCN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: NC(=O)c1ccc(NC(=O)NCCCN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Yield: 70.8 %

Procedure:
A solution of 1-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}-3-(4-cyanophenyl)urea dihydrochloride monohydrate (10.0 g; 19.9 mmole), glacial acetic acid (120 ml), and concentrated hydrochloric acid (80 ml) was heated at 80° C. for 30 minutes. The mixture was then poured over ice, and basified with aqueous potassium hydroxide. The product was extracted with methylene chloride, dried (sodium sulfate), and the salt precipitated out ethereal hydrochloric acid. Several recrystallizations from ethanol provided the title compound (3.54 g; 38% yield) as colorless crystals, m.p. 224°-226° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.C([O-])([O-])=O.[Na+].[Na+].[Cl:27][C:28]1[C:47](I)=[CH:46][C:31]([C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][C:42]([Cl:45])([F:44])[F:43])=[CH:37][CH:36]=2)=[O:33])=[CH:30][N:29]=1>COCCOC.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]>[Cl:27][C:28]1[C:47]([C:11]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=[CH:9][CH:10]=2)=[CH:46][C:31]([C:32]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([O:41][C:42]([Cl:45])([F:43])[F:44])=[CH:39][CH:40]=2)=[O:33])=[CH:30][N:29]=1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (9.45 g, 34.0 mmol), Na2CO3 (39.2 mL, 78 mmol) and PdCl2(dppf) (0.956 g, 1.307 mmol) were added to 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage 48.3, 12 g, 26.1 mmol) in DME (160 mL). The mixture was evacuated/purged 3 times with argon, and stirred at 80° C. for 22 h. The RM was diluted with EtOAc (350 mL), washed with water (4×150 mL) and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 850 g, EtOAc/n-hexane (1:2)) and crystallized from iPr2O/EtOAc to give the title product as a white solid. HPLC (Condition 7) tR=7.523 min, UPLC-MS (Condition 3) tR=1.22 min, m/z=483/485 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[OH-].[Na+]>O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:12][CH2:11][CH2:10][CH2:9][S:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1
Reactant: BrCCCCCCBr
Reactant: Cc1ccc(SCCCO)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(SCCCOCCCCCCBr)cc1
Yield: 66 %

Procedure:
3-[(4-Methylphenyl)thio]-1-propanol (4.0 g), 1,6-dibromohexane (16.06 g), 40% sodium hydroxide solution (40 ml) and TAB (1 g) were stirred together at room temperature for 18 h. The mixture was diluted with water (150 ml), extracted with ethyl acetate (2×150 ml), which was dried and evaporated in vacuo to give a colourless oil. Purification by FCC eluting with System A (0:20→1:19) gave the title compound (5.0 g) as a colourless oil. T.l.c. (System A 1:9) Rf 0.53.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH:8]([C:11]([O:13]CC)=O)[C:6](=[O:7])[N:5]([CH3:16])[C:3]1=[O:4].[F:17][C:18]([F:34])([F:33])[C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)=[N:23][CH:24]=1.C(O)C>C1(C)C=CC=CC=1>[CH3:16][N:5]1[C:6](=[O:7])[CH:8]([C:11](=[O:13])[NH:30][C:29]2[CH:31]=[CH:32][C:26]([O:25][C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:34])([F:17])[F:33])=[CH:24][N:23]=3)=[CH:27][CH:28]=2)[C:9](=[O:10])[N:2]([CH3:1])[C:3]1=[O:4]
Reactant: CCOC(=O)C1C(=O)N(C)C(=O)N(C)C1=O
Reactant: Nc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN1C(=O)C(C(=O)Nc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)C(=O)N(C)C1=O

Procedure:
1.60 g (0.007 mol) of 1,3-dimethyl-5-ethoxycarbonylbarbituric acid and 1.78 g (0.007 mol) of 4-(5-trifluoromethylpyrid-2-yloxy)aniline are suspended in 20 ml of toluene. The suspension is heated to reflux for 16 hours, during which time ethanol escapes. After cooling, the precipitate is isolated by filtration, washed with toluene and dried, affording 1,3-dimethyl-5-[4-(5-trifluoromethylpyrid-2-yloxy)phenylcarbamoyl]barbituric acid of the formula ##STR24## with a melting point of 180°-181° C.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16]C)=[O:14])=[C:5]([NH:18][CH:19]([CH3:21])[CH3:20])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[OH-].[K+].Cl.C([O-])([O-])=O.[K+].[K+].CI>C(O)C.CN(C=O)C.O>[F:26][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH3:16])=[O:14])=[C:5]([NH:18][CH:19]([CH3:21])[CH3:20])[C:4]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1NC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCO
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OC)c1NC(C)C
Yield: 74.4 %

Procedure:
A mixture of 7.61 g (0.020 mol) of product of Example 63, 6.7 g (0.118 mol) of KOH and 30 ml of H2O in 200 ml of ethanol was refluxed for 16 hours. The reaction mixture was poured into 250 ml containing 50 ml of concentrated HCl, extracted with ether, dried (MgSO4) and concentrated in vacuo to a dark oil. This oil, 5.53 g (0.040 mol) of K2CO3 and 3.75 ml (0.060 mol) of methyl iodide in 50 ml of DMF was stirred at room temperature for 19 hours. The reaction mixture was poured into water, extracted with ether, dried (MgSO4) and concentrated in vacuo to 8.18 g of dark oil. This oil was chromatographed on the HPLC using 5% ethyl acetate/cyclohexane as eluting solvent affording 5.51 g (74.4%) of orange oil. A portion of this oil, 1.41 g, was kugelrohr distilled at 40 Pa, pot temperature 104° C., and 1.37 g of product was collected as a light yellow oil, nD25 1.4765.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:56])[C:30]([CH3:55])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:56])[C:30]([CH3:55])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][CH2:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)=[C:42]([CH:46]=2)[C:43]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: COc1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3ccccc3)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.2 %

Procedure:
p-Methoxyaniline (0.038 g, 0.308 mmol), triethylamine (0.031 g, 0.308 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.052 g, 0.308 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-benzyloxybenzoic acid (0.065 g, 0.154 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) to obtain the titled compound (0.066 g, 0.125 mmol, 81%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[C:21]1([CH3:30])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH:28]=O>>[CH3:30][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[N:1][C:2]2[C:3]([C:12]=1[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9]
Reactant: Cc1ccccc1CC=O
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Product: Cc1ccccc1-c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and o-Tolyl-acetaldehyde following the procedure of Example 457: MS (ESI) m/z 380.126; HRMS: calcd for C23H16F3NO+H+, 380.12567; found (ESI, [M+H]+), 380.126.