Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:19][C:18]([NH:20][CH3:21])=[N:17][CH:16]=2)=[CH:11][CH:10]=1)[C:5]([OH:7])=[O:6])[CH3:2].[OH-].[Na+].[CH3:24]O>S(=O)(=O)(O)O.O>[CH2:1]([O:3][C@@H:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[S:19][C:18]([NH:20][CH3:21])=[N:17][CH:16]=2)=[CH:13][CH:14]=1)[C:5]([O:7][CH3:24])=[O:6])[CH3:2]
Reactant: CO
Reactant: CCO[C@@H](Cc1ccc(-c2cnc(NC)s2)cc1)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCO[C@@H](Cc1ccc(-c2cnc(NC)s2)cc1)C(=O)OC
Yield: 67 %

Procedure:
0.5 g (1.6 mmol) of 2(S)-ethoxy-3-[4-(2-methylaminothiazol-5-yl)phenyl]propanoic acid in 10 ml of methanol and a few drops of sulfuric acid is heated at 60° C. for 2 hours. The reaction medium is cooled, diluted with water, neutralized to pH 7 with aqueous 1M sodium hydroxide solution and then extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a 50/50 heptane/ethyl acetate mixture. 0.34 g (67%) of methyl 2(S)-ethoxy-3-[4-(2-methylaminothiazol-5-yl)phenyl]propanoate is obtained in the form of a yellow solid.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]3[CH:12]=[N:13][N:14]=[C:7]3[C@@H:6]([CH2:15][CH3:16])[N:5]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:4]=2[N:3]=1.[CH3:22][NH2:23].C(O)(C(F)(F)F)=O.C(=O)([O-])[O-]>C(O)C.C(#N)C.O>[CH:17]1([N:5]2[C:4]3[N:3]=[C:2]([NH:23][CH3:22])[N:11]=[CH:10][C:9]=3[N:8]3[CH:12]=[N:13][N:14]=[C:7]3[C@H:6]2[CH2:15][CH3:16])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC[C@@H]1c2nncn2-c2cnc(Cl)nc2N1C1CCCC1
Reactant: CN
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1c2nncn2-c2cnc(NC)nc2N1C1CCCC1
Temperature: 50 °C
Yield: 61 %

Procedure:
In a vial containing (R)-7-chloro-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine (70 mg, 0.23 mmol) was added a solution of methylamine in ethanol (2 mL, 2M soln.) The vessel was sealed then heated at 50° C. for 18 hours. After cooling, the solvent was removed under reduced pressure and the crude product was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 □M, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The free base was obtained by passing the TFA salt in acetonitrile/water through a carbonate cartridge to afford the title compound as a white powder (42 mg, 61% yield). Submitted as a free base.
Reaction SMILES: C[N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][CH:5]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:6]2.[OH-].[Na+].[O-][Mn](=O)(=O)=O.[K+]>C1COCC1.O>[CH:7]12[NH:2][CH:3]([CH2:10][CH2:9][CH2:8]1)[CH2:4][CH:5]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH2:6]2
Reactant: CN1C2CCCC1CC(NC(=O)OC(C)(C)C)C2
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CC2CCCC(C1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a solution of the carbamate from Step A (430 mg, 1.69 mmol) in THF (2 mL) at 0° C. was added a solution of sodium hydroxide (2.0 g, 50 mmol) in water (20 mL), followed by a solution of KMnO4 (2.0 g, 12.6 mmol) in water (100 mL). The mixture was allowed to warm to room temperature and stirred overnight. Additional KMnO4 (2.0 g, 12.6 mmol) solution was added at room temperature and the mixture was stirred for additional 1 h. The mixture was extracted with methylene chloride. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to afford tert-butyl 9-azabicyclo[3.3.1]nonan-3-ylcarbamate (360 mg, 89%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 4.32 (br s, 1H), 3.66 (br s, 1H), 3.33-3.00 (m, 2H), 2.25-2.00 (m, 2H), 1.85-1.48 (m, 5H), 1.45 (s, 9H), 1.40-1.35 (m, 2H), 1.09-1.02 (m, 2H); MS (ESI+) m/z 241 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[C:41]([F:43])[CH:42]=1)[CH2:5][N:6]1[C:10]([Br:11])=[CH:9][N:8]=[C:7]1[CH:12]([NH:32][C:33](=[O:39])OC(C)(C)C)[CH2:13][C:14]1[CH:22]=[C:21]([CH3:23])[C:20]2[C:16](=[CH:17][N:18](COCC[Si](C)(C)C)[N:19]=2)[CH:15]=1.Cl.C(C1NC=CN=1)(C1NC=CN=1)=O.[NH:57]1[CH2:62][CH2:61][CH:60]([N:63]2[CH2:72][C:71]3[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=3)[NH:65][C:64]2=[O:73])[CH2:59][CH2:58]1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:40]=[C:41]([F:43])[CH:42]=1)[CH2:5][N:6]1[C:10]([Br:11])=[CH:9][N:8]=[C:7]1[CH:12]([NH:32][C:33]([N:57]1[CH2:58][CH2:59][CH:60]([N:63]2[CH2:72][C:71]3[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=3)[NH:65][C:64]2=[O:73])[CH2:61][CH2:62]1)=[O:39])[CH2:13][C:14]1[CH:22]=[C:21]([CH3:23])[C:20]2[C:16](=[CH:17][NH:18][N:19]=2)[CH:15]=1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc(Br)n2Cc2cc(F)cc(F)c2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2ncc(Br)n2Cc2cc(F)cc(F)c2)cc2c[nH]nc12
Temperature: 0 °C
Reaction time: 72 h

Procedure:
tert-Butyl 1-(1-(3,5-difluorobenzyl)-5-bromo-1H-imidazol-2-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethylcarbamate (16.0 mg, 0.024 mmol) was dissolved in a minimum amount of ethyl acetate, and treated with hydrochloric acid (4 N in dioxane, 1.0 mL). The mixture was stirred under nitrogen for 3 days. After removal of the solvents, the crude mixture was treated with diethyl ether to give a precipitate which was filtered. The resulting solid was dissolved in dimethylformamide (1.0 mL), cooled to 0° C., and treated with carbonyl diimidazole (4.0 mg, 0.025 mmol, 1.1 equiv) and N′N-diisopropylethylamine (16.7 μL, 3 equiv). The reaction was stirred for 5 min at 0° C., warmed to room temperature, stirred for 10 min, and treated with 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (5.8 mg, 0.025, 1.1 equiv). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by column chromatography to afford 7.5 mg (52%, 2 steps). 1H-NMR (CD3OD, 500 MHz) δ 1.40-1.58 (m, 4H), 2.42 (s, 3H), 2.61-2.72 (m, 2H), 3.14-3.24 (m, 2H), 3.92-4.06 (m, 2H), 4.15 (s, 2H), 4.25-4.38 (m, 1H), 4.10-5.24 (m, 2H), 5.42 (m, 1H), 6.32 (s, 1H), 6.33 (s, 1H), 6.61-6.78 (m, 3H), 6.82 (s, 1H), 6.90-6.99 (m, 1H), 7.08-7.13 (m, 2H), 7.86 (s, 1H). Mass spec.: 705.2 (MH)+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[N:5]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>O1CCCC1>[Cl:13][C:6]1[N:5]=[C:4]([NH:3][C:14](=[O:16])[CH3:15])[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.2 %

Procedure:
To a suspension of sodium hydride (120 mg, 5 mmole) in tetrahydrofuran(10 ml), a solution of 2-amino-3-nitro-6-chloropyridine (870 mg, 5 mmole) in 20 ml of tetrahydrofuran (20 ml) was added. The reaction mixture was stirred at room temperature for 30 min. A solution of acetic anhydride (377 μl, 6 mmole) in tetrahydrofuran (10 ml) was added and stirred at room temperature overnight. The reaction mixture was quenched with water and concentrated under reduced pressure. The crude product was dissolved in dichloromethane and washed with brine. The organic layer was dried with sodium sulfate and then concentrated under vacuo. The crude was purified by flash chromatography, eluting 78% hexane: 22% ethyl acetate to give a yellow product (88 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:24])[CH2:10][N:11]2[CH:15]=[C:14]([N+:16]([O-])=O)[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:12]2)[CH:5]=[CH:6][CH:7]=1>[Pd].CO.ClCCl>[NH2:16][C:14]1[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:12][N:11]([CH2:10][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[O:24])[CH:15]=1
Reactant: CCOC(=O)c1nn(CC(=O)Nc2cccc(F)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1nn(CC(=O)Nc2cccc(F)c2)cc1N
Yield: 88.2 %

Procedure:
A mixture of ethyl 1-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-4-nitro-1H-pyrazole-3-carboxylate (0.168 g, 0.5 mmol) was hydrogenated over 10% palladium on carbon (0.034 g) in a mixture of methanol (6 ml) and dichloromethane (3 ml) for 3 hours. The mixture was filtered through Celite and the filtrate was evaporated to leave ethyl 4-amino-1-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazole-3-carboxylate (0.135 g, 88% yield):
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]3[C:43](=[CH:44][CH:45]=2)[C:42](=[O:46])[N:41]([CH2:47][C:48]([F:51])([F:50])[F:49])[CH2:40]3)O1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:37]3[CH:38]=[C:39]4[C:43](=[CH:44][CH:45]=3)[C:42](=[O:46])[N:41]([CH2:47][C:48]([F:51])([F:50])[F:49])[CH2:40]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(CC(F)(F)F)C3=O)OC1(C)C
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CN(CC(F)(F)F)C5=O)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethyl)isoindolin-1-one. LCMS (M+H)+=505.0.
Reaction SMILES: [CH3:1][CH:2]([C:16]([OH:18])=[O:17])[C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:7]([F:9])[CH:8]=1.CO.S(=O)(=O)(O)O>C(OCC)(=O)C.O>[CH3:1][C@H:2]([C:16]([OH:18])=[O:17])[C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:7]([F:9])[CH:8]=1
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: C[C@H](C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Reaction time: 5 h

Procedure:
A sample of 6.2 g (25 mmol) of R,S flurbiprofen was combined with 40 g of methanol and stirred until dissolved. The solution was treated with 3.14 g (21 mmol) of cis (1R,2S)-1-aminoindan-2-ol, seeded with a small amount of (1R,2S)-1-aminoindan-2-ol (S)-flurbiprofen diastereomer, and allowed to crystallize over a period of 17 hours at ambient temperature. The mixture was then cooled and held at 4° C. for 5 hours. The solids were isolated by filtration, washed with 35 mL methanol, and dried to afford 3.8 g (38M % yield) of white crystals. The acid was released by dissolving the solid in 200 mL of an ethyl acetate-water (50/50; v/v) mixture and treating the solution with 3 g of 5N aqueous sulfuric acid. After mixing, the aqueous phase was decanted and the organic phase washed twice with 100 mL of water. The organic phase was then evaporated under vacuum. The weight of the solid residue was 2.1 g. The rotation [α]D of this solid was -18.8 (c=1, ethanol) corresponding to (S)-flurbiprofen of 44.6% enantiomeric excess.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]([CH2:18][OH:19])[CH2:16][OH:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:19][CH2:18][CH:15]([NH:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH2:16][OH:17]
Reactant: OCC(CO)NC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: OCC(CO)NC1CCNCC1
Yield: 99.8 %

Procedure:
34.5 g of 1-benzyl-4-(1,3-dihydroxyprop-2-ylamino)-piperidine are dissolved in 400 ml of methanol, combined with 3.4 g of 20% palladium/charcoal and hydrogenated with hydrogen at 24-28° C. at 2.2 bar. Then the catalyst is filtered off and the solvent is eliminated in vacuo. 22.7 g of 4-(1,3-dihydroxyprop-2-ylamino)-piperidine are obtained as an oil which is used without further purification for the next reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21](Br)[C:20]=2[CH3:26])=[CH:12][CH:11]=1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O1CCOCC1.O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:20]=2[CH3:26])=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1c(Br)cccc1C(=O)NCc1ccc(C(=O)Nc2ccccc2N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(C(=O)NCc2ccc(C(=O)Nc3ccccc3N)cc2)cccc1-c1ccccc1
Reaction time: 0.33 h
Yield: 51.3 %

Procedure:
45 mg of N-(2-aminophenyl)-4-((3-bromo-2-methylbenzamido) methyl)benzamide obtained in Example 68 (0.103 mmol), phenyl boronic acid (19 mg, 0.154 mmol), tetrakis(triphenylphosphin)palladium (7 mg, 0.006 mmol), and sodium bicarbonate (33 mg, 0.308 mmol) were dissolved in 5 mL of dioxane/H2O mixture (v/v, 4:1). The resulting mixture was subjected to microwave equipment (Biotage AB) for 20 min at 150° C. Ethyl acetate was added to the resulting mixture, dried with anhydrous magnesium sulfate, and filtered with Celite. The filtrate was dried under a reduced pressure, and subjected to a column chromatography (ethyl acetate:methanol=9:1 (v:v)). The resulting mixture was dissolved in ethanol and dried to obtain the title compound (23 mg, 52%).
Reaction SMILES: [CH2:1]([CH:3]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[CH:17]=2)(=[O:15])=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:24])[CH:10]=2)[N:5]2[CH:25]=[CH:26][CH:27]=[C:4]12)[CH3:2].[Br:28]N1C(=O)CCC1=O>C(Cl)Cl>[Br:28][C:25]1[N:5]2[C:6]3[C:11]([N:12]([S:13]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[CH:17]=4)(=[O:15])=[O:14])[CH:3]([CH2:1][CH3:2])[C:4]2=[CH:27][CH:26]=1)=[CH:10][C:9]([F:24])=[CH:8][CH:7]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC1c2cccn2-c2ccc(F)cc2N1S(=O)(=O)c1ccc(O)c(C)c1
Solvent: ClCCl
Product: CCC1c2ccc(Br)n2-c2ccc(F)cc2N1S(=O)(=O)c1ccc(O)c(C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a 50 ml round bottom flask with addition funnel was added 30 ml of methylene chloride and 0.38 g (1 mmol) of the product from Example 19. The flask was cooled to −78° C. and a solution of 0.18 g (1 mmol) of N-bromosuccinimide in 10 ml of methylene chloride was slowly added via addition funnel. After addition was complete, the reaction was allowed to stir at this temperature for 1 hr, then cooling removed. When the reaction had warmed to room temperature it was extracted with 20 ml of saturated sodium bicarbonate solution and separated. The aqueous layer was extracted twice with 10 ml of methylene chloride and the combined organic layers were dried (MgSO4) and concentrated. The crude solid was subjected to column chromatography eluting with 40% ethyl acetate:hexane to yield 0.32 g (69%) of solid which was crystallized from ethyl acetate:hexane to produce colorless crystals, mp 119° C. (dec).
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3](=[O:34])[O:4][CH:5]([C:12]1[N:13]([CH3:33])[C:14]([C:23]2[S:24][C:25]3[N:26]=[CH:27][N:28]=[C:29]([NH2:32])[C:30]=3[N:31]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1)[C:6]1C=CC=CC=1.[CH:36](=O)[CH2:37][CH:38](C)C>>[CH3:1][N:2]([CH3:35])[C:3](=[O:34])[O:4][CH:5]([C:12]1[N:13]([CH3:33])[C:14]([C:23]2[S:24][C:25]3[N:26]=[CH:27][N:28]=[C:29]([NH2:32])[C:30]=3[N:31]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1)[CH2:6][CH:37]([CH3:38])[CH3:36]
Reactant: CC(C)CC=O
Reactant: CN(C)C(=O)OC(c1ccccc1)c1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C
Product: CC(C)CC(OC(=O)N(C)C)c1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 97 but using isovaleraldehyde in place of benzaldehyde. Pale yellow oil (54 mg, 77%);
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][C@H:6]1[NH:11][C:10](=[O:12])[CH2:9][O:8][CH2:7]1.[NH:16]1[CH:20]=[CH:19][CH:18]=[N:17]1.C([O-])([O-])=O.[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.[Cu]Cl>[N:16]1([C:2]2[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=2)[CH2:5][C@H:6]2[NH:11][C:10](=[O:12])[CH2:9][O:8][CH2:7]2)[CH:20]=[CH:19][CH:18]=[N:17]1
Reactant: O=C1COC[C@@H](Cc2cccc(I)c2)N1
Reactant: c1cn[nH]c1
Agent: Cl[Cu]
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=C1COC[C@@H](Cc2cccc(-n3cccn3)c2)N1
Temperature: 25 °C

Procedure:
A mixture of (R)-5-(3-iodo-benzyl)-morpholin-3-one A-10 (1.0 g, 3.15 mmol), pyrazole (322 mg, 4.73 mmol), K2CO3 (872 mg, 6.31 mmol), copper(I) chloride (31 mg, 0.32 mmol) and L-proline (73 mg, 0.63 mmol) in DMF (8 mL) was heated under argon to 110° C. for 24 h. The reaction mixture was cooled to RT and partitioned between water and DCM before being filtered through a celite plug. The layers were separated and the aqueous phase was re-extracted with DCM (2×). The combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give the crude product that was purified by flash chromatography (eluting with a gradient of 50% to 100% EtOAc in hexane) to give the title compound as a white solid. LC-MS B: tR=0.51 min; [M+H]+=257.86.
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1)(=[O:4])=[O:3].[Cl:14][C:15]1[CH:32]=[CH:31][C:18]2[N:19]([CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:20]([CH2:22]Cl)=[N:21][C:17]=2[CH:16]=1>>[Cl:14][C:15]1[CH:32]=[CH:31][C:18]2[N:19]([CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:28])=[O:29])[C:20]([CH2:22][N:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[N:6]3)=[N:21][C:17]=2[CH:16]=1
Reactant: CS(=O)(=O)CCCn1c(CCl)nc2cc(Cl)ccc21
Reactant: CS(=O)(=O)c1n[nH]c2ccccc12
Product: CS(=O)(=O)CCCn1c(Cn2nc(S(C)(=O)=O)c3ccccc32)nc2cc(Cl)ccc21

Procedure:
Example 1-8 was prepared in analogy to Example 1-2 by using above 3-(methylsulfonyl)-1H-indazole and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole instead of 3-(methylsulfonyl)-1H-indol e and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([C:12]2[NH:13][C:14](=[O:27])[C:15]3[C:16](=[C:18]([CH2:25][CH3:26])[N:19]([CH2:21][CH2:22][O:23][CH3:24])[N:20]=3)[N:17]=2)=[CH:10][C:9](I)=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].B(O)(O)[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=1>O1CCOCC1.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>[CH2:1]([O:5][C:6]1[C:11]([C:12]2[NH:13][C:14](=[O:27])[C:15]3[C:16](=[C:18]([CH2:25][CH3:26])[N:19]([CH2:21][CH2:22][O:23][CH3:24])[N:20]=3)[N:17]=2)=[CH:10][C:9]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ncc(I)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
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: [K+]
Solvent: C1COCCO1
Product: CCCCOc1ncc(-c2cccc(C(F)(F)F)c2)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Yield: 70 %

Procedure:
5-(2-Butoxy-5-iodo-3-pyridinyl)-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Example 1) (140 mg, 0.28 mmol), K2CO3 (78 mg, 0.56 mmol) and 3-trifluoromethylboronic acid (60 mg, 0.34 mmol) were stirred together in aqueous dioxan under a nitrogen atmosphere. The mixture was immersed in a pre-heated oil bath at 120° C. for a few minutes and Pd(PPh3)4 (34 mg, 0.028 mmol) was added. The mixture was heated at reflux for 2 h and then cooled. The cooled mixture was concentrated and partitioned between ethyl acetate and water. This was then filtered through an Arbocel® pad to remove the palladium residues and the organic layer separated, washed with sodium bicarbonate solution then brine, dried (MgSO4) and concentrated. Recrystallisation from ethyl acetate gave the title compound (101 mg, 70%).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40](OC)=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(C1N=C[N:52]([C:54]([C:67]2[CH:72]=[CH:71][CH:70]=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.C1(N)CCCC1>>[CH:54]1([NH:52][C:40]([C:35]2[CH:34]=[CH:33][C:32]3[C:37](=[CH:38][CH:39]=[C:30]([C:2]([OH:1])([C:6]4[N:7]=[CH:8][NH:9][CH:10]=4)[CH:3]([CH3:4])[CH3:5])[CH:31]=3)[CH:36]=2)=[O:41])[CH2:67][CH2:72][CH2:71][CH2:70]1
Reactant: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: NC1CCCC1
Product: CC(C)C(O)(c1ccc2cc(C(=O)NC3CCCC3)ccc2c1)c1c[nH]cn1

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (2.83 g) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with cyclopentylamine (0.16 ml) in a similar manner as described in Example 24-(i) to give the titled compound (509 mg) as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](/[CH:18]=[CH:19]/[C:20]2[C:28]3[C:23](=[CH:24][C:25]([CH:29]=O)=[CH:26][CH:27]=3)[NH:22][N:21]=2)[CH:13]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:29][C:25]3[CH:24]=[C:23]4[C:28]([C:20](/[CH:19]=[CH:18]/[C:14]5[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=5)=[N:21][NH:22]4)=[CH:27][CH:26]=3)[C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Reactant: O=C1Cc2cc(Br)cnc2N1
Product: O=C1Nc2ncc(Br)cc2C1=Cc1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Yield: 84.4 %

Procedure:
The title compound (E/Z=5:4, 75 mg, 84%) was synthesized as a yellow solid according to the method described for Example A67 (oil temp 75° C., reflux 2 h) using 5-bromo-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (44.5 mg, 0.21 mmol) and (E)-3-(2-(pyridin-3-yl)vinyl)-1H-indazole-6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.64 (s, 0.45H), 13.56 (s, 0.48H), 11.50 (s, 0.91H), 8.94 (s, 0.43H), 8.91 (s, 0.97H), 8.48 (d, J=3.6 Hz, 0.99H), 8.43-8.37 (m, 0.98H), 8.33 (d, J=8.0 Hz, 0.52H), 8.28-8.17 (m, 2.36H), 8.11 (d, J=8.8 Hz, 0.50H), 8.03 (s, 0.56H), 7.94 (s, 1.02H), 7.77-7.69 (2 doublets partially overlapping, J=17.2 Hz, 1.07H, vinylic proton), 7.64-7.54 (m, 1.54H), 7.45-7.41 (2 doublets overlapping, J=8.8 Hz, 1.00H); MS ESI 444.3 [M+H]+, calcd for [C22H14BrN5O+H]+ 444.1.
Reaction SMILES: Cl[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][S:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[O:25]([C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][S:4][N:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Oc1ccccc1
Reactant: Clc1nsnc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(Oc2nsnc2-c2ccccc2)cc1
Temperature: 120 °C
Yield: 898.8 %

Procedure:
Under a dry nitrogen atmosphere 4.1 g (0.0021 mole) of 3-chloro-4-phenyl-1,2,5-thiadiazole was added to a stirred mixture of 3.73 g (0.0027 mole) of potassium carbonate and 2.4 g (0.0026 mole) of phenol in 50 ml of N,N-dimethylformamide. After complete addition the mixture was heated at 120° C. for 21 hours. The mixture was cooled, poured into 400 ml of ice water and the mixture extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to leave a residue. The residue was purified by column chromatography on silica gel, eluted with n-hexane:methylene chloride (1:1) to yield 4.8 g of 3-phenoxy-4-phenyl-1,2,5-thiadiazole, Compound 38 of Table I.