Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)(=O)[CH3:2].Cl.[OH:14][NH2:15]>N1C=CC=CC=1.C(O)C>[C:1](=[N:15][OH:14])([C:4]1[CH:5]=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)c1cnc2ccsc2c1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NO)c1cnc2ccsc2c1
Temperature: 80 °C
Yield: 76.9 %

Procedure:
To a solution of 6-acetylthieno[3,2-b]pyridine (3.78 g, 21.3 mmol) in pyridine (40 ml) and ethanol (40 ml), under a nitrogen atmosphere, was added hydroxyl amine hydrochloride (5.0 g, 72 mmol). After the reaction mixture was heated at 80° C. for three hours, the solvents were removed under reduced pressure on a rotary evaporator and the residue was diluted with ice water to give crystalline product. This solid was collected by filtration and dissolved in ethyl acetate/methanol, dried over anhydrous sodium sulfate and filtered through charcoal. The solvents were evaporated to give pure product (3.15 g, 77% yield) which was used as is. A small portion was recrystallized from methanol for microanalysis, m.p 210°-213° C.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]([CH3:13])[C:6]([CH2:8][O:9]C(=O)C)=[O:7].C(=O)([O-])[O-].[K+].[K+]>CO.O>[Br:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]([CH3:13])[C:6](=[O:7])[CH2:8][OH:9]
Reactant: CC(=O)OCC(=O)N(C)Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(Cc1ccccc1Br)C(=O)CO
Reaction time: 1.5 h

Procedure:
To a solution of acetic acid [(2-bromo-benzyl)-methyl-carbamoyl]-methyl ester (11.0 g, 36.8 mmol) in methanol (250 mL) is added a solution of potassium carbonate (7.63 g, 55.2 mmol) in water (45 mL). After stirring for 90 minutes the reaction is concentrated to near dryness and then dissolved in dichloromethane. The resulting solution is washed with brine, dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (methanol-dichloromethane, 1:99 to 3:47) to furnish N-(2-bromo-benzyl)-2-hydroxy-N-methyl-acetamide; MS: (ESI) m/z 258.1, 260.1 (M+H)+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][CH:10]1[CH:13]([CH:14]=[CH2:15])[N:12]([Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:11]1=[O:23].[CH2:24]=[O:25]>O1CCCC1>[CH3:9][C:10]1([CH2:24][OH:25])[CH:13]([CH:14]=[CH2:15])[N:12]([Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[C:11]1=[O:23]
Reactant: C=CC1C(C)C(=O)N1[Si](C)(C)C(C)(C)C
Reactant: C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC1N([Si](C)(C)C(C)(C)C)C(=O)C1(C)CO
Reaction time: 0.17 h

Procedure:
To a solution of freshly prepared lithium diisopropylamide (7.82 mmoles) in 36 ml anhydrous tetrahydrofuran under a nitrogen atmosphere at -75° C. is added a solution of 3-methyl-[1-(t-butyldimethylsilyl)-4-vinyl-2-azetidinone], 24, (1.60 g, 7.11 mmoles) in 10 ml anhydrous THF. The resulting yellow solution of the lithium enolate is, after 16 minutes, treated with excess formaldehyde (see Example 15, below). In 10 minutes, the reaction is quenched by adding 30 ml of a saturated aqueous ammonium chloride solution. This mixture is extracted with 50 ml and 25 ml portions of ethyl acetate. The combined ethyl acetate solutions are washed with 50 ml of brine and dried over anhydrous magnesium sulfate. The drying agent is removed by filtrate is evaporated in vacuo to give the crude product as a yellow oil. Purification by chromatography on silica gel eluting with 10% ethyl acetate/chloroform gives 3-methyl-[1-(t-butyldimethylsilyl)-3-(hydroxymethyl)-4-vinyl-2-azetidinone], 25. ##STR40##
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([N:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[CH2:24][OH:25])[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:6].B(O)(O)[C:27]1[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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.O>[OH:25][CH2:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[C:17]1[CH:16]=[C:4]([C:5]([NH:7][CH2:8][C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[O:6])[CH:3]=[C:2]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[CH:18]=1
Reactant: Cc1ccc(CNC(=O)c2cc(Br)cc(N3CCC[C@H]3CO)c2)cn1
Reactant: Cc1ccc(B(O)O)cc1
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: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(N3CCC[C@H]3CO)c2)cc1

Procedure:
To a mixture of (S)-3-bromo-5-(2-(hydroxymethyl)pyrrolidin-1-yl)-N-((6-methylpyridin-3-yl)methyl)benzamide (65 mg, 0.16 mmol), p-tolylboronic acid (24 mg, 0.18 mmol), toluene (4 mL), cesium carbonate (57 mg, 0.18 mmol), and water (0.2 mL) under argon was added tetrakis(triphenylphosphine)palladium(0) (9.2 mg, 0.0080 mmol). The reaction mixture was heated under reflux for 5 h. After cooling, the mixture was filtered through Celite and the filter cake was washed with EtOAc. The filtrate was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 30-80% CH3CN/water [10 mM Et2NH]) to afford a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[C:4]([N:14]2[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]2)[CH:3]=1.[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([NH2:28])[N:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[Cl:20][C:21]1[CH:26]=[C:25]([O:13][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[N:14]2[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]2)[C:9]([F:12])([F:11])[F:10])[N:24]=[C:23]([NH2:28])[N:22]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](O)C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(Cl)nc(N)n2)C(F)(F)F)n1
Temperature: 80 °C

Procedure:
To a solution of (1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethanol (40 g, 138 mmol) in dioxane (400 mL) was added 4,6-dichloropyrimidin-2-amine (113 g, 690 mmol) and Cs2CO3 (132 g, 405 mmol). The mixture was heated for 24 h at 80° C. The reaction was then cooled to RT and filtered. The solvent was removed in vacuo, then CH2Cl2 and heptane was added. The solvent volume was reduced until a solid precipitated out. The solid was filtered and the procedure repeated several times to provide 4-chloro-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]pyrimidin-2-amine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38]Cl.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:34])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: CN(C)CCCCl
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Temperature: 90 °C

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.458 g) is dissolved in DMF (10 mL), and K2CO3 (0.69 g) and 3-dimethylaminopropyl chloride hydrochloride (0.42 g) are added. The reaction mixture is heated to 90° C. for 6 h. Water is added and a dark solid formed, which is isolated by decanting the liquid. Column chromatography (elution with 1-20% MeOH/CHCl3) gave 0.103 g of a solid. Crystallization by dissolving in CH2Cl2 with a few drops of MeOH and adding to a 1:1 solution of pentane/Et2O gave 0.072 g of the title compound as a solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C@@H:18]3[CH:23]4[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]4)[CH2:19]3)=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH:26]([N:29]=[C:30]=[O:31])([CH3:28])[CH3:27]>C1COCC1.CN(C=O)C>[CH:26]([NH:29][C:30](=[O:31])[O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C@@H:18]3[CH:23]4[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]4)[CH2:19]3)=[O:17])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)([CH3:28])[CH3:27]
Reactant: O=C(Nc1ccc(-c2ccc(CO)cc2)cc1)[C@H]1CN2CCC1CC2
Reactant: CC(C)N=C=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)NC(=O)OCc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
35 mg (0.10 mmol) of (3R)-N-[4′-(hydroxymethyl)-1,1′-biphenyl-4-yl]-1-azabicyclo-[2.2.2]octane-3-carboxamide are dissolved in 1 ml of a 1:1 THF/DMF mixture. 17 mg (0.21 mmol) of isopropyl isocyanate are added, and the mixture is stirred at 60° C. overnight. The solvent is removed under reduced pressure, and the crude product is purified by preparative HPLC. 23 mg (52% of theory) of the title compound are obtained.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=[CH:9][C:4]2=[CH:3][CH:2]=1.[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C:24]#[C:25][C:7]2[CH:8]=[CH:9][C:4]3[N:5]([N:1]=[CH:2][CH:3]=3)[CH:6]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Oc1ccc2ccnn2c1)C(F)(F)F
Reactant: C#Cc1ccccc1
Product: C(#Cc1ccc2ccnn2c1)c1ccccc1

Procedure:
The title compound, light yellow solid, MS: m/e=219.2 (M+H+), can be prepared in accordance with the general method of example 1 from trifluoro-methanesulfonic acid pyrazolo[1,5-a]pyridin-6-yl ester (example 33, step 2) and phenylacetylene.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[S:9][CH:10]=[CH:11][C:5]=2[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:1][N:2]2[C:7](=[O:8])[C:6]3[S:9][CH:10]=[CH:11][C:5]=3[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:3]2)=[O:27])=[CH:21][CH:20]=1
Reactant: Nn1nc(-c2ccccc2)c2ccsc2c1=O
Reactant: O=C(O)Cc1ccc(F)cc1
Product: O=C(Cc1ccc(F)cc1)Nn1nc(-c2ccccc2)c2ccsc2c1=O

Procedure:
The product from Example 29B and 2-(4-fluorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.71 (s, 2H) 7.18 (t, J=8.85 Hz, 2H) 7.41 (dd, J=8.54, 5.80 Hz, 2H) 7.48-7.65 (m, 4H) 7.63-7.78 (m, 2H) 8.36 (d, J=5.19 Hz, 1H) 11.80 (s, 1 H); MS (ESI) m/z 380 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12])=[C:5]([N+:15]([O-])=O)[CH:4]=1>C(O)(=O)C.[Zn]>[NH2:15][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)/C=C/c1ccc(OC)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1ccc(OC)cc1N
Temperature: 50 °C
Reaction time: 4 h
Yield: 23.4 %

Procedure:
To a solution of methyl (2E)-3-(4-methoxy-2-nitrophenyl)acrylate (Intermediate 5, 4.9 g, 20.66 mmol) in acetic acid (150 mL) at room temperature under nitrogen was added zinc powder (7.7 g, 118 mmol) in portions. After 4 hours, another 5 g of zinc was added and the resulting reaction mixture was heated at 50° C. for two hours. The reaction mixture was then cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was chromatographed on silica gel with hexanes/ethyl acetate (3:1) to give 1.0 g (23% yield) of product as a yellow solid, mp 149° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][OH:16]>>[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][O:16][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Cc1cccc(CO)c1
Product: Cc1cccc(COc2ccncc2[N+](=O)[O-])c1
Yield: 89.8 %

Procedure:
In accordance with the same procedures as in Preparation 2, except for using 4-chloro-3-nitropyridine prepared in Step 1 of Preparation 1 and 3-methylbenzyl alcohol, the titled compound was obtained as a yellow solid. (Yield: 89.8%)
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][C:12]([CH3:19])([CH2:17]O)[C:13]([O:15][CH3:16])=[O:14].CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1>[CH3:11][C:12]([CH3:19])([CH2:17][O:1][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=[N+]([O-])c1ncccc1O
Reactant: COC(=O)C(C)(C)CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)COc1cccnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.9 %

Procedure:
3-Hydroxynitropyridine (10.0 g, 64 mmol), methyl 2,2-dimethyl-3-hydroxypropionate (9.29 g, 70.4.0 mmol) and PPH3 (15.15 g, 76.8 mmol) were dissolved in dioxane (500 mL). DIAD (14.5 mL, 76.8 mmol) was added at 0° C. over 5 min and the mixture was stirred at rt for 4 h then refluxed overnight. The mixture was evaporated, dissolved in ethyl acetate, washed with water, dried over magnesium sulfate and evaporated in vacuo to afford the title compound (9.1 g, 61%). 1H NMR (300 MHz, DMSO-d6) δ 8.22 (d, J=1.4 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.70 (m, 1H), 4.43 (s, 2H), 3.59 (s, 3H), 1.17 (s, 6H)
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:15][CH2:14]2)=[O:12])=[O:8])=[CH:5][CH:4]=1)#[N:2].[SH2:27]>N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][CH2:10][C:11]([N:13]2[CH2:14][CH2:15][CH:16]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:18]2)=[O:12])=[O:8])=[CH:25][CH:26]=1)(=[S:27])[NH2:2]
Reactant: S
Reactant: COC(=O)COC1CCN(C(=O)CNC(=O)c2ccc(C#N)cc2)CC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COC(=O)COC1CCN(C(=O)CNC(=O)c2ccc(C(N)=S)cc2)CC1
Reaction time: 24 h

Procedure:
A solution of 1.5 g of methyl [[1-[N-(p-cyanbenzoyl)glycyl]-4-piperidinyl]oxy]acetate in 215 ml of pyridine/triethylamine 40:3 is saturated with hydrogen sulphide and left at room temperature for 24 hours. After removing the solvent, the residue is taken up in ethyl acetate and washed with saturated sodium chloride solution. The organic extracts are dried and concentrated. After chromatography of the residue on silica gel with ethyl acetate followed by ethyl acetate/methanol, there are isolated 1.34 g of methyl [[1-[N-[p-(thiocarbamoyl)benzoyl]-glycyl]-4-piperidinyl]oxy]acetate, MS (FAB): 394 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH:8]=O)[CH:4]=[N:3]1.[C:10]([S:14]([NH2:16])=[O:15])([CH3:13])([CH3:12])[CH3:11]>C1COCC1.[Cl-].[Na+].O>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5](/[CH:8]=[N:16]/[S:14]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:15])[CH:4]=[N:3]1
Reactant: CC(C)(C)S(N)=O
Reactant: Cc1c(C=O)cnn1C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(/C=N/S(=O)C(C)(C)C)cnn1C
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of 1,5-dimethyl-1H-pyrazole-4-carbaldehyde (Zhumal Obshchei Khimii 1980, 50, 2370-5, 2.0 g, 16.1 mmol), tert-butylsulfinamide (2.05 g, 16.9 mmol), and Ti(OEt)4 (6.76 ml, 32.2 mmol) in THF (32 ml) was heated under reflux for 18 h under nitrogen. After being cooled to rt, the mixture was poured into brine (32 ml) with stirring. The resulting suspension was filtered through a plug of Celite, and the filter cake was washed with EtOAc. The filtrate was transferred to a separation funnel, and organic layer was washed with brine. Then the aqueous layer was washed with EtOAc and the combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel chromatography (CH2Cl2:MeOH=50:1-30:1) to give the desired product as a white solid (3.55 g, 97% yield). 1H NMR (300 MHz, CDCl3) δ 1.23 (9H, s), 2.52 (3H, s), 3.83 (3H, s), 7.81 (1H, s), 8.49 (1H, s). MS (ESI) m/z 228 (M+H)+
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9](=[O:24])[N:10]([CH2:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Cl:8][C:7]1[CH:6]=[CH:5][N:4]2[C:9](=[O:24])[N:10]([CH2:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[N:11]=[C:3]2[C:2]=1[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(Cl)ccn2c1=O
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
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: Cc1ccccc1
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(Cl)ccn2c1=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 63.5 %

Procedure:
To a suspension of 8-bromo-7-chloro-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (506 mg, 1.2 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (984 mg, 4.8 mmol), and 2.0 M aqueous sodium carbonate (2.6 mL) in toluene (10 mL) was added (Ph3P)4Pd (208 mg, 0.18 mmol) in one portion, and the resulting yellow mixture was vigorously stirred under argon at 100° C. Analysis by HPLC/MS after 2.5 h indicated about 70% of starting 8-bromo-7-chloro-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one remained. Additional (Ph3P)4Pd (60 mg, 0.05 mmol) was added. After stirring for 3 h more, the same amount of catalyst was again added, and the reaction mixture was stirred at 100° C. under argon for 5 h more. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (40 mL×3). The combined EtOAc extracts were washed with water, then saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product, which was purified using a silica gel cartridge (80 g) eluted with a gradient of EtOAc (0-100%) in hexanes to afford the title compound as a white foam (320 mg, 62%). HPLC/MS: retention time=2.14 min, [M+H]+=420.1.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[S:16](Cl)(=[O:18])=[O:17])([CH3:3])[CH3:2].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>>[CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[S:16]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1)(=[O:18])=[O:17])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Reactant: c1ccc2[nH]ccc2c1
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)n2ccc3ccccc32)c(C(C)C)c1
Yield: 88 %

Procedure:
The title compound was prepared from 2,4,6-triisopropyl-benzene sulfonyl chloride and 1H-indole, according to Method A, described above. Yield 88%; mp 131-133° C.; 1H NMR (CDCl3) δ 7.41-7.65 (m, 3H), 7.18-7.28 (m, 4H), 6.65-6.68 (dd, J=8 Hz, 1H), 4.15-4.31 (m, 2H), 2.81-2.97 (m, 1H), 1.28 and 1.29 (2s, 6H), 0.98-1.12 (m, 12H).
Reaction SMILES: [ClH:1].Cl.C(OC([N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([N:37]4[CH2:42][CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39][CH2:38]4)=[O:36])=[CH:30][CH:29]=3)([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[O:17])[CH2:12][CH2:11]1)=O)(C)(C)C.Cl>O1CCOCC1.C1(C)C=CC=CC=1>[ClH:1].[ClH:1].[N:13]1([C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]([N:37]4[CH2:38][CH2:39][NH:40][CH2:41][CH2:42]4)=[O:36])=[CH:32][CH:33]=3)([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[O:17])[CH2:12][CH2:11][NH:10][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccc(C(C)(C)c3ccc(OC(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc2)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)(c1ccc(OC(=O)N2CCNCC2)cc1)c1ccc(OC(=O)N2CCNCC2)cc1

Procedure:
8.3 g of 2,2-bis[4-(4-tert-butoxycarbonyl-1-piperazinylcarbonyloxy)phenyl]propane dihydrochloride are dissolved in 50 ml of abs. dioxane, and 9.5 ml of an approx. 20% solution of hydrogen chloride in dioxane are added to this solution while stirring. The mixture is stirred overnight, after which it is diluted with toluene and the precipitate is filtered off with suction. After drying in vacuo, 5.7 g of the title compound, having a m.p. of from 200° C. (decomposition), are obtained.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][N:8]1[C:16]2[C:15](=[O:17])[N:14]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:13]([C:25]3[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=3)=[N:12][C:11]=2[C:10]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([N:14]2[C:15](=[O:17])[C:16]3[N:8]([CH2:7][C:6]([OH:40])=[O:5])[N:9]=[C:10]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:11]=3[N:12]=[C:13]2[C:25]2[CH:26]=[CH:27][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:29][CH:30]=2)=[CH:23][CH:22]=1
Reactant: CC(C)c1ccc(-c2nc3c(-c4ccccc4)nn(CC(=O)OC(C)(C)C)c3c(=O)n2-c2ccc(Cl)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc(-c2nc3c(-c4ccccc4)nn(CC(=O)O)c3c(=O)n2-c2ccc(Cl)cc2)cc1

Procedure:
To [6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-7-oxo-3-phenyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidin-1-yl]-acetic acid tert-butyl ester (20.0 mg, 0.036 mmol) are added DCM (0.5 mL) and TFA (0.5 mL), The resultant solution is stirred at room temperature for 4 hours. Removal of the solvent under reduced pressure provides crude [6-(4-chlorophenyl)-5-(4-isopropyl-phenyl)-7-oxo-3-phenyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidin-1-yl]-acetic acid, which is used directly for next reaction without further purification.
Reaction SMILES: C(O[CH2:5][C:6]1[C:7]2[N:8]([C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1)(=O)C.[SH:17][C:18]1[NH:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>Br.C(O)(=O)C>[CH3:15][C:13]1[N:14]=[C:7]2[C:6]([CH2:5][S:17][C:18]3[NH:22][C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[N:19]=3)=[CH:11][CH:10]=[CH:9][N:8]2[C:12]=1[CH3:16]
Reactant: CC(=O)OCc1cccn2c(C)c(C)nc12
Reactant: Sc1nc2ccccc2[nH]1
Agent: Br
Solvent: CC(=O)O
Product: Cc1nc2c(CSc3nc4ccccc4[nH]3)cccn2c1C
Temperature: 25 °C
Yield: 106.4 %

Procedure:
A mixture of 2.0 g (12 mmole) of 3-(acetoxymethyl)-2-pyridinamine, 1.7 g (17 mmole) of 3-chloro-2-butanone, and one crystal of potassium iodide was heated at 100° for 4.5 hours. The mixture was allowed to cool and was partitioned between aqueous potassium carbonate and dichloromethane. The organic phase was separated, washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The solid was triturated with diethyl ether and collected by filtration to yield 738 mg of 8-(acetoxymethyl)-2,3-dimethylimidazo[1,2-a]pyridine, as confirmed by the nmr and infrared spectra and by elemental analysis. [Calcd. for C12H14N2O2 : C, 66.04; H, 6.47; N, 12.84. Found: C, 66.01; H, 6.38; N, 13.05.] A mixture of 700 mg (3.2 mmole) of 8-(acetoxymethyl)-2,3-dimethylimidazo[1,2-a]pyridine and 482 mg (3.2 mmole) of 2-mercaptobenzimidazole in 10 ml of 15% hydrogen bromide in acetic acid was heated on a steam bath. After being cooled to room temperature, the mixture was partitioned between 5% aqueous sodium hydroxide and dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated to an oil. Spinning disk chromatography on silica gel (using 1% by volume ethanol-dichloromethane as eluent) yielded 1.05 g of the title compound Structure assignment was supported by the nmr and infrared spectra.