Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[C:5]([NH2:6])=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.[C:17](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[Br:1][C:2]1[CH:8]=[C:7]([O:9][C:10]([F:11])([F:13])[F:12])[C:5]([NH:6][CH3:17])=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1
Reactant: Nc1c(OC(F)(F)F)cc(Br)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNc1c(OC(F)(F)F)cc(Br)cc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
A solution of 4-bromo-2-nitro-6-(trifluoromethoxy)aniline (1.962 g, 6.52 mmol, commercially available from, for example, Apollo Scientific) in N,N-dimethylformamide (DMF) (80 mL) was cooled with an ice/water bath to ˜0° C. for 10 min. Cesium carbonate (4.25 g, 13.04 mmol) was then added and stirred, and the colour changed from yellow to red. After 10 min, methyl iodide (0.408 mL, 6.52 mmol) was added and the mixture was allowed to return to rt with stirring under nitrogen for 3 h. LCMS showed 90% conversion to the desired product with no starting material remaining, and ˜10% formation of an impurity. The reaction mixture was partitioned using water (400 mL) and EtOAc (400 mL), and the aqueous layer re-extracted with EtOAc (2×400 mL). The combined organics were backwashed with water (400 mL) and then passed through a hydrophobic frit and concentrated in vacuo to give the crude product as a yellow oil. The sample was loaded in dichloromethane and purified on silica (Si) (100 g) using 100% cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the required product (1.368 g, 67%) as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]([C:14]2[C:18]3[N:19]=[C:20](Cl)[N:21]=[CH:22][C:17]=3[S:16][CH:15]=2)=[O:13])=[N:7][C:8]=1[O:9][CH3:10].[C@@H:24]1([NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH2:30].O.ClCCl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]([C:14]2[C:18]3[N:19]=[C:20]([NH:30][C@@H:25]4[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]4[NH2:31])[N:21]=[CH:22][C:17]=3[S:16][CH:15]=2)=[O:13])=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(NC(=O)c2csc3cnc(Cl)nc23)nc1OC
Reactant: N[C@@H]1CCCC[C@@H]1N
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(NC(=O)c2csc3cnc(N[C@@H]4CCCC[C@@H]4N)nc23)nc1OC
Yield: 48.1 %

Procedure:
To a solution of 0.0817 g (0.233 mmole) 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid (5,6-dimethoxy-pyridin-2-yl)-amide in 2.33 mL of dioxane was added 0.168 mL (1.4 mmole) of cis-cyclohexane-1,2-diamine. The mixture was heated at 100 degrees for over night. Water and dichloromethane were added, separated. The aqueous layer was washed with dichloromethane twice. The organic layer was washed with aqueous sodium carbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-0.7 N ammonia solution in methanol (gradient 100:0-90:10) gave 0.048 g of 2-(cis-2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic acid (5,6-dimethoxy-pyridin-2-yl)-amide as a light yellow solid. MH+/Z=429.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].C(O[C:9](=[O:26])[CH2:10][CH:11]([OH:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])C.[CH2:27](Br)[CH:28]=[CH2:29].[Cl-].[NH4+]>C1COCC1>[CH2:1]([C:9]([OH:26])([CH2:10][CH:11]([OH:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:29][CH:28]=[CH2:27])[CH:2]=[CH2:3]
Reactant: CCCCCCCCCCCCCC(O)CC(=O)OCC
Reactant: C=CCBr
Reactant: C=CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC(O)(CC=C)CC(O)CCCCCCCCCCCCC

Procedure:
To a small amount of freshly prepared allyl magnesium bromide and 1.7 g of Mg (0.07 mole) covered with THF was added a solution of 3.7 g of 3-hydroxyhexadecanoic acid ethyl ester (0.0123 mole) and 6.05 g (0.05 mole) of allyl bromide in 100 ml of THF. The addition proceeded so as to maintain a reflux temperature. The mixture was heated at refluxing temperature for 1 hr., cooled, and poured into saturated aq. ammonium chloride solution. The mixture was extracted with ether and the ether solution was dried over MgSO4 and distilled to dryness. The crude product weighed 5.0 g and could be used without further purification. The product could be purified by column chromatography on silica gel using ethyl acetate-hexane (15:85) as the eluant; δ (CDCl3), 1.28(CH2), 4.90-5.25(m, =CH2) and 5.4-6.2(m,=CH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[CH2:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH3:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:28]([CH2:26][CH3:27])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Reactant: CCNc1ccccn1
Product: CCN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2Cl)cc1)c1ccccn1
Yield: 64 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzenesulfonamide (Intermediate 8), and 2-(ethylamino)-pyridine, the title compound was isolated as a yellow solid in 64% yield (96% purity by HPLC).
Reaction SMILES: [OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O.[NH2:17][C:18](=O)[C@@H:19]([NH:38][C:39]([C@@H:41]1[CH2:46][CH2:45][CH2:44][CH2:43][N:42]1[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:40])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]3[O:34][C:33](=[O:35])[N:32]([CH3:36])[C:31]=3[CH:37]=2)=[CH:23][CH:22]=1.C(N(CC)CC)C.O>ClCCl>[C:18]([C@@H:19]([NH:38][C:39]([C@@H:41]1[CH2:46][CH2:45][CH2:44][CH2:43][N:42]1[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:40])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]3[O:34][C:33](=[O:35])[N:32]([CH3:36])[C:31]=3[CH:37]=2)=[CH:23][CH:22]=1)#[N:17]
Reactant: Cn1c(=O)oc2ccc(-c3ccc(C[C@H](NC(=O)[C@@H]4CCCCN4C(=O)OC(C)(C)C)C(N)=O)cc3)cc21
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1c(=O)oc2ccc(-c3ccc(C[C@@H](C#N)NC(=O)[C@@H]4CCCCN4C(=O)OC(C)(C)C)cc3)cc21
Reaction time: 3 h
Yield: 75.1 %

Procedure:
(Methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt (137 mg) was added to a solution of (S)-tert-butyl 2-((S)-1-amino-3-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)-1-oxopropan-2-ylcarbamoyl)piperidine-1-carboxylate (120 mg) and triethylamine (0.128 ml) in dichloromethane (1 mL) and stirred for 3 h. Water was added and the mixture was extracted with DCM (3 times). The organic layers were dried over (magnesium sulfate), evaporated and purified by flash silica chromatography eluting with acetone 1:2 isohexane/acetone to give the subtitle compound (87 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([CH3:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>CN(C)C=O.C(Cl)Cl>[CH3:1][C:2]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([CH3:13])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C(=O)O)c(C)c(C)c1C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Cl)c(C)c(C)c1C
Reaction time: 3.5 h
Yield: 142.8 %

Procedure:
A 3 L 3-necked flask is equipped with a condenser, argon inlet, thermowell, magnetic stirrer. The flask is purged with argon then charged with 2,3,4,5-tetramethylbenzoic acid (138.3 g, 0.776 mol), methylene chloride (1.5 L), thionyl chloride (73.5 mL, 1.01 mol) and N, N-dimethylformamide (2.0 mL, 0.026 mol). The resulting suspension is heated to reflux, after a clear solution is formed, heating is continued for 3.5 hours. The solution is allowed to cool then concentrated in vacuo. Last traces of thionyl chloride are removed by co-distillation with toluene (2×100 mL). The remaining oil is dried under high vacuum then used without further purification. Additional reactions are carded out to produce a total of 218 g of 2,3,4,5-tetramethylbenzoyl chloride.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=1)[C:12]([C:14]1[CH:22]=[C:21]2[C:17](/[C:18](=[CH:24]/O)/[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[CH2:37][CH2:36]1>CCOC(C)=O>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=1)[C:12]([C:14]1[CH:22]=[C:21]2[C:17](/[C:18](=[CH:24]/[NH:47][C:44]3[CH:45]=[CH:46][C:41]([N:38]4[CH2:37][CH2:36][N:35]([CH3:34])[CH2:40][CH2:39]4)=[CH:42][CH:43]=3)/[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: O=C1Nc2cc(C(=O)c3cccc(NCc4ccccc4)c3)ccc2/C1=C/O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(N/C=C3\C(=O)Nc4cc(C(=O)c5cccc(NCc6ccccc6)c5)ccc43)cc2)CC1
Temperature: 65 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
A small screw cap test tube was charged with 6-(3-Benzylamino-benzoyl)-3-[1-hydroxy-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one (prepared below, 0.021 g, 0.056 mmol) and THF (1 mL). To the resulting solution was added 4-(4-Methyl-piperazin-1-yl)-phenylamine (10.7 mg, 0.056 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature. The yellow solid was dissolved in 5 mL of a solvent mixture containing 98% EtOAc/2% i-prOH and washed with water (2×5 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was chromatographed over silica (95/5 chloroform/Hexanes w/0.5% NEt3) to afford the title compound in 51% yield (15.5 mg, 0.028 mmol).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[S:21][C:20]([C:22]([OH:24])=O)=[CH:19][C:9]=3[N:10]=[C:11](C3C=NC=CC=3)[N:12]=2)[CH2:3][CH2:2]1.ON1C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)O.C(N(CC)C(C)C)(C)C.[Cl-:59].[NH4+:60]>CN(C=O)C.CCOC(C)=O>[Cl:59][C:11]1[N:12]=[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[C:8]2[S:21][C:20]([C:22]([NH2:60])=[O:24])=[CH:19][C:9]=2[N:10]=1
Reactant: O=C(O)c1cc2nc(-c3cccnc3)nc(N3CCOCC3)c2s1
Reactant: [Cl-]
Reactant: [NH4+]
Agent: CN(C)C(O)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a mixture of 4-morpholino-2-(pyridine-3-yl)thieno[3,2-d]pyrimidine-6-carboxylic acid (610 mg, 2.04 mmol), 1-hydroxy-7-azabenzotriazole (56 mg, 0.4 mmol), O-(7-azabenzotriazol-1-yl)-(N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU; 1.2 g, 3.1 mmol), and N,N-diisopropylethylamine (1.4 mL, 8.1 mmol) in DMF (3 mL) was added ammonium chloride (330 mg, 6.1 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine. The aqueous layer was extracted with EtOAc. The combined organics were washed with saturated NaHCO3 and brine then dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-20% MeOH in CH2Cl2) to afford 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carboxamide (490 mg, 81% yield).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].[CH2:10]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:11]#[CH:12].C(N(CC)CC)C>C1(C)C=CC=CC=1.O>[O:16]1[CH2:17][CH2:18][N:13]([CH2:10][C:11]2[O:8][N:7]=[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:12]=2)[CH2:14][CH2:15]1
Reactant: C#CCN1CCOCC1
Reactant: CCOC(=O)/C(Cl)=N\O
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(CN2CCOCC2)on1

Procedure:
To the solution of ethyl chlorooximidoacetate (0.588 g, 3.88 mmol) and 4-(prop-2-ynyl)morpholine (0.971 g, 7.76 mmol) in toluene (5 mL) was added solution of triethylamine (0.54 mL, 3.88 mmol) in toluene (5 mL) dropwise. The resultant mixture was stirred at RT for 5 h. After the completion of the reaction as evidenced by LC-MS, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic solvent was then dried over anhydrous sodium sulfate and evaporated. The crude product was purified by Combiflash (Heptane:EtOAc eluent). Yield 0.2 g. 1H NMR (400 MHz; MeOD): δ 1.38 (t, 3H), 2.53 (m, 4H), 3.69 (m, 4H), 3.78 (d, 2H), 4.41 (q, 2H), 6.73 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14](=[O:15])[CH2:13][C:12](C)(C)[CH2:11][C:10]1=[O:18].[C:19](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:19][O:18][C:10]1[CH2:11][CH2:12][CH2:13][C:14](=[O:15])[C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C2C(=O)CC(C)(C)CC2=O)c(C)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC1=C(c2ccc(C)cc2C)C(=O)CCC1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A solution of 10.00 g (0.0409 mol) of 2-(2',4'-dimethylphenyl)-5,5-dimethyl-1,3-cyclohexanedione, 21.42 g (0.155 mol) of anhydrous potassium carbonate, 17.59 g (0.124 mol) iodomethane, and 500 ml of anhydrous acetone was refluxed overnight. The reaction mixture was then cooled to room temperature, filtered, and the acetone removed. The residual solid was taken up in 250 ml of CH2Cl2, washed with water, 0.25 N NaOH, 1 N HCl, and water again. The solution was dried (MgSO4) and the solvent removed. The resulting solid was recrystallized from isopropyl ether to give 7.60 g (72% yield) of a white crystalline solid, m.p. 122°-23° C. The compound prepared by the above synthesis has the following structure: ##STR27##
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:12]([NH:14][C@H:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=1)[CH3:16])=[O:13].O[Li:31].O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:12]([NH:14][C@H:15]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([O-:23])=[O:22])=[CH:25][CH:26]=1)[CH3:16])=[O:13].[Li+:31]
Reactant: [Li]O
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)C2CCCCN2Cc2cccc(C)c2)cc1
Solvent: O
Product: Cc1cccc(CN2CCCCC2C(=O)N[C@@H](C)c2ccc(C(=O)[O-])cc2)c1
Product: [Li+]

Procedure:
The title compound E2 (60 mg) was prepared according to the general procedure for esters hydrolysis starting from methyl 4-((1S)-1-(1-(3-methylbenzyl)piperidine-2-carboxamido)ethyl)benzoate (D19) (42 mg). (LiOH H2O: 1.75 eq; reaction time: 3 hrs)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2N=CN=C(NNC(OC(Cl)(Cl)Cl)=O)C=2C2C=CC=CC=2)=CC=1.Cl[CH2:53][C:54]1[CH:55]=[CH:56][C:57]([C:60]([F:63])([F:62])[F:61])=[N:58][CH:59]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[CH:12][N:11]3[C:14](=[O:17])[N:15]([CH2:53][C:54]4[CH:59]=[N:58][C:57]([C:60]([F:63])([F:61])[F:62])=[CH:56][CH:55]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]nc2c(-c3ccccc3)c(-c3ccc(Cl)cc3)ncn12
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: O=C(NNc1ncnc(-c2ccc(Cl)cc2)c1-c1ccccc1)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(-c3ccccc3)c(-c3ccc(Cl)cc3)ncn12
Temperature: 60 °C

Procedure:
To a stirred solution of 7-(4-chlorophenyl)-8-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one and/or trichloromethyl 2-(6-(4-chlorophenyl)-5-phenylpyrimidin-4-yl)hydrazinecarboxylate (32.2 mg, 0.10 mmol) in DMF (2 mL) at room temperature under argon was added 5-(chloromethyl)-2-(trifluoromethyl)pyridine (29.4 mg, 0.15 mmol), followed by K2CO3 (27.6 mg, 0.20 mmol). The resulting mixture was heated at 60° C. for 1 h. The crude product was purified by silica gel column chromatography eluted with ethyl acetate-hexanes, then lyophilized from 1,4-dioxane, to obtain the title compound (18.3 mg) as an off-white lyophilate. HPLC/MS: retention time=3.90 min, [M+H]30 =482. 1H NMR (CDCl3): δ 8.80 (d, J=1.5 Hz, 1H), 8.70 (s, 1H), 7.94 (dd, J=7.9, 1.5 Hz, 1H), 7.69 (d, J=7.9 Hz, 2H), 7.28-7.47 (m, 7H), 7.20 (d, J=7.2 Hz, 2H), 5.22 (s, 2H). N-alkylation, rather than O-alkylation, was demonstrated by the presence of a 13C NMR resonance at 46.8 ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]2=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][N:4]2[N:3]=1.CCN(C(C)C)C(C)C.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]2[CH2:33][NH:34][CH2:35][C:28]=12>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:34]2[CH2:33][C:29]3[C:28](=[N:27][CH:32]=[CH:31][CH:30]=3)[CH2:35]2)[C:5]2=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][N:4]2[N:3]=1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)ccn2n1
Reactant: c1cnc2c(c1)CNC2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Clc1nc(N2Cc3cccnc3C2)c2c(-c3ccccc3)ccn2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.1 %

Procedure:
2,4-Dichloro-5-phenylpyrrolo[2,1-f][1,2,4]triazine (50.0 mg, 0.189 mmol) was dissolved in THF (3 mL) and then DIPEA (0.0990 mL, 0.568 mmol) was added, followed by the addition of 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (0.0270 g, 0.227 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure and water (5 mL) was added to the resulting residue. The aqueous solution was extracted with EtOAc (2×25 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by CombiFlash (REDISEP®, silica gel, 12 g, 30% EA/petroleum ether) to afford 2-chloro-5-phenyl-4-(5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)pyrrolo[2,1-f][1,2,4]triazine (29.0 mg, 44.0%) as a brown solid. LCMS Condition B-79: retention time 1.70 min, [M+1]=348.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.38 (br s, 2H), 4.84 (br s, 2H), 6.80 (d, J=2.8 Hz, 1H), 7.25 (dd, J=7.7 Hz, J=4.9 Hz, 1H), 7.35-7.54 (m, 5H), 7.64 (br s, 1H), 7.90 (d, J=2.7 Hz, 1H), 8.34 (d, J=4.3 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:10]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH:17]=[O:18].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[N:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[C:3]=2[CH:17]=[O:18])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=Cc1c(Cl)n(-c2cccnc2)c2ncccc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3cccnc3n2-c2cccnc2)CC1
Temperature: 95 °C
Yield: 85 %

Procedure:
A solution of 2-chloro-1-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (46 mg, 0.179 mmol) in 1,4-dioxane (4 mL) is treated with piperazine-1-carboxylic acid tert-butyl ester (157 mg, 0.843 mmol) and the resulting yellow solution is heated-to 95° C. under a reflux condenser for 29 hours. The reaction mixture is evaporated to give a red oil. The residue is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (3:1, increasing to 2:1 to 1:1). Fractions containing the product are combined and the solvent evaporated to give 62 mg of 4-(3-formyl-1-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester as a orange waxy solid (85% yield). MS: m/e 408 (M+H), 430 (M+Na). 1H NMR (300 MHz, CDCl3): 10.29 (1H, s), 8.78 (1H, d), 8.74 (1H, dd), 8.50 (1H, d), 8.20 (1H, dd), 7.94 (1H, dm), 7.59 (1H, dd), 7.22 (1H, dd), 3.39-3.28 (8H, m), 1.46 (9H, s).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[CH:13]([Si:15]([CH3:18])([Cl:17])[Cl:16])Cl.O=P(Cl)(Cl)Cl>[Cl-].[Al+3].[Cl-].[Cl-].CCCCCC>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:13]([Si:15]([CH3:18])([Cl:17])[Cl:16])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[F:5]
Reactant: Fc1ccccc1
Reactant: C[Si](Cl)(Cl)C(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Product: C[Si](Cl)(Cl)C(c1ccccc1F)c1ccccc1F
Reaction time: 1 h
Yield: 65.5 %

Procedure:
In a 100 ml, three-necked, frame dried, round bottom flask, aluminum chloride 1.679 (12.5 mmol), fluorobenzene 37.93 ml (404 mmol), and (dichloromethyl)methyldichlorosilane 7.08 ml (50.5 mmol) were reacted for 2 hours as in EXAMPLE 1. The aluminum chloride catalyst was quenched with POCl3 1.15 ml (12.5 mmol) and then stirred for another 1 hour to complete the deactivation. Freshly distilled hexane (50 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic solution. After hexane and fluorobenzene were distilled, the reaction products were vacuum distilled to give 10.49 g of [bis(fluorophenyl)methyl]methyldichlorosilane as a mixture of isomers (bp; 103° C./0.2 torr, yield; 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:25][O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:25][O:26][C:27](=[O:28])[C:29]1[CH:34]=[CH:33][C:32]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:24])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)[C:11]([F:13])([F:14])[F:12])=[C:2]([Cl:1])[CH:7]=2)=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.7 %

Procedure:
To a solution of 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (64 mg) in CH2Cl2 (1.5 ml) were added 4-methoxycarbonylphenyl-boronic acid (96 mg), copper-(II)-acetate (96 mg), molecular sieve and pyridine (70 mg). The mixture was stirred at room temperature under an air atmosphere with exclusion of moisture for 18 hours. The mixture was filtered, diluted with CH2Cl2 and washed with 1 M HCl. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 4:1=>0:1) to give the title compound (91 mg) as a colorless foam. MS (m/e, ISP neg. ion)=494.1 [M−H+].
Reaction SMILES: [Br:1][CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[O:4].[CH2:13]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CO>C(O)C>[Br-:1].[CH2:13]([C:20]1[CH:25]=[CH:24][N+:23]([CH:2]([C:3]([C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=2)=[O:4])[CH3:12])=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(Br)C(=O)c1ccc(O)cc1
Reactant: c1ccc(Cc2ccncc2)cc1
Solvent: CCO
Solvent: CO
Product: CC(C(=O)c1ccc(O)cc1)[n+]1ccc(Cc2ccccc2)cc1
Product: [Br-]

Procedure:
In the condensation step, the condensation reaction between 2-bromo-4'-hydroxypropiophenone and 4-benzylpyridine is smoothly promoted in the presence of methanol and/or ethanol whereby a ketone compound of the general formula: ##STR2## i.e. 4-benzyl-1-[1-(4-hydroxyphenylcarbonyl)ethyl]-pyridinium bromide is formed in the reaction mixture. The time and the temperature adopted for the condensation reaction are usually 3-6 hours and 60°-90° C., respectively. The reaction mixture thus obtained is directly subjected as such, without isolating the above condensation product, to the catalytic reduction in the subsequent step. In this case, an additional amount of methanol and/or ethanol may be supplied to the reaction mixture.