Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])[CH2:4]1)[CH3:2]>[OH-].[OH-].[Pd+2].C(OCC)(=O)C>[CH2:1]([N:3]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1)[CH3:2]
Reactant: CCN1CC[C@H](C(=O)OCc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCN1CC[C@H](C(=O)O)C1
Reaction time: 4 h
Yield: 92 %

Procedure:
A mixture of benzyl (S)-1-ethylpyrrolidine-3-carboxylate (Intermediate 190, 0.563 g), 20% palladium hydroxide on carbon (0.056 g), ethyl acetate (9 mL) and IMS (1 mL) was degassed and hydrogenated for 4 hours. The catalyst was removed by filtration, washed with ethyl acetate and the filtrate was concentrated in vacuo to give (S)-1-ethylpyrrolidine-3-carboxylic acid (0.318 g) as a solid.
Reaction SMILES: C1C(C=O)=CC2OCOC=2C=1.FC1C=CC(C=O)=CC=1.[C-]#N.[K+].[F:24][C:25]1[CH:43]=[CH:42][C:28]([CH:29](O)[C:30](=[O:40])[C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)=[CH:27][CH:26]=1.C1(C(C(C2C=CC=CC=2)O)=O)C=CC=CC=1.[NH:60]1[CH2:66][CH2:65][CH2:64][CH2:63][NH:62][C:61]1=[S:67].[ClH:68]>CC(C)=O.C(O)C>[ClH:68].[F:24][C:25]1[CH:43]=[CH:42][C:28]([CH:29]2[S:67][C:61]3=[N:60][CH2:66][CH2:65][CH2:64][CH2:63][N:62]3[C:30]2([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[OH:40])=[CH:27][CH:26]=1
Reactant: S=C1NCCCCN1
Reactant: O=C(c1ccc2c(c1)OCO2)C(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C(c1ccccc1)C(O)c1ccccc1
Agent: O=Cc1ccc(F)cc1
Solvent: CC(C)=O
Solvent: CCO
Product: OC1(c2ccc3c(c2)OCO3)C(c2ccc(F)cc2)SC2=NCCCCN21

Procedure:
A mixture consisting of 12 g. of piperonal 8.4 ml. of p-fluorobenzaldehyde, 6 g. of potassium cyanide, and 80 ml. of 65% ethanol is reacted as described in Example 20, giving 11.7 g. of 4'-fluoro-3,4-methylenedioxybenzoin as an uncrystallizable oil. 9.0 g. of this benzoin is converted to its methanesulfonate ester by the procedure of Example 20, yielding 9.8 g. of ester as an uncrystallizable oil. The reaction of 4.9 g. of the crude methanesulfonate ester, and 1.16 g. of hexahydro-2H-1,3-diazepin-2-thione in 80 ml. of acetone, followed by treatment with 5 ml of 2 N ethanolic hydrogen chloride gives the title compound melting at 211°-213° C.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].C(Cl)Cl.[CH2:21]([CH:23]1[O:25][CH2:24]1)Cl>[Br-].C([N+](CC)(CC)CC)C>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:21][CH:23]2[CH2:24][O:25]2)=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCC1CO1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccc(OCC2CO2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
4-Hydroxybenzophenone (10.0 g; 50.5 mmol) was dissolved in epichlorohydrine (50 mL). Tetraethylammonium bromide (0.1 g; 0.48 mmol) was added and the reaction mixture was heated to 100° C. for 30 h under reflux. Near quantitative conversion of the starting material was confirmed by TLC. The reaction mixture was cooled to 30° C. and 50% aqueous NaOH (6.06 g, 75.7 mmol) was added dropwise to the vigorously stirred solution. The stirring was continued for a further 3 h at this temperature. The reaction mixture was then poured into methylene chloride (200 mL) and washed with water (3×50 mL). The organic layer was separated, dried over magnesium sulfate, filtered and evaporated to dryness. The crude product was recrystallised from methyl tert-butyl ether to yield 2-(4-benzoylphenoxymethyl)oxirane (10.66 g; 83% yield) as a white crystalline solid.
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].[CH3:17][N:18]1[C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)=[N:21][C:20]([C:31]([F:34])([F:33])[F:32])=[N:19]1>C1(C)C=CC=CC=1>[CH3:16][N:5]1[C:6](=[O:7])[CH:8]([C:11](=[O:13])[NH:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][C:22]3[N:18]([CH3:17])[N:19]=[C:20]([C:31]([F:34])([F:33])[F:32])[N:21]=3)=[CH:25][CH:26]=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: Cn1nc(C(F)(F)F)nc1Oc1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CN1C(=O)C(C(=O)Nc2ccc(Oc3nc(C(F)(F)F)nn3C)cc2)C(=O)N(C)C1=O
Temperature: 25 °C

Procedure:
22.8 g of 1,3-dimethyl-5-ethoxycarbonylbarbituric acid and 25.8 g of 1-methyl-3-trifluoromethyl-5-(4-aminophenoxy)-1H-1,2,4-triazole are heated under reflux in 200 ml of toluene for 4 hours. The crude product, which precipitates on cooling to room temperature, is isolated by filtration, washed with diethyl ether and dried. Yield: 39.2 g (89% of theory). Melting point: 202°-204° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25](OC)=[O:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([CH2:25][OH:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(Cc2c(-c3ccccc3)[nH]c3cc(OC)ccc23)n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(Cc3cccc(CO)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 104.5 %

Procedure:
To a solution of methyl 6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylate (1.2 g) in methanol/tetrahydrofuran (6 mL/6 mL) was added sodium borohydride (305 mg) at room temperature. The mixture was stirred at room temperature for 3.5 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution. The organic layer was separated, washed with a saturated aqueous ammonium chloride solution and saturated brine successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the title compound (1.16 g). 1H-NMR (CDCl3) δ ppm: 3.86 (3H, s), 4.00-4.10 (1H, m), 4.41 (2H, s), 4.70-4.78 (2H, m), 6.76 (1H, dd, J=2.3, 8.8 Hz), 6.91 (1H, d, J=2.3 Hz), 6.96-7.04 (2H, m), 7.31-7.38 (2H, m), 7.39-7.59 (5H, m), 8.05 (1H, br s).
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][C:10]([O:12]C)=O)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[NH:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17]>CO>[OH:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][OH:20])[C:10](=[O:12])[CH2:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: OCCNCCO
Reactant: COC(=O)Cn1ccnc1[N+](=O)[O-]
Solvent: CO
Product: O=C(Cn1ccnc1[N+](=O)[O-])N(CCO)CCO
Temperature: 25 °C
Reaction time: 96 h
Yield: 96.5 %

Procedure:
A mixture of 4.00 g (21.6 mmol) of methyl 2-nitroimidazole-1-acetate and 4.0 g (38.0 mmol) of diethanolamine in 60.0 ml of methanol was stirred four days at room temperature. After removing the excess diethanolamine, the product was dissolved in 10 ml of methanol and chromatographed through a column of silica gel (70-230 mesh). Elution with 10% methanol in methylene chloride afforded 5.38 g (96%) of product as a hard gum that crystallized after several days to a cream colored hygroscopic solid on silica gel with 20% methanol in methylene chloride (Rf 0.47) and analyzed correctly for C9H14N4O5. The solubility of SR-2555 in 0.9% saline solution was over 300 mg/ml.
Reaction SMILES: [NH2:1][C@H:2]([CH3:5])[CH2:3][OH:4].[Cl:6][C:7]1[N:12]=[C:11](Cl)[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][N:8]=1>C(#N)C.C(OC(=O)C)C>[Cl:6][C:7]1[N:12]=[C:11]([NH:1][C@H:2]([CH3:5])[CH2:3][OH:4])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][N:8]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: C[C@@H](N)CO
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@H](CO)Nc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 315 mg (4.2 mmol) of (R)-2-Amino-propan-1-ol in 5 ml of acetonitrile is added slowly to a suspension of 388 mg (2.0 mmol) of 2,4-dichloro-5-nitro-pyrimidine in 20 ml acetonitrile at −30° C. to −20° C. The batch is stirred for 3 hours at −30° C. to −20° C. The batch is diluted with ethylacetate and ice water. The batch is extracted with ethyl acetate (3×). The combined organic phases are washed with NaCl solution, dried (Na2SO4), filtered and concentrated by evaporation. 350 mg (1.51 mmol, corresponding to 76% of theory) of the product is obtained.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[NH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[CH2:23][CH2:22][CH2:21]2>>[CH2:23]1[C:24]2[C:20](=[CH:19][C:18]([NH:17][C:2]3[CH:16]=[CH:15][C:5]4[C:6](=[O:14])[NH:7][C:8]5[C:13]([C:4]=4[CH:3]=3)=[CH:12][CH:11]=[CH:10][N:9]=5)=[CH:26][CH:25]=2)[CH2:21][CH2:22]1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: Nc1ccc2c(c1)CCC2
Product: O=c1[nH]c2ncccc2c2cc(Nc3ccc4c(c3)CCC4)ccc12
Yield: 29.1 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (1000 mg, 0.43 mmol) and 5-aminoindan (87 mg; 0.65 mmol) to provide 247 (41 mg, 26% yield) as a brown solid. LC-MS (M+H (parent)=328, obsd.=328).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])=[O:12])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2=[N:6][CH:7]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[CH:28]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].ClCCl.CO>[OH:16][CH2:15][C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:33][C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)[N:3]=2)[N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=1)=[O:12])([CH3:18])[CH3:17]
Reactant: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Nc1cccnc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3cccnc3)nc12
Temperature: 150 °C
Yield: 17.6 %

Procedure:
A mixture of 2-bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 338 μmol), pyridin-3-amine (47.8 mg, 507 μmol), xantphos (58.7 mg, 101 μmol), Pd2(dba)3 (31.0 mg, 33.8 μmol) and cesium carbonate (220 mg, 677 μmol) in dioxane (2 mL) was heated in a microwave at 150° C. for 20 min. The mixture was cooled then filtered through a pad of celite. The filtrate was concentrated in vacuo then purified by chromatography (silica, 40-100% ethyl acetate in hexanes gradient then dichloromethane/methanol) to give N-(1-hydroxy-2-methylpropan-2-yl)-2-(pyridin-3-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (32 mg, 59.6 μmol, 18%) as a light yellow solid. (EI/CI) m/z: 472.3 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:67]=[CH:66][C:53]2[N:54]=[C:55]([CH:57]([NH2:65])[CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[NH:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:67]=[CH:66][C:53]2[NH:54][C:55]([CH:57]([NH:65][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH:16]=[CH:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CC=CC1
Reactant: NC(Cc1ccccc1)c1nc2ccc(Cl)cc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NC(Cc2ccccc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CC=CC1
Yield: 90 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and rac.-1-(5-chlorobenzimidazol-2-yl)-2-phenylethylamine in tetrahydrofuran. Yield: 90%; Rf value: 0.52 (silica gel; dichloromethane/ethanol=9:1); C28H25ClN4O2 (484.99); mass spectrum: (M+H)+=485/487 (chlorine isotope).
Reaction SMILES: N1C=CC=CC=1.S(Cl)(Cl)=O.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]1[C:20]([OH:22])=O.[NH2:23][CH:24]1[N:30]=[C:29]([C:31]2[C:36]([O:37][CH3:38])=[CH:35][C:34]([CH3:39])=[CH:33][C:32]=2[O:40][CH3:41])[C:28]2[CH:42]=[CH:43][CH:44]=[CH:45][C:27]=2[N:26]([CH3:46])[C:25]1=[O:47]>ClCCl.O>[CH3:38][O:37][C:36]1[CH:35]=[C:34]([CH3:39])[CH:33]=[C:32]([O:40][CH3:41])[C:31]=1[C:29]1[C:28]2[CH:42]=[CH:43][CH:44]=[CH:45][C:27]=2[N:26]([CH3:46])[C:25](=[O:47])[CH:24]([NH:23][C:20]([C:12]2[NH:11][C:19]3[C:14]([CH:13]=2)=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:22])[N:30]=1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: COc1cc(C)cc(OC)c1C1=NC(N)C(=O)N(C)c2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(C)cc(OC)c1C1=NC(NC(=O)c2cc3ccccc3[nH]2)C(=O)N(C)c2ccccc21
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
0.47 ml of pyridine is dissolved in 10 ml of dichloromethane, cooled to -5° C., and 0.68 ml of thionyl chloride is added dropwise, the mixture is stirred for 20 minutes at the same temperature and then 208 mg of indole-2-carboxylic acid are added portionwise with stirring for 30 minutes. 400 mg of 3-amino-1,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-1,4-benzodiazepin-2-one are added portionwise and the reaction mixture is then allowed to return to room temperature and is stirred for 16 hours. Water is added to the reaction mixture and the precipitate formed is filtered off and dried to give white crystals of N-[2,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-1H-2-indolecarboxamide melting with decomposition at 310° C.; Yield=79%.
Reaction SMILES: [CH:1]([O:14][C:15](=[O:32])[C@H:16]([N:23]([C:28](=[O:31])[CH:29]=[CH2:30])[O:24][CH2:25]C=C)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl>[CH:1]([O:14][C:15](=[O:32])[C@H:16]([N:23]1[C:28](=[O:31])[CH:29]=[CH:30][CH2:25][O:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=CCON(C(=O)C=C)[C@@H](C(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)[C@@H](c1ccccc1)N1OCC=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.6 %

Procedure:
Bis(tricyclohexylphosphine)benzylidene ruthenium dichloride (0.11 g, 0.1289 mmol) was weighed directly into a 50 mL flask, placed under a N2 atmosphere, and dry CH2Cl2 (10 mL) was added, followed by a solution of 6g (1.1020 g, 2.5778 mmol) in dry CH2Cl2 (15 mL). The purple reaction mixture was refluxed for 3 h, an additional 0.11 of catalyst was added, and refluxing was continued for another 2 hours. The mixture was then allowed to cool to room temperature and filtered through a short, densely-packed pad of Silica Gel 60H for thin layer chromatography (φ˜3.8 cm, 1˜2 cm), which was washed with CH2Cl2 (5×20 mL). Evaporation gave a brown oil which was purified via column chromatography (5% EtOAc-hexanes→30% EtOAc-hexanes) to afford 0.500 g (50% yield) of 7g as a brown oil. 1H NMR (400 MHz) in CDCl3 (J, Hz): δ 4.3375 (ddd, 1H, NOCHH), 4.6139 (ddd, 1H, NOCHH), 6.0447 (dt, 1H, NOCH2CH═CH), 6.3715 (s, 1H, NCH), 6.7020 (dt, 1H, NOCH2CH), 6.9626 (s, 1H, CHPh2), 7.10-7.40 (m, 15H, ArH). MS (CI, isobutane), m/z: 400 (M++1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@H:29]([CH3:34])[C:30](OC)=[O:31])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[CH3:35][NH2:36]>>[CH3:35][NH:36][C:30](=[O:31])[C@H:29]([O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2)[CH3:34]
Reactant: CN
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Product: CNC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Yield: 86 %

Procedure:
Using the same procedure as in Example 5, methyl (2R)-2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.55 mmol) was reacted with methylamine to give the title compound as a beige solid (213 mg, 86%); NMR Spectrum 1.65 (d, 3H), 2.67 (d, 3H), 5.16 (q, 1H), 5.77 (s, 2H), 6.96 (d, 1H), 7.00 (d, 1H), 7.29 (m, 1H), 7.36 (d, 1H), 7.72 (m, 4H), 8.17 (s, 1H), 8.38 (m, 1H), 8.53 (m, 3H), 10.68 (br s, 1H); Mass spectrum MH+ 454.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][SiH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1>ClCCl>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:11][CH2:12][SiH:13]([Br:1])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: BrBr
Reactant: Fc1ccc(C2CC[SiH2]CC2)cc1
Solvent: ClCCl
Product: Fc1ccc(C2CC[SiH](Br)CC2)cc1

Procedure:
Subsequently, 11.8 g of bromine was added to a solution of 14.0 g of 4-(p-fluorophenyl)-1-silacyclohexane in 100 ml of dichloromethane to obtain 4-(p-fluorophenyl)-1-bromo-1-silacyclohexane. The reaction solution was concentrated and the resultant residue was dissolved in 50 ml of diethyl ether, followed by dropping in 100 ml of a THF solution of 1 mole/liter of n-heptylmagnesium bromide at room temperature. The reaction mixture was poured into 200 ml of 5% hydrochloric acid and extracted with ethyl acetate. The resultant ethyl acetate solution was washed with brine, dried and concentrated, followed by purification through silica gel chromatography to obtain 19.0 g (yield: 90%) of the intended product. The results of IR and NMR analyses are shown below.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[Br:12][C:13]1[C:14]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:15]2[CH:21]=[N:20][NH:19][C:16]2=[N:17][CH:18]=1.[C:28]([O:32][C:33]([NH:35][C@H:36]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1)[C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Br:12][C:13]1[C:14]([N:22]2[CH2:23][CH2:24][N:25]([C:37](=[O:38])[C@H:36]([NH:35][C:33](=[O:34])[O:32][C:28]([CH3:29])([CH3:30])[CH3:31])[CH2:40][C:41]3[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=3)[CH2:26][CH2:27]2)=[C:15]2[CH:21]=[N:20][NH:19][C:16]2=[N:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: Brc1cnc2[nH]ncc2c1N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(Br)cnc3[nH]ncc23)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
DIEA (0.0687 mL, 0.394 mmol) was added to a solution of 5-bromo-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.050 g, 0.0986 mmol, see Example 11), (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.0295 g, 0.099 mmol) and TBTU (0.0380 g, 0.118 mmol) in DCM (1 mL) and stirred at room temperature for 16 hours. The reaction was concentrated to dryness. The resulting residue was dissolved in THF/MeOH (2 mL, 1:1), and an aqueous LiOH solution (1 mL, 2M) was added. The solution was stirred for 30 minutes, and then ether (20 mL) was added. The organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate, 1:1) to give (R)-tert-butyl 1-(4-(5-bromo-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-(4-chlorophenyl)-1-oxopropan-2-ylcarbamate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (R)-2-amino-1-(4-(5-bromo-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-(4-chlorophenyl)propan-1-one dihydrochloride (0.015 g, 29%). MS APCI (+) m/z 463.1 detected.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:23])[CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22].[N:24]1([C:29](N)=[NH:30])C=CC=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]([CH2:2][CH2:3][N:4]([CH3:23])[CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22])[C:29]([NH2:30])=[NH:24]
Reactant: N=C(N)n1cccn1
Reactant: CN(CCN)C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCNC(=N)N)C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 8 h

Procedure:
To a stirred solution of 14e (218 mg, 0.67 mmol) and 1H-pyrazole-1-carboxamidine hydrochloride50 (196 mg, 1.34 mmol) in anhydrous DMF (5 mL) was added DIEA (479 mg, 0.65 mL, 3.7 mmol) under nitrogen at 5° C. Stirring was continued at room temperature overnight. The reaction mixture was concentrated to dryness and the product was purified by column chromatography (silica gel 230-400 mesh, elution with 4:1:0.3 chloroform:methanol:NH4OH). The desired fractions were combined, concentrated, and dried in vacuo to give a white solid: yield 219 mg (89%), MS: m/z 366 (M+H)+; 1HNMR (DMSO-d6) δ 8.34 (s, 1H, H-8), 8.15 (s, 1H, H-2), 7.48, 7.37, 7.28 (bs, NHs), 5.87 (d, 1H, H-1′, J1′,2′=5.2 Hz), 5.50 (d, 1H, 2′-OH, J2′-2′OH=5.7 Hz), 5.28 (d, 1H, 3′-OH, J3′-3′OH=4.5 Hz), 4.65 (ddd, 1H, H-2′, J1′,2′=5.2 Hz, J2′,3′=5.1 Hz, J2′-2′OH=5.7 Hz), 4.12 (ddd, 1H, H-3′, J2′,3′=5.1 Hz, J3′,4′=4.6 Hz, J3′-3′OH=4.5 Hz), 4.0-4.10 (bm, 1H, H-4′), 3.30-3.50 (bm, 2H, 5′-CH2), 3.12-3.28 (bm, 2H, NH—CH2), 2.55-2.65 (bm, 2H, N(CH3)—CH2), 2.25 (bs, 3H, N—CH3); UV λmax, nm, pH 1, 256.3 (∈ 10,900), pH 7, 259 (∈ 11,300), pH 13, 259 (∈ 11,000). Anal. (C14H23N9O3.0.05CHCl3.3.5H2O) C, H, N.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH2:20]O)[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1.S(Cl)([Cl:26])=O>C(Cl)Cl>[Cl:26][CH2:20][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[C:3]([C:2]([F:23])([F:22])[F:1])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Oc2cccc(C(F)(F)F)c2)c(C(F)(F)F)c1
Solvent: ClCCl
Product: FC(F)(F)c1cccc(Oc2ccc(CCl)cc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.7 %

Procedure:
To a suspension of (3-(trifluoromethyl)-4-{[3-(trifluoromethyl)phenyl]oxy}phenyl) methanol (300 mg, 0.892 mmol) in DCM (4 mL) was added thionyl chloride (0.130 mL, 1.784 mmol) dropwise under nitrogen. The mixture was stirred at room temperature for 2 h. The mixture was stirred at room temperature for 2 h. The reaction was quenched with water, adjusted pH about 7 and extracted with DCM. The organic layer was separated and concentrated to afford the crude title compound (430 mg, 0.970 mmol, 109% yield) which can be used in next step directly.