Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[CH3:12].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:20]=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C=O)C>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:20]=[N:21][C:22]([NH:25][C:9](=[O:11])[CH2:8][C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[C:3]([CH3:12])[CH:4]=2)=[CH:23][CH:24]=1
Reactant: Cc1cc(CC(=O)O)cnc1Cl
Reactant: Nc1ccc(-c2ccccn2)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cc(CC(=O)Nc2ccc(-c3ccccn3)cn2)cnc1Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2-(6-chloro-5-methylpyridin-3-yl)acetic acid 74-4 (57 mg, 0.31 mmol), 2,3′-bipyridin-6′-amine 124-1 (51 mg, 0.30 mmol), 1,3-dicyclohexylcarbodiimide (75 mg, 0.36 mmol) and 4-(dimethylamino)pyridine (6 mg, 0.06 mmol) in DMF (1.2 mL) was stirred at room temperature for 10 hours. The reaction mixture was filtered through celite, washed and diluted with ethyl acetate (30 ml) and extracted with water 930 ml×2). The organic phase was dried over Na2SO4 and concentrated by evaporation. The residue was subjected to silica gel column chromatography with ethyl acetate as eluent to give N-(2,3′-bipyridin-6′-yl)-2-(6-chloro-5-methylpyridin-3-yl)acetamide 124-2 as white solid.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7]I)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:13][CH:12]([NH:27][C:28](=[O:50])[C@H:29]([CH2:46][CH:47]([CH3:49])[CH3:48])[C@H:30](CC=C)[C:31]([NH:33]CC2C=C(F)C=C(F)C=2)=[O:32])[C:11]1=[O:51].C([O-])(=O)CCC([O-])=O.CN1C2C=CC=CC=2C(C2C=CC=CC=2)=NC(N)C1=O>>[CH3:9][N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:13][C@H:12]([NH:27][C:28](=[O:50])[C@H:29]([CH2:46][CH:47]([CH3:49])[CH3:48])[C@H:30]([CH2:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:31]([NH2:33])=[O:32])[C:11]1=[O:51]
Reactant: ICCC1CCCC1
Reactant: C=CC[C@H](C(=O)NCc1cc(F)cc(F)c1)[C@@H](CC(C)C)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Agent: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Agent: O=C([O-])CCC(=O)[O-]
Product: CC(C)C[C@@H](C(=O)N[C@H]1N=C(c2ccccc2)c2ccccc2N(C)C1=O)[C@H](CCC1CCCC1)C(N)=O

Procedure:
A procedure analogous to the preparation of Example 5 was followed. The appropriate succinate ester was prepared using the method disclosed in PCT publication WO 98/51665, using 2-(cyclopentyl)ethyl iodide for R3—X in place of allyl bromide (see Scheme 2). The anti-succinate half-ester was coupled to (S)-isomer benzodiazepine (30) using the procedures of Step 1. After Steps 2 and 3, the title compound was isolated. MS (M+H)=475; (M+Na)+=497.2.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=2)=[N:4][CH:3]=1.[CH2:21]([C:23]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.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>[CH2:21]([C:23]1[C:30]([C:2]2[S:6][C:5]([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=3)=[N:4][CH:3]=2)=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])[CH3:22]
Reactant: CCc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1ccc(-c2ncc(Br)s2)cc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Temperature: 130 °C
Yield: 48.3 %

Procedure:
To a solution of 5-bromo-2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3-thiazole (D67) (120 mg), 2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (D5) (77 mg) and tripotassium phosphate (157 mg) in 1,2-dimethoxyethane (DME) (3 mL) and water (0.750 mL) stirred under nitrogen at room temperature was added Pd(Ph3P)4 (34.1 mg) in one charge. The reaction vessel was sealed and heated under microwave at 130° C. for 15 min. After cooling the reaction, the reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (250 mL) and saturated brine (50 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give 2-ethyl-3-{2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}benzaldehyde (D72) (60 mg). MS (ES): C22H20F3NO2S requires 419. found 420.0 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[NH:8][C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([F:29])=[CH:11][N:10]=2)=[O:5])[CH3:2].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[N:8]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([F:29])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2[nH]c1=O
Reactant: BrCc1ccccc1
Product: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2n(Cc2ccccc2)c1=O

Procedure:
This compound was prepared from 6-fluoro-4-[4-(furan-2-carbonyl)-piperazin-1-yl]-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (81) and benzyl bromide according to General Procedure B. Yield 391 mg (47%), MP 119° C.; 1H-NMR (DMSO-d6): δ 1.27 (t, J=7.2 Hz, 3H), 3.15 (m, 4H), 3.92 (m, 4H), 4.29 (q, J=7.2 Hz, 2H), 5.54 (s, 2H), 6.65 (dd, J=1.6, 3.2, Hz, 1H), 7.05 (d, J=3.6 Hz, 1H), 7.20 (m, 5H), 7.87 (d, J=3.2 Hz, 1H), 8.18 (dd, J=2.8, 8.8 Hz, 1H), 8.74 (d, J=2.8 Hz, 1H); EIMS: 505 (M+1). Anal. (C27H25FN4O5) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>CC(O)C>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH3:25])[N:15]=[CH:14][N:13]=[C:12]2[N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: Cc1ccc2c(c1)CCN2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4cc(C)ccc43)c2cc1OC
Yield: 94 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 94% yield from 5-methyl-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 180°-181° C.; GC/MS: 321 (M+); anal. RP18-HPLC RT: 4.37 min.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:9])=[C:6]([CH3:8])[CH:7]=1.O[CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].S(=O)(=O)(O)O.O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([I:9])=[CH:4][C:3]=1[CH2:11][N:12]1[C:16](=[O:17])[C:15]2[C:14](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]1=[O:22]
Reactant: Cc1cc(Br)ccc1I
Reactant: O=C1c2ccccc2C(=O)N1CO
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(Br)c(CN2C(=O)c3ccccc3C2=O)cc1I
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 5-bromo-2-iodo toluene (512 mg, 1.72 mmol) in trifluoroacetic acid (5 mL) was added N-(hydroxymethy) phthalimide (305 mg, 1.72 mmol). The mixture developed a pink color. The solution was stirred at room temperature for 22 hours then concentrated sulfuric acid (1 mL) was added. The homogeneous solution was stirred for 18 hours at room temperature. Water was added and the precipitated solid collected by filtration and dried in a current of air (0.776 gm). This material, which by proton NMR analysis contained approximately 15% of an isomeric product, was carried forward to the following procedure without further purification. 1H NMR (400 MHz, CDCl3) δ7.85 (m, 2H) 7.76(m, 2H) 7.5 (s, 1H) 7.38(s, 1H) 4.84(s, 2H) 2.31(s, 3H).
Reaction SMILES: Cl.Cl.[N:3]1([C:8]2[CH:22]=[CH:21][C:11]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]3)=[O:13])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.C(=O)([O-])[O-].[K+].[K+].O.[C:30]1([CH2:36][CH2:37][C:38](Cl)=[O:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[N:3]1([C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([NH:20][C:38](=[O:39])[CH2:37][CH2:36][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:21][CH:22]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: NC1CCN(C(=O)c2ccc(-n3ccnc3)cc2)CC1
Reactant: O=C(Cl)CCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(CCc1ccccc1)NC1CCN(C(=O)c2ccc(-n3ccnc3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[4-(1H-Imidazol-1-yl)benzoyl]-4-piperidinamine dihydrochloride (4.46 g, 13.0 mmol) and potassium carbonate (6.67 g, 52.0 mmol) are dissolved in methylene chloride (60 mL) and water (30 mL) and the mixture is cooled with an ice bath. A solution of 3-phenylpropionyl chloride (2.72 g, 16.2 mmol) in methylene chloride (15 mL) is added dropwise over 15 min, and the mixture is stirred at room temperature for 2 hr. The phases are separated, and the organic phase is washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and evaporated. Chromatography of the residue on silica gel followed by recrystallization from acetonitrile affords the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH3:11])=[O:9])[CH:3]=1.[Li+].[CH3:13]C([N-]C(C)C)C.CI>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH3:11])=[O:9])[C:3]=1[CH3:13]
Reactant: CC(C)[N-]C(C)C
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CNC(=O)c1nccc(Cl)c1C
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 9.2 %

Procedure:
To a solution of 4-chloro-N-methylpyridine-2-carboxamide (0.700 g, 4.12 mmol) in THF was added LDA (4.12 mL, 2M in THF, 8.24 mmol) dropwise at −78° C. under an atmosphere of argon. The mixture was allowed to stir for 90 min at −78° C. and then methyl iodide (1.51 mL, 24.71 mmol) was added. After stirring for 90 min, the solution was allowed to warm to 0° C. The reaction was quenched at 0° C. with sat. sodium hydrogen sulfite and extracted with EtOAc. The combined organic solutions were washed with water, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give the desired product (0.070 g, 23%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]=[C:4]2[NH:14][CH:15]=[CH:16][C:3]=12.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:17][C:16]1[C:3]2[C:4](=[N:5][CH:6]=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]=2[Cl:1])[NH:14][CH:15]=1
Reactant: Clc1c(-c2ccccc2)cnc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Clc1c(-c2ccccc2)cnc2[nH]cc(Br)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
4-Chloro-5-phenyl-1H-pyrrolo[2,3-b]pyridine (0.912 g, 3.99 mmol) was placed in CHCl3 (5 mL) at room temperature. N-Bromosuccinimide (0.710 g, 3.99 mmol) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was diluted with DCM and washed with saturated NaHCO3. The organic fraction was dried, filtered, and concentrated to give the crude product 3-bromo-4-chloro-5-phenyl-1H-pyrrolo[2,3-b]pyridine (1.1 g, 89.7% yield).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.C(=O)(O)[O-].[Na+].[CH3:35][C:36]1[N:37]([CH2:41][CH2:42][CH2:43][NH2:44])[CH:38]=[CH:39][N:40]=1>C(Cl)Cl>[CH3:35][C:36]1[N:37]([CH2:41][CH2:42][CH2:43][NH:44][C:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=23)=[O:18])[CH:38]=[CH:39][N:40]=1
Reactant: O=C(O)c1cccc2oc(-c3ccccc3)nc12
Reactant: Cc1nccn1CCCN
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nccn1CCCNC(=O)c1cccc2oc(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
A 100-mL one-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 2-phenylbenzoxazole-4-carboxylic acid (0.190 g, 0.79 mmol), DMF (0.588 g, 8.00 mmol) and anhydrous methylene chloride (15 mL). The resulting solution was treated with oxalyl chloride (1.46 g, 11.5 mmol) dropwise over 5 min and stirred at ambient temperature under nitrogen for 2 h. After this time, the reaction mixture was evaporated to a solid residue which was dissolved in anhydrous methylene chloride (15 mL). The resulting solution was treated with sodium bicarbonate (0.672 g, 8.00 mmol) and stirred at ambient temperature under nitrogen for 15 min. After this time, a solution of 3-(2-methylimidazol-1-yl)propylamine (0.332 g, 2.39 mmol) in anhydrous methylene chloride (5 mL) was added and the mixture stirred for a further 20 h. The reaction mixture was then diluted with methylene chloride (50 mL) and washed with 10% aqueous potassium carbonate (10 mL) followed by water (20 mL). The organic phase was dried over sodium sulfate, filtered and evaporated to a solid residue which was further purified by preparative HPLC to give 0.040 g (14% yield) of N-[3-(2-methylimidazol-1-yl)propyl]-2-phenylbenzoxazole-4-carboxamide as a white solid: mp 145-148° C.; 1H NMR (300 MHz, CD3OD) δ 8.33 (m, 2H), 8.03 (dd, J=7.8, 0.9 Hz, 1H), 7.86 (dd, J=8.2, 0.9 Hz, 1H), 7.69-7.59 (m, 4H), 7.52 (t, J=8.0 Hz, 1H), 7.38 (d, J=2.1 Hz, 1H), 4.32 (t, J=7.1 Hz, 2H), 3.67 (t, J=7.1 Hz, 2H), 2.65 (s, 3H), 2.31 (m, 2H); MS (ESI) m/z 361 [M+H]+.
Reaction SMILES: C([N:8]([C@@H](C1C=CC=CC=1)C)[C@@H:9]1[CH2:13][CH2:12][CH2:11][C@:10]1([CH2:18][CH3:19])[C:14]([O:16][CH3:17])=[O:15])C1C=CC=CC=1.C(O)=O>CO.[Pd]>[NH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@:10]1([CH2:18][CH3:19])[C:14]([O:16][CH3:17])=[O:15]
Reactant: CC[C@]1(C(=O)OC)CCC[C@H]1N(Cc1ccccc1)[C@H](C)c1ccccc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CC[C@]1(C(=O)OC)CCC[C@H]1N
Yield: 70.3 %

Procedure:
According to the procedure of Example 53, Step 2, using crude methyl (1S,2R)-2-{benzyl[(1R)-1-phenylethyl]amino}-1-ethylcyclopentanecarboxylate (1.103 g), 4.4% formic acid in methanol (30 mL) and 10% Pd/C (2 g), methyl (1S,2R)-2-amino-1-ethylcyclopentanecarboxylate (441 mg, 2.12 mmol, 21%) was obtained as a colorless solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.78 (t, J=7.45 Hz, 3H) 1.42 (ddd, J=21.10, 7.58, 7.45 Hz, 1H) 1.50-1.78 (m, 5H) 1.92 (ddd, J=21.03, 7.42 Hz, 1H) 2.01-2.12 (m, 1H) 2.16-2.26 (m, 1H) 3.31 (s, 1H) 3.68 (s, 3H) 8.15 (s, 2H).
Reaction SMILES: [C:1]([N:5]1[CH2:25][CH2:24][CH2:23][C:8]2[CH:9]=[C:10]3[C:19]4[CH:18]=[C:17]([Br:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:26])([CH3:4])([CH3:3])[CH3:2].[Br:27]N1C(=O)CCC1=O>CN(C=O)C.O>[C:1]([N:5]1[CH2:25][CH2:24][CH2:23][C:8]2[C:9]([Br:27])=[C:10]3[C:19]4[CH:18]=[C:17]([Br:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2c(cc1Br)-c1cc3c(n1CC2)C(=O)N(C(C)(C)C)CCC3
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1Br)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCC3
Reaction time: 0.25 h
Yield: 94 %

Procedure:
To a solution of 340 mg of 13b in 3 ml of DMF was added in small portions 160 mg of N-bromosuccinimide. After stirring for an additional 15 minutes the reaction mixture was diluted with 3 ml of water and stirred for an additional 15 minutes. The precipitate was filtered and dried, to give 380 mg of 13c, as white crystalline material. Mp: 218-220° C. MS-ESI: [M+1] 495.06, 497.06, 499.08. NMR (CDCl3) δ 1.53 (s, 9, tertC4H9), 1.95 (m, 2, CH2), 2.71 (t, 2, CH2), 2.97 (t, 2, CH2), 3.38 (t, 2, CH2), 4.45 (t, 2, CH2) 6.77, 8.56 (2×s, 2, Ar—H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].Cl[C:24]1[N:29]=[CH:28][N:27]=[C:26]2[NH:30][N:31]=[CH:32][C:25]=12.C(N(C(C)C)CC)(C)C>C(O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([N:13]3[CH2:14][CH2:15][N:16]([C:24]4[N:29]=[CH:28][N:27]=[C:26]5[NH:30][N:31]=[CH:32][C:25]=45)[CH2:17][CH2:18]3)=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:20])[F:21]
Reactant: Clc1ncnc2[nH]ncc12
Reactant: Fc1ccc(-c2cnc(N3CCNCC3)[nH]2)cc1C(F)(F)F
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-c2cnc(N3CCN(c4ncnc5[nH]ncc45)CC3)[nH]2)cc1C(F)(F)F
Yield: 79.7 %

Procedure:
Combine 1-[5-(4-Fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperazine (195 mg, 1.00 equiv; 0.620 mmoles); 4-Chloro-1H-pyrazolo[3,4-d]pyrimidine (1.00 equiv; 0.620 mmoles; 96 mg); isopropyl alcohol (3 mL); diisopropylethylamine (1 mL) and heat in a microwave reactor at 80° C. for 60 min. Evaporate the reaction mixture and purify on silica gel with 5% MeOH/DCM. Combine the fractions to give 213.2 mg (0.494 mmol, 80%) of 4-{4-[5-(4-Fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine. Dissolve the free base in DCM/MeOH and add 1.0 eq 1M HCl in ether. Concentrate the mixture to give 237.2 mg 4-{4-[5-(4-Fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine hydrochloride.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:9][C@H:5]2[O:6][CH2:7][CH2:8][C@@:4]2([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH2:3]1.[CH3:28][O:29][C@H:30]1[C:35](=O)[CH2:34][CH2:33][O:32][CH2:31]1>>[CH3:28][O:29][C@H:30]1[C@@H:35]([NH:1][C@@H:2]2[CH2:9][C@H:5]3[O:6][CH2:7][CH2:8][C@@:4]3([C:10]([N:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:19])[CH2:16][CH2:17]3)=[O:11])[CH2:3]2)[CH2:34][CH2:33][O:32][CH2:31]1
Reactant: N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)C1
Reactant: CO[C@@H]1COCCC1=O
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)C1

Procedure:
The product of Step H was prepared from the reaction of the product of Step G and (R)-3-methoxydihydro-2H-pyran-4(3H)-one (Intermediate 1) following the procedure described in Example 1, Step H. Calculated for C26H37N3O6: 488.3 (M+1). found: 488.1.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]=O)[N:6]=1.[CH3:9][O:10][C:11](=[O:32])[CH:12]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1.O>[CH3:9][O:10][C:11](=[O:32])[CH:12]=[CH:7][C:5]1[N:6]=[C:2]([Br:1])[S:3][CH:4]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1csc(Br)n1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C=Cc1csc(Br)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
Dissolve 2-bromothiazole-4-carbaldehyde (3.00 g, 15.62 mmol) in tetrahydrofuran (52 mL) and add methyl(triphenylphosphoranylidene)acetate (5.33 g. 15.62 mmol). Stir the mixture overnight at room temperature. Dilute the mixture with water and extract twice using diethyl ether. Dry the combined organics over sodium sulfate, filter, and concentrate. Purify via silica gel chromatography using a 0-30% gradient of EtOAc/hexanes to give 3.13 g (81%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][C:4]=1[OH:11].[H-].[Na+].FC(F)(F)S(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[O:11][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:9]=[O:10]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COc1cc(C=O)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCC(F)(F)F
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
To a solution of 3.96 g of vaniline (e-1) (26.0 mmol) in 26 ml of dry DMF was added 1.04 g of 60% NaH (26.0 mmol) slowly, and the mixture was stirred for 30 min. in a stream of nitrogen. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (6.64 g: 28.6 mmol) was added dropwise to the mixture and stirred overnight at room temperature. The reaction solution was poured into water and extracted with ether. The ether layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluting with benzene-AcOEt to give 5.98 g of the objective compound 3-methoxy-4-(2,2,2-trifluoroethoxy)benzaldehyde (f-1) (Yield: 98.2%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][CH:5]([F:35])[C:6]([N:8]1[C@@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27]OS(C)(=O)=O)=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:34])[CH3:33])=[O:7]>>[CH3:1][N:2]([CH2:27][C:24]1[N:25]=[CH:26][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C@H:11]3[O:10][C:9]([CH3:34])([CH3:33])[N:8]([C:6](=[O:7])[CH:5]([F:35])[F:4])[C@@H:12]3[CH2:13][F:14])=[CH:16][CH:17]=2)=[CH:22][CH:23]=1)[CH3:3]
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(COS(C)(=O)=O)nc3)cc2)[C@H](CF)N1C(=O)C(F)F
Reactant: CNC
Product: CN(C)Cc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 610.1 %

Procedure:
To a stirred solution of dimethyl amine (2.0M solution in tetrahydrofuran) (0.31 mL, 0.028 mmol) in tetradhyrofuran (5 mL) is added methanesulfonic acid 5-{4-[(4R,5R)-3-(2,2-difluoro-acetyl)-4-fluoromethyl-2,2-dimethyl-oxazolidin-5-yl]-phenyl}-pyridin-2-ylmethyl ester (0.1 g, 0.212 mmol) and stirred at room temperature overnight. The solvent is evaporated in vacuo and the crude material is purified by combi-flash chromatography using 10% methanol in CH2Cl2 as an eluent to afford the title compound (0.072 g). 1H-NMR (400 MHz, DMSO-d6) δ: 1.53 (s, 3H), 1.60 (S, 3H), 2.21 (s, 6H), 3.56 (s, 2H), 4.56-4.58 (m, 0.5H), 4.66-4.72 (m, 1H), 4.80-4.84 (m, 0.5H), 4.90-4.94 (m, 1H), 5.26 (d, J=3.76 Hz, 1H), 6.64 (t, J=52.36 Hz, 1H), 7.50 (d, J=8.08 Hz, 1H), 7.59 (d, J=8.08 Hz, 2H), 7.78 (d, J=8.12 Hz, 2H), 8.07-8.09 (m, 1H), 8.81 (s, 1H). LC-MS (m/z): [M+H]=422.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:18][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccccc1-c1ccc(C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Yield: 59.6 %

Procedure:
2.0 g (8.8 mmol) of methyl 2-(4'-methylphenyl)benzoate, 1.6 g (9.0 mmol) of N-bromosuccinimide and 0.05 g of α,α'-azobis(isobutyronitrile) [another name; 2,2'-azobis(isobutyronitrile)] were dissolved in carbon tetrachloride (110 ml), followed by heating under reflux for 2 hours. The resultant mixture was filtered to remove insolubles, and then vacuum concentration was effected. The residue was recrystallized from a n-hexane/isopropyl ether mixed solvent to give 1.6 g of the title compound (yield; 59%).