Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:23])=[C:4]([NH:10][C:11]([N:13]2[CH2:17][C@H:16]([OH:18])[CH2:15][C@H:14]2[C:19]([O:21][CH3:22])=[O:20])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].COC([C@@H]1[C@@H](O[Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])CCN1C(NC1C=CC(C#N)=C(Cl)C=1C)=O)=O>>[Cl:1][C:2]1[C:3]([CH3:23])=[C:4]([NH:10][C:11]([N:13]2[CH2:17][C@H:16]([O:18][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:15][C@H:14]2[C:19]([O:21][CH3:22])=[O:20])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COC(=O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)Nc1ccc(C#N)c(Cl)c1C
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)Nc1ccc(C#N)c(Cl)c1C
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)Nc1ccc(C#N)c(Cl)c1C

Procedure:
The title compound was prepared from compound 56B (150 mg, 0.44 mmol) in a manner analogous to that described for compound 55B to afford a white solid (156.3 mg, 79%), mp 129-131° C. HPLC: 3.38 min (retention time) (Conditions: YMC S-5 C-18 (4.6×250 mm), eluting with 0-100% B, 4 min gradient. (A=90% H2O-10% CH3CN-0.1% TFA and B=10% H2O-90% CH3CN-0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm. Chiral HPLC: retention time=9.80 min (99.9%); Conditions: AD (4.6×250 mm); Eluted with 20% isopropanol in heptane for 30 min at 1 mL/min. MS (ES) m/z 452 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[F:5][C:6]([F:18])([F:17])[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=O.[C:19](#[N:21])C>>[F:5][C:6]([F:18])([F:17])[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[CH2:11][N:3]1[CH2:2][CH2:1][N:4]([CH2:11][C:10]2[CH:14]=[CH:15][CH:16]=[C:8]([O:7][C:6]([F:5])([F:17])[F:18])[CH:9]=2)[C:19]1=[NH:21]
Reactant: NCCN
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Reactant: CC#N
Product: N=C1N(Cc2cccc(OC(F)(F)F)c2)CCN1Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared in three steps as described in Procedure D. In the first step, ethylenediamine was reacted in acetonitrile with 3-(trifluoromethoxy)benzoylchloride (2 eq) in the presence of TEA to give the N,N′-dibenzoylated ethylenediamine upon aqueous work-up. After the last step (reaction with cyanogen bromide), the crude product was isolated upon aqueous work-up, recrystallized from diethyl ether and the title compound isolated as the hydrogen bromide salt. MS (ES+) m/z 434 ([M+1]+, 100); HR-MS: 434.1299 ([M+1]+, C19H18F6N3O2; calc. 434.13032).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.C1C(=O)N([Br:16])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][Br:16])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)cn1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(Br)cn1
Temperature: 50 °C

Procedure:
To a mixture of 5-bromo-2-methylpyridine (46.5 g, 0.27 mol) in CCl4 (800 mL) was added NBS (53 g, 0.297 mol) and benzoylperoxide (4.7 g) and refluxed for 2 h in presence of light. The reaction mixture was cooled to 50° C. and filtered off the solid succinimide. The filtrate was concentrated and the crude 5-bromo-2-bromomethylpyridine was used for next reaction.
Reaction SMILES: [CH:1]([C:4]1[S:22][C:7]2[NH:8][C:9](=[O:21])[N:10]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:11](=[O:12])[C:6]=2[CH:5]=1)([CH3:3])[CH3:2].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[N:41]=[C:40](C(Cl)(Cl)Cl)[O:39][N:38]=2)=[CH:27][CH:26]=1.C(=O)([O-])[O-:47].[K+].[K+]>C(#N)C>[CH:1]([C:4]1[S:22][C:7]2[N:8]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:47])[O:39][N:38]=4)=[CH:27][CH:26]=3)[C:9](=[O:21])[N:10]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:11](=[O:12])[C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: CC(C)c1cc2c(=O)n(CCN3CCOCC3)c(=O)[nH]c2s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)c1cc2c(=O)n(CCN3CCOCC3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
A mixture of 6-isopropyl-3-(2-morpholin-4-ylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.5 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.83 g), potassium carbonate (0.43 g) and acetonitrile (20 mL) was stirred at room temperature for 2 hr. Insoluble material was filtered off, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (4 mL) and methanol (4 mL). 1N Aqueous sodium hydroxide solution (4 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 4 with water and 1N hydrochloric acid, and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.46 g, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][N:18]([C:21](Cl)=[O:22])[CH2:17][CH2:16]1.[F:24][CH:25]([F:34])[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:24][CH:25]([F:34])[O:26][C:27]1[CH:28]=[CH:29][C:30]([NH:31][C:21]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:22])=[CH:32][CH:33]=1
Reactant: COc1cc2ncnc(C3CCN(C(=O)Cl)CC3)c2cc1OC
Reactant: Nc1ccc(OC(F)F)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(OC(F)F)cc4)CC3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
To a solution of 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl chloride (46.9 mg, 0.14 mmol), as prepared in Example 3a, in DMSO (1 mL) was added 4-(difluoromethoxy)aniline (26.6 mg, 0.17 mmol), followed by DIEA (35.9 mg, 0.28 mmol). The mixture was heated at 100° C. with stirring. After 2 h, it was cooled to room temperature and partitioned between EtOAc and water. The combined EtOAc extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc→5% MeOH/EtOAc as eluent) to afford the title compound as a white solid (20.4 mg, 32%). 1H NMR (300 MHz, CDCl3) δ 9.09 (s, 1H), 7.40 (s, 1H), 7.38 (d, J=8.99 Hz, 2H), 7.27 (s, 1H), 7.07 (d, J=8.93 Hz, 2H), 6.48 (s, 1H), 6.45 (t, J=74.22 Hz, 1H), 4.28 (m, 2H), 4.08 (s, 3H), 4.07 (s, 3H), 3.62 (m, 1H), 3.20 (td, J=13.02 and 2.64 Hz, 2H), 2.14 (m, 2H), 2.01 (m, 2H). LC-MS (ESI) calcd mass 458.2, found 459.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:20][C@H:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH3:22])=[O:9])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)cnc1Cc1ccc(F)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(4-fluorobenzyl)nicotinic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 9.15 (1H, d, J=7.7 Hz), 8.63 (1H, d, J=2.4 Hz), 7.96–7.92 (3H, m), 7.50 (2H, d, J=8.4 Hz), 7.15–6.96 (4H, m), 5.19–5.09 (1H, m), 4.17 (1H, d, J=14.0 Hz), 4.08 (1H, d, J=14.0 Hz), 3.85 (3H, s), 1.42 (2H, d, J=7.0 Hz); MS (ESI) m/z 427 (M+H)+, 425 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](OC)=[O:12])[CH:9]=2)[CH:4]=[N:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][OH:12])[CH:9]=2)[CH:4]=[N:3]1
Reactant: COC(=O)c1ccc2cnn(C)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc2ccc(CO)cc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97.8 %

Procedure:
A solution of methyl 1-methyl-1H-indazole-6-carboxylate (230 mg, 1.21 mmol, PREPARATION 4) in anhydrous THF (4 mL) was cooled to 0° C., LiAlH4 (92 mg, 2.42 mmol) was added in portions below 0° C., and the mixture was then stirred at 0° C. for 1.5 h, added water:10% NaOH: water=0.2 mL: 0.2 mL: 0.6 mL carefully, filtered, and the filtrate was concentrated and purified by silica gel flash column to give 192 mg of crude product which was used directly for next step (98%). [M+H] Calc'd for C9H10N2O, 163; Found, 163.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](C)=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19]O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([CH3:19])=[C:11]([CH2:12][OH:14])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(OCc2ccccc2)cccc1C(=O)O
Reactant: CO
Solvent: C1CCOC1
Product: Cc1ccc(OCc2ccccc2)cc1CO
Reaction time: 2 h

Procedure:
To a solution of 3-(benzyloxy)-2-methylbenzoic acid (300 mg) in THF (10 mL) was added a 1.0 M solution of borane-THF complex in THF (1.85 mL) over 30 min. After stirring for 2 hr, methanol (20 mL) was added dropwise to the reaction mixture over 20 min. Methanol (10 mL) was added to the reaction mixture, and the solvent was evaporated under reduced pressure to give the title compound (280 mg) as a white solid. This compound was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([OH:10])=[O:9].[Si](C=[N+]=[N-])(C)(C)[CH3:12]>ClCCl.CO.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([O:10][CH3:12])=[O:9]
Reactant: O=C(O)c1cnccc1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cnccc1Cl
Temperature: 0 °C

Procedure:
To a suspension of 4-chloro-3-pyridinecarboxylic acid (3.630 g) in dichloromethane (20 mL) and methanol (8 mL) stirred under argon at 0° C. was added TMS-diazomethane 2M in Et2O (17.28 mL) dropwise. The reaction mixture was stirred at room temperature for 1 h. The solvents were evaporated in vacuo and the crude product was added to a silica gel column and was eluted with cyclohexane/EtOAc=7/3. The evaporation of the collected fractions gave 2.7 g of the title compound as a colourless solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].F[B-](F)(F)F.N1([O:45][C:46](N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(O)=O.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][N:20]([CH:46]=[O:45])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCNC3)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=CO
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCN(C=O)C3)cc1
Reaction time: 8 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-ethylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.248 g, 0.604 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.263 g, 0.819 mmol) and Formic acid (0.0346 mL, 0.917 mmol) were combined then added dry N,N-Dimethylformamide (2.50 mL, 32.3 mmol) followed by N,N-Diisopropylethylamine (0.583 mL, 3.35 mmol). The reaction mixture stirred for overnight. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 8.23 (d, J=20.5, 1H), 8.17 (d, J=8.7, 2H), 7.48 (d, J=8.7, 2H), 6.16 (t, J=5.1, 1H), 4.64 (dd, J=18.2, 11.9, 1H), 4.41 (dd, J=73.9, 18.2, 1H), 3.91 (d, J=17.0, 1H), 3.84 (d, J=11.1, 1H), 3.76 (dd, J=15.6, 12.5, 2H), 3.70-3.61 (m, 2H), 3.59-3.36 (m, 3H), 3.18-3.05 (m, 2H), 2.85-2.58 (m, 2H), 1.91-1.65 (m, 2H), 1.06 (t, J=7.2, 3H), 0.89-0.77 (m, 3H). LC/MS-m/z+439.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH2:11]([NH:13][CH3:14])[CH3:12]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([N:13]([CH2:11][CH3:12])[CH3:14])=[O:10])=[N:6][CH:7]=1
Reactant: CCNC
Reactant: O=C(O)c1cnc(Cl)cn1
Product: CCN(C)C(=O)c1cnc(Cl)cn1
Yield: 81.4 %

Procedure:
The title compound (I-7a) was prepared by a method analogous to that described for the preparation of SM-1 using 5-chloropyrazine-2-carboxylic acid (2 g, 12.62 mmol) and ethyl-methyl-amine (0.846 g, 13.9 mmol) to afford the title compound 5-chloro-N-ethyl-N-methylpyrazine-2-carboxamide (SM-4: 2.05 g, 81%) as a clear oil
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[C@@H:23]2[CH2:27][C@H:26]([N:28]3[CH:32]=[C:31]([CH2:33][OH:34])[CH:30]=[N:29]3)[C@@H:25]([OH:35])[C@H:24]2[OH:36])=[C:16]([NH:37][CH2:38][CH:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:15]=1)=[O:13].FC(F)(F)C(O)=O.O[C@@H]1[C@H](O)[C@@H](N2C=C(C)C=N2)C[C@H]1N1C=NC2C1=NC(NC1CCC(N[C:104]([NH:106][CH:107]3[CH2:112][CH2:111][N:110]([C:113]4[CH:118]=[CH:117][CH:116]=[CH:115][N:114]=4)[CH2:109]C3)=[O:105])CC1)=NC=2NCC(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1N1CC[C@@H](NC(N2C=CN=C2)=O)C1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:114]1[CH:115]=[CH:116][CH:117]=[CH:118][C:113]=1[N:110]1[CH2:111][CH2:112][C@@H:107]([NH:106][C:104](=[O:105])[NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([N:28]4[CH:32]=[C:31]([CH2:33][OH:34])[CH:30]=[N:29]4)[C@@H:25]([OH:35])[C@H:24]3[OH:36])=[C:16]([NH:37][CH2:38][CH:39]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:15]=2)=[O:13])[CH2:109]1
Reactant: NCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1
Reactant: Cc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NC5CCC(NC(=O)NC6CCN(c7ccccn7)CC6)CC5)nc43)[C@H](O)[C@@H]2O)c1
Agent: O=C(N[C@@H]1CCN(c2ccccn2)C1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1)N[C@@H]1CCN(c2ccccn2)C1

Procedure:
This compound is prepared from 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (2-amino-ethyl)-amide trifluoroacetate (first step a) using a procedure analogous to that of 1-{4-[9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-methyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-ylamino]-cyclohexyl}-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-urea trifluoroacetate (Example 42) replacing N-[1-(2-pyridinyl)-4-piperidinyl]-1H-imidazole-1-carboxamide with imidazole-1-carboxylic acid ((R)-1-pyridin-2-yl-pyrrolidin-3-yl)-amide. MS (ES+) m/e 786 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C:8]2[O:9][CH:10]=[C:11]([C:13]([OH:15])=O)[N:12]=2)=[CH:5][CH:4]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:28]2([CH2:33][NH:34]C(C3N=C(CC4C=CC(OC)=CC=4)SC=3)=O)[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:28]2([CH2:33][NH:34][C:13]([C:11]3[N:12]=[C:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=4)[O:9][CH:10]=3)=[O:15])[CH2:29][CH2:30][CH2:31][CH2:32]2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(Cc2nc(C(=O)O)co2)cc1
Reactant: COc1ccc(Cc2nc(C(=O)NCC3(c4ccc(OC)c(OC)c4)CCCC3)cs2)cc1
Product: COc1ccc(Cc2nc(C(=O)NCC3(c4ccc(OC)c(OC)c4)CCCC3)co2)cc1
Yield: 66 %

Procedure:
Starting from 2-(4-Methoxy-benzyl)-oxazole-4-carboxylic acid (25 g, 0.1 mmol) and [2-(3,4-Dimethoxy-phenyl)-2-methyl]-propylamine (47 mg, 0.2 mmol) following a similar procedure reported for the preparation of 2-(4-Methoxy-benzyl)-thiazole-4-carboxylic acid[1-(3,4-dimethoxy-phenyl)-cyclopentylmethyl]-amide, the amide (30 mg, 66%) was obtained as a white solid. ESI-MS m/z calc. 450.5, found 451.2 (M+1)+. Retention time of 3.51 minutes 1H NMR (400 MHz, CDCl3) δ 1.68-2.19 (m, 8H), 3.50 (d, J=6.3 Hz, 2H), 3.81 (s, 3H), 3.88 (s, 3H), 3.92 (s, 3H), 4.00 (s, 2H), 6.73-6.88 (m, 6H), 7.20 (d, J=8.7 Hz, 2H), 8.07 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][CH:26]3[CH2:29][CH2:28][N:27]3[C:30](=[O:34])[CH2:31][C:32]#[N:33])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:35][C:36]([N:40]1[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]1)([CH3:39])[CH:37]=O.N1CCCC1.[Si](Cl)(C)(C)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][CH:26]3[CH2:29][CH2:28][N:27]3[C:30]([C:31](=[CH:37][C:36]([CH3:39])([N:40]3[CH2:41][CH2:42][N:43]([CH3:46])[CH2:44][CH2:45]3)[CH3:35])[C:32]#[N:33])=[O:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CN1CCN(C(C)(C)C=O)CC1
Reactant: N#CCC(=O)N1CCC1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Agent: C[Si](C)(C)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: CN1CCN(C(C)(C)C=C(C#N)C(=O)N2CCC2Cn2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
To a mixture of 3-[2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidin-1-yl]-3-oxo-propanenitrile (100.6 mg, 0.220 mmol) and 2-methyl-2-(4-methylpiperazin-1-yl)propanal (118.2 mg, 0.660 mmol) in DCM (5 mL) in an ice bath was added pyrrolidine (0.11 mL, 1.32 mmol) and TMS-Cl (0.11 mL, 0.880 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour. The crude reaction mixture was loaded on silca gel plate, purified by MeOH:CH2Cl2 to obtain 2-[2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidine-1-carbonyl]-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enenitrile (19 mg) as a white powder. LC-MS (ES, m/z): 610 [M+H]
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1.[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[Br:11][C:7]1[CH:6]=[C:5]([C:8]([OH:10])=[O:9])[CH:4]=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: Cc1ccc(C(=O)O)cc1Br

Procedure:
Briefly described, p-toluic acid 2 is refluxed with N-bromo-succinimide and benzoyl peroxide in dry benzene to give a bromo-p-toluic acid 3 which, upon reaction with nitric acid, is converted to 3-nitro-4-bromomethyl benzoic acid 4. This is believed to be a new compound and represents a parent compound in the synthesis forming the subject matter of this invention. At slightly higher temperatures, above -10° C., the corresponding dinitro derivative 4a predominates.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[C:5]([OH:14])[N:4]([CH3:15])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:22]([O:25][CH2:26][CH2:27]Br)(=[O:24])[CH3:23]>CN(C)C=O.Cl>[C:22]([O:25][CH2:26][CH2:27][O:14][C:5]1[N:4]([CH3:15])[N:3]=[C:2]([NH2:1])[C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OCCBr
Reactant: Cc1ccc(-c2c(N)nn(C)c2O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1c(-c2ccc(C)cc2)c(N)nn1C
Reaction time: 0.75 h
Yield: 12.7 %

Procedure:
To 3-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-ol (Preparation 3b) (855 mg) in dimethylformamide (10 ml) at room temperature was added cesium carbonate (4.11 g) and 2-bromoethyl acetate (703 mg), the mixture was stirred for 45 minutes. The reaction was diluted with 2M hydrochloric acid (10 ml) and extracted with ether (2×100 ml). The organic fractions were combined, washed with water (2×100 ml) and brine (100 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 30 g) eluted with ethyl acetate:hexane (5:1) to yield the title compound as a white solid (155 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([SH:15])[CH2:12][CH2:13][SH:14].B(F)(F)F.[CH3:20]COCC>C.ClC(Cl)Cl.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:9]2[S:15][CH2:11][CH2:12][CH2:13][S:14]2)[CH3:20])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: SCCCS
Reactant: CCOCC
Agent: C
Agent: FB(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(c1ccc(Br)cc1)C1SCCCS1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To the compound p-bromoacetophenone (36.85 g, 185 mmol) in trichloromethane methane (300 ml) was added 1,3-propanedithiol (25 g, 230 mmol) and boron trifluoride etherate (3 ml). The resulting mixture was stirred at room temperature for 48 hours. The mixture was diluted with dichloromethane (500 ml), washed twice with 10% sodium hydroxide (200 ml), water, and brine, and then dried (Na2SO4). The product was concentrated to an oil. A portion was stirred with ether (100 ml) and a crystalline product was formed. The crystalline product was recovered by filtration and purified by recrystallization to yield 4-bromo-1-(1,3-dithian-2-yl)ethylbenzene.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][NH:12][CH:13]=1.Cl[CH2:20][C:21]1[CH:40]=[CH:39][C:24]([O:25][CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30][C:31]=2[CH3:32])=[CH:23][CH:22]=1.CN(C)C=O>O>[CH3:32][C:31]1[O:30][C:29]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[N:28][C:27]=1[CH2:26][O:25][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:12]2[CH:13]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=3)[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11]2)=[CH:40][CH:39]=1
Reactant: CCOC(=O)c1c[nH]cc1-c1ccccn1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1-c1ccccn1
Reaction time: 1 h
Yield: 96.8 %

Procedure:
Sodium hydride (60%, oily, 0.22 g) was added to a mixture of ethyl 4-(2-pyridyl)pyrrole-3-carboxylate (1.10 g), 4-(4-chlorometylphenoxymethyl)-5-methyl-2-phenyloxazole (1.83 g) and N,N-dimethylformamide (25 ml) at 0° C., and the mixture was stirred for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-(2-pyridyl)pyrrole-3-carboxylate (2.43 g, yield: 97%) was obtained as an oily substance from the fraction eluted with tetrahydrofuran-hexane (1:1, volume ratio).
Reaction SMILES: C([S:4][CH:5]([CH2:11][C:12](=[O:27])[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)C.C(SC(CC(=O)C1C=CC(OC2C=CC=CC=2)=CC=1)C(OCC)=O)(=O)C>>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][C:16]2[CH:17]=[CH:18][C:13]([C:12]([CH2:11][CH:5]([SH:4])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:27])=[CH:14][CH:15]=2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)C(CC(=O)c1ccc(Oc2ccc(Cl)cc2)cc1)SC(C)=O
Agent: CCOC(=O)C(CC(=O)c1ccc(Oc2ccccc2)cc1)SC(C)=O
Product: CCOC(=O)C(S)CC(=O)c1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 75.9 %

Procedure:
The procedure in Example 26 was followed, except that 4.07 g of ethyl 2-acetylthio-3-[4-(4-chlorophenoxy)benzoyl]-propionate were used in place of ethyl 2-acetylthio-3-(4-phenoxybenzoyl)propionate, to give 2.77 g of ethyl 3-[4-(4-chlorophenoxy)benzoyl]-2-mercaptopropionate.