Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[N:8]2[C:9](=[O:21])[C:10]3[NH:11][CH:12]=[N:13][C:14]=3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:7]2=[N:6][N:5]=1.[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[O:21]=[C:9]1[N:8]2[C:4]([CH2:3][NH:2][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:5][N:6]=[C:7]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:14]2[N:13]=[CH:12][NH:11][C:10]1=2
Reactant: O=C(O)c1ccccc1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(CN)nnc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(CNC(=O)c3ccccc3)nnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
The mixture of 3-(aminomethyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one hydrochloride (160 mg, 0.51 mmol), [B] benzoic Acid (0.069 g, 0.56 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.25 g, 0.56 mmol) and triethylamine (0.21 mL, 1.5 mmol) in DMF (10 mL) was stirred at room temperature overnight. The reaction mixture was purified by preparative LCMS to yield the desired product (150 mg, 77%). LCMS calculated for C19H22N7O2 (M+H): 380.2. found: 380.2.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:20]C)[CH2:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@:4]2([OH:25])[CH:22]([OH:24])[CH3:23])[CH3:2]>Cl.CO.O>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@:4]2([OH:25])[CH:22]([OH:24])[CH3:23])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@]2(O)C(C)O)CC(OC)=CC4
Agent: Cl
Solvent: O
Solvent: CO
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@]2(O)C(C)O
Yield: 53.6 %

Procedure:
Hydrolyze dl-13-ethyl-17β-hydroxy-17-(1-hydroxyethyl)-3-methoxygona-2,5(10)-diene (0.70 g) in hydrochloric acid-methanol-water. Recrystallize from ethyl acetate to obtain the title compound (0.36 g), m.p. 159°-164°; ultraviolet absorption peak at 240 mμ (ε15,230), infrared absorption peaks at 3.0 μ (strong), 6.05 μ.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH3:10])[CH:5]=[C:4](Cl)[N:3]=1.[Si:19]([O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Si:19]([O:26][CH:27]1[CH2:28][CH2:29][N:30]([C:4]2[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([NH:8][C@H:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=3)[CH3:10])[CH:5]=2)[CH2:31][CH2:32]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OC1CCNCC1
Reactant: C[C@H](Nc1cc(Cl)nc(Cl)n1)c1ccc(F)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](Nc1cc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)nc(Cl)n1)c1ccc(F)cn1
Temperature: 130 °C
Yield: 49.2 %

Procedure:
A mixture of 2,6-dichloro-N-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]pyrimidin-4-amine (Preparation 10a, 0.66 g, 2.31 mmol), 4-(tert-butyl-dimethylsilanyloxy)piperidine (prepared as described in WO2004/006926, 0.60 g, 2.77 mmol) and cesium carbonate (1.13 g, 3.46 mmol) in N,N′-dimethylformamide (15 mL) was stirred and heated to 130° C. in a sealed tube for 2 hours. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate (×3). The combined organic extract was washed with water and brine, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (hexanes to 6:4 hexanes/ethyl acetate) to give the title compound (0.53 g, 50%) as a white solid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1>O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[C:11]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]2)=[CH:5][CH:4]=1
Reactant: O=C1CCCC(=O)C1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: O
Product: O=C1CCCC(=NNc2ccc(Br)cc2)C1

Procedure:
A solution of 4-bromophenylhydrazine hydrochloride (2.24 g) and 1,3-cyclohexanedione (1.23 g) in water (60 ml) was stirred at room temperature for 1 h, giving a precipitate. The solid title compound was filtered off and dried (1.63 g). t.l.c (D), Rf 0.35 On cooling a second crop was obtained (0.395 g)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N:23]1[C:27]([CH3:28])=[N:26][C:25]([NH2:29])=[N:24]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:29][C:25]2[N:26]=[C:27]([CH3:28])[N:23]([C:17]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=3[Cl:15])[N:24]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1nc(N)nn1-c1ccc(Cl)cc1Cl
Product: Cc1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)nn1-c1ccc(Cl)cc1Cl

Procedure:
Prepared in analogy to example 1 step h) starting from 4-oxo-piperidine-1-carboxylic acid tert-butyl ester and 1-(2,4-dichloro-phenyl)-5-methyl-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a light yellow solid (yield=34%).
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[N+](=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][O:4][CH:2]([CH3:3])[CH3:1])[CH3:12]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)O
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)COC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
To a solution of 2-propanol (0.776 mL, 10.0 mmol) in dichloromethane (33 mL) is added rhodium (II) acetate dimer (22 mg) followed by ethyl diazoacetate (1.05 mL, 10.0 mmol). The reaction mixture is stirred at RT for 30 min. The reaction mixture is filtered through celite, and the filtrate is evaporated and the residue is vacuum distilled at 150° C. to give 750 mg of the product 405. 1H NMR (CDCl3) δ 4.21 (q, 2H), 4.06 (s, 2H), 3.73 (m, 1H), 1.29 (t, 3H), 1.22 (s, 3H), 1.19 (s, 3H); MS: m/z 147 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C@H:6]1[CH2:11][N:10]([S:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:25])[CH:21]=3)[CH:16]=2)(=[O:14])=[O:13])[CH2:9][C@H:8]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[NH:7]1)=[O:4].C(N(CC)C(C)C)(C)C.[Br:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1.O>ClCCl>[CH3:30][O:29][C:27]([CH2:26][C@H:8]1[CH2:9][N:10]([S:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:25])[CH:21]=3)[CH:16]=2)(=[O:13])=[O:14])[CH2:11][C@H:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])[N:7]1[C:45](=[O:46])[C:44]1[CH:48]=[CH:49][C:41]([Br:40])=[CH:42][CH:43]=1)=[O:28]
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: COC(=O)C[C@H]1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C[C@H](CC(=O)OC)N1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)C[C@H]1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C[C@H](CC(=O)OC)N1C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
In dichloromethane (8 ml), the trans-2,6-bis(methoxycarbonylmethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine (79.7 mg) was dissolved. Under ice cooling, N,N-diisopropylethylamine (68.0 μl) and a solution of 4-bromobenzoyl chloride (51.0 mg) in dichloromethane (2 ml) were added to the resulting solution, followed by stirring at room temperature for 5.5 hours. Water was added to the reaction mixture to separate the organic layer. The organic layer was washed with saturate aqueous NaCl solution, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (n-hexane:ethyl acetate=l:1), whereby the title compound (113 mg, 98%) was obtained as pale yellow amorphous powder.
Reaction SMILES: [CH2:1]([CH:4]([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH3:17])=[O:9])[C:5]([O-])=[O:6])[CH:2]=[CH2:3].[BH4-].[Li+].O.Cl>O1CCCC1>[CH2:1]([CH:4]([CH2:5][OH:6])[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH3:17])[OH:9])[CH:2]=[CH2:3]
Reactant: C=CCC(C(=O)[O-])C(=O)c1ccccc1CC
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC(CO)C(O)c1ccccc1CC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-allyl-3-(2-ethylphenyl)-3-oxopropionate (7.3 g.) in dry tetrahydrofuran (THF) (40 ml.) was added during 10 minutes to a stirred suspension of lithium borohydride (1.32 g.) in dry THF (40 ml.) at 0° C. under a nitrogen atmosphere. The mixture was then stirred at room temperature for 18 hours, cooled to 0°-5° C. and water (40 ml.) added. The aqueous mixture was acidified to pH 2 (concentrated hydrochloric acid) and extracted with ethyl acetate (3×120 ml.). The combined extracts were washed with saturated brine, dried (MgSO4) and evaporated. The residual oil (6.1 g.) was purified by chromatography on silica (180 g.) using 3:7 v/v ethyl acetate/petroleum ether (b.p.60°-80° C.) to give 2-allyl-1-(2-ethylphenyl)propane-1,3-diol (containing approximately 4:1 erythro- to threo-forms) as an oil (4.0 g.); NMR: 1.19 (3H,m), 2.04 (5H,m), 2.59 (2H,m), 3.76 (2H,m), 5.02 (3H,m), 5.67 (1H,m), 7.17 (3H,m), and 7.47 (1H,m)ppm.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1.C([Li])CCC.CN(C)[C:18](=[O:20])[CH3:19].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][C:18](=[O:20])[CH3:19])[CH:4]=1
Reactant: Cc1cc(N(C)C)ccn1
Reactant: CC(=O)N(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)Cc1cc(N(C)C)ccn1
Temperature: 0 °C

Procedure:
To a stirred solution of 4-dimethylamino-2-methylpyridine (1.30 g) in tetrahydrofuran (13 ml) was added a solution of n-butyllithium in n-hexane (1.56M, 7.34 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (1.15 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml×3). The combined organic layer was washed with brine, dried over sodium sulfate and-evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 50 g, 20% methanol in dichloromethane) to give 1-(4-dimethylaminopyridin-2-yl)propan-2-one (1.29 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:28][CH2:27][CH:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([O:53][CH3:54])[C:39]=1[OH:55]>>[NH2:29][CH:26]1[CH2:27][CH2:28][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:42]5[CH:41]=[C:40]([O:53][CH3:54])[C:39]([OH:55])=[C:38]([Cl:37])[CH:43]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])=[CH:19][N:20]=2)[CH2:25]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(Nc4cnc(N5CCC(N)C5)nc4)c3c2)cc(Cl)c1O
Yield: 20.9 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyrimidin-2-yl)pyrrolidin-3-ylcarbamate (100 mg, 0.18 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (77 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (20 mg, 21% over 2 steps) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.35 (s, 1H), 8.48 (s, 2H), 8.29 (dd, J=8.8, 1.9 Hz, 1H), 8.21 (s, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.09 (s, 1H), 6.89 (s, 1H), 4.04 (m, 2H), 3.94 (s, 3H), 3.89 (m, 1H), 3.79 (m, 2H), 2.82 (s, 1H), 2.52 (ddd, J=14.8, 12.7, 6.4 Hz, 1H), 2.23 (dt, J=11.6, 6.2 Hz, 1H), 1.21 (s, 4H); ESI MS m/z 531 [C28H27ClN6O3+H]+; HPLC 99.9% (AUC), tR=10.11 min.
Reaction SMILES: [OH:1][C@H:2]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:7]([O:8][C@@H:9]2[O:17][C@H:16]([CH2:18][OH:19])[C@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[C:24]([O:1][C@H:2]1[O:21][C@H:20]([CH2:22][O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:7]([O:8][C@@H:9]2[O:17][C@H:16]([CH2:18][O:19][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:14]([O:15][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:13][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:10]2[O:11][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:5]([O:6][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:3]1[O:4][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)O[C@@H]2COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
α-Lactose (2.3 g, 6.38 mmol) was dissolved in 30 ml of anhydrous pyridine, benzoyl chloride (8.9 ml, 76.6 mmol) was added thereto at 0° C., and the mixture was stirred for 8 hrs at room temperature. After the reaction was completed, the reaction mixture was extracted with ethyl acetate, and successively washed with 1 N HCl, saturated NaHCO3 and brine. The extract was dried over MgSO4, concentrated under a reduced pressure, and purified by column chromatography (ethyl acetate:n-hexane=1:3), to obtain the title compound as a white solid (7.19 g).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9](OC(C)=O)=[O:10].[CH3:15][O:16][C:17]1[N:22]=[CH:21][C:20]([NH:23][C:24]2[C:29]([C:30]3[N:38]=[C:37]([CH3:39])[N:36]=[C:35]4[C:31]=3[N:32]=[CH:33][NH:34]4)=[CH:28][C:27]([CH2:40][N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)=[CH:26][N:25]=2)=[CH:19][CH:18]=1.C(Cl)Cl>CN(C=O)C.[NH4+].[Cl-].O.CCOC(C)=O>[CH3:15][O:16][C:17]1[N:22]=[CH:21][C:20]([NH:23][C:24]2[N:25]=[CH:26][C:27]([CH2:40][N:41]3[CH2:42][CH2:43][N:44]([C:9](=[O:10])[CH3:8])[CH2:45][CH2:46]3)=[CH:28][C:29]=2[C:30]2[N:38]=[C:37]([CH3:39])[N:36]=[C:35]3[C:31]=2[N:32]=[CH:33][NH:34]3)=[CH:19][CH:18]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(Nc2ncc(CN3CCNCC3)cc2-c2nc(C)nc3[nH]cnc23)cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Nc2ncc(CN3CCN(C(C)=O)CC3)cc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
Triethylamine (42.2 mg, 0.417 mmol) and Ac2O (0.013 mL, 0.139 mmol) were added to a stirred solution of N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-(piperazin-1-ylmethyl)pyridin-2-amine (60 mg, 0.139 mmol) in DCM (3 mL, 46.6 mmol) and DMF (0.5 mL, to improve solubility) at room temperature. The mixture was stirred for 1 h and then diluted with NH4Cl(aq), water (10 mL) and EtOAc (10 mL each). The separated aqueous layer was extracted with EtOAc (3×15 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was heated at 60° C. with excess of Na2CO3 (50 mg) in CH3CN (5 mL) and water (1 mL) for 2 h. The resulting suspension was concentrated and washed with a minimal amount of cold MeOH to give 1-(4-((6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9H-purin-6-yl)pyridin-3-yl)methyl)piperazin-1-yl)ethanone (37 mg, 56%) as a yellow solid. LCMS (API-ES) m/z 474 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 13.63 (br. s., 1H) 12.64 (br. s., 1H) 9.73 (br. s., 1H) 8.60 (s, 1H) 8.54 (br s., 1H) 8.03-8.30 (m, 2H) 6.85 (d, J=8.61 Hz, 1H) 3.85 (s, 3H) 3.53 (br. s., 2H) 3.39-3.49 (m, 4H) 2.85 (s, 3H) 2.25-2.46 (m, 4H) 1.97 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[CH:6][C:3]=1[CH:4]=O.[NH2:17][C:18]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([O:27][CH3:28])[C:19]=1[C:20]#[N:21].[BH4-].[Na+]>C1(C)C=CC=CC=1.CO>[F:26][C:25]1[C:18]([NH:17][CH2:4][C:3]2[CH:6]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)[CH:8]=[CH:9][C:2]=2[F:1])=[C:19]([C:22]([O:27][CH3:28])=[CH:23][CH:24]=1)[C:20]#[N:21]
Reactant: O=Cc1cc(-c2cccc(F)c2)ccc1F
Reactant: COc1ccc(F)c(N)c1C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
To a solution of 2-fluoro-5-(3-fluorophenyl)benzaldehyde (505 mg, 2.32 mmol, 1.2 eq) and 2-amino-3-fluoro-6-methoxy-benzonitrile (320 mg, 1.93 mmol, 1 eq) in toluene (30 mL) was added 4 Å molecular sieves (10 g). The mixture was heated at reflux for 4 h, then filtered to remove the molecular sieves. The filtrate was concentrated and the residue obtained was dissolved in methanol (30 mL). NaBH4 (109.6 mg, 2.9 mmol, 1.5 eq) was added and the reaction stirred for 2 h at room temperature. The reaction was quenched by addition of water, and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 50:1) to give the title compound as an off-white solid (610 mg, 72%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=2[OH:22])=[O:11])[CH:6]=[CH:7][CH:8]=1>O1CCCC1.[Pd]>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[OH:22])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ccc([N+](=O)[O-])cc1O
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2)c(O)c1

Procedure:
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-nitrophenyl) urea (1.00 g, 2.9 mmol) was subjected to catalytic reduction in tetrahydrofuran (50 ml) using 5% palladium on carbon (0.20 g). The reaction mixture was filtered through a path of celite. Evaporation of the filtrate and subsequent recrystallization of the crude product from methanol/water 1:1 (50 ml) afforded the title compound. 0.68 g (75%) of the title compound was isolated. M.p. 200°-202° C.
Reaction SMILES: C([Li])CCC.ClCCC[CH:10]([O:18][CH:19]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=1)[CH2:20][CH2:21]CCl)C1C=CC=C(C)N=1.[CH3:31][N:32]=[C:33]=[S:34].C>CCCCCC.C(O)C.CN(P(N(C)C)(N(C)C)=O)C.O1CCCC1>[CH3:31][NH:32][C:33]([C:19]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=2)[CH2:20][CH2:21][CH2:10][O:18]1)=[S:34]
Reactant: CN=C=S
Reactant: Cc1cccc(C(CCCCl)OC(CCCCl)c2cccc(C)n2)n1
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=S)C1(c2cccc(C)n2)CCCO1
Reaction time: 0.08 h
Yield: 49.3 %

Procedure:
To a 1.6M solution (3,150 cc) of n-butyllithium in hexane maintained under an atmosphere of nitrogen at between -65° and -70° C., a mixture (1,680 cc) of anhydrous tetrahydrofuran and anhydrous hexamethylphosphorotriamide (50:50 by volume) is added slowly, followed by a solution of 3-chloropropyl(6-methyl-2-pyridyl)methyl ether (360 g) in a mixture (1,080 cc) of anhydrous tetrahydrofuran and anhydrous hexamethylphosphorotriamide (50:50 by volume) added dropwise in the course of 1 hour. After 5 minutes' stirring, a solution of methyl isothiocyanate (158 g) in a mixture (432 cc) of anhydrous tetrahydrofuran and anhydrous hexamethylphosphorotriamide (50:50 by volume) is added in the course of 35 minutes. The mixture is stirred for 1 hour at -60° C. and distilled water (4,800 cc) is then added slowly, the temperature being allowed to rise to about 20° C. The mixture is stirred for 5 minutes and then extracted with ethyl acetate (2,400 cc). The aqueous phase is decanted and extracted 4 times with ethyl acetate (6,000 cc in total). The organic liquors are combined, washed twice with aqueous sodium chloride solution (1,800 cc in total) at a concentration of 180 g per liter, and then extracted 3 times with 2N aqueous hydrochloric acid solution (4,500 cc in total). The acidic aqueous extracts are combined, washed twice with diethyl ether (3,000 cc in total) and then brought to a pH in the region of 8 using 10N aqueous sodium hydroxide solution. The mixture is extracted 4 times with ethyl acetate (10 liters in total). The organic extracts are combined, washed twice with distilled water (3.6 liters in total), dried over anhydrous magnesium sulphate in the presence of decolorising charcoal (18 g) for 1 hour and then filtered. The filtrate is concentrated to a small volume under reduced pressure (30 mm Hg; 4 kPa) at a temperature in the region of 35° C. The crystallised product is separated by filtration, washed with isopropanol (180 cc) and dried in a stream of air. The product obtained (118 g) is dissolved in boiling absolute ethanol (472 cc). To the solution is added decolorising charcoal (1 g), and the mixture is filtered hot. The filter is washed with a little boiling ethanol, and the solution is then cooled in an ice bath for 1 hour. The crystals which appear are separated by filtration, washed with ice-cooled absolute ethanol (120 cc) and dried in a stream of air at 20° C. N-Methyl-2-(6-methyl-2-pyridyl)-2-tetrahydrofurancarbothioamide (110 g), m.p. 151.4° C., is thereby obtained.
Reaction SMILES: I[CH2:2][C:3]1[N:4]=[C:5]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[O:6][CH:7]=1.[BH3-]C#N.[Na+]>CN(P(N(C)C)(N(C)C)=O)C>[CH3:2][C:3]1[N:4]=[C:5]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[O:6][CH:7]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1nc(CI)co1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1coc([C@@H](C)NC(=O)OC(C)(C)C)n1
Reaction time: 4 h
Yield: 38 %

Procedure:
To a solution of (R)-tert-butyl 1-(4-(iodomethyl)oxazol-2-yl)ethylcarbamate (660 mg, 1.87 mmol) in HMPA (10 mL), was added NaCNBH3 (470 mg, 7.5 mmol). The reaction was stirred for 4 h. and poured into ice-cold water and extracted with hexanes. The organic layer was dried on Na2SO4, concentrated, and chromatographed on silica gel (10% ethyl acetate/90% hexanes) to yield 38% of (R)-tert-butyl 1-(4-methyloxazol-2-yl)ethylcarbamate.