Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33](O)=[C:32]([CH3:38])[CH:31]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33]([O:1][CH2:2][CH:3]2[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[CH2:4]2)=[C:32]([CH3:38])[CH:31]=1
Reactant: Cc1cc(Br)cc(C)c1O
Reactant: CN1CCCC(CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1OCC1CCCN(C)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 66.2 %

Procedure:
3-Hydroxymethyl-1-methylpiperidine (0.4 mL, 3.14 mmol) and triphenylphosphine (1.01 g, 3.85 mmol) were added to a solution of 4-bromo-2,6-dimethylphenol (517 mg, 2.57 mmol) in tetrahydrofuran (10 mL) at 0° C. under dry nitrogen, followed by the dropwise addition of diethyl azodicarboxylate (0.57 mL, 3.60 mmol). The mixture was stirred at 0° C. for 4 hours and the solvent removed in vacuo. The residue was purified on silica gel, eluting with 5% methanol in dichloromethane containing 0.25% ammonium hydroxide, to give 3-(4-bromo-2,6-dimethylphenoxymethyl)-1-methylpiperidine as an oil (531 mg, 66%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Br:21]Br>CCOCC>[Br:21][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: BrBr
Reactant: CCOC(=O)C(C)c1cccc(C(C)=O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CCOC(=O)C(C)c1cccc(C(=O)CBr)c1

Procedure:
To a cooled vigorously stirred mixture containing ethyl 2-(m-acetyl phenyl)propionate (0.1 mole) dissolved in dry ether (100 ml) and a pinchful of aluminum chloride is added dropwise 0.1 mole bromine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[CH3:19][C:20]1([CH3:27])[O:24][CH:23]([CH:25]=[CH2:26])[CH2:22][O:21]1.C(N(CCCC)CCCC)CCC>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.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]>[Cl:8][C:6]1[CH:7]=[C:2]([CH:26]=[CH:25][CH:23]2[CH2:22][O:21][C:20]([CH3:27])([CH3:19])[O:24]2)[N:3]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:5]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: C=CC1COC(C)(C)O1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: CC1(C)OCC(C=Cc2cc(Cl)nc(SCc3cccc(F)c3F)n2)O1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (product of example 1 step ii) (0.5 g), tris(dibenzylideneacetone)dipalladium(0) (45 mg), 2,2-dimethyl-4-vinyl-1,3-dioxolane (630 mg), tri-n-butylamine (610 mg) and tetra-n-butylammonium chloride (460 mg) in anhydrous N,N-dimethylformamide (6.5 ml) were heated at 90° C. for 3 h. then stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was purified by flash silica-gel chromatography eluting with 10% diethyl ether in iso-hexane to give the sub-title compound as a yellow viscous oil. Yield: 98 mg.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[O:15]([CH2:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]O)[Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:15]([CH2:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][C:41]1[CH:40]=[CH:39][CH:38]=[C:34]2[C:35]([NH:36][C:32](=[O:42])[C:33]=12)=[O:37])[Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CO)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Cc2cccc3c2C(=O)NC3=O)c1
Reaction time: 3 h
Yield: 85.4 %

Procedure:
A solution of diisopropyl azodicarboxylate (7.41 g, 36.6 mmol) in THF (23 mL) was added dropwise to a suspension of 3-(tert-butyldimethylsiloxymethyl)-benzyl alcohol (9.25 g, 36.6 mmol), phthalimide (5.39 g, 36.6 mmol) and tripheylphosphine (9.61 g, 36.6 mmol) in THF (50 mL) at room temperature, and the resulting mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with diethyl ether and stirred at room temperature for 30 minutes. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The concentration residue was purified by the use of a silica gel column (silica gel 500 mL; hexane−ethyl acetate=10/1−7/1) to obtain the title compound (11.93 g, 85%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14](O)=[O:15])=[N:9]2)=[C:4]([C:17]([N:19]2[C@H:28]([CH2:29][OH:30])[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[CH:3]=1.[CH2:31]([NH:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH3:34].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([N:35]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:31][CH2:32][CH2:33][CH3:34])=[O:15])=[N:9]2)=[C:4]([C:17]([N:19]2[C@H:28]([CH2:29][OH:30])[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[CH:3]=1
Reactant: CCCCNCCCC
Reactant: Cc1cc(C(=O)O)nn1-c1ccc(Br)cc1C(=O)N1Cc2ccccc2C[C@H]1CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN(CCCC)C(=O)c1cc(C)n(-c2ccc(Br)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (S)-1-(4-bromo-2-(3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5-methyl-1H-pyrazole-3-carboxylic acid (10.0 g, 21.3 mmol) in DMF (100 mL) were added dibutylamine (3.7 mL, 21.3 mmol), EDC.HCl (6.1 g, 31.9 mmol), HOBT (3.3 g, 21.3 mmol) followed by stirring at RT for 12 h. The reaction mixture was diluted with water, extracted with EtOAc (100 mL×2), twice. The combined organic layers were washed with water (100 mL), brine (50 mL), dried over sodium sulphate and concentrated invacuo. The residue was purified on silica gel (100-200 mesh) to afford the title compound as a hygroscopic solid, 4.5 g (36%). Rf=0.44 (55% EtOAc in hexane); 1H NMR (400 MHz, DMSO-d6): δ 8.00-7.40 (m, 3H), 7.30-6.80 (m, 4H), 6.50-6.20 (m, 1H), 5.10-4.00 (m, 3H), 4.00-2.40 (m, 9H), 2.40-2.00 (m, 3H), 1.60-0.50 (m, 14H); LC-MS: m/z 581.4 (M+H); HPLC: 90.74% (RT=9.216 min., method C).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]([F:35])([F:34])[O:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:33][C:30]4[CH:31]=[CH:32][C:27]([O:26][C:25]([F:24])([F:34])[F:35])=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(OC(F)(F)F)cc4)ncnc32)CC1
Yield: 29.7 %

Procedure:
4-[4-(4-Trifluoromethoxy-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (12.8 mg, 30%) was prepared using the procedure described for the preparation of Example 41 by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.09 mmol) with 4-(trifluoromethoxy)-phenol (Avocado Research Chemicals; 16 mg, 0.09 mmol) in the presence of potassium carbonate (27 mg, 0.195 mmol). Mass spectrum MH+=480.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:13][C:12]=2[C:24]([NH2:26])=[O:25])=[CH:7][CH:6]=1.[CH3:27][NH:28]CC1C=CC=CC=1>CO.[Pd]>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[C:14]1[O:15][C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:28][CH3:27])=[CH:6][CH:7]=2)=[C:12]([C:24]([NH2:26])=[O:25])[N:13]=1
Reactant: CNCc1ccccc1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCCCl)cc1
Agent: [Pd]
Solvent: CO
Product: CNCCOc1ccc(-c2oc(-c3c(F)cccc3F)nc2C(N)=O)cc1

Procedure:
The title compound was prepared by reaction of 5-(4-(2-chloroethoxy)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide with N-methylbenzylamine, according to the procedure described in example S-1, step c, followed by deprotection with the H-cube hydrogenation system (full H2 mode, 10% Pd\C catalyst, 1 ml/min, 60° C., 0.05M in MeOH). 1H NMR (DMSO) δ 2.35 (3H, s), 2.87 (2H, t), 4.10 (2H, t), 7.05-7.15 (2H, m), 7.35-7.45 (2H, m), 7.60-7.80 (3H, m), 8.20-8.30 (2H, m). LCMS (2) 2.55 min; m/z (ES+) 374.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=[O:9].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1.CN1C(=O)N(C)CCC1>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=[O:9])[CH3:16]
Reactant: O=c1cccc[nH]1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)Cn1ccccc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a suspension of 60% sodium hydride dispersion in mineral oil (220 mg, 5.5 mmol) in cold (0° C.) THF is added 2-pyridone (475 mg, 5.0 mmol) in THF (4 mL) and DMPU (2 mL) followed by ethyl bromoacetate (0.556 mL, 5.0 mmol), and the reaction is stirred at RT for 1 h. The reaction is quenched with water, and extracted with EtOAc. The organic layer is separated, evaporated, and the residue purified by chromatography on silica gel; elution with EtOAC:dichloromethane:heptane (50:30:20) gives 690 mg of the product 425. 1H NMR (CDCl3) δ 7.35 (m, 1H), 7.21 (d, 1H), 6.57 (d, 1H), 6.19 (t, 1H), 4.62 (s, 2H), 4.23 (q, 2H), 1.28 (t, 3H); MS: m/z 182 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4].[C:25](Cl)([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26]>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26])[CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4]
Reactant: COC(=O)C1CC(NCc2ccccc2)CN1C(=O)OC(C)(C)C
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C1CC(N(Cc2ccccc2)C(=O)OCC(Cl)(Cl)Cl)CN1C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of a corresponding 4-[(benzylamino)]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in DCM, cooled to 0 degree is added TrocCl and TEA. The mixture is stirred overnight, washed with Na2CO3, brine, dried and concentrated in vacuo to give 4-[(benzyl)-(2,2,2-trichloro-ethoxycarbonyl)-amino]-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester 2-methyl ester (19).
Reaction SMILES: [CH3:1][Si:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([CH3:14])=[CH2:13])[CH:7]=1)([CH3:4])[CH3:3].[CH3:15][SiH:16]([CH3:18])[Cl:17]>[Pt].[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.COC1C=CC(O)=CC=1>[Cl:17][Si:16]([CH3:18])([CH3:15])[CH2:13][CH:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][Si:2]([CH3:1])([CH3:3])[CH3:4])[CH:7]=1)[CH3:14]
Reactant: C[SiH](C)Cl
Reactant: C=C(C)c1cccc(O[Si](C)(C)C)c1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [Pt]
Agent: COc1ccc(O)cc1
Product: CC(C[Si](C)(C)Cl)c1cccc(O[Si](C)(C)C)c1
Yield: 83.8 %

Procedure:
The following were added to a four-neck flask equipped with a stirrer, reflux condenser, addition funnel, and thermometer: 165 g (0.8 mol) m-isopropenylphenyl trimethylsilyl ether from step (1), 0.2 g 4-methoxyphenol, and 100 ppm as platinum of 2 weight % isopropanolic chloroplatinic acid solution. While stirring and heating at 50 to 60 degrees Centigrade, 83.5 g (0.88 mol) dimethylchlorosilane was dripped in from the addition funnel over 5 hours. After the completion of the reaction, distillation in vacuo afforded 202 g (0.67 mol) of the target material. The yield was 84%. Some properties of this product are reported below.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=O)[CH2:6][CH2:5]2.[BH4-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)cnc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1cnc2c(c1)CCCN2
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.2 %

Procedure:
To a cooled (0° C.) solution of 6-bromo-3,4-dihydro-1H-[1,8]naphthyridin-2-one (10.0 g, 44.0 mmol) in THF (500 mL) is added sodium borohydride (8.3 g, 220 mmol) followed by boron trifluoride diethyl ether complex (38.7 mL, 308 mmol), dropwise. The resulting mixture is allowed to warm and stir at room temperature for 16 h. The reaction is carefully quenched with the dropwise addition of 1N HCl (15 mL). Once quenched, additional 1N HCl (85 mL) is added and the mixture is stirred at room temperature for 16 h. The mixture is concentrated, diluted with water and made basic (pH 8) with the addition of powdered sodium bicarbonate. The mixture is extracted with EtOAc and the combined organic layers are washed with brine, dried (Na2SO4) and concentrated to obtain the title compound (9.3 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.[F:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]=1[O:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23](Cl)[CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[F:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]=1[O:20][C:21]1[CH:22]=[CH:23][N:24]=[C:25]([NH:7][C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[CH:26]=1
Reactant: CCOC(=O)c1ccc(F)c(Oc2ccnc(Cl)c2)c1
Reactant: Cc1csc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)c1ccc(F)c(Oc2ccnc(Nc3nc(C)cs3)c2)c1
Yield: 81.5 %

Procedure:
Using the method of Example 3, Step B, 4-methylthiazol-2-amine (0.600 g, 5.26 mmol), ethyl 4-fluoro-3-(2-chloropyridin-4-yloxy)benzoate (1.55 g, 5.26 mmol), potassium phosphate (1.23 g, 5.78 mmol), Pd2(dba)3 (0.120 g, 0.131 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.084 g, 0.131 mmol) were reacted to provide ethyl 4-fluoro-3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoate (1.60 g, 77% yield). 1H NMR (CDCl3) δ 10.16 (bs, 1H), 8.20 (d, 1H), 7.97 (m, 1H), 7.86 (dd, 1H), 7.26 (t, 1H), 6.48 (dd, 1H), 6.29 (d, 1H), 6.28 (d, 1H), 4.38 (q, 2H), 2.18 (s, 3H), 1.38 (t, 3H); Mass spectrum (esi) m/z 374 (100) (M+H).
Reaction SMILES: [F:1][C:2]1[C:18]([CH:19]=O)=[C:17]([B:21]2[O:25]C(C)(C)C(C)(C)[O:22]2)[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:13][CH3:14])[N:6]=1.[BH4-].[Na+].Cl>CO>[F:1][C:2]1[C:18]2[CH2:19][O:22][B:21]([OH:25])[C:17]=2[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:13][CH3:14])[N:6]=1
Reactant: COc1nc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C=O)c2F)ccc1C#N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(Oc2ccc3c(c2F)COB3O)ccc1C#N
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 20.1 %

Procedure:
A solution of 6-(2-fluoro-3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-methoxynicotinonitrile (1.45 g, 3.64 mmol) in methanol (15 mL) was put on an ice water bath. Sodium borohydride was added in portions. The reaction was stirred at 0° C. for five minutes and then stirred at room temperature for 2 hours. The reaction was cooled again to 0° C. on an ice water bath and sodium borohydride (0.034 g, 0.91 mmol) was added. The reaction was stirred at room temperature for 1 hour. The reaction was again cooled to 0° C. and sodium borohydride (0.034 g, 0.91 mmol) was again added. The reaction was stirred at room temperature for one hour. The reaction was neutralized to pH 6 to 7 using 1 M HCl. The solution was then extracted using ethyl acetate and 0.5 M boronic acid solution in water. The organic layer was washed two more times with the 0.5 M boronic acid solution, then washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give 6-(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-2-methoxynicotinonitrile (0.220 g, 20% yield). ES(−)MS m/z=300 (M−H)−; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.67 (s, 3H), 5.11 (s, 2H), 6.82 (d, J=8.2 Hz, 1H), 7.39 (t, J=6.8, J=7.5 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 8.28 (d, J=8.2 Hz, 1H), 9.47 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12](I)=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:30]=[C:29]([CH3:31])[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([C:28]2[C:29]([CH3:31])=[CH:30][C:21]([CH3:20])=[C:22]([CH:27]=2)[C:23]([O:25][CH3:26])=[O:24])=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1nc(COCc2ccccc2)[nH]c1I
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2[nH]c(COCc3ccccc3)nc2C(F)(F)F)c(C)cc1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 36.5 %

Procedure:
Into a 50-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-((benzyloxy)methyl)-5-iodo-4-(trifluoromethyl)-1H-imidazole (compound 219.2, 500 mg, 1.31 mmol) in dioxane (8 mL). Methyl 2,4-dimethyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1, 450 mg, 1.55 mmol), Pd(dppf)Cl2 (0.1 g) and an aqueous solution of potassium carbonate (2 M) (3.25 mL) were added to the reaction. The reaction mixture was stirred for 1 h at 80° C., then diluted with 20 mL of H2O. The aqueous phase was extracted with 2×30 mL of ethyl acetate. The combined organic layers were washed with 2×30 mL of brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/20-1/4) as eluent to yield 0.2 g (37%) of the title compound as a light yellow solid.
Reaction SMILES: [I:1]/[CH:2]=[CH:3]\[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:41][C:42]1([F:46])[CH2:45][NH:44][CH2:43]1>C(Cl)Cl>[F:41][C:42]1([F:46])[CH2:45][N:44]([C:4](=[O:6])/[CH:3]=[CH:2]\[I:1])[CH2:43]1
Reactant: FC1(F)CNC1
Reactant: O=C(O)/C=C\I
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(/C=C\I)N1CC(F)(F)C1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 49.8 %

Procedure:
A solution of (Z)-3-iodoacrylic acid (1a) (2.75 g, 1.0 eq.) in CH2Cl2 (25.0 mL) was cooled to 0° C. and sequentially treated with DIPEA (1.96 g, 1.1 eq), HATU (5.78 g, 1.1 eq) and 3,3-difluoroazetidine hydrochloride (1.98 g, 1.1 eq). The reaction mixture was stirred at 0° C. for 2-3 hr before being filtered, and concentrated under reduced pressure affording 3.5 g of crude compound. Purification by column chromatography (silica gel, elution with EtOAc/hexane) afforded 1.89 g of pure desired compound. Yield (49.87%). Mass: (ES+) 273.8 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[NH:16][C:17](=[O:27])[N:18]3[CH2:23][CH2:24][C:25]#[N:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]#[C:37][CH3:38].Cl>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]([CH2:35][C:36]#[C:37][CH3:38])[C:17](=[O:27])[N:18]3[CH2:23][CH2:24][C:25]#[N:26])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC#CCBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2[nH]c(=O)n3CCC#N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCn1c(=O)n(CCC#N)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 19 h

Procedure:
4-[9-(2-Cyano-ethyl)-8-oxo-8,9-dihydro-7H-purin-6-yl]piperazine-1-carboxylic acid t-butyl ester (623 mg) was dissolved in N,N-dimethylformamide (10 mL). Potassium carbonate (300 mg) and 1-bromo-2-butyne (0.18 mL) were then added to this solution. The reaction solution was stirred at room temperature for 19 hours, then water (20 mL) and 1 N hydrochloric acid (5 mL) were added. This was then twice extracted with ethyl acetate, and the obtained organic layer was washed with water and saturated brine. The resulting organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (484 mg).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:32])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH2:30][CH3:31])[N:9]=3)[CH2:2]1.[C:33](O)(=[O:37])[C@@H:34]([CH3:36])[OH:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH2:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([C:33](=[O:37])[C@H:34]([OH:35])[CH3:36])[CH2:4]4)[N:7]3[CH3:32])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: C[C@@H](O)C(=O)O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)[C@@H](C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 8-azetidin-3-ylmethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (57 mg, 0.13 mmol), D-lactic acid (14 mg, 0.16 mmol) and DIPEA (27 μL, 0.16 mmol) in DCM (2 mL) and DMF (1.5 mL) was added HATU (60 mg, 0.16 mmol). The resulting yellow mixture was stirred for 2 h at r.t. then partitioned between DCM and H2O. The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) followed by Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 679 as a cream foam (23 mg, 35%). LCMS: RT 2.92 min, [M+H]+ 505.2. 1H NMR (CDCl3, 400 MHz): δ 8.00-7.98 (1 H, m), 7.81-7.70 (1 H, m), 7.26 (2 H, s), 4.49-4.20 (7 H, m), 3.91 (1 H, dd, J=10.38, 5.67 Hz), 3.86 (5 H, t, J=4.71 Hz), 3.76-3.75 (3 H, m), 3.36-3.35 (4 H, m), 3.18-3.15 (2 H, m), 1.44 (3 H, t, J=7.46 Hz), 1.34 (3 H, dd, J=6.68, 4.79 Hz)