Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8](=[O:25])[CH:9]([C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=1)[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.I([O-])(=O)(=O)=[O:31].[Na+].CO>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8](=[O:25])[CH:9]([C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=1)[S:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:31]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COc1cccc(CN(C)C(=O)C(Sc2ccccc2)c2cc(Cl)cc(Cl)c2)c1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cccc(CN(C)C(=O)C(c2cc(Cl)cc(Cl)c2)S(=O)c2ccccc2)c1

Procedure:
A mixture of the acetamide derivative from step 5 above (1.5 g), sodium metaperiodate (1.15 g), methanol (30 ml) and water (20 ml) was heated under reflux for 2 hours. The reaction mixture was filtered and the filtrate concentrated to dryness. The residue was purified by chromatography on silica gel using ethyl acetate as eluent, giving N-(3-methoxybenzyl)-N-methyl-2-(3,5-dichlorophenyl)-2-(phenylsulfinyl)acetamide (1.2 g) as a viscous oil.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:19](/B(O)O)=[CH:20]\[CH2:21][CH2:22][CH2:23][CH3:24]>>[CH:19](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:20]\[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCC/C=C/B(O)O
Reactant: Brc1cnc2ccc(NCc3cccnc3)nn12
Product: CCCC/C=C/c1cnc2ccc(NCc3cccnc3)nn12
Yield: 50 %

Procedure:
Prepared from the product of step A and (E)-1-hexeneboronic acid according to general procedure 2 providing the title compound (75 mg, 50%) as a brown solid; 1H NMR (300 MHz, CD3OD) δ 8.60 (s, 1H), 8.42-8.40 (m, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.57 (d, J=9.7 Hz, 1H), 7.41-7.37 (m, 2H), 6.71-6.47 (m, 3H), 4.60 (s, 2H), 2.24-2.18 (m, 2H), 1.44-1.32 (m, 4H), 0.93 (t, J=7.0 Hz, 3H); 13C NMR (75 MHz, CD3OD) δ 154.8, 149.5, 148.6, 137.9, 137.5, 137.4, 133.2, 129.1, 128.7, 125.9, 125.2, 116.7, 113.2, 43.9, 34.4, 32.8, 23.3, 14.4; HPLC tR=11.4 min (Luna), 96.0%; ES-MS: (M+H)=308 m/z.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12](=[O:23])[CH:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=1>CS(C)=O>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12](=[O:23])[CH:13]([O:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=2)=[CH:20][CH:21]=1)[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CC(Oc1ccc(O)cc1)C(=O)OCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)OCCOCc1ccccc1
Temperature: 90 °C

Procedure:
31.6 g of 2-benzyloxyethyl-2-(4-hydroxyphenoxy)propionate were dissolved in 100 ml of dimethylsulfoxide, 15.2 g of potassium carbonate were added thereto, then the mixture was heated at 90° C. for one hour with stirring. 20.0 g of 2-chloro-5-trifluoromethylpyridine were added dropwise to this solution which was then maintained at 90° C. for a further two hours. After cooling the reaction solution to room temperature, it was poured into ice-water, then extracted with ether. The ether layer was dried and filtrated, and the ether was distillated off. The end product of 2-benzyloxyethyl-2-[4-(5-trifluoromethyl-2-pyridyloxy)-phenoxy]propionate (a compound also produced in Example 20) was obtained in a yield of 41.0 g (m.p. 44°-47° C.).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.I[CH2:28][CH3:29].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1>>[CH2:28]([N:12]1[C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:2]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)=[CH:3][C:4]=3[C:5]=2[N:14]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:19][CH:20]=2)[C:13]1=[O:26])[CH3:29]
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: CCI
Product: CCn1c(=O)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(-c4cccnc4)ccc3ncc21

Procedure:
The title compound is prepared in a similar manner as described in Example 1 by reacting 2-[4-(8-bromo-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-2-methyl-propionitrile (Example 1h) with iodoethane (Fluka, Buchs, Switzerland) and using 3-pyridineboronic acid. ES-MS: 434 (M+H)+; analytical HPLC: tret=2.55 min (Grad 1).
Reaction SMILES: [F:1][C:2]1([F:52])[C:6]2[N:7]([CH2:14][C:15]([NH:17][C@H:18]([C:28]3[C:33]([C:34]4[CH:35]=[CH:36][CH:37]=[C:38]5[C:42]=4[N:41]([CH3:43])[N:40]=[C:39]5[NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[CH:32][N:31]=[C:30](SC)[N:29]=3)[CH2:19][C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=3)=[O:16])[N:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[C:5]=2[C@H:4]2[CH2:51][C@@H:3]12.C1C=C(Cl)C=C(C(OO)=O)C=1.C(N(CC)C(C)C)(C)C.Cl.[CH3:74][C:75]1([OH:79])[CH2:78][NH:77][CH2:76]1>C(Cl)Cl>[F:1][C:2]1([F:52])[C:6]2[N:7]([CH2:14][C:15]([NH:17][C@H:18]([C:28]3[C:33]([C:34]4[CH:35]=[CH:36][CH:37]=[C:38]5[C:42]=4[N:41]([CH3:43])[N:40]=[C:39]5[NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[CH:32][N:31]=[C:30]([N:77]4[CH2:78][C:75]([OH:79])([CH3:74])[CH2:76]4)[N:29]=3)[CH2:19][C:20]3[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=3)=[O:16])[N:8]=[C:9]([C:10]([F:11])([F:13])[F:12])[C:5]=2[C@H:4]2[CH2:51][C@@H:3]12
Reactant: CC1(O)CNC1
Reactant: CSc1ncc(-c2cccc3c(NS(C)(=O)=O)nn(C)c23)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)n1
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nc(NS(C)(=O)=O)c2cccc(-c3cnc(N4CC(C)(O)C4)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)c21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Compound 36B (30 mg, 0.039 mmol) was dissolved in 3 mL of CH2Cl2 and to it was added m-CPBA (17.5 mg, 77%, 0.078 mmol). The reaction mixture was allowed to stir at rt for 20 min. To the reaction mixture was added N,N-diisopropylethylamine (0.2 mL, 0.017 mmol) and 3-methylazetidin-3-ol hydrochloride (34 mg, 0.39 mmol). The reaction mixture was allowed to stir at room temperature for 30 min and then partitioned between EtOAc and brine. The organic layer was separated, washed with brine and dried over Na2SO4 and concentrated. The residue was purified by RP-HPLC eluting with acetonitrile/H2O (with 0.1% TFA) to afford the title product. 1H NMR (400 MHz, methanol-d4) δ 8.53 (dd, 1H), 8.25 (d, 1H), 7.83 (m, 1H), 7.36-6.52 (m, 3H), 6.47-6.22 (m, 2H), 4.85 (m, 3H), 4.40-3.94 (m, 4H), 3.75-2.67 (m, 8H), 2.51 (m, 2H), 1.60 (s, 3H), 1.51-1.23 (m, 1H), 1.18-0.88 (m, 1H). MS (m/z): 808.01 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([CH2:17][C:18]([OH:20])=O)=[C:11]3[N:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]([CH2:17][C:18]([N:36]([CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34][CH3:35])=[O:20])=[C:11]3[N:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCCNCCC
Reactant: O=C(O)Cc1c(-c2ccc(Cl)cc2)nn2cccnc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cc1c(-c2ccc(Cl)cc2)nn2cccnc12
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
A mixture of 3.5 g (0.012 mole) of 2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine-3-acetic acid and 3.2 g (0.015M) of 1,1'-carbonyldiimidazole (75%) in 150 ml of dry tetrahydrofuran was stirred under nitrogen for 30 minutes, then nitrogen was bubbled through the solution for 3 hours. The reaction mixture was treated with 1.2 g (0.012 mole) of dipropylamine and stirred for 16 hours. The reaction mixture was concentrated in vacuo. The crude residue was dissolved in 50 ml of methylene chloride and washed with water, saturated sodium bicarbonate, and again with water, then dried over magnesium sulfate and concentrated in vacuo to a solid residue (3.9 g). Recrystallization from 2-propyl ether:hexane yielded 3.4 g (76.4%) of pale yellow crystals, mp 104°-106° C.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[F:10])=[N+:2]=[N-:3].Cl[CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH3:18])=[O:16].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[F:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N:1]1[C:13]([CH2:12][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:14]([C:15]([O:17][CH3:18])=[O:16])[N:3]=[N:2]1
Reactant: [N-]=[N+]=Nc1ccccc1F
Reactant: COC(=O)CC(=O)CCl
Reactant: C1COCCN1
Product: COC(=O)c1nnn(-c2ccccc2F)c1CN1CCOCC1

Procedure:
A solution of 1-azido-2-fluorobenzene, prepared according to Platz, M. S. et al. J. Org. Chem. 1989, 54, 5938-5945 (500 mg; 3.65 mmol; 1 eq.) and methyl 4-chloroacetoacetate (823 mg; 5.47 mmol; 1.5 eq.) in morpholine (10 ml) was stirred at 50° C. overnight. The reaction mixture was evaporated. Water was added (20 mL) and was extracted with EtOAc (2×20 mL). Combined organic phases were extracted with 3 portions of HCl 1 N. Combined aqueous phases were made alkaline with NaOH 5N and were extracted with EtOAc (3×20 mL). Organic layers were dried over magnesium sulfate and evaporated, affording the title product as a dark red oil. It was used in the next step without further purification. HPLC (Method A) Rt 1.81 min. (Purity: 82.5%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:10]=1[CH:11]=O)=[O:5])[CH3:2].[CH:27]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:10]=1[CH2:11][NH:32][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2)n(-c2ccccc2F)c1C=O
Reactant: NC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2)n(-c2ccccc2F)c1CNC1CCCC1
Yield: 57 %

Procedure:
A solution of 2-(4-chloro-phenyl)-1-(2-fluoro-phenyl)-5-formyl-1H-imidazole-4-carboxylic acid ethyl ester I-5e-2 (1000 mg, 2.68 mmol), cyclopentylamine (251 mg, 2.95 mmol), NaBH(OAc)3 (796 mg, 3.76 mmol) in dichloroethane was stirred for 17 h at room temperature. The reaction was concentrated in vacuo and the residue was diluted with CHCl3. The organic solution was washed with sat'd aq. NaHCO3 and sat'd aq. NaCl, dried, and concentrated under vacuum. The crude residue was purified on SiO2-gel (Flash 40s) using a solvent gradient of 30% EtOAc/hexanes to 80% EtOAc/hexanes to give the desired product (I-5f) as a yellow oil (680 mg, 57%): +APCI MS (M+1) 442.2.
Reaction SMILES: [O-]CC.[Na+].[C:5]([NH:8][CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:7])[CH3:6].[CH3:20][C:21]([N+:27]([O-:29])=[O:28])([CH3:26])[CH2:22][CH2:23][CH2:24]I>C(O)C>[C:5]([NH:8][C:9]([CH2:24][CH2:23][CH2:22][C:21]([CH3:26])([N+:27]([O-:29])=[O:28])[CH3:20])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:7])[CH3:6]
Reactant: CC(C)(CCCI)[N+](=O)[O-]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCCC(C)(C)[N+](=O)[O-])(NC(C)=O)C(=O)OCC
Yield: 83.4 %

Procedure:
20% Sodium ethoxide (3.74 g, 11 mmol) and diethyl 2-acetamidomalonate (2.39 g, 11 mmol) were dissolved in ethanol (10 ml). A solution of 4-methyl-4-nitropentyl iodide (2.57 g, 10 mmol) in ethanol (8 ml) was added and the mixture was refluxed under heating for 5 h. Ethanol was evaporated by concentration under reduced pressure and ethyl acetate (50 ml) was added. The mixture was washed with water (20 ml) and saturated brine (20 ml). Ethyl acetate was evaporated by concentration under reduced pressure and the residue was purified by silica gel column chromatography to give the objective compound (2.89 g, yield 83.4%).
Reaction SMILES: C(NC(C)C)(C)C.O1CCCC1.C([Li])CCC.[NH2:18][C:19]1[C:20]([Cl:28])=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23].[N:29]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:30]=[O:31]>CCCCCC>[CH2:32]([NH:29][C:30](=[O:31])[NH:18][C:19]1[C:20]([Cl:28])=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23])[CH2:33][CH2:34][CH3:35]
Reactant: Nc1cccc(C(=O)O)c1Cl
Reactant: CCCCN=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCNC(=O)Nc1cccc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.3 %

Procedure:
To N,N-diisopropylamine (1.72 mL, 0.0122 mol) in tetrahydrofuran (12 mL, 0.14 mol), was added 1.6 M n-butyllithium in hexane (7.6 mL) at −78° C. under an atmosphere of nitrogen. After 30 minutes, 3-amino-2-chlorobenzoic acid (586, 1.00 g, 0.00583 mol) was added. After another 30 minutes, 1-isocyanatobutane (2.60 mL, 0.0233 mol) was added at −78° C. under an atmosphere of nitrogen and allowed to stir for two hours. The reaction mixture was warmed up to room temperature and stirred at room temperature for 30 minutes. The reaction was quenched with 1M HCl (aqueous) solution and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with dichloromethane:methanol:acetic acid 40:2:1 to give the compound as an off-white solid (587, 147 mg, 9%).
Reaction SMILES: [C:1]([O:6][CH2:7]Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Na+].[I-].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([F:42])=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:36][C@@H:37]([OH:41])[C:38]([OH:40])=[O:39])[NH:26][C:27]([C:29]3[O:33][N:32]=[C:31]([O:34][CH3:35])[CH:30]=3)=[O:28])=[CH:20][CH:19]=2)[CH:17]=1.CCN(C(C)C)C(C)C>CC(C)=O.C(O)(=O)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([F:42])=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][N:25]([CH2:36][C@@H:37]([OH:41])[C:38]([O:40][CH2:7][O:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[O:39])[NH:26][C:27]([C:29]3[O:33][N:32]=[C:31]([O:34][CH3:35])[CH:30]=3)=[O:28])=[CH:22][CH:23]=2)[CH:17]=1
Reactant: CCCC(=O)OCCl
Reactant: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)on1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)OCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(OC)no1
Temperature: 65 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
A mixture of chloromethyl butyrate (16.2 μL, 129 μmol) and NaI (19.4 mg, 129 μmol) in acetone (0.7 mL, 10 mmol) was heated at 65° C. for 1 hour. The mixture was then cooled to room temperature and a mixture of (R)-3-[N-(5′-Chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid (20.0 mg) and DIPEA (15.0 mL, 0.1 mmol) in acetone (0.3 mL) was added. The resulting mixture was stirred at room temperature for 1 hour then concentrated. The residue was dissolved in AcOH (2.0 mL), filtered, and purified by reverse phase preparative HPLC. The desired fractions were combined and freeze dried to yield a white solid. The solid was dissolved in acetic acid (1.5 mL), filtered and purified by reverse phase preparative HPLC to yield the title compound (6.5 mg, purity 100%). MS m/z [M+H]+ calc'd for C26H27ClFN3O8, 564.15. found. 564.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C:6](=[O:31])[N:5]([CH3:32])[C:4]=2[N:3]=1.C([Li])CCC.[CH:38](=[O:40])[CH3:39]>C1COCC1.O>[Si:24]([O:23][CH2:22][CH2:21][CH2:20][N:7]1[C:8](=[O:19])[C:9]2[N:10]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[C:2]([CH:38]([OH:40])[CH3:39])=[N:3][C:4]=2[N:5]([CH3:32])[C:6]1=[O:31])([C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:25])[CH3:26]
Reactant: CC=O
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1nc2c(c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 22.3 %

Procedure:
Step 1 8-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.25 g, 0.46 mmol, intermediate 77) was dissolved in THF (5 mL) and cooled to −78° C. To the clear solution was added 2.5 M n-butyllithium in hexanes (0.20 mL, 0.51 mmol) dropwise. The reaction was stirred in the cold for 5 min and acetaldehyde (0.13 mL, 2.31 mmol) was added. The reaction was warmed to room temperature and stirred for 1 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to leave a golden oil. The oil was purified using two 1000 microns preparative TLC plates eluted with 50% ethyl acetate/hexanes. Target band was extracted with ethyl acetate and the solvent was removed under reduced pressure to give 1-(3-((tert-butyldimethysilyl)oxy)propyl)-7-(4-chlorobenzyl)-8-(1-hydroxyethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.052 g, 30% yield) as a clear oil. LCMS retention time=4.490 min and 97% purity, LCMS MH+ 507.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:12]([OH:14])=[O:13])[C:9]([OH:11])=[O:10].S(Cl)(Cl)=O.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1)([O-:21])=[O:20]>C1(C)C=CC=CC=1.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:9]([O:11][C:25]1[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=1)=[O:10])[C:12]([O:14][C:25]1[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=1)=[O:13]
Reactant: O=C(O)C(C(=O)O)c1ccccc1F
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)C(C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccccc1F
Temperature: 30 °C
Yield: 77.7 %

Procedure:
To a 1 L flask was added toluene (500 mL), 2-(2-fluorophenyl)propanedioic acid (100 g, 0.479 moles) and N,N-dimethylformamide (6.92 g) at 25° C. under a nitrogen atmosphere. The reaction mixture was initially heated to 30° C. and thionyl chloride (127.53 g, 1.071 moles) was added dropwise over a period of 20 minutes at 25-30° C. After the addition, the reaction mixture was heated to 48-50° C. and this temperature maintained for 3.5 hours. Toluene (300 mL) was then added to the reaction mixture in one portion, followed by the addition of solid 4-nitrophenol (148.09 g total, 1.064 moles) in ten portions over a period of 15 minutes. After the addition, the reaction mixture was maintained at 49-55° C. for 1.5 hours. The reaction mixture was then concentrated under reduced pressure at 40-45° C. to remove toluene. The resulting residue was triturated using cold methanol (300 mL, approximately 5° C.) to yield an off-white solid which was isolated by filtration, washed with cold methanol (2×150 mL, approximately 5° C.) and dried under reduced pressure at 45° C. to give the title compound (163.8 g, 71.6%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([NH2:18])=[S:17])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20]([Br:23])[CH:21]=[CH2:22]>>[BrH:23].[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[NH:18])[S:17][CH2:22][CH:21]=[CH2:20])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cccc(NC(N)=S)c1
Reactant: C=CCBr
Product: Br
Product: C=CCSC(=N)Nc1cccc(CNC(=O)OC(C)(C)C)c1
Yield: 34 %

Procedure:
Using the compound obtained in Example 24 as a starting material and also using allyl bromide as a reagent, the same procedure of Example 4 gave 118 mg of the titled compound (yield, 34%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([O:10][CH3:11])[CH2:7][N:6]1C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:4].C(Cl)Cl.C(O)(C(F)(F)F)=O>O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([O:10][CH3:11])[CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)[C@H]1C[C@@H](OC)CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H]1C[C@@H](OC)CN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a flask containing 3 (4.67 g, 11.6 mmol) was added a solution of CH2Cl2 (27 mL), water (0.3 mL), and TFA (3.0 mL, 38.9 mmol). The solution was stirred at RT for 3 h before concentrating under reduced pressure to reveal impure 4. MS: APCI (AP+): 160.1 (M)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:23]=1[O:31][CH3:32].[CH3:33][PH:34](=[O:36])[CH3:35]>>[Cl:20][C:13]1[C:14]([F:19])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH:10]([O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:25]2[CH:26]=[CH:27][C:22]([P:34]([CH3:35])([CH3:33])=[O:36])=[C:23]([O:31][CH3:32])[CH:24]=2)[CH:3]=1)[CH3:11]
Reactant: C[PH](C)=O
Reactant: CC(Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: COc1cc(B(O)O)ccc1Br
Product: COc1cc(-c2cnc(N)c(OC(C)c3c(Cl)ccc(F)c3Cl)c2)ccc1P(C)(C)=O

Procedure:
The title compound was prepared from 5-bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine, 4-bromo-3-methoxyphenyl boronic acid, and dimethylphosphine oxide following the same procedures as Example 1 Step 1 and Step 3; ESMS: m/z 483 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5](N)[CH:4]=1.N([O-])=O.[Na+].[CH3:14][N:15]1[C:19](=[O:20])[CH:18]=[CH:17][C:16]1=[O:21].C1C=CC=CC=1>Cl.O.CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[C:16]([N:15]([CH3:14])[C:19](=[O:20])[CH:18]=2)=[O:21])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N)c1
Reactant: CN1C(=O)C=CC1=O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: COc1cccc(C2=CC(=O)N(C)C2=O)c1
Temperature: 0 °C

Procedure:
A 92.3 g portion of m-anisidine is dissolved in 225 ml of concentrated hydrochloric acid, 150 ml of water and 150 g of ice and cooled to 0° C. This mixture is diazotized carefully with vigorous stirring at 0°-5° C. with 52.5 g of sodium nitrite in 120 ml of water. This mixture is then added to 83.25 g of N-methylmaleimide in 225 ml of acetone at 0° C. The pH is adjusted to 3.0 and 25.5 g of cuprous chloride dihydrate is added in one portion followed by 200 ml of acetone, with stirring. Evaporation of the acetone and decantation of the aqueous layer leaves a black residue which is boiled with one liter of benzene, dried over magnesium sulfate and filtered through a Buchner funnel containing 50 g of activated magnesium silicate. The residue is boiled with one liter of benzene and filtered through activated magnesium silicate. The dark filtrate is evaporated under reduced pressure and then heated for 10 minutes with 100 ml of 2,6-lutidine to insure dehydrochlorination. This solution is combined with 500 ml of water and 400 ml of pyridine and filtered. The crystalline cake is pressed free of dark oil and then boiled with 500 ml of 90% ethanol. This is cooled and filtered giving 2-(m-methoxyphenyl)-N-methylmaleimide as orange crystals, m.p. 138°-146° C.