Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=3)=[CH:25][N:24]=2)=[CH:19][CH:18]=1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:44]1[CH2:48][CH2:47][C@H:46]([C:49]([O:51][CH3:52])=[O:50])[CH2:45]1.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>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[CH:25][C:26]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:33][CH:34]=3)=[CH:27][N:28]=2)=[CH:19][CH:18]=1)[C:13]([N:44]1[CH2:48][CH2:47][C@H:46]([C:49]([O:51][CH3:52])=[O:50])[CH2:45]1)=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)OCc4ccccc4)C(=O)O)cc3)nc2)cc1
Reactant: COC(=O)[C@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)OCc4ccccc4)C(=O)N4CC[C@H](C(=O)OC)C4)cc3)nc2)cc1
Reaction time: 4 h
Yield: 52 %

Procedure:
Prepared using General Procedure 7. To a stirring solution of (S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoic acid INT-22 (2082 mg, 2.75 mmol), methyl (S)-pyrrolidine-3-carboxlate HCl (545 mg, 3.30 mmol), and DIEA (1523 μl, 8.25 mmol) in DMF (6 mL) cooled to 0° C. was slowly added a solution of HATU (1254 mg, 3.30 mmol) in DMF (5 mL) in a drop-wise fashion The reaction mixture was allowed to warm slowly and stirring continued for 4 h. The reaction mixture was poured onto ice-water and the solid was filtered. The solid was dissolved in EA (50 mL), dried over MgSO4, evaporated and purified by chromatography (EA/hexane) to provide 932 mg (52%) of methyl (S)-1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-3-carboxylate. LCMS-ESI (m/z) calculated for C40H46N4O6: 678.3. found 679.3 [M+H]+, tR=4.50 min (Method 16).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18]Cl)[CH3:12]>>[CH2:11]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH3:1])[CH3:12]
Reactant: CCOCCOCCCl
Reactant: Cc1nc2ccccc2[nH]1
Product: CCOCCOCCn1c(C)nc2ccccc21
Yield: 84 %

Procedure:
1-[2-(2-Ethoxyethoxy)ethyl]-2-methyl-1H-benzimidazole was synthesized as in Synthesis Example 1 except that an equimolar amount of 2-methylbenzimidazole was used instead of benzimidazole and an equimolar amount of 2-chloroethyl 2-ethoxyethyl ether was used instead of 2-chloroethyl methyl ether. Yield 84%.
Reaction SMILES: [NH2:1][C@H:2]([CH3:20])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([N+:17]([O-:19])=[O:18])[C:12]([C:15]#[N:16])=[N:13][CH:14]=2)=[N:5]1.[C:21]([C:24]1[CH:28]=[C:27]([C:29](O)=[O:30])[NH:26][N:25]=1)(=[O:23])[CH3:22]>>[C:21]([C:24]1[CH:28]=[C:27]([C:29]([NH:1][C@H:2]([CH3:20])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[N:13][C:12]([C:15]#[N:16])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=3)=[N:5]2)=[O:30])[NH:26][N:25]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: C[C@@H](N)Cn1ccc(-c2cnc(C#N)c([N+](=O)[O-])c2)n1
Product: CC(=O)c1cc(C(=O)N[C@H](C)Cn2ccc(-c3cnc(C#N)c([N+](=O)[O-])c3)n2)[nH]n1
Yield: 18.5 %

Procedure:
(R)-5-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-3-nitropicolinonitrile (0.62 g, 1.14 mmol) was coupled with 3-acetyl-1H-pyrazole-5-carboxylic acid (0.39 g, 2.50 mmol) using the method of Example 34(d). Crude product was purified twice by CombiFlash (1st column: silica, eluent: 0-10% MeOH in DCM; 2nd column: C-18, eluent: 0-100% MeCN in water) to yield 86 mg (19%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.23 (d, 3H), 2.56 (s, 3H), 4.33 (dd, 1H), 4.55 (dd, 1H), 4.58-4.67 (m, 1H), 6.83-6.86 (m, 1H), 7.29-7.31 (broad s, 1H), 7.65 (d, 1H), 8.91-8.94 (broad s, 1H), 9.64-9.67 (m, 1H).
Reaction SMILES: C[N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH2:14][CH2:15][O:16][CH2:17][CH3:18])[C:12]3[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=3[N:10]=2)[CH2:4][CH2:3]1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:27]([O:26][C:24]([N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH2:14][CH2:15][O:16][CH2:17][CH3:18])[C:12]3[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=3[N:10]=2)[CH2:4][CH2:3]1)=[O:25])[CH3:28]
Reactant: CCOCCn1c(N2CCCN(C)CC2)nc2ccccc21
Reactant: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOCCn1c(N2CCCN(C(=O)OCC)CC2)nc2ccccc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Combine 1-methyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1.79 g, 5.9 mmol) and ethyl chloroformate (0.75 mL, 7.8 mmol) in toluene (20 mL). Heat to 80° C. After 2 hours, cool the reaction mixture and dilute with ethyl acetate. Extract with a saturated aqueous sodium bicarbonate solution, dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 1-ethoxycarbonyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf =0.87 (silica gel, dichloromethane/methanol, 90/10). Combine 1-ethoxycarbonyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (17.2 g, 47.6 mmol), hydrazine hydrate (40 mL), and potassium hydroxide (40.7 g, 725 mmol) in ethylene glycol (150 mL). Heat to reflux. After 5 hours, cool the reaction mixture and dilute with water (500 mL). Extract three times with dichloromethane. Combine the dichloromethane layers and extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound: Rf =0.25 (silica gel, dichloromethane/methanol, 90/10).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](Cl)(C)C.CC1(C)[O:19][C:18](=O)[CH2:17][C:16](=[O:21])[O:15]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:19]=[C:18]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:17][C:16]([OH:21])=[O:15]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)CC(=O)Nc1ccccc1
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a solution of aniline (13 mL, 143 mmol) in DCM (290 mL) was added TMSCl (18.2 mL, 143 mmol) at room temperature and the reaction mixture was stirred for 1 hour. [Rigo, B.; Fasseur, D.; Cauliez, P. and Couturier, D. Tetrahedron Lett.; 30; 23; 1989; 3073-3076.]. 2,2-Dimethyl-1,3-dioxane-4,6-dione (20.6 g, 143 mmol) was added and combined reaction mixture was stirred overnight at room temperature, poured into saturated NaHCO3 solution and extracted with EtOAc. The aqueous phase was collected, acidified with cone. HCl to pH˜3 by addition of 2N HCl and extracted with DCM. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure affording 3-oxo-3-(phenylamino)propanoic acid (1, 16.82 g, 65% yield) as a white solid. MS (m/z): 180.0 (25%) (M+H), 202.0 (100%) (M+Na).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:38][C:39]1[CH:44]=[C:43]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH:42]=[CH:41][N:40]=1>C(Cl)Cl.C(N(CC)CC)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:14]([N:48]1[CH2:49][CH2:50][N:45]([C:43]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:38])[CH:44]=2)[CH2:46][CH2:47]1)=[O:16])[C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:5])([CH3:6])[CH3:7]
Reactant: Cc1cc(N2CCNCC2)ccn1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(N2CCN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)(C)C)CC2)ccn1
Yield: 90.1 %

Procedure:
To a solution of Boc-D-tert-leucine (0.23 g) in methylene chloride (5 ml) were added HOBt (0.20 g), WSC (0.29 g) and triethylamine (0.28 ml) under ice-cooling, and the reaction mixture was mixed at 0° C. for 15 minutes. Then, 1-(2-methyl-4-pyridinyl)piperazine (0.18 g) obtained in Example 114b) was added thereto, and further mixed at room temperature for 13 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The reaction mixture was washed with an aqueous potassium carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and then the residue was purified with basic silica gel column (ethyl acetate) to obtain the title compound as a colorless solid (0.35 g, 90%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:36][N:37]([CH2:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43])[CH3:38].Cl>O1CCOCC1.CC(O)C>[CH3:38][N:37]([CH2:39][C:40]1[CH:41]=[C:42]([NH:43][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([NH:23][C:24](=[O:33])[C:25]5[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=5[F:32])[CH:22]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH:44]=[CH:45][CH:46]=1)[CH3:36]
Reactant: CN(C)Cc1cccc(N)c1
Reactant: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)c1c(F)cccc1F
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(CN(C)C)c3)n2)cc1NC(=O)c1c(F)cccc1F
Temperature: 80 °C
Yield: 35.2 %

Procedure:
To a solution of N-[5-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-(methyloxy)phenyl]-2,6-difluorobenzamide (30 mg, 0.06 mmol) in 1,4-dioxane (6 mL) and 2-propanol (3 mL) was added 3-[(dimethylamino)methyl]aniline (27 mg, 0.18 mmol) followed by 4M HCl in dioxane (0.076 ml, 0.31 mmol). After heating overnight at 80° C., the reaction was quenched with saturated NaHCO3 (25 mL), solvent removed by rotary evaporation, the aqueous layer extracted with DCM (25 mL), organic layer concentrated, and purified by column chromatography (5-50% EtOAc in hexanes) to provide the product (12.8 mg, 35%) as an off-white solid. ESIMS (M+H)+=606. 1H NMR (400 MHz, DMSO-d6) δ 2.12 (s, 6H), 3.33 (bs, 2H), 3.86 (s, 3H), 6.57 (d, 1H, J=5.49 Hz), 6.85 (d, 1H, J=7.14 Hz), 7.07-7.10 (t, J=6.78 Hz, 1H), 7.15-7.19 (m, 4H), 7.35-7.38 (m, 1H), 7.41-7.45 (m, 1H), 7.50-7.54 (m, 1H), 7.63 (d, 1H, J=6.78 Hz), 7.69 (s, 1H), 8.23 (d, 1H, J=5.49 Hz), 8.32 (s, 1H), 8.49-8.50 (m, 1H), 8.80-8.82 (m, 1H), 9.50 (s, 1H), 10.19 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][OH:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13](Cl)(=[O:16])[CH2:14][CH3:15]>>[C:13]([O:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])(=[O:16])[CH2:14][CH3:15]
Reactant: CCC(=O)Cl
Reactant: O=C(NO)OCc1ccccc1
Product: CCC(=O)ONC(=O)OCc1ccccc1

Procedure:
[(Benzyloxy)carbonyl]amino propanoate is prepared from N-(benzyloxycarbonyl) hydroxylamine and propionyl chloride according to Scheme 1. (3.6 g, 89%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.18 (1H, s), 7.32-7.43 (5H, m), 5.22 (2H, s), 2.50 (2H, q, 7.6 Hz), 1.22 (3H, t, 7.6 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][CH3:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]=1[CH2:22]Br>>[C:1]([O:5][C:6](=[O:9])[N:7]([CH2:22][C:14]1[C:15]([N+:19]([O-:21])=[O:20])=[CH:16][CH:17]=[CH:18][C:13]=1[Br:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cccc(Br)c1CBr
Agent: [H-]
Agent: [Na+]
Product: CN(Cc1c(Br)cccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of methyl-carbamic acid tert-butyl ester from Preparation 1 (5.347 g, 40.76 mmol) in 200 ml anhydrous dimethylformanide was added sodium hydride (2 g of a 60% suspension in mineral oil, 50 mmol) portion-wise at 0° C. The solution was stirred with a magnetic stirrer at 0° C. for 30 minutes, at which time the initial off-gassing had completed. 1-bromo-2-bromomethyl-3-nitro-benzene (12 g, 40.7 mmol) was added in one portion and the reaction mixture was stirred at 0° C. for an hour. The solution was allowed to warm to room temperature and the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extract with ethyl acetate and the combined organic fractions were washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by flash chromatography to give (2-bromo-6-nitro-benzyl)-methyl-carbamic acid tert-butyl ester as a yellow oil (11.761 g, 84%). MS: (M+H)+345.1.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:13])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[OH-].[K+]>C1COCC1.C(OCC)C>[CH2:15]([O:13][C@H:10]([CH2:11][O:12][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCBr
Reactant: OC[C@@H](O)COCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOC[C@H](COCc1ccccc1)OCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(benzyloxy)propane-1,2-diol (1 eq) in THF (0.3 M) was added n-tetrabutylammonium bromide (0.2 eq), 1-bromododecane (4 eq) and potassium hydroxide (5 eq). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl ether, washed with water, 1 N hydrochloric acid, water, and brine, dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% EtOAc/Hex to give the product.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[C:5]([CH3:24])[C:6]([O:22][CH3:23])=[CH:7][CH:8]=2)[N:3]=1.[F:25][C:26]([F:33])([F:32])[C:27]1[CH:31]=[CH:30][NH:29][N:28]=1>>[CH3:23][O:22][C:6]1[C:5]([CH3:24])=[C:4]2[C:9]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:11][C:2]([N:29]3[CH:30]=[CH:31][C:27]([C:26]([F:33])([F:32])[F:25])=[N:28]3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: COc1ccc(COc2cc(Cl)nc3c(C)c(OC)ccc23)cc1
Reactant: FC(F)(F)c1cc[nH]n1
Product: COc1ccc(COc2cc(-n3ccc(C(F)(F)F)n3)nc3c(C)c(OC)ccc23)cc1
Yield: 19 %

Procedure:
Compound 87c was synthesized from compounds 46b and 86a following the procedure as described for compound 86a, as a white solid in 19% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.O.[NH2:10][NH2:11]>C1COCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:10][NH2:11])=[CH:6][CH:7]=1
Reactant: NN
Reactant: Clc1ccc(Cl)nn1
Solvent: C1CCOC1
Solvent: O
Product: NNc1ccc(Cl)nn1

Procedure:
A solution of 3,6-dichloropyridazine (3 g, 20.14 mmol) and hydrazine monohydrate (1 g, 20.14 mmol) in 20 mL THF in a sealed tube was heated at 80° C. for 5 h. Solvent was evaporated and the crude was used in the next step without purification (3.56 g, 100%). LCMS (method B): [MH]+=145.1, tR=0.574 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[CH:3]1.[NH2:10][C@@H:11]([CH3:28])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:25]=[C:24]([F:26])[C:21]([C:22]#[N:23])=[C:20]([Cl:27])[CH:19]=2)=[N:14]1>>[Cl:27][C:20]1[CH:19]=[C:18]([C:15]2[CH:16]=[CH:17][N:13]([CH2:12][C@@H:11]([NH:10][C:7]([C:5]3[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=3)=[O:9])[CH3:28])[N:14]=2)[CH:25]=[C:24]([F:26])[C:21]=1[C:22]#[N:23]
Reactant: Cn1cnc(C(=O)O)c1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn(C)cn1

Procedure:
The title compound was prepared using the method of Example 247 starting from 1-methyl-1H-imidazole-4-carboxylic acid and (S)-4-[1-(2-aminopropyl)-1H-pyrazol-3-yl]-2-chloro-6-fluorobenzonitrile (which can be prepared according to Example 34(c)). The crude product was purified by flash chromatography on silica gel by using CH2Cl2-MeOH as a gradient eluent (100:0-99:1). The resulting product was triturated in diethyl ether at RT to afford the title product. 1H NMR (400 MHz, DMSO-d6): 1.21 (31-1, d), 3.74 (3H, s), 4.26 (1H, distorted dd), 4.42 (1H, distorted dd), 4.56 (1H, m), 6.60 (1H, d), 7.43 (1H, d), 7.49 (1H, d), 7.50 (1H, d), 7.75 (1H, dd), 7.87 (1H, m), 7.97 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]([CH3:13])=[CH:4][N:3]=1.O[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[C@H:20]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19][CH2:18]2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C@H:20]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19][CH2:18]3)[C:5]([CH3:13])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1NCCCO
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(Cl)ncc3C)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.8 %

Procedure:
To a solution of 3-[(2-chloro-5-methyl-4-pyrimidinyl)amino]-1-propanol (Example 339, 1.77 g, 8.81 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 970 mg, 8.81 mmol) in THF (33 mL) were added PPh3 (2.31 g, 8.81 mmol) and ADDP (2.22 g, 8.81 mmol). The reaction mixture was vigorously stirred at rt for 24 h, after which additional amounts of PPh3 (2.31 g, 8.81 mmol) and ADDP (2.22 g, 8.81 mmol) were added. After an additional 24 h, the reaction mixture was diluted with hexanes, filtered through Celite®, and the filtrate concentrated under reduced pressure. The residue was then purified by silica gel chromatography (2:1 to 1:1 hexanes/EtOAc) to give the product (1.70 g, 99%). 1H NMR (400 MHz, CDCl3) δ 1.29 (t, 3H), 1.75-1.80 (m, 1H), 2.02 (s, 3H), 2.12-2.18 (m, 2H), 2.38-2.46 (m, 2H), 2.72 (dd, 1H), 2.84-2.2.92 (m, 2H), 3.52-3.55 (m, 1H), 3.73 (q, 2H), 4.13 (t, 2H), 4.18 (q, 2H), 6.70 (d, 1H), 6.77 (s, 1H), 7.08 (d, 1H), 7.78 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][O:8][C:7]=12.[CH3:11][O-:12].[Na+]>O1CCOCC1.O>[CH3:11][O:12][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][O:8][C:7]=12
Reactant: C[O-]
Reactant: Clc1nccc2ccoc12
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1nccc2ccoc12
Yield: 89.9 %

Procedure:
A solution of 7-chlorofuro[2,3-c]pyridine (1.1 g) was stirred at room temperature under dry nitrogen in 1,4-dioxane (40 ml). Sodium methoxide (1.2 g) was added and the resulting mixture heated at reflux overnight. The mixture was diluted with water (100 ml) then extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with brine (50 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo to give the title compound (0.96 g) as a brown oil.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9]([CH3:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].[CH:14]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15].O>O1CCCC1>[I:1][C:2]1[C:10]2[C:9]([CH3:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])[CH:3]=1
Reactant: Cc1ncnc2[nH]cc(I)c12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncnc2c1c(I)cn2[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 5-iodo-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (19, 323.6 mg, 1.25 mmol) in 8 mL of tetrahydrofuran under nitrogen, sodium hydride (57.41 mg, 60% in mineral oil, 1.44 mmol) was added. The reaction was stirred at room temperature for 10 minutes, then triisopropysilyl chloride (3, 0.304 mL, 1.44 mmol) was added. The reaction was stirred at room temperature for 2 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][Cl:29].C(OCC)(=O)C>C(#N)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([O:19][CH2:27][CH2:28][Cl:29])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(OCCCl)c2ccccc12
Yield: 58.3 %

Procedure:
N-tert-butyloxycarbonyl-4-amino-1-naphthol (2.0 g, 7.72 mmol), potassium carbonate (5.34 g, 38.6 mmol) and 1-bromo-2-chloroethane (1.28 ml, 15.4 mmol) are heated to 80° C. in anhydrous acetonitrile (40 ml) under a nitrogen atmosphere for 1 day. The mixture is poured into ethyl acetate (250 ml) and washed with water (500 ml). The aqueous layer is re-extracted with ethyl acetate (2×100 ml), the organic layers combined and dried over anhydrous sodium sulfate. The organic layers are evaporated to dryness and the residue purified by column chromatography on silica gel eluted with 20% ethyl acetate in hexanes to give [4-(2-chloro-ethoxy)-naphthalen-1-yl]-carbamic acid tert-butyl ester (1.448 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:17]=[CH:16][C:15]2[N:14]([CH3:18])[C:13](=[O:19])[C@@H:12]([CH2:20][CH3:21])[N:11]([CH:22]([CH3:24])[CH3:23])[C:10]=2[N:9]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(C(F)(F)F)=O>>[CH2:20]([C@H:12]1[N:11]([CH:22]([CH3:23])[CH3:24])[C:10]2[N:9]=[C:8]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[NH:1][S:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:33])=[O:32])[N:17]=[CH:16][C:15]=2[N:14]([CH3:18])[C:13]1=[O:19])[CH3:21]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3N)nc2N1C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3NS(=O)(=O)c3ccccc3)nc2N1C(C)C

Procedure:
The title compound was prepared similarly to the methods described in Example 114, with (R)-2-(3-aminopyridin-4-yl)-7-ethyl-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 93) instead of (R)-2-(3-aminopyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 91) and with benzene sulfonylchloride instead of chloromethylcarbonate. LCMS (0.05% TFA): 467.2 m/z (M+H)+; 1H-NMR (DMSO-d6, 500 MHz): δ: 12.90 (s, 1H), 8.77 (s, 1H), 8.42 (d, 1H, J=5 Hz), 8.23 (s, 1H), 8.10 (d, 1H, J=5.5 Hz), 7.68 (d, 2H, J=7.5 Hz), 7.56 (t, 1H, J=7.5 Hz), 7.45 (t, 2H, J=7.5 Hz), 4.47 (m, 2H), 3.35 (s, 3H), 1.87 (m, 1H), 1.75 (m, 1H), 1.39 (d, 6H, J=6.5 Hz), 0.77 (t, 3H, J=7.5 Hz).