Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([C:14]1[S:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:17][CH:18]=1)=[O:13].Br[CH:30]([CH2:38][CH3:39])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([CH2:10][CH2:11][C:12](=[O:13])[C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH:4]=[CH:5][C:6]=1[O:9][CH:30]([CH2:38][CH3:39])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]
Reactant: CCC(Br)C(=O)OC(C)(C)C
Reactant: O=C(CCc1ccc(O)c(Cl)c1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Product: CCC(Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)OC(C)(C)C

Procedure:
Tert-butyl 2-(2,3-dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-butanoate is prepared from 3-(2,3-dichloro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl 2-bromobutanoate according to general procedure D.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].[CH3:12][O:13][C:14](=[O:21])[C@@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[NH2:16]>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][C@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([O:13][CH3:12])=[O:21])=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1F
Reactant: COC(=O)[C@H](N)CC(C)C
Product: COC(=O)[C@@H](CC(C)C)NC(=O)c1ccc(F)c(C)c1

Procedure:
Prepared in a similar manner to example 4 using 4-fluoro-3-methylbenzoic acid and D-leucine methyl ester. MS (M+H, 282).
Reaction SMILES: C(O)(C)(C)C.[C:6]1([C:14]([CH2:16][C:17]2[CH:24]=[CH:23][C:20]([O:21][CH3:22])=[CH:19][CH:18]=2)=[O:15])[CH:13]=[CH:12][C:9]([O:10][CH3:11])=[CH:8][CH:7]=1.CC(C)([O-])C.[K+].CO[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[O:36]>CCCCCC>[CH3:22][O:21][C:20]1[CH:19]=[CH:18][C:17]([C:16]([C:14]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[CH:12][CH:13]=2)=[O:15])=[CH:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:24][CH:23]=1
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Reactant: COC=CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)(C)O
Product: COC(=O)CC=C(C(=O)c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To 430 ml of tert-butanol were added 128 g of deoxyanisoine, 67.3 g of potassium tert-butoxide and 116 g of methyl 3-methoxyacrylate, and the mixture was stirred at 70° C. for 3 hours. To the resulting mixture was added n-hexane, and the mixture was allowed to stand at room temperature. A formed precipitate was filtered and dissolved by adding 1,000 ml of ethyl acetate and 300 ml of 3N-sulfuric acid. An organic layer was separated, washed with 3N-sulfuric acid and saturated brine and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to give 153 g (yield 90%) of methyl 4,5-bis(4-methoxyphenyl)-5-oxo-3-pentenoate as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1.[BH4-].[Na+].Cl>O1CCCC1.C(O)C>[Br:1][C:2]1[CH:10]=[C:9]([CH2:11][OH:12])[C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1
Reactant: O=Cc1cc(Br)cc2c1OCC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: OCc1cc(Br)cc2c1OCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Bromo-2,3-dihydrobenzo[b]furan-7-carbaldehyde (11.42 g), was dissolved in 50 ml of tetrahydrofuran and 50 ml of ethanol, then 2 g of sodium borohydride was added thereto, and the mixture was stirred overnight at room temperature. 1 N hydrochloric acid was added to the reaction mixture which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed, to give (5-bromo-2,3-dihydrobenzo[b]furan-7-yl)methanol. This product was treated in the same way as Production Example 90b) to give 12.6 g of the title compound.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=2)[C:21]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=O)[CH2:13][CH2:12]1)[CH3:3].C1(C)C=CC=CC=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:48]2)=CC=1.[OH-].[Na+].[ClH:63]>>[ClH:63].[CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=2)[C:21]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[S:48])[CH2:13][CH2:12]1)[CH3:3]
Reactant: CC(C)Oc1ccccc1N1CCN(Cc2cccc(C(=O)N3CCCCC3)c2)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccccc1N1CCN(Cc2cccc(C(=S)N3CCCCC3)c2)CC1
Temperature: 90 °C

Procedure:
A solution of 1-[3-[[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]methyl]benzoyl]piperidine (CP #36, 3.86 g, 0.0092 mol) and toluene (50 mL) was treated with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (2.22 g, 0.0055 mole) and the resulting mixture was heated at 90° C. for 1 h. The reaction was cooled followed by the addition of toluene (50 mL), and mixed thoroughly with excess 3N sodium hydroxide solution. The organic layer was separated, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated to an oily residue. Chromatography of this material on flash silica, using 1.5-2.5% methanol in methylene chloride, afforded CP #1 which was converted to its hydrochloride salt in ethereal hydrochloric acid, 3.61 g (77%), m.p. 221°-224° C. (dec, uncorrected). The structural assignment was supported by 1H NMR, chemical-ionization MS, and IR data.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]([CH3:13])[C:8]([O:10]CC)=[O:9])[NH:4][N:3]=1.O.[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:6]=[C:5]([CH:7]([CH3:13])[C:8]([OH:10])=[O:9])[NH:4][N:3]=1
Reactant: CCOC(=O)C(C)c1cc(C)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(C)C(=O)O)[nH]n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76.3 %

Procedure:
To a solution of 1.24 g (6.8 mmol) of ethyl 2-(3-methyl-1H-pyrazol-5-yl)propanoate from step B above in 20 mL of methanol and 5 mL of water was added 1.5 mL (7.5 mmol) of an aqueous 5.0 M sodium hydroxide solution. The resulting mixture was stirred at ambient temperature for 2.5 h and then evaporated in vacuo to remove the methanol. The aqueous phase was extracted with ethyl acetate (2×75 mL) then acidified with a 2 N hydrochloric acid solution until a pH of 4 was achieved. The aqueous solution was extracted with ethyl acetate (5×50 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated to yield the title compound as a yellow gum (0.80 g, 76%). 1H NMR (CDCl3, 500 MHz) δ 10.23 (br s, 1H), 7.26 (s, 1H), 5.97 (s, 1H), 3.87 (q, J=7.3 Hz, 1H), 2.26 (s, 3H), 1.59 (d, J=7.3 Hz, 3H). LC-MS: m/z (ES) 155 (MH)+.
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:15][CH:14]([CH2:16][OH:17])[CH2:13]2)(=O)=O)=CC=1.[N:18]1[C:26]([NH2:27])=[C:25]2[C:21]([N:22]=[CH:23][NH:24]2)=[N:20][CH:19]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:27][C:26]1[N:18]=[CH:19][N:20]=[C:21]2[C:25]=1[N:24]=[CH:23][N:22]2[C@@H:12]1[CH2:13][C@H:14]([CH2:16][OH:17])[CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)OC2CC(CO)C2)cc1
Reactant: Nc1ncnc2nc[nH]c12
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2[C@H]1C[C@@H](CO)C1
Reaction time: 18 h

Procedure:
To a solution of 720 mg (2.0 mmol) of 3[[(4-methylphenyl)sulfonyl]oxy]cyclobutanemethanol, benzoate ester (95% trans isomer and 5% cis isomer) in 20 ml of dry dimethylformamide under nitrogen was added adenine (405 mg, 3 mmol), 18-crown-6 (528 mg, 2 mmol), and potassium carbonate (414 mg, 3 mmol). The mixture was stirred at 110° for 18 hours and then concentrated in vacuo to a residue. Water was added and the suspension was adjusted to pH 7.0 using 1N hydrochloric acid. Removal of solvent in vacuo gave a residue, which was chromatographed over 200 ml of LPS-1 silica gel using 4% methanol in dichloromethane to give 430 mg of desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)([OH:36])[CH2:9][NH:10][C:11]2[N:19]=[C:18](Cl)[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:21]2[CH2:25][C@H:24]([NH:26][C:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])=[O:28])[C@@H:23]([OH:34])[C@H:22]2[OH:35])=[CH:4][CH:3]=1.[C:44]([NH:51][C@@H:52]1[CH2:56][CH2:55][NH:54][CH2:53]1)([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45].[I-].[Na+]>C(#N)C>[Cl:43][C:40]1[CH:39]=[CH:38][C:37]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([OH:36])[CH2:9][NH:10][C:11]2[N:19]=[C:18]([N:54]3[CH2:55][CH2:56][C@@H:52]([NH:51][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:53]3)[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:21]2[CH2:25][C@H:24]([NH:26][C:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])=[O:28])[C@@H:23]([OH:34])[C@H:22]2[OH:35])=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(O)(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(O)(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O
Reaction time: 1 h

Procedure:
A suspension of acetic acid ((1S,2R,3S,4R)-4-{6-[2,2-bis-(4-chloro-phenyl)-2-hydroxy-ethylamino]-2-chloro-purin-9-yl}-2,3-dihydroxy-cyclopentylcarbamoyl)-methyl ester (intermediate ZL; 1 equivalent) and (3R)-(+)-3-(Boc-amino)pyrrolidine (4 equivalents) in acetonitrile is treated with a catalytic amount of sodium iodide and then heated using microwave radiation in a Personal Chemistry Emrys™ Optimizer microwave reactor at 160° C. After 1 hour, the solvent is removed in vacuo; purification by column chromatography/crystallisation affords the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([OH:15])[CH2:13][CH2:12][C@H:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([O:15][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:13][CH2:12][C@H:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@H]1CC[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Ethyl (1S,3R,4R)-3-(tert-butoxycarbonylamino)-4-hydroxycyclohexane-1-carboxylate (53.5 g) and triethylamine (130 ml) were dissolved in dichloromethane (500 ml), and methanesulfonyl chloride (42 ml) was added dropwise while cooling the solution to −10° C. to −15° C. After stirring for 20 minutes at the same temperature, the mixture was heated to room temperature over 30 minutes and further stirred for 2 hours. The reaction mixture was cooled to 0° C., 0.5N hydrochloric acid (800 ml) was added dropwise, and the mixture was extracted with dichloromethane. The resultant organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude ethyl (1S,3R,4R)-3-(tert-butoxycarbonylamino)-4-(methane-sulfonyloxy)cyclohexane-1-carboxylate.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[C:23]([C:30]4[CH:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=4)[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:29][CH:27]([F:28])[C:25]1[CH:24]=[C:23]([C:30]2[CH:31]=[N:32][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:34][CH:35]=2)[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=3)[CH:20]=2)[N:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)ccn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.9 %

Procedure:
To a cooled and stirred solution of 3-{4-[4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide (0.16 g) in dichloromethane (4 ml) was added TFA (4 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by column chromatography on silica gel (dichloromethane/MeOH/NH4OH 16:1:0.1) and trituration (diethyl ether) yielded the title compound as a white solid (0.056 g, 22%). MS (ISP) 508.1 [(M+H)+]; mp 264.5° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:32][C@H:33]3[CH2:37][CH2:36][C:35](=[O:38])[CH2:34]3)[C:17]([NH:19][C:20]3[N:25]=[CH:24][C:23]([CH2:26][C:27]([O:29]CC)=[O:28])=[CH:22][CH:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.[OH-].[Na+].C(O)C.[ClH:44]>C1COCC1>[ClH:44].[CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:32][C@H:33]3[CH2:37][CH2:36][C:35](=[O:38])[CH2:34]3)[C:17]([NH:19][C:20]3[N:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][CH:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:11])=[O:12])[CH2:3][CH2:2]1
Reactant: CCOC(=O)Cc1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)Cc1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propionic acid (110 mg) in dichloromethane (3 mL) were added sequentially oxalyl chloride (0.03 mL) and a catalytic amount of DMF under ice-cooling, followed by stirring for 1 hour, and then ethyl (6-aminopyridin-3-yl)acetate (58 mg) and pyridine (0.05 mL) were added thereto under ice-cooling, followed by stirring for 2 hours. To the reaction mixture were added water and ethyl acetate. The organic layer was sequentially washed with water, saturated aqueous sodium bicarbonate, and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain ethyl [6-({(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoyl}amino)pyridin-3-yl]acetate (57 mg) as a pale yellow amorphous substance. To a solution of the obtained ethyl [6-({(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoyl}amino)pyridin-3-yl]acetate (57 mg) in THF (3 mL) was added 1 M aqueous sodium hydroxide solution (0.22 mL), and further added a drop of ethanol, followed by stirring at room temperature overnight. To the reaction solution was added 1 M hydrochloric acid (0.22 mL) to adjust the pH to 4, followed by dilution with saturated brine and dichloromethane for liquid separation. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated under reduced pressure. To a solution of the residue in ethyl acetate (3 mL) was added a 4 M hydrogen chloride/ethyl acetate solution (0.07 mL) under ice-cooling, followed by stirring for 10 minutes under ice-cooling, and the solvent was then evaporated under reduced pressure. To the residue was added ethyl acetate (3 mL), and the precipitate was collected by filtration and dried under reduced pressure to obtain [6-({(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoyl}amino)pyridin-3-yl]acetic acid hydrochloride (30 mg) as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[N:18]=[CH:17][C:16]2[N:15]([CH3:19])[C:14](=[O:20])[C@@H:13]([CH2:21][CH3:22])[N:12]([CH:23]([CH3:25])[CH3:24])[C:11]=2[N:10]=1.[C:26](O)([C:28](F)(F)F)=[O:27]>>[CH2:21]([C@H:13]1[N:12]([CH:23]([CH3:24])[CH3:25])[C:11]2[N:10]=[C:9]([C:8]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[CH2:2][NH:1][C:26](=[O:27])[C:28]3[CH:6]=[CH:7][CH:8]=[CH:3][CH:2]=3)[N:18]=[CH:17][C:16]=2[N:15]([CH3:19])[C:14]1=[O:20])[CH3:22]
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CN)nc2N1C(C)C
Reactant: O=C(O)C(F)(F)F
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CNC(=O)c3ccccc3)nc2N1C(C)C

Procedure:
The title compound was prepared similarly to the methods described in Example 102, with (R)-2-(3-(aminomethyl)pyridin-4-yl)-7-ethyl-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 126) instead of (R)-2-(3-aminopyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 91). LCMS (0.05% TFA): 445.2 m/z (M+H)+; 1H-NMR (MeOD, 500 MHz): δ: 8.89 (bs, 1H), 8.82 (bs, 1H), 8.43 (d, 1H, J=5.0 Hz), 8.24 (s, 1H), 7.80 (d, 2H, J=7.5 Hz), 7.57 (t, 1H, J=7.5 Hz), 7.47 (t, 2H, J=7.5 Hz), 5.12 (d, 2H, J=6 Hz), 4.73 (m, 1H), 4.49 (m, 1H), 3.42 (s, 3H), 1.99 (m, 1H), 1.81 (m, 1H), 1.46 (t, 6H, J=7.5 Hz), 0.87 (t, 3H, J=7.5 Hz).
Reaction SMILES: [N:1]1[O:2][CH:3]=[C:4]2[C:9]=1[CH2:8][CH2:7][NH:6][CH2:5]2.Cl[C:11]1[N:16]=[C:15]([Cl:17])[CH:14]=[CH:13][N:12]=1.CCN(C(C)C)C(C)C>CCO>[Cl:17][C:15]1[N:16]=[CH:11][N:12]=[C:13]([N:6]2[CH2:7][CH2:8][C:9]3=[N:1][O:2][CH:3]=[C:4]3[CH2:5]2)[CH:14]=1
Reactant: c1onc2c1CNCC2
Reactant: Clc1ccnc(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(N2CCc3nocc3C2)ncn1
Temperature: 150 °C
Yield: 69.7 %

Procedure:
4,5,6,7-Tetrahydro-isoxazolo[4,3-c]pyridine (162.0 mg, 1.3 mmol), 2,4-dichloropyrimidine (213.9 mg, 1.4 mmol), and DIPEA (421.6 mg, 0.57 mL, 3.3 mmol) in 3 mL of EtOH were added to a 5 mL microwave vial and microwave heated for 5 minutes at 150° C. The solvent was evaporated and the residue purified by chromatography (Biotage 25 S eluting with 100 mL each of 0, 10, 20, 30, and 40% THF/petroleum ether) to afford 215.3 mg, (69.7% yield) of the product. MS 237.2 (AP+, 100).
Reaction SMILES: [CH2:1]([N:4]([CH3:26])[C:5](=[O:25])[C:6]1[C:18]([I:19])=[C:17]([N:20]=[C:21]=[O:22])[C:16]([I:23])=[C:8]([C:9]([N:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])=[O:10])[C:7]=1[I:24])[CH:2]=[CH2:3].[CH2:27]([OH:31])[CH2:28][CH2:29][OH:30]>ClCCl>[CH2:13]([N:11]([CH3:12])[C:9]([C:8]1[C:16]([I:23])=[C:17]([NH:20][C:21]([O:30][CH2:29][CH2:28][CH2:27][O:31][C:21](=[O:22])[NH:20][C:17]2[C:16]([I:23])=[C:8]([C:9](=[O:10])[N:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])[C:7]([I:24])=[C:6]([C:5](=[O:25])[N:4]([CH2:1][CH:2]=[CH2:3])[CH3:26])[C:18]=2[I:19])=[O:22])[C:18]([I:19])=[C:6]([C:5](=[O:25])[N:4]([CH2:1][CH:2]=[CH2:3])[CH3:26])[C:7]=1[I:24])=[O:10])[CH:14]=[CH2:15]
Reactant: C=CCN(C)C(=O)c1c(I)c(N=C=O)c(I)c(C(=O)N(C)CC=C)c1I
Reactant: OCCCO
Solvent: ClCCl
Product: C=CCN(C)C(=O)c1c(I)c(NC(=O)OCCCOC(=O)Nc2c(I)c(C(=O)N(C)CC=C)c(I)c(C(=O)N(C)CC=C)c2I)c(I)c(C(=O)N(C)CC=C)c1I
Reaction time: 18 h

Procedure:
To a solution of N,N′-Diallyl-2,4,6-triiodo-5-isocyanato-N,N′-dimethyl-isophthalamide in dichloromethane was added 1,3-propane diol (0.5 equivalent). The reaction mixture was stirred for 18 hours and then purified by column chromatography to give) [3,5-Bis-(allyl-methyl-carbamoyl)-2,4,6-triiodo-phenyl]-carbamic acid 3-[3,5-bis-(allyl-methyl-carbamoyl)-2,4,6-triiodo-phenyl]carbamoyloxy-propyl ester. A cis-dihydroxylation using OsO4 and NMMO was performed and the crude mixture was purified by preparative HPLC to give {3,5-Bis-[bis-(2,3-dihydroxy-propyl)-carbamoyl]-2,4,6-triiodo-phenyl}-carbamic acid 3-{3,5-Bis-[bis-(2,3-dihydroxy-propyl)-carbamoyl]-2,4,6-triiodo-phenylcarbamoyloxy}propyl ester as a white powder after freeze drying.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([O:12][CH3:13])[C:3]=1[CH:4]=[N:5]O>CC(O)=O.[Zn]>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([O:12][CH3:13])[C:3]=1[CH2:4][NH2:5]
Reactant: COc1cc(Cl)cc(Cl)c1C=NO
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1cc(Cl)cc(Cl)c1CN
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A suspension of 2,4-dichloro-6-methoxybenzaldehyde oxime (2.24 mmol) in 3 mL AcOH was cooled to 0° C. and zinc dust (8.53 mmol) was added. The reaction mixture was stirred at RT for 2 h. It was filtered over a pad of celite and washed with EtOAc and MeOH. The filtrate was conc. and redissolved in water (pH 4 with 2N HCl solution). It was washed once with EtOAc, the ageous phase was basified with 1M NaOH solution, extracted 3 times with EtOAc and DCM. The comb. org. layers were dried over MgSO4 and conc. in vacuo to give the desired product as yellow solid.
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]1[C:22]([CH2:28][CH3:29])=[N:23][CH:24]=[CH:25][C:26]=1[Cl:27]>CN(C=O)C>[Cl:27][C:26]1[CH:25]=[CH:24][N:23]=[C:22]([CH2:28][CH3:29])[C:21]=1[CH2:20][S:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]([F:12])([F:10])[F:11])[N:3]=1
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Reactant: CCc1nccc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nccc(Cl)c1CSc1nc(O)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (884 mg, 4.5 mmol) was dissolved in anhydrous DMF (30 mL), and then potassium carbonate (1.87 g, 13.5 mmol) and 3-(bromomethyl)-4-chloro-2-ethylpyridine (5.4 mmol) in DMF (10 mL) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 3-10% DCM/MeOH to afford 2-{[(4-chloro-2-ethylpyridin-3-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (391 mg, 25% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 1.19 (t, J=7.4 Hz, 3H), 2.93 (q, J=7.4 Hz, 2H), 4.66 (s, 2H), 6.69 (s, 1H), 7.43 (d, J=5.3 Hz, 1H), 8.40 (d, J=5.3 Hz, 1H).
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>C(Cl)Cl>[C:18]([N:7]1[CH2:8][CH2:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: c1cnc2c(c1)CNCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2ncccc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-1,6-naphthyridine (4.9 g, 36.5 mmol) in CH2Cl2 at 0° C. was added triethylamine (6.1 ml, 43.8 mmol) and acetyl chloride (3.11 ml, 43.8 mmol) dropwise and the reaction was allowed to warm to room temperature and stirred for a further 18 h. The reaction mixture was partitioned between H2O and CH2Cl2, the layers were separated and the aqueous layer was extracted twice more with CH2Cl2. The combined organic layers were dried over MgSO4 and evaporated under reduced pressure to afford a residue which was purified on silica gel, eluting with EtOAc/MeOH/0.88NH3 (95/5/1, v/v). This afforded the subtitle compound (58%) as an oil. Rf 0.60 (CH2Cl2/MeOH/0.88NH3 84/14/2, v/v). 1H NMR (CDCl3) δ: 2.15 (3H, s), 3.04 (2H, m), 3.75 and 3.90 (2H, 2×m), 4.60 and 4.70 (2H, 2×s), 7.10 (1H, m), 7.42 (1H, m), 8.42 (1H, m).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][C:20]([F:23])([F:22])[F:21])[NH2:15]>>[F:11][C:12]1[CH:13]=[C:14]([NH:15][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[CH:16]=[CH:17][C:18]=1[O:19][C:20]([F:22])([F:23])[F:21]
Reactant: Nc1ccc(OC(F)(F)F)c(F)c1
Reactant: O=C(O)c1cccc(I)c1
Product: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cccc(I)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 30.1 using 3-iodobenzoic acid and 3-fluoro-4-(trifluoromethoxy)aniline to afford the title compound as a white solid. UPLC-MS (Condition 1) tR=3.39 min, m/z=425.9 [M+H]+, m/z=423.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.32-7.40 (m, 1H) 7.54-7.62 (m, 1H) 7.64 (dd, 1H) 7.93-8.01 (m, 3H) 8.29 (s, 1H) 10.64 (s, 1H).