Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([C:13]1[CH:51]=[CH:50][C:16]([CH2:17][N:18]([CH3:49])[CH2:19][C:20]([O:22][C@H:23]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]3[CH2:48][CH2:47]3)[CH:35]=2)[CH2:24][C:25]2[C:30]([Cl:31])=[CH:29][N+:28]([O-:32])=[CH:27][C:26]=2[Cl:33])=[O:21])=[CH:15][CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.O1CCOCC1.C([O-])(O)=O.[Na+]>C(Cl)Cl.Cl>[Cl:33][C:26]1[CH:27]=[N+:28]([O-:32])[CH:29]=[C:30]([Cl:31])[C:25]=1[CH2:24][C@@H:23]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:42])[F:43])=[C:36]([O:44][CH2:45][CH:46]2[CH2:47][CH2:48]2)[CH:35]=1)[O:22][C:20](=[O:21])[CH2:19][N:18]([CH3:49])[CH2:17][C:16]1[CH:15]=[CH:14][C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:51][CH:50]=1
Reactant: CN(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)Cc1ccc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)Cc1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-4-(2-(2-((4-(N-(tert-butoxycarbonyl)methylsulfonamido)benzyl)(methyl)amino)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.250 g, 0.323 mmol) in DCM (15 ml), HCl 4M in dioxane (2 ml, 8.00 mmol) was added, and the solution was stirred at RT overnight. The mixture was portioned between DCM and 5% NaHCO3, and the organic layer was dried over sodium sulfate. The solvent was removed, and the crude was purified by flash chromatography on silica gel cartridge (DCM:MeOH=99:1 to 97:3) to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(methyl(4-(methylsulfonamido)benzyl)amino)-acetoxy)ethyl)pyridine 1-oxide, free base (0.120 g, 0.178 mmol, 55.1% yield), as a colorless amorphous solid. This product was dissolved in DCM (12 ml) and HCl 4M in dioxane (0.089 ml, 0.356 mmol) was added; the mixture was stirred at RT for 2 hours, and volatiles were removed under vacuum. The product was further dissolved in DCM and washed with 5% NaHCO3. The organic phase was dried over Na2SO4, and the crude was purified by chromatography on silica gel cartridge (DCM/EtOAc 90/10 to EtOAc 100%) followed by a further filtration through a silica gel cartridge (DCM/MeOH 99/1 to 98/2) to give 0.090 g of free base. This product was dissolved in 5 ml of DCM, and HCl 4M in dioxane (0.044 ml, 0.177 mmol) was added. The mixture was stirred at RT for 1 hour. The solvent was removed to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(methyl-(4-(methylsulfonamido)benzyl)amino)acetoxy)ethyl)pyridine 1-oxide hydrochloride (0.095 g, 0.134 mmol, 41.5% yield, MS/ESI+ 673.99 [MH]+)
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:28])=[C:4]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([Cl:8])=[CH:6][CH:7]=1.ClCCl.[C:32]1(=[O:46])[N:36]([CH2:37][C:38](Cl)=[O:39])[C:35](=[O:41])[C:34]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:33]12>O>[Si:11]([O:10][CH2:9][C:4]1[C:5]([Cl:8])=[CH:6][CH:7]=[C:2]([NH:1][C:38](=[O:39])[CH2:37][N:36]2[C:35](=[O:41])[C:34]3=[CH:42][CH:43]=[CH:44][CH:45]=[C:33]3[C:32]2=[O:46])[C:3]=1[Cl:28])([C:24]([CH3:25])([CH3:27])[CH3:26])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(N)c1Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1c(Cl)ccc(NC(=O)CN2C(=O)c3ccccc3C2=O)c1Cl)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.1 %

Procedure:
To a mixture of 3-amino-1-(tert-butyldiphenylsilyloxy-methyl)-2,6-dichlorobenzene (348 mg) triethylamine (0.15 ml) and dichloromethane (3.5 ml) was added phthalimidoacetyl chloride (186 mg) under ice-cooling, and the mixture was stirred for 1.5 hours at ambient temperature. Water was added thereto, and the resulting precipitates were collected by vacuum filtration and washed with diisopropyl ether to give 1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichloro-3-(phthalimidoacetylamino)benzene (460 mg) as crystals.
Reaction SMILES: C([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:10]([O:29]CC2C=CC=CC=2)=[N:9]1)C1C=CC=CC=1.C1(C)C=CC=CC=1>O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C:11]2[C:10](=[O:29])[NH:9][NH:8][C:13](=[O:14])[C:12]=2[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:27][CH:26]=1
Reactant: O=c1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c(OCc2ccccc2)nn1Cc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1[nH][nH]c(=O)c(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a round bottom flask was added 2-benzyl-6-(benzyloxy)-4,5-bis(4-chlorophenyl)pyridazin-3(2H)-one (15.5 gm, 30.21 mmol), toluene (70 ml) and alumina chloride (10.08 gm, 75.54 mmol). The reaction was stirred at 90° C. for 2 h. After this time, the reaction was cooled to 0° C. and water (200 ml) was slowly added to the reaction. The solution was extracted with ethyl acetate (3 L). The organic layer was washed with water (200 ml) and saturated aqueous NaCl (200 ml). The organic layer was dried (MgSO4), filtered and concentrated. The title compound, 4,5-bis(4-chlorophenyl)-1,2-dihydropyridazine-3,6-dione, was obtained as a solid and used in the without further purification. MS (M+H)=330.9, 333.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC[N:32]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:32])=[O:23])=[CH:20][CH:19]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1ccc(Nc2nc(-c3ccc(C(=O)O)cc3)nc3scnc23)cc1OC
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Nc2nc(-c3ccc(C(N)=O)cc3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.9 %

Procedure:
To a mixture of 4-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (210 mg, 0.52 mmol), EDCI (147 mg, 0.77 mmol), HOBt (104 mg, 0.77 mmol) and Et3N (104 mg, 1.07 mmol) in DCM (20 mL) was bubbled ammonia until saturation. The mixture was stirred at room temperature for 3 h, then was filtered and the filtrate was concentrated to give residue which was purified by column chromatography (DCM:MeOH=50:1) to afford 4-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamide (38 mg, 22%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 9.14 (s, 1H), 8.30 (s, 1H), 8.27 (s, 1H), 7.87 (s, 1H), 7.84 (s, 1H), 7.62 (d, 1H, J=2.4 Hz), 7.32-7.28 (m, 1H), 6.92 (d, 1H, J=9.0 Hz), 3.75 (s, 3H), 3.72 (s, 3H). LC-MS: 599 [M+H]+, tR=1.54 min. HPLC: 95.59% at 214 nm, 95.99% at 254 nm, tR=4.594 min. LC-MS: 408 [M+H]+, tR=1.392 min. HPLC: 95.38% at 214 nm, 96.23% at 254 nm, tR=5.259 min.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:8]=[C:9]([CH2:14][C:15]([OH:17])=[O:16])[C:10](=[O:13])[NH:11][N:12]=1.[CH2:18](O)[CH3:19]>>[CH2:18]([O:16][C:15](=[O:17])[CH2:14][C:9]1[C:10](=[O:13])[NH:11][N:12]=[C:7]([OH:6])[CH:8]=1)[CH3:19]
Reactant: CCO
Reactant: O=C(O)Cc1cc(O)n[nH]c1=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(O)n[nH]c1=O
Temperature: 88 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
Concentrated sulfuric acid (0.04 mL, 0.75 mmol) was added to a solution of (6-hydroxy-3-oxo-2,3-dihydro-pyridazin-4-yl)-acetic acid (Example 182-(1); 259 mg, 1.52 mmol) in ethanol (3.2 mL), and the mixture was heated while stirring at an external temperature of 84 to 92° C. for four hours. The mixture was left to stand at room temperature overnight. Then, the resulting solid was collected by filtration and sequentially washed with water and ether to give the title compound (246 mg, 82%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[S:12][C:11]2=[N:13][CH:14]=[C:15]([I:16])[N:10]2[N:9]=1.[NH2:17][C:18]1[CH:19]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:22][C:23]=1[O:24][CH3:25]>O1CCOCC1>[I:16][C:15]1[N:10]2[C:11]([S:12][C:8]([C:20]3[CH:19]=[C:18]([NH2:17])[C:23]([O:24][CH3:25])=[N:22][CH:21]=3)=[N:9]2)=[N:13][CH:14]=1
Reactant: Brc1nn2c(I)cnc2s1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ncc(-c2nn3c(I)cnc3s2)cc1N
Yield: 66.3 %

Procedure:
Dioxane (5 mL) and 2M aq Na2CO3 (1.5 mL) were added to 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (200 mg) and (5-amino-6-methoxypyridin-3-yl)boronic acid pinacol ester (200 mg), and the suspension was degassed under vacuum and filled with argon (3×). PdCl2(PPh3)2 (90 mg) was quickly added, and the reaction mixture was stirred at reflux for 2 h. Water was added, and a precipitate formed that was filtered off and washed with water followed by ether and ether/MeOH 10:1 and dried to give the desired product (150 mg) that was used without further purification in the subsequent step. HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=4.12 min, [M+H]+ m/z 373.9.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=[CH:8][C:7]=1[OH:17])[CH:4]=[CH2:5].[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22]Cl>C1(C)C=CC=CC=1>[CH3:18][N:19]([CH2:20][CH2:21][CH2:22][O:17][C:7]1[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:11][C:6]=1[CH2:3][CH:4]=[CH2:5])[CH3:24]
Reactant: CN(C)CCCCl
Reactant: C=CCc1cc(OCCCC)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCc1cc(OCCCC)ccc1OCCCN(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
Sodium hydride (106 mg) was added to a solution of 2-allyl-4-butoxyphenol (500 mg) in toluene (40 ml). The reaction mixture was heated to reflux. A solution of 3-dimethylaminopropyl chloride (437 mg) in toluene (20 ml) was added to the refluxing reaction mixture and heating continued for a further 8 hours. The reaction mixture was cooled to ambient temperature, evaporated and the residue dissolved in water (10 ml). The resulting solution was extracted with ethyl acetate (4×15 ml). The ethyl acetate extracts were combined, dried (MgSO4) and evaporated to give an oil which was further purified by flash column chromatography on silica gel (Merck Art No 9385) using a 50:50:0.1 mixture of ethyl acetate, hexane and triethylamine as eluent to give N,N-dimethyl-3-(2-allyl-4-butoxyphenoxy)propylamine as yellow oil (556 mg); microanalysis, found: C, 74.5; H, 10.2; N, 4.8% C18H29NO2 requires: C, 74.2; H, 10.0; N, 4.8%; NMR([CD3 ]2SO): 0.91(3H,t), 1.42(2H,m), 1.65(2H,m), 1.82(2H,m), 2.15(6H,s), 2.38(2H,t), 3.27(2H,d), 3.88(4H,m), 5.2(2H,m), 5.92(1H,m), 6.7(2H,m) and 6.82(1H,m); m/z 292(M+H).
Reaction SMILES: [Na].[Br:2][CH:3]([CH2:13][C:14](Br)([Br:16])[Br:15])[C:4]([CH3:12])([CH3:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl>C(O)C>[Br:2][CH:3]([CH:13]=[C:14]([Br:15])[Br:16])[C:4]([CH3:12])([CH3:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(C)(C)C(Br)CC(Br)(Br)Br
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC(C)(C)C(Br)C=C(Br)Br
Reaction time: 2 h
Yield: 52 %

Procedure:
Two milliliters of an ethanolic solution containing 92 mg (4 mmoles) of sodium was added dropwise to a cold solution of 1.95 g (4 mmoles) of ethyl 4,6,6,6-tetrabromo-3,3-dimethylhexanoate in 10 ml of absolute ethanol. The cooled mixture was stirred for 2 hours, then poured into chilled 1N hydrochloric acid. The acidic mixture was extracted with diethyl ether, and the extract was washed successively with saturated aqueous sodium bicarbonate and sodium chloride. The washed extract was dried over magnesium sulfate and distilled to give 846 mg (52% yield) of ethyl 4,6,6-tribromo-3,3-dimethyl-5-hexenoate , b.p. 130°-133°/0.3 mm.
Reaction SMILES: [F:1][C:2]1([F:15])[O:7][C:6]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:5]=2[O:4][C:3]1([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]#[CH:24].C1(C)C=CC=CC=1>C(#N)C>[CH2:24]([NH:12][C:10]1[CH:9]=[CH:8][C:6]2[O:7][C:2]([F:1])([F:15])[C:3]([F:13])([F:14])[O:4][C:5]=2[CH:11]=1)[C:23]#[CH:22]
Reactant: Nc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: C#CCNc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Temperature: 67.5 °C
Reaction time: 24 h

Procedure:
Another method to prepare the titled compound is as follows. 2,2,3,3-Tetrafluoro-6-aminobenzodioxane (50.2 g, 225 mmol) and potassium carbonate (43.54 g, 315 mmol) were suspended into acetonitrile (250 mL), stirred in a 1-liter three-necked flask equipped with an overhead mechanical stirrer, and treated with ˜80% propargyl bromide in toluene (33.5 g, ˜225 mmol). The mixture was slowly heated to 65-70° C. over about three hours. Stirring was continued at that temperature for 24 hours, at which time the heat was turned off and the mixture was permitted to cool to room temperature. The mixture was filtered through a glass fritted funnel, and the solids were rinsed with acetonitrile (300 mL). The filtrate was concentrated, reconcentrated thrice from hexanes, and chromatographed on silica (0 to 1 to 2 to 4% EtOAc/hexanes) to give the titled compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][C:22]1([CH3:28])[O:27][CH2:26][CH2:25][NH:24][CH2:23]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:24]3[CH2:25][CH2:26][O:27][C:22]([CH3:28])([CH3:21])[CH2:23]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: CC1(C)CNCCO1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: CC1(C)CN(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)CCO1

Procedure:
The title compound was synthesized in analogy to Example 47b), using 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 1 b) and 2,2-dimethylmorpholine (CAS 147688-58-2) as starting materials and isolated as colorless oil. MS (EI): m/e=382.5 [MH+].
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[C:19]=3[NH:24][C:25]([O:27][C@@H:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[F:36])[CH3:29])=[O:26])=[CH:14][C:13]=2[CH3:37])=[CH:8][CH:7]=1)C.[OH-].[Li+]>CO.O>[F:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C@H:28]([O:27][C:25]([NH:24][C:19]1[C:20]([CH3:23])=[N:21][O:22][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C:4]([OH:38])=[O:3])=[CH:11][CH:10]=2)=[C:13]([CH3:37])[CH:14]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3F)cc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(-c2onc(C)c2NC(=O)O[C@H](C)c2ccccc2F)ccc1-c1ccc(CC(=O)O)cc1

Procedure:
(4′-{4-[(R)-1-(2-Fluoro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-2′-methyl-biphenyl-4-yl)-acetic acid ethyl ester (0.282 g, 0.53 mmol) was hydrolyzed with lithium hydroxide in methanol and water, and the crude material was purified by preparative HPLC to give the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)=[O:10].[CH3:21][NH:22][CH2:23][CH2:24][OH:25].C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:25][CH2:24][CH2:23][N:22]([CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)=[O:10]
Reactant: CNCCO
Reactant: O=C(CCCCCCCBr)Nc1ccc(C(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCO)CCCCCCCC(=O)Nc1ccc(C(=O)O)cc1
Temperature: 60 °C

Procedure:
To a mixture of 4-[(8-bromooctanoyl)amino]benzoic acid (50 mg, 0.15 mmol, as prepared in Intermediate 36) in N,N-dimethylformamide (2 ml) was added 2-(methylamino)ethanol (24 microliters, 0.3 mmol, 2 equivalents, commercially available e.g. from Aldrich) followed by N,N-diisopropylethylamine (0.13 mL, 0.8 mmol, about 5 equivalents), and the resulting solution was heated at 60° C. for 16 hours. The solvent was removed by evaporation, and the residue was purified by Mass Directed Automated Preparative HPLC (Method A). Fractions containing product were pooled and evaporated to dryness to give the title compound (25.4 mg) as a pale brown solid. LCMS showed MH+=337; TRET=2.03 min.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10]C)=[O:9].[H-].[Na+].I[CH2:22][CH3:23].Cl.O1CCOCC1>CN(C=O)C>[CH2:22]([N:12]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:3]1[C:2]([CH3:1])=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=[CH:5][N:4]=1)[CH3:23]
Reactant: CCI
Reactant: COC(=O)c1ccnc(NC2CCOCC2)c1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCN(c1nccc(C(=O)O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 3-methyl-2-[(oxan-4-yl)amino]pyridine-4-carboxylate (67 mg, 0.27 mmol) in dry DMF (1.0 ml), was added to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 16 mg, 0.4 mmol) in DMF (0.3 ml) at 0° C. under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction was then treated with iodoethane (16 μl, 0.20 mmol) and stirred for 30 minutes, and then treated again with iodoethane (16 μl, 0.20 mmol) and stirred for a further 30 minutes. The reaction mixture was added to a suspension of sodium hydride (16 mg, 0.4 mmol) in DMF (0.3 ml) at 0° C. Once addition was complete, the reaction mixture was allowed to reach room temperature and stirred for 1 hour before treating with iodoethane (2×16 μl, 0.40 mmol). The reaction mixture was stirred for a further 30 minutes. Sodium hydride (16 mg, 0.4 mmol) was added to the reaction mixture and the mixture stirred for 45 minutes before treating with iodoethane (2×16 μl, 0.40 mmol) and stirred for 15 minutes before adding under nitrogen to a solution of 4M HCl/dioxane (5.0 ml) with cooling.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1.CN(C)C=O.[H-].[Na+].I[CH:30]([CH3:32])[CH3:31]>O>[NH2:1][C:2]1[N:3]([CH:30]([CH3:32])[CH3:31])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1
Reactant: CC(C)I
Reactant: Cc1cc(C)c(-c2cn(C)c3nc(N)[nH]c(=O)c23)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2cn(C)c3nc(N)n(C(C)C)c(=O)c23)c(C)c1
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
To a solution of 2-amino-5-mesityl-7-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (156 mg, 0.55 mmol) and N,N-dimethylformamide (5 ml) was added sodium hydride (60% in oil, 24 mg, 0.60 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of 2-iodopropane (102 mg, 0.60 mmol) and N,N-dimethylformamide (2 ml) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 3 hours, the mixture was diluted with water (20 ml) and extracted with ethyl acetate (50 ml×2). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (3:1) to give 88 mg (49%) of the title compound.
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:21][CH2:20][C:19]([C:23]([O:25]C)=[O:24])(F)[CH2:18]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(Cl)Cl.C[OH:31].[NH4+].[OH-]>>[CH2:1]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:21][CH2:20][C:19]([C:23]([OH:25])=[O:24])([OH:31])[CH2:18]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCc1ccc(CN2CCC(F)(C(=O)OC)C2)cc1
Reactant: CO
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCCCCCCc1ccc(CN2CCC(O)(C(=O)O)C2)cc1

Procedure:
The title compound was prepared using an analogous procedure described in EXAMPLE 34, Step E substituting (R/S)-1-(4-nonylphenyl)methyl-3-hydroxypyrrolidin-3-yl carboxylic acid, methyl ester (from Step A) for (R/S)-1-(4-nonylphenyl)methyl-3-fluoropyrrolidin-3-yl carboxylic acid, methyl ester: RF: 0.15 (90:10:1 v/v/v CH2Cl2/MeOH/NH4OH); 1H-NMR (500 MHz, CD3OD) δ 0.89 (t, J=6.9, 3H), 1.28-1.33 (m, 12H), 1.60-1.63 (m, 2H), 2.10 (m, 1H), 2.49 (m, 1H), 2.64 (t, J=7.7, 2H), 3.25 (m, 1H), 3.49-3.62 (m, 3H), 4.38 (ABq, J=13.0, 2H), 7.28 (d, J=7.8, 2H), 7.42 (d, J=7.8, 2H); ESI-MS 348 (M+H); LC-1: 3.0 min.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][N:16]([CH:49]2[CH2:51][CH2:50]2)[C:17](=[O:48])[CH:18]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][O:38][C:39]3[C:44]([Cl:45])=[CH:43][C:42]([CH3:46])=[CH:41][C:40]=3[Cl:47])=[CH:31][CH:30]=2)[CH2:19][NH:20]C(=O)OC(C)(C)C)[CH:12]=[C:11]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[N:10]=1)(C(C)(C)C)(C)C.Cl>C(Cl)Cl>[NH2:20][CH2:19][CH:18]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][O:38][C:39]2[C:40]([Cl:47])=[CH:41][C:42]([CH3:46])=[CH:43][C:44]=2[Cl:45])=[CH:31][CH:30]=1)[C:17]([N:16]([CH:49]1[CH2:50][CH2:51]1)[CH2:15][C:13]1[CH:12]=[C:11]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[N:10]=[C:9]([OH:8])[CH:14]=1)=[O:48]
Reactant: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(O[Si](C)(C)C(C)(C)C)n1
Agent: Cl
Solvent: ClCCl
Product: COCCCc1cc(CN(C(=O)C(CN)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a CH2Cl2 solution (0.03 M) of tert-butyl (3-[{[2-{[tert-butyl(dimethyl)silyl]oxy}-6-(3-methoxypropyl)pyridin-4-yl]methyl}(cyclopropyl)amino]-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from the previous step (1 eq.) was added HCl (4.0 M dioxane solution, 60 eq.). The resulting solution was stirred at RT for 3 h and the volatiles were removed in vacuo. The resulting residue was recrystallized from ether-dichloromethane to afford the title compound as a white solid. MS (ESI+): 616.1.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([Cl:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[CH3:16][O:17][C:18]1[CH:33]=[CH:32][C:21]([CH2:22][NH:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:13][C:6]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([N:23]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][C:21]2[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:33][CH:32]=2)[N:3]=[C:4]([S:14][CH3:15])[N:5]=1
Reactant: CCOC(=O)CCCNCc1ccc(OC)cc1
Reactant: CCOC(=O)c1c(Cl)nc(SC)nc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN(Cc1ccc(OC)cc1)c1nc(SC)nc(Cl)c1C(=O)OCC
Temperature: 80 °C
Yield: 57.3 %

Procedure:
The mixture of ethyl 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylate (7.9 g, 29.88 mmol) and ethyl 4-((4-methoxybenzyl)amino)butanoate (5 g, 19.92 mmol) in DMF (500 mL) and DIPEA (4.6 g, 35.85 mmol) was heated at 80° C. for 2 h. The reaction mixture was then cooled to room temperature and crushed ice was added. The reaction mixture was extracted with EtOAc (3×100 mL), and the combined EtOAc layer was dried over sodium sulphate, filtered and evaporated under reduced pressure to give a residue which was purified by column chromatography (silica gel, gradient 0-5% EtOAc in hexanes) to afford ethyl 4-chloro-6-((4-ethoxy-4-oxobutyl)(4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (5.5 g, 40%). 1H NMR (400 MHz, CDCl3): δ 7.12 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 4.66 (s, 2H), 4.16 (q, J=6.8 Hz, 2H), 4.10 (q, J=7.2 Hz, 2H), 3.79 (s, 3H), 3.42 (t, J=7.6 Hz, 2H), 2.45 (s, 3H), 2.24 (t, J=6.8 Hz, 2H), 1.94 (quintet, J=7.2 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H), 1.22 (t, J=7.2 Hz, 3H). LCMS [M+H]: 482