Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]3[CH2:16][N:15]([C:17]([N:19]4[CH2:24][C:23]([CH3:26])([CH3:25])[N:22]([CH3:27])[CH2:21][C@@H:20]4[CH3:28])=[O:18])[C:14]([CH3:30])([CH3:29])[C:11]=3[NH:12][N:13]=2)[C:5]([F:31])=[CH:4][N:3]=1.[CH2:32](B1OC(C)(C)C(C)(C)O1)[CH:33]=[CH2:34].C(=O)([O-])[O-].[Cs+].[Cs+].O>[Pd].C1COCC1>[F:31][C:5]1[C:6]([NH:8][C:9]2[C:10]3[CH2:16][N:15]([C:17]([N:19]4[CH2:24][C:23]([CH3:26])([CH3:25])[N:22]([CH3:27])[CH2:21][C@@H:20]4[CH3:28])=[O:18])[C:14]([CH3:30])([CH3:29])[C:11]=3[NH:12][N:13]=2)=[N:7][C:2]([CH2:32][CH2:33][CH3:34])=[N:3][CH:4]=1
Reactant: C[C@H]1CN(C)C(C)(C)CN1C(=O)N1Cc2c(Nc3nc(Cl)ncc3F)n[nH]c2C1(C)C
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1ncc(F)c(Nc2n[nH]c3c2CN(C(=O)N2CC(C)(C)N(C)C[C@@H]2C)C3(C)C)n1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a pressure vessel was added [3-(2-Chloro-5-fluoro-pyrimidin-4-ylamino)-6,6-dimethyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-5-yl]-((S)-2,4,5,5-tetramethyl-piperazin-1-yl)-methanone (0.150 g, 0.330 mmol), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.12 g, 6.66 mmol), cesium carbonate (0.543 g, 1.66 mmol), dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.0408 g, 0.0498 mmol), H2O (0.3 mL), and THF (3 mL). The suspension was purged with argon for 2 min, then stirred at 100° C. for 15 h. The cooled solution was filtered to remove undissolved solids and the volatiles removed in vacuo. The residue was redissolved in MeOH (5 mL) and 10% palladium on carbon (0.0400 g, 0.380 mmol) was added. The suspension was evacuated and backfilled with hydrogen for 3 times and allowed to stir for 15 h under hydrogen. The suspension was filtered through Celite, the filter cake washed with CH2Cl2, and the filtrate concentrated. Preparative HPLC provided the desired product I1 as a white solid (0.025 g, 14%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][CH:12]([CH3:14])[CH3:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:15]Br.OS(O)(=O)=O>CC(O)=O.CO>[Br:15][C:7]1[C:3]([C:4]([OH:6])=[O:5])=[C:2]([CH3:1])[C:10]([O:11][CH:12]([CH3:14])[CH3:13])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: Cc1c(OC(C)C)cccc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(OC(C)C)ccc(Br)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To a solution of 2-methyl-3-(propan-2-yloxy)benzoic acid (Cpd NN, 1.08 g, 5.56 mmol) in AcOH (5 mL) was added Br2 (888 mg, 5.56 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum to give an oil. The crude oil was dissolved in MeOH (20 mL) then H2SO4 was added and the resulting mixture was heated at 65° C. for 2 hours. The reaction mixture was concentrated under vacuum and the residue dissolved in EtOAc. The organic layer was washed with water and brine, dried with Na2SO4, and concentrated under vacuum to give 6-bromo-2-methyl-3-(propan-2-yloxy)benzoic acid (Cpd OO, 1.3 g, 86%) as an oil which solidified to a tan solid upon standing.
Reaction SMILES: C(O)(C(F)(F)F)=O.Cl[C:9]1[CH:14]=[C:13]([N:15]2[CH:24]([CH3:25])[CH2:23][C:22]3[C:17](=[CH:18][C:19]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)=[CH:20][CH:21]=3)[CH2:16]2)[N:12]=[C:11]([NH2:32])[N:10]=1.[NH:33]1[CH2:38][CH2:37][CH2:36][C@H:35]([NH:39]C(=O)OC(C)(C)C)[CH2:34]1>>[NH2:39][C@H:35]1[CH2:36][CH2:37][CH2:38][N:33]([C:9]2[CH:14]=[C:13]([N:15]3[CH:24]([CH3:25])[CH2:23][C:22]4[C:17](=[CH:18][C:19]([C:26]5[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=5)=[CH:20][CH:21]=4)[CH2:16]3)[N:12]=[C:11]([NH2:32])[N:10]=2)[CH2:34]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(Cl)nc(N)n1
Solvent: O=C(O)C(F)(F)F
Product: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(N2CCC[C@H](N)C2)nc(N)n1

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 118 starting from 4-chloro-6-[3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine and tert-butyl(3S)-piperidin-3-ylcarbamate (CNH Technologies, Cat. No. C-3102S). LCMS (M+H)+: m/z=419.2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:21]=[CH:20][C:11]2[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[C:13]([CH3:15])[O:14][C:10]=2[CH:9]=1.[Cl:22][C:23]1[N:28]=[C:27](Cl)[CH:26]=[CH:25][N:24]=1.O>CN(C=O)C>[Cl:22][C:23]1[N:28]=[C:27]([O:7][C:8]2[CH:21]=[CH:20][C:11]3[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=2)[CH:26]=[CH:25][N:24]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CNC(=O)c1c(C)oc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(C)oc2cc(Oc3ccnc(Cl)n3)ccc12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Potassium carbonate (1.5 mmol) was added to a solution of 6-hydroxy-N,2-dimethylbenzofuran-3-carboxamide (1 mmol) in 5 ml DMF. After 30 mins, 2,4-dichloropyrimidine (1 mmol) was added and the reaction mixture was stirred overnight at 60° C. Water was added. The resultant solid was filtered, washed with water, and dried to give 6-(2-chloropyrimidin-4-yloxy)-N,2-dimethylbenzofuran-3-carboxamide in a yield of 82%, as a solid, which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:12][CH:13]3[CH2:15][C:14]3([F:17])[F:16])[S:7](=[O:11])(=[O:10])[N:8]([CH3:9])[C:4]=2[CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:16][C:14]1([F:17])[CH2:15][CH:13]1[CH2:12][N:6]1[C:5]2[CH:18]=[CH:19][C:2]([C:22]3[CH:23]=[C:24]([CH:25]=[CH:26][C:21]=3[F:20])[C:27]([O:29][CH3:30])=[O:28])=[CH:3][C:4]=2[N:8]([CH3:9])[S:7]1(=[O:11])=[O:10]
Reactant: CN1c2cc(Br)ccc2N(CC2CC2(F)F)S1(=O)=O
Reactant: COC(=O)c1ccc(F)c(B(O)O)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(F)c(-c2ccc3c(c2)N(C)S(=O)(=O)N3CC2CC2(F)F)c1
Temperature: 100 °C

Procedure:
5-bromo-1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (4-1) (100 mg, 0.28 mmol, 1 eq), [2-fluoro-5-(methoxycarbonyl)phenyl]boronic acid (84 mg, 0.43 mmol, 1.5 eq), cesium carbonate (185 mg, 0.57 mmol, 2.0 eq) and bis(tri-t-butylphosphine)palladium(0) (29 mg, 0.06 mmol, 0.2 eq) were combined in dioxane (1.5 mL) and water (0.3 mL). The resulting mixture was heated in the microwave at 100° C. for 10 minutes. The reaction mixture was diluted with EtOAc (10 mL), washed with water (2 mL) and brine (2 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (12 g SiO2, 0-70% EtOAc in hexanes) to afford methyl 3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl}-4-fluorobenzoate (17-1) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.14 (dd, J=1.6, 6.0 Hz, 1 H); 8.01 (m, 1 H); 7.21 (m, 2 H); 6.95 (t, J=1.2 Hz, 1 H); 6.90 (d, J=6.4 Hz, 1 H); 3.94 (s, 3 H); 3.91 (d, J=5.6 Hz, 2 H); 3.33 (s, 3 H); 2.14 (m, 1 H); 1.64 (m, 1 H); 1.39 (m, 1 H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][NH:27][CH2:26]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:26]2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: Clc1ccc2c(c1)CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Nc1c(F)c(N2Cc3ccc(Cl)cc3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 69.6 %

Procedure:
268 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 154 mg of 5- chloroisoindoline, 274 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 270 mg of the target compound.
Reaction SMILES: [F-].[CH2:2]([N+](CCCC)(CCCC)CCCC)[CH2:3][CH2:4]C.[Si]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([O:42][CH3:43])[N:36]=2)=[O:34])=[CH:29][C:28]=1[Cl:44])(C(C)(C)C)(C)C.O>O1CCCC1>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([C:33]([C:30]2[CH:31]=[CH:32][C:27]([O:26][CH:3]([CH3:4])[CH3:2])=[C:28]([Cl:44])[CH:29]=2)=[O:34])=[N:36][C:37]=1[O:42][CH3:43]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: COc1nc(C(=O)c2ccc(O[Si](C)(C)C(C)(C)C)c(Cl)c2)ccc1Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(C(=O)c2ccc(OC(C)C)c(Cl)c2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (3.39 mL) was added to a solution of (4-{[tert-butyl(dimethyl)silyl]oxy}-3-chlorophenyl)(5-chloro-6-methoxypyridin-2-yl)methanone (700 mg) in tetrahydrofuran (10 mL) at room temperature, and the mixture was stirred at room temperature for two hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (10 mL), and 2-iodopropane (333 μL) and potassium carbonate (464 mg) were sequentially added at room temperature, followed by stirring at 65° C. for three hours. The reaction solution was returned to room temperature and water was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the title compound as a colorless oil (538 mg, 93%).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16]2[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=2)=[CH:10]3)=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([CH:31]2[CH2:35][CH2:34][CH2:33][NH:32]2)[CH2:27][CH2:26]1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:21]([N:20]1[C:16]([C:11]2[N:12]=[C:13]3[C:14]4[CH:15]=[C:2]([N:32]5[CH2:33][CH2:34][CH2:35][CH:31]5[CH:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)[CH:3]=[CH:4][C:5]=4[O:6][CH2:7][CH2:8][N:9]3[CH:10]=2)=[N:17][CH:18]=[N:19]1)([CH3:23])[CH3:22]
Reactant: CN1CCC(C2CCCN2)CC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(N3CCCC3C3CCN(C)CC3)ccc1OCC2
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of 13-bromo-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene (200 mg, 0.540 mmol), 1-methyl-4-(pyrrolidin-2-yl)piperidine (108 mg, 0.640 mmol), Pd(PtBu3)2 (7 mg, 0.015 mmol), NaOtBu (155 mg, 1.62 mmol) in toluene (2 ml) in a seal tube was degassed with N2 for three times. The resulting mixture was stirred at 110° C. for 1 h. The solid was filtered off through Celite. The filtrate was concentrated to give the crude product, which was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to afford 161. The (R) and (S) enantiomers were further purified and separated by chiral HPLC (AD column, 30% EtOH (0.1% DEA) in n-Hexane isocratic) to give 6 mg of one enantiomer and 11 mg of the other (5% total yield)
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:12]/[C:13]1[C:20]([Cl:21])=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[Cl:22])=[N+]=[N-]>C1(C)C=CC=CC=1>[Cl:22][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([Cl:21])[C:13]=1[N:12]1[CH:11]=[C:5]2[CH:6]=[N:7][CH:8]=[C:9]([F:10])[C:4]2=[N:1]1)[C:17]#[N:18]
Reactant: N#Cc1cc(Cl)c(/N=C/c2cncc(F)c2N=[N+]=[N-])c(Cl)c1
Solvent: Cc1ccccc1
Product: N#Cc1cc(Cl)c(-n2cc3cncc(F)c3n2)c(Cl)c1
Temperature: 25 °C
Yield: 75.2 %

Procedure:
A suspension of 4-{[1-(4-azido-5-fluoro-pyridin-3-yl)-meth-(E)-ylidene]-amino}-3,5-dichlorobenzonitrile (4.0 g, 12.0 mmol) in toluene (50 mL) was heated under reflux for 1 hour and then cooled to room temperature. The precipitated solid was removed by filtration and washed sequentially with toluene, ethyl acetate, and 1:1 ethyl acetate:DCM. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography (0-100% ethyl acetate in cyclohexane) to afford the title compound as an off-white solid (2.77 g, 75% yield). 1H NMR (300 MHz, CDCl3): δ 9.11 (d, J=2.2 Hz, 1H), 8.36 (d, J=2.4 Hz, 1H), 8.24 (d, J=3.4 Hz, 1H), 7.85 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.OS(O)(=O)=O.[CH3:19][CH2:20]O>CCOC(C)=O>[OH:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:19][CH3:20])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: O=C(O)c1cc(O)c2[nH]ncc2c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(O)c2[nH]ncc2c1
Yield: 73 %

Procedure:
A solution of 7-hydroxy-1H-indazole-5-carboxylic acid (1.08 g, 6.06 mmol) in EtOH (50 mL) containing conc. H2SO4 (0.34 mL) was heated at reflux overnight. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3. The aqueous phase was back extracted with EtOAc (3×). The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated to afford ethyl 7-hydroxy-1H-indazole-5-carboxylate (918 mg, 73%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[O:14][C:15]2[C:20]([C:21](=[O:23])[CH:22]=1)=[C:19]([O:24][CH3:25])[CH:18]=[C:17]([O:26][CH3:27])[C:16]=2[C@@H:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH3:36])[CH2:30][C@H:29]1[OH:37].C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[O:14][C:15]2[C:20]([C:21](=[O:23])[CH:22]=1)=[C:19]([O:24][CH3:25])[CH:18]=[C:17]([O:26][CH3:27])[C:16]=2[C@@H:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH3:36])[CH2:30][C@H:29]1[O:37][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CCCN1CC[C@@H](c2c(OC)cc(OC)c3c(=O)cc(-c4ccccc4Cl)oc23)[C@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCN1CC[C@@H](c2c(OC)cc(OC)c3c(=O)cc(-c4ccccc4Cl)oc23)[C@H](OS(C)(=O)=O)C1

Procedure:
Methanesulfonyl chloride (0.178 g, 1.55 mmol), compound of example 129 (0.55 g, 1.2 mmol) and triethylamine (1 mL) in CHCl3 (10 mL), were reacted as described in example 3, method A to obtain (±)-trans-methanesulfonic acid 4-[2-(2-chloro-phenyl)-5,7-dimethoxy-4-oxo-4H-chromen-8-yl]-1-propyl-piperidin-3-yl ester. This was dissolved in dry IPA at 80-90° C., anhydrous NaOAc (0.49 g, 5.98 mmol) was added, and the reaction mixture was processed as in example 3, method A to give an oily residue which was purified using a silica gel column and 1% IPA+1% liquor NH3 in CHCl3 as eluant to obtain the title compound.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[CH:29]=[C:28]([C:37]([N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)=[O:38])[CH:27]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].[CH2:45](OC(CCC1C(OCCCC(OCC)=O)=CC=CC=1CCCCCCOC1C=C(C=C(C2C=CSC=2)C=1)C(O)=O)=O)C.C(OC(N1CCCNCC1)=O)(C)(C)C>>[C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[CH:29]=[C:28]([C:37]([N:39]3[CH2:44][CH2:45][CH2:43][NH:42][CH2:41][CH2:40]3)=[O:38])[CH:27]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]
Reactant: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCNCC3)cc(-c3ccsc3)c2)c1CCC(=O)O
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Agent: CC(C)(C)OC(=O)N1CCCNCC1
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCCNCC3)cc(-c3ccsc3)c2)c1CCC(=O)O

Procedure:
The title compound was prepared by the same method as 4-(2-(2-carboxy-ethyl)-3-{6-[3-(piperazine-1-carbonyl)-5-thiophen-3-yl-phenoxy]-hexyl}-phenoxy)-butyric acid starting from 3-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-5-thiophen-3-yl-benzoic acid and [1,4]diazepane-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][N:19]=[C:18](F)[CH:17]=2)=[N:5][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:7][CH:8]=1.C([O-])(O)=[O:24].[Na+]>>[F:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][NH:19][C:18](=[O:24])[CH:17]=2)=[N:5][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:7][CH:8]=1
Reactant: Fc1cc(-c2nc(NC3CCOCC3)ncc2F)ccn1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: O=c1cc(-c2nc(NC3CCOCC3)ncc2F)cc[nH]1
Reaction time: 2.5 h
Yield: 97 %

Procedure:
1M HCl (15 mL) was added to 5-fluoro-4-(2-fluoropyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (0.26 g, 0.89 mmol). The suspension was heated at reflux. After 2.5 hours, the suspension was neutralized with NaHCO3, and the solid was collected by vacuum filtration. This was suspended in MeOH and evaporated to yield 4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.25 g, 0.86 mmol, 97% yield). 1H NMR (400 MHz, (CD3)2SO) δ 11.80 (br s, 1H), 8.48 (d, 1H), 7.52 (d, 1H), 7.40 (d, 1H), 6.83 (br s, 1H), 6.65-6.61 (m, 1H), 3.90-3.84 (m, 3H), 3.43-3.36 (m, 2H), 1.88-1.81 (m, 2H), 1.57-1.46 (m, 2H); m/z (APCI-pos) M+1=291.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH:7][CH:12]([C:14]2[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])[CH:8]=1
Reactant: Cc1ccc(F)cc1N
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: Cc1ccc(F)cc1NC(C)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 61.7 %

Procedure:
5-fluoro-2-methylaniline (102 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(5-fluoro-2-methylphenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (56 mg, 61%) as a white solid. Mass Spectrum: M+H+ 454. NMR Spectrum (DMSOd6): 1.60 (d, 3H), 2.20 (s, 3H), 2.69 (bs, 3H), 2.93 (bs, 3H), 3.53-3.65 (m, 4H), 3.72-3.80 (m, 4H), 5.08-5.18 (m, 1H), 5.62 (s, 1H), 5.73 (d, 1H), 6.52 (d, 1H), 6.92 (dd, 1H), 7.18 (dd, 1H), 7.58 (d, 1H), 7.80 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([O:25][CH3:26])[CH2:9][C@H:10]([CH2:21][CH2:22][CH2:23][CH3:24])[C:11]([NH:13][O:14]C2CCCCO2)=[O:12])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([O:25][CH3:26])[CH2:9][C@H:10]([CH2:21][CH2:22][CH2:23][CH3:24])[C:11]([NH:13][OH:14])=[O:12])=[CH:4][CH:3]=1
Reactant: CCCC[C@@H](C[C@@H](OC)c1ccc(F)cc1)C(=O)NOC1CCCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC[C@@H](C[C@@H](OC)c1ccc(F)cc1)C(=O)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a solution of (2S)-2-((R)-2-(4-fluorophenyl)-2-methoxyethyl)-N-(tetrahydro-2H-pyran-2-yloxy)hexanamide (43 mg, 0.12 mmol) in 3 mL DCM was slowly added 3 mL TFA followed by stirring for 30 min at room temperature. The solvent was evaporated and the product isolated by flash column chromatography eluting with 0% to 10% methanol/DCM to give 26 mg of the title compound as white solid.
Reaction SMILES: C(OC([N:8]([C:13]1[CH:52]=[CH:51][C:16]([C:17]([O:19][CH2:20][CH2:21][C:22]([O:24][C@H:25]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:45])[F:44])=[C:38]([O:46][CH2:47][CH:48]3[CH2:50][CH2:49]3)[CH:37]=2)[CH2:26][C:27]2[C:32]([Cl:33])=[CH:31][N+:30]([O-:34])=[CH:29][C:28]=2[Cl:35])=[O:23])=[O:18])=[CH:15][C:14]=1[O:53][CH2:54][CH:55]1[CH2:57][CH2:56]1)[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.O1CCOCC1>C(Cl)Cl.Cl>[Cl:35][C:28]1[CH:29]=[N+:30]([O-:34])[CH:31]=[C:32]([Cl:33])[C:27]=1[CH2:26][C@@H:25]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:44])[F:45])=[C:38]([O:46][CH2:47][CH:48]2[CH2:50][CH2:49]2)[CH:37]=1)[O:24][C:22](=[O:23])[CH2:21][CH2:20][O:19][C:17](=[O:18])[C:16]1[CH:51]=[CH:52][C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:14]([O:53][CH2:54][CH:55]2[CH2:56][CH2:57]2)[CH:15]=1
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)OCCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1ccc(C(=O)OCCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 85.7 %

Procedure:
To a solution of (S)-4-(2-(3-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoyloxy)propanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.450 g, 0.523 mmol) in dry DCM (15 ml), 4M HCl in dioxane (0.654 ml, 2.62 mmol) was added. The resulting mixture was stirred at RT for 4 days. The solvent was evaporated and the residue was purified by trituration with Et2O (30 ml) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoyloxy)propanoyloxy)ethyl)-pyridine 1-oxide (0.340 g, 0.448 mmol, 86% yield, MS/ESI+759.31 [MH]+, [αD]=−8.9, c=0.6, DCM).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H-].[Na+].[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br.O>O1CCCC1>[CH3:1][N:2]([CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([Br:14])[CH:16]=1)[C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCC(=O)NC
Reactant: BrCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCC(=O)N(C)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
5 g (31.8 mmol) of N-methyloctanamide (1a) are added at 0° C. to a suspension of 1.4 g (35 mmol) of sodium hydride (60% in grease) in 60 mL of tetrahydrofuran. The reaction mixture is stirred for 30 minutes at room temperature and a solution of 8.9 g (35 mmol) of 3-bromobenzyl bromide in 15 mL of tetrahydrofuran is then added. The mixture is stirred for 16 hours at room temperature. The reaction is stopped by adding 100 mL of water and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (75/25 heptane/ethyl acetate). 7.4 g of N-methyl-N-(3-bromobenzyl)octanamide are obtained. Yield=71%.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][CH3:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH3:11])[C:13](=[O:14])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CNC1CCN(C(C)=O)CC1
Reactant: O=C(Cl)OCc1ccccc1
Product: CC(=O)N1CCC(N(C)C(=O)OCc2ccccc2)CC1
Yield: 54 %

Procedure:
The amine obtained in Stage A is treated with benzyl chloroformate in accordance with the process described in Stage B of Example 1 to obtain the desired carbamate.