Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Br:5][C:6]1[N:7]=[C:8]([NH:26][C:27]([CH3:43])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:28])[C:9](=[O:25])[N:10]([C:12]2[CH:13]=[C:14]([CH:20]=[C:21]([F:24])[C:22]=2[CH3:23])[C:15](OCC)=[O:16])[CH:11]=1.C([Mg]Cl)(C)C.Cl>C1COCC1>[Br:5][C:6]1[N:7]=[C:8]([NH:26][C:27]([CH3:43])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH3:28])[C:9](=[O:25])[N:10]([C:12]2[CH:13]=[C:14]([CH:20]=[C:21]([F:24])[C:22]=2[CH3:23])[C:15]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:16])[CH:11]=1
Reactant: NC1CC1
Reactant: CCOC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(NC(C)(C)c3ccccc3OCc3ccccc3)c2=O)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1cc(Br)nc(NC(C)(C)c2ccccc2OCc2ccccc2)c1=O
Temperature: 75 °C
Reaction time: 16 h

Procedure:
Cyclopropylamine (1.86 mL) was added to 3-[5-bromo-3-[[1-methyl-1-[2-(phenyl methoxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-5-fluoro-4-methyl-benzoic acid, ethyl ester (Example 169e, 1.6 g) in THF (24 mL) under nitrogen at room temperature and isopropylmagnesium chloride (5.28 mL of a 2M solution in THF) was then added dropwise over 10 min. The resulting solution was stirred at 75° C. for 16 h. After cooling to room temperature, the solution was acidified with 2M HCl and extracted into dichloromethane. The organic fractions were concentrated in vacuo to give the subtitle compound (0.7 g).
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:5]=[C:6]([CH2:32][CH2:33][CH3:34])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:8]=1[C:9]([O:11]CC)=[O:10])[CH3:3].O.[OH-].[Li+]>>[OH:1][CH:2]([C:4]1[N:5]=[C:6]([CH2:32][CH2:33][CH3:34])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:8]=1[C:9]([OH:11])=[O:10])[CH3:3]
Reactant: CCCc1nc(C(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCc1nc(C(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 64.9 %

Procedure:
Following a procedure similar to that described in Example 36, 0.82 g of ethyl 4-(1-hydroxyethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 40(c)] was hydrolyzed using 0.43 g of lithium hydroxide monohydrate, to give 0.50 g of the title compound as a powder, melting at 198°-201° C.
Reaction SMILES: C=O.[CH3:3][NH:4][CH3:5].[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2.[C:16]([O-])(O)=O.[Na+].[OH-].[Na+]>CCO.CC(O)=O>[Cl:6][C:7]1[CH:8]=[C:9]2[C:5](=[CH:14][CH:15]=1)[NH:4][CH:3]=[C:10]2[CH2:11][N:12]([CH3:16])[CH3:13]
Reactant: CNC
Reactant: O=C([O-])O
Reactant: Clc1ccc2[nH]ccc2c1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CN(C)Cc1c[nH]c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution of aqueous formaldehyde (37%, 2.95 mL, 66.0 mmol) and dimethylamine (40%, 5.30 mL, 66.0 mmol) in 20 mL EtOH was cooled to 0° C. 5-Chloroindole (4.0 g, 26.4 mmol) was dissolved in a HOAc:EtOH mixture (1:1, 40 mL) and added dropwise to the reaction mixture. After stirring at this temperature for 2 h, the mixture was allowed to warm to room temperature and stir overnight. The mixture was added to a sat'd solution of NaHCO3. 1 N NaOH was added until the pH was between 9-10. The resulting mixture was extracted with CH2Cl2 (3×). The organics were combined and washed with a sat'd aq. NaCl, dried over MgSO4, filtered and concentrated in vacuo to give 4.65 g (85%) of 5-chloro-3-[(dimethylamino)methyl] indole as a yellow powder. Without further purification, 5-chloro-3-[(dimethylamino)methyl] indole (4.65 g, 22.4 mmol) was dissolved in dimethylformamide (80 mL) at room temperature with stirring. To this was added KCN (2.18 g, 33.5 mmol) in H2O (10 mL). The mixture was warmed to 140° C. and stirred for 14 h. H2O was added and the mixture was extracted with EtOAc (2×). The organics were combined and washed with sat'd brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by SiO2 flash chromatography (3:2, Heptane:EtOAc) to give 2.65 g (63%) of 5-chloroindole-3-acetonitrile. 1H NMR (DMSO-d6, 300 MHz) δ 11.30 (br s, 1 H), 7.63 (s, 1 H), 7.42-7.38 (m, 2 H), 7.05 (d, J=6.0 Hz, 1 H), 5.70 (s, 2 H),
Reaction SMILES: [CH3:1][Si:2]([CH2:5][NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=[O:21])([CH3:4])[CH3:3].[CH3:22]O.C=O.[C:26](=[O:29])([O-])[O-].[K+].[K+]>ClCCl>[CH3:22][O:29][CH2:26][N:6]([CH2:5][Si:2]([CH3:3])([CH3:4])[CH3:1])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=[O:21]
Reactant: C[Si](C)(C)CNCCc1ccccc1N1CCCCC1=O
Reactant: O=C([O-])[O-]
Reactant: CO
Agent: C=O
Agent: [K+]
Solvent: ClCCl
Product: COCN(CCc1ccccc1N1CCCCC1=O)C[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 223.8 %

Procedure:
1-[2-(2-{[(Trimethylsilyl)methyl]amino}ethyl)phenyl]piperidin-2-one a5-1 (912 mg, 3 mmol, 1 eq) is slowly added at −10° C. to a solution of methanol (220 μl, 5.4 mmol, 1.8 eq) and aqueous formaldehyde (37%, 600 μl). The reaction mixture is stirred at 0° C. for 1 h. Potassium carbonate (2 g) is added and the mixture is stirred 1 h at 0° C. Dichloromethane (15 ml) is added, the mixture obtained is dried over MgSO4, filtered, and the filtrate is concentrated under vacuum to afford 2.34 g of 1-[2-(2-{(methoxymethyl)[(trimethylsilyl)methyl]amino}ethyl)phenyl]piperidin-2-one a5-2.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][C@H:21](O)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@@H:23]3[CH2:22][CH2:21][CH2:20][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:24]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
Temperature: 70 °C
Reaction time: 72 h
Yield: 41.1 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (4.0 g, 15.32 mmol, 1.0 eq), (S)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (4.313 g, 21.44 mmol, 1.4 eq), and PPh3 (8.031 g, 30.64 mmol, 2.0 eq) in dry THF (200 mL), DIAD (4.658 g, 22.98 mmol, 1.5 eq) was added at room temperature. The reaction mixture was stirred at 70° C. for 72 h. The reaction mixture was concentrated and purified by silica gel chromatography (eluted with PE:EtOAc=1:1) to afford (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (2.8 g, 41.2% in yield).
Reaction SMILES: C([N:3]([CH2:6]C)CC)C.[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13](C(O)=O)=[C:12]2[NH:22][C@@H:23]1[CH2:27][CH2:26][O:25][CH2:24]1.P(N=[N+]=[N-])(=O)(OC1C=CC=CC=1)[O:29]C1C=CC=CC=1>CN(C=O)C.O>[Br:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[NH:3][C:6](=[O:29])[N:22]([C@@H:23]4[CH2:27][CH2:26][O:25][CH2:24]4)[C:12]=3[C:11]=2[CH:10]=1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: O=C(O)c1cnc2ccc(Br)cc2c1N[C@@H]1CCOC1
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2cnc3ccc(Br)cc3c2n1[C@@H]1CCOC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
Triethylamine (2.60 ml, 18.69 mmol) was added to 6-bromo-4-[[(3R)-tetrahydrofuran-3-yl]amino]quinoline-3-carboxylic acid (2.1 g, 6.23 mmol) in DMF (30 mL) and the resulting mixture stirred at ambient temperature for 1 h. Diphenyl phosphorazidate (3.43 g, 12.46 mmol) was added and the resulting mixture stirred at 60° C. overnight. The reaction mixture was diluted with water (300 mL) and the solids collected by filtration to afford the desired material as a yellow solid (2.0 g, 96%). NMR Spectrum: 1H NMR (300 MHz, DMSO-d6) δ 2.42-2.45 (2H, m), 3.85-3.90 (1H, m), 4.05-4.16 (2H, m), 4.16-4.25 (1H, m), 5.62-5.72 (1H, m), 7.16-7.18 (1H, m), 7.74 (1H, d), 7.97 (1H, d), 8.68 (1H, s), 8.73 (1H, s), 11.84 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=334.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].[CH3:7][CH:8]([C:12]([OH:14])=O)[C:9]([OH:11])=O.C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][N:2]1[C:9](=[O:11])[CH:8]([CH3:7])[C:12](=[O:14])[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: CC(C(=O)O)C(=O)O
Reactant: CNC(=O)NC
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC1C(=O)N(C)C(=O)N(C)C1=O
Temperature: 90 °C
Yield: 41.5 %

Procedure:
75 g (0.85 mol) of 1,3-dimethylurea and 102 g (0.86 mol) of methyl malonic acid were dissolved in 300 ml of glacial acetic acid at 65° C. To the solution was added 330 ml of acetic anhydride, the temperature was gradually raised and the mixture was refluxed by heating at 90° C. for 6 hours. The reaction solution was concentrated under reduced pressure, and benzene was added to the residue. The crystals thus-deposited were collected by filtration and recrystallized from benzene to obtain 60 g of 1,3,5-trimethylbarbituric acid. Yield: 42%, Melting Point: 83° to 85° C.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([OH:10])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[CH:32]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([NH:22][C:23]1[CH:44]=[CH:43][CH:42]=[C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]3[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]4[CH2:40][CH2:41]4)=[O:38])[N:35]=3)[CH:32]=2)[CH:24]=1)=[O:10]
Reactant: Cn1ncc(C(=O)O)c1Cl
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cn1ncc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c1Cl
Yield: 8.6 %

Procedure:
In the same manner as in Example 18-4 and using 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (291 mg, 1.81 mmol), tetrahydrofuran (10 mL), oxalyl chloride (236 μL, 2.72 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.647 mmol), N,N-dimethylformamide (2 drops) and N,N-dimethylacetamide (10 mL) as starting materials, the title compound (25.0 mg, 9%) was obtained as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[S:14][CH:15]=[C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH:30]=[N:29][N:28]=[N:27]4)=[CH:22][CH:21]=3)[N:17]=2)[CH2:9]1)=O)(C)(C)C.[ClH:31]>ClCCl.CO.O1CCOCC1>[NH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[S:14][CH:15]=[C:16]([CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH:30]=[N:29][N:28]=[N:27]4)=[CH:24][CH:25]=3)[N:17]=2)[CH2:9]1.[ClH:31]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)C1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1cc(-n2cnnn2)ccc1OCc1csc(C2CCNC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (from Example 102) (411 mg, 0.959 mmol) in dichloromethane (10 mL) and methanol (2 mL) were treated with 1 mL of 4N HCl in dioxane. The resulting solution was stirred at room temperature for 30 minutes. The solvents were removed in vacuo to afford the desired product as an HCl salt.
Reaction SMILES: [NH3:1].[CH:2]1([CH2:8][C:9](Cl)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>C(Cl)(Cl)Cl>[CH:2]1([CH2:8][C:9]([NH2:1])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N
Reactant: O=C(Cl)CC1CCCCC1
Solvent: ClC(Cl)Cl
Product: NC(=O)CC1CCCCC1
Yield: 87.8 %

Procedure:
Aqueous ammonia was added to solution of 2-cyclohexylacetyl chloride (500 mg, 3.11 mmol) in CHCl3 (10 ml). After completion of reaction, the reaction mixture was diluted with CHCl3 (2×30 ml). The organic layer was washed with saturated sodium bicarbonate solution, brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under vacuum, crude compound was washed with hexane (2×8 ml) and dried to afford 400 mg (87.8%) of 2-cyclohexylacetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[C:17]([CH2:22][OH:23])=[N:18][O:19][C:20]=2[CH3:21])=[O:9])=[CH:4][CH:3]=1.C(Cl)Cl.CCN(CC)CC.[S:34](Cl)([CH3:37])(=[O:36])=[O:35]>O>[CH3:37][S:34]([O:23][CH2:22][C:17]1[C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:8](=[O:9])[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:20]([CH3:21])[O:19][N:18]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1onc(CO)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1onc(COS(C)(=O)=O)c1-c1ccccc1C(=O)c1ccc(Cl)cc1

Procedure:
To a round bottomed flask was added (4-chlorophenyl)(2-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)phenyl)methanone (47.2 mg, 0.144 mmol), DCM, and Et3N (40.1 μl, 0.288 mmol). The solution was cooled to 0° C. before addition of Ms-Cl (13.47 μl, 0.173 mmol). The reaction was stirred at 0° C. for 30 min before addition of water. The layers were separated and the aqueous was extracted with DCM. The combined organics were dried over Na2SO4, filtered, and concentrated to afford crude (4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazol-3-yl)methyl methanesulfonate. To a round bottomed flask was added (4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazol-3-yl)methyl methanesulfonate (58.4 mg, 0.144 mmol), DMF, and sodium azide (28.1 mg, 0.432 mmol). The reaction was stirred at room temperature for 2 h before diluting with water and extracting the aqueous with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated to afford crude (2-(3-(azidomethyl)-5-methylisoxazol-4-yl)phenyl) (4-chlorophenyl)methanone. To a round bottomed flask was added (2-(3-(azidomethyl)-5-methylisoxazol-4-yl)phenyl)(4-chlorophenyl)methanone (50.8 mg, 0.144 mmol), toluene (3 mL), and trimethylphosphine solution (216 μl, 1M in toluene, 0.216 mmol). The reaction was stirred at room temperature over 2 days before purifying via Biotage (EtOAc/hex) to afford 6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,3-e]azepine. LC/MS m/z 309 [M+H]+; 1H NMR (400 MHz, Acetone) δ 7.70-7.76 (m, 1H), 7.63-7.70 (m, 1H), 7.32-7.49 (m, 6H), 5.10 (br. s, 1H), 4.10 (br. s, 1H), 2.68 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:6]([Br:7])=[C:5]([Br:8])[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[F:31][C:28]1[CH:27]=[CH:26][C:25]([N:22]2[CH2:21][CH2:20][N:19]([C:17](=[O:18])[CH2:16][N:3]3[C:2]([Br:1])=[C:6]([Br:7])[C:5]([Br:8])=[N:4]3)[CH2:24][CH2:23]2)=[CH:30][CH:29]=1
Reactant: Brc1n[nH]c(Br)c1Br
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(Cn1nc(Br)c(Br)c1Br)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 3,4,5-Tribromo-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 6.96–7.2 (m, 2H), 6.84–6.9 (m, 2H), 5.4 (s, 2H), 3.74–3.8 (m, 2H), 3.6–3.68 (m, 2H), 3.04–3.14 (m, 4H). 13C NMR (400 MHz, CDCl3): 164.4, 158, 156, 144.2, 128, 118.4, 118.2, 116, 100, 52.8, 50.2, 50.0, 46.0, 42.2.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:7]=[C:8]([C:11]([OH:13])=[O:12])[S:9][CH:10]=1.[CH2:14](O)[CH3:15]>>[Br:5][C:6]1[CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:9][CH:10]=1
Reactant: O=C(O)c1cc(Br)cs1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(Br)cs1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
Thionyl chloride (8.8 mL, 121 mmol) was added slowly to a solution of 4-bromothiophene-2-carboxylic acid (5.0 g, 24.2 mmol) in ethanol (30 mL) at room temperature. The reaction mixture was warmed up to 65° C. and stirred for 4 hours. Removal of solvent and excess reagent under vacuum afforded the crude product ethyl 4-bromothiophene-2-carboxylate (1015), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:8]=2)[C:5]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.O[C@@H:30]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]([O:33][CH2:34][CH3:35])=[O:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:12]=2)[C:5]([C:22]2[CH:23]=[CH:24][C:25]([O:28][C@H:30]([CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H](O)Cc1ccccc1
Reactant: CCCCCCCCOc1ccc(-n2c(C)ccc2-c2ccc(O)cc2)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOc1ccc(-n2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 39.6 %

Procedure:
To a solution of 4-[5-methyl-1-(4-octyloxyphenyl)-1H-pyrrol-2-yl]phenol (740 mg, 1.96 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (570 mg, 2.94 mmol) and triphenylphosphine (770 mg, 2.94 mmol) in toluene (2 ml) was added 1,1′-(azodicarbonyl)dipiperidine (741 mg, 2.94 mmol) and the mixture was stirred at 80° C. for 12 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate anhydride and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 420 mg (yield: 39.6%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:19]1[C:24]([C:25]#[N:26])=[CH:23][CH:22]=[CH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:19]3[N:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]#[N:26])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCNCC1
Reactant: N#Cc1cccnc1Cl
Product: N#Cc1cccnc1N1CCC(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC1
Yield: 99.9 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-[(3,4-dichlorophenyl)sulfonyl]piperidine (150 mg, 0.51 mmol) was reacted with 2-chloro-3-cyanopyridine (85 mg, 0.61 mmol) to afford the title compound (202 mg), a white solid, in 77% yield.
Reaction SMILES: [NH2:1][C:2]([C@H]1[C@H]2C[C@H](C=C2)[C@H]1[NH:11][C:12]1[C:17](F)=[CH:16][N:15]=[C:14]([NH:19]C2C=CC(N3CCN(C)CC3)=C(C)C=2)[N:13]=1)=[O:3].C(O)(C(F)(F)F)=O>CO>[NH3:1].[CH3:2][OH:3].[NH2:19][C:14]1[N:13]=[C:12]([NH2:11])[CH:17]=[CH:16][N:15]=1
Reactant: Cc1cc(Nc2ncc(F)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n2)ccc1N1CCN(C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: N
Product: Nc1ccnc(N)n1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A sealed tube charged with enantiomerically pure mono-SNAr product 57a (2.25 g, 8 mmol), aniline 7 (1.80 g, 8.8 mmol), TFA (1.12 mL) and methanol (18 mL) was stirred at 100° C. for 24 hours. The resulting viscous but homogeneous solution was concentrated and the residue was chromatographed (silica gel, CH2Cl2 then 2-5% 2N NH3/MeOH in CH2Cl2) to afford the expected 2,4-diaminopyrimidine derivative 60a (2.28 g, 63%; purity: 95% AUC; enantiomeric purity: greater than 99% as determined by chiral HPLC. The chiral analytical data, 1H NMR and LCMS analyses were found to be identical with the enantiomer designated E1; [α]DRT +44.4° (c 1.0, MeOH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:19])([CH3:18])[C:14]([F:17])([F:16])[F:15])[N:10]=[C:9]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])=[CH:4][CH:3]=1.[CH3:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32].C([O-])([O-])=O.[K+].[K+]>>[F:15][C:14]([F:17])([F:16])[C:13]([C:11]1[N:10]=[C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH:39]=3)=[CH:3][CH:4]=2)[CH:12]=1)([OH:19])[CH3:18]
Reactant: CC(O)(c1cn(-c2ccc(Br)cc2)c(-c2ccccc2C(F)(F)F)n1)C(F)(F)F
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(O)(c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2ccccc2C(F)(F)F)n1)C(F)(F)F
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
A mixture of 2-[1-(4-bromophenyl)-2-(2-trifluoromethyl-phenyl)-1H-imidazol-4-yl]-1,1,1-trifluoro-propan-2-ol (0.11 g, 0.23 mmol), 3-methanesulfonyl-phenylboronic acid (54 mg, 0.27 mmol), K2CO3 (95 mg, 0.69 mmol), Cl2Pd(dppf).DCM (15 mg, 8 mol %) and H2O (0.25 mL) in DME (2.5 mL) was sparged with Argon for 5 min and then heated at 80° C. as a sealed flask. After 90 min the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 35:65 to 80:20) to give the title compound (116 mg, 89%) as a white solid. 1H-NMR (DCM-d2): δ 8.09 (m, 1H), 7.91 (m, 1H), 7.84 (m, 1H), 7.78 (d, 1H), 7.66 (m, 1H), 7.59 (d, 2H), 7.49-7.57 (m, 2H), 7.33 (m, 2H), 7.25 (d, 2H), 4.40 (s, 1H), 3.06 (s, 3H), 1.75 (s, 3H); MS (ES): 555 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]([OH:15])[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][C:9]=1[OH:10])[CH3:2].[CH2:16]([O:18]C1C=CC=CC=1O)[CH3:17].[C:26]([OH:30])(=[O:29])[CH:27]=[O:28]>>[C:16]([O:15][CH:11]([C:6]1[CH:7]=[CH:8][C:9]([O:10][C:27](=[O:28])[CH3:26])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[C:12]([OH:14])=[O:13])(=[O:18])[CH3:17].[C:1]([O:30][C:26](=[O:29])[CH3:27])(=[O:3])[CH3:2]
Reactant: CCOc1cc(C(O)C(=O)O)ccc1O
Reactant: CCOc1ccccc1O
Reactant: O=CC(=O)O
Product: CC(=O)OC(C)=O
Product: CCOc1cc(C(OC(C)=O)C(=O)O)ccc1OC(C)=O
Temperature: 0 °C

Procedure:
Intermediate 2, (3-ethoxy-4-hydroxyphenyl)hydroxy-acetic acid can be prepared by addition of base to an aqueous mixture of 2-ethoxyphenol and glyoxylic acid cooled to 0° C. Intermediate 3, acetoxy-(4-acetoxy-3-ethoxyphenyl)-acetic acid, can be formed by the addition of acetic anhydride to intermediate 2 dissolved in dichloromethane (DCM) and pyridine, cooled in an ice bath. Intermediate 3 dissolved in a short chain alcohol is reduced under hydrogen to provide intermediate 4, (4-acetoxy-3-ethoxyphenyl)-acetic acid, which is reacted with an excess of propanol and a catalytic amount of concentrated H2SO4 to form the propyl ester, intermediate 5, (3-ethoxy-4-hydroxyphenyl)-acetic acid propyl ester. Finally, intermediate 5 is reacted with a compound of the structure X—CH2C(═O)N(Et)2, where X is a leaving group, in the presence of potassium carbonate to provide the active agent, compound 1.