Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:16][O:17]S(C)(=O)=O)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1>>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([O:17][CH2:16][CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:8][CH:9]=2)=[O:33])=[CH:37][CH:36]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(F)cc2)cc1
Reactant: Oc1ccc(Cl)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2ccc(Cl)cc2)NS(=O)(=O)c2ccc(F)cc2)cc1
Yield: 74 %

Procedure:
The procedure described in Example 125 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (300 mg) was reacted with 4-chlorophenol (153 mg) to obtain (RS)-3-(4-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)propanamide (236.25 mg).
Reaction SMILES: [CH:1]1([C:4]2[NH:9][C:8](=[O:10])[C:7]([CH:11]([NH:14][C:15]([CH:17]3[CH2:20][CH2:19][CH2:18]3)=O)[CH2:12][CH3:13])=[N:6][N:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>>[CH:17]1([C:15]2[N:6]3[C:7]([C:8](=[O:10])[NH:9][C:4]([CH:1]4[CH2:3][CH2:2]4)=[N:5]3)=[C:11]([CH2:12][CH3:13])[N:14]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: CCC(NC(=O)C1CCC1)c1nnc(C2CC2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(C2CCC2)n2nc(C3CC3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 1, 350 mg (1.28 mmol) crude N-[1-(3-cyclopropyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]cyclobutanecarboxamide, 200 mg (1.28 mmol) phosphoric trichloride are stirred at reflux for 3 hours, proportionate amounts of the solvents are used.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C@@H:17]4[CH2:21][CH2:20][NH:19][CH2:18]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:3][CH2:2]1.C[Si]([N:31]=[C:32]=[O:33])(C)C>>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C@@H:17]4[CH2:21][CH2:20][N:19]([C:32]([NH2:31])=[O:33])[CH2:18]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:2][CH2:3]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)[C@@H]3CCNC3)ccc2n1CC1CC1
Reactant: C[Si](C)(C)N=C=O
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)[C@@H]3CCN(C(N)=O)C3)ccc2n1CC1CC1

Procedure:
The title compound was prepared according to the procedure described in STEP D of Example 6 using 1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-5-[(3R)-pyrrolidine-3-sulfonyl]-1H-1,3-benzodiazole (STEP D) and trimethylsilyl isocyanate instead of methanesulfonyl chloride.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][CH:24]=1)(=O)C.CO.[OH-].[Na+]>C1COCC1.O>[I:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4])=[CH:28][CH:27]=1
Reactant: CC(=O)OCCCCCCCCCCCCCCCCCCc1ccc(I)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: OCCCCCCCCCCCCCCCCCCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
18-(p-Iodophenyl)octadecyl acetate 42 (1.55 g, 3.01 mmol) was dissolved in THF (10 ml), MeOH (5 ml) and solution of NaOH (240 mg, 6.03 mmol) in H2O (1 ml) was added. The reaction mixture was stirred at room temperature for 2 h, quenched with aqueous NaHCO3 solution and extracted with EtOAc. Extract was dried over Na2SO4 and evaporated. Silica gel chromatography in hexane-EtOAc (95:5, 90:10) gave the product, 1.36 g (95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29]S(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: Oc1cccnc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2cccnc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The procedure described in Example 105 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (101.7 mg) was reacted with 3-hydroxypyridine to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(pyridin-3-yloxy)propanamide (62.5 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:13])[CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1)[CH3:2].[CH3:15][CH:16](O)[CH:17]=[CH2:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:15]([CH:8]1[C:7]([CH3:13])([CH3:14])[C:6]2[C:10](=[CH:11][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:9]1=[O:12])[CH:16]=[CH:17][CH3:18]
Reactant: C=CC(C)O
Reactant: CCc1ccc2c(c1)C(=O)CC2(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1C(=O)c2cc(CC)ccc2C1(C)C
Yield: 70 %

Procedure:
A solution of 9.1 g of 6-ethyl-3,3-dimethyl-1-indanone, 9.98 ml of 3-buten-2-ol and 250 mg of p-toluenesulfonic acid in 100 ml of 2,2-dimethoxypropane was boiled under reflux for 88 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 6:1). In addition to 2.0 g of educt, there were obtained 8.2 g (70%) of (RS)-2-(2-buten-1-yl)-6-ethyl-3,3-dimethyl-1-indanone as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)[C:25](Cl)=[O:26].[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl.CCOC(C)=O>[CH3:32][O:31][C:29]1[CH:28]=[C:24]([CH:23]=[C:22]([O:21][CH3:20])[CH:30]=1)[C:25]([C:10]1[C:11]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:12]=2[S:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:26]
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2cc(OC)cc(OC)c2)cc1
Reaction time: 17 h
Yield: 48 %

Procedure:
To a well-stirred solution of 2-(4′-methoxyphenyl)-6-methoxybenzo[b]thiophene (0.615 g, 2.27 mmol) and 3,5-dimethoxybenzoyl chloride (1.37 g, 6.83 mmol) in CH2Cl2 (45 mL) was added AlCl3 (1.21 g, 9.09 mmol) portion-wise over a 15 minute period. After 17 hours, water was added, and the product was isolated initially by extraction with CH2Cl2 and subsequently by extraction with EtOAc. The organic layers were separately washed with brine and then combined and dried over MgSO4. Purification by flash chromatography (silica gel, 60:40 EtOAc/hexane) afforded the title compound (0.475 g, 1.09 mmol, 48%) as an off-white solid. Recrystallization (hexane/ethanol) afforded a highly pure, crystalline sample with mp 114-120° C.: 1H-NMR (CDCl3, 360 Mhz): δ=7.59 (d, J=8.9 Hz, 1H, ArH), 7.32 (d, J=8.5 Hz, 2H, ArH), 7.32 (d, J=2.4 Hz, 1H, ArH), 6.98 (dd, J=9.0, 2.4 Hz, 1H, ArH), 6.94 (d, J=2.1 Hz, 2H, ArH), 6.76 (d, J=8.7 Hz, 2H, ArH), 6.52 (t, J=2.4 Hz, 1H, ArH), 3.89 (s, 3H, —OCH3), 3.76 (s, 3H, —OCH3), 3.71 (s, 6H, —OCH3); 13C-NMR (CDCl3, 90 Mhz): δ=194.0, 160.5, 159.8, 157.7, 143.9, 140.0, 139.3, 133.8, 130.3, 130.1, 126.0, 124.1, 114.9, 114.0, 107.6, 106.1, 104.4, 55.6, 55.5, 55.2. HRMS (EI) M+ calcd for C25H22O5S 434.1188, found 434.1245. Anal. Calcd. for C25H22O5S: C, 69.11; H, 5.10; S, 7.38. Found: C, 69.00; H, 5.16; S, 7.34.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:11]#N.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.CO.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=[O:39].[Na+].[K+]>C(Cl)Cl.O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=[O:39]
Reactant: C[Si](C)(C)OC(C#N)c1c(Cl)ccc(F)c1Cl
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCCCCC
Product: C[Si](C)(C)OC(C=O)c1c(Cl)ccc(F)c1Cl
Temperature: -64 °C
Reaction time: 2 h

Procedure:
To a 100 mL three-necked RBF were added 2-(2,6-dichloro-3-fluorophenyl)-2-((trimethylsilyl)oxy)acetonitrile (0.50 g, 1.711 mmol) and DCM (9 ml). The reaction mixture was purged with nitrogen and cooled to −64° C. Under a nitrogen atmosphere, diisobutylaluminum hydride, 1.0 M solution in hexane (2.6 ml, 2.6 mmol) was added dropwise. The mixture was stirred at −64° C. After 2 h, the reaction was quenched. While maintaining temp <−65° C., MeOH (1.4 ml, 34.2 mmol) was carefully added dropwise to the reaction mixture followed by saturated Rochelle salt solution (5 mL). The mixture was allowed to reach room temperature and stirred for 30 min. Water and DCM were added and the aqueous layer was extracted with DCM. The combined organic layer washed with brine, dried over anhydrous MgSO4, and concentrated to afford 2-(2,6-dichloro-3-fluorophenyl)-2-((trimethylsilyl)oxy)acetaldehyde as a colorless oil (0.517 g, crude).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C)CCN(C)C.C([Li])(CC)C.[CH2:25]1[O:28][C@@H:26]1[CH3:27].B(F)(F)F.CCOCC.OS(O)(=O)=O>O1CCCC1.O>[F:1][C:2]([F:10])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:25][C@H:26]([OH:28])[CH3:27]
Reactant: C[C@@H]1CO1
Reactant: FC(F)(F)Oc1ccccc1
Agent: CN(C)CCN(C)C
Agent: FB(F)F
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)Cc1ccccc1OC(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of trifluoromethoxybenzene (5.29 mL) and N,N,N′,N′-tetramethylethylene-diamine (5.96 mL) in tetrahydrofuran (80 mL) at −78° C. was added sec-butyllithium (32 mL, 1.4 M solution) over 50 minutes. After 2 hours a cooled (−78° C.) solution (R)-(+)-propylene oxide (4.20 mL) in tetrahydrofuran (20 mL) was added over 15 minutes, followed by boron trifluoride diethyl etherate (1.89 mL) over 20 minutes. The reaction mixture was stirred at −78° C. for 2 hours after which aqueous solution of H2SO4 (0.3 M, 50 mL) and water (10 mL) was added. The mixture let to warm up to room temperature after which it was extracted with diethyl ether (2×100 mL). The combined organic phases were washed with brine, dried with Na2SO4 and concentrated. Evaporation residue was purified by separation method E (ethyl acetate-heptane). (Yield 1.40 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:23])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([OH:22])[CH:15]=2)=[C:5]([O:24][CH2:25][C:26]([O:28]C)=[O:27])[C:4]=1[CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33].[OH-].[K+].Cl>CO>[C:26]([CH2:25][O:24][C:5]1[C:4]([CH2:30][CH2:31][CH:32]([CH3:33])[CH3:34])=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[C:6]=1[C:11](=[O:23])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([OH:22])[CH:15]=1)([OH:28])=[O:27]
Reactant: COC(=O)COc1c(CCC(C)C)c(OC)cc(OC)c1C(=O)CCc1ccc(OC)c(O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2OCC(=O)O)cc1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.3 %

Procedure:
Then, 3.0 g of 1-(4,6-dimethoxy-2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(3-hydroxy-4-methoxyphenyl)-1-propanone was dissolved in 30 ml of methanol, and 18 ml of a 5% aqueous solution of potassium hydroxide was added to the solution and the mixture was stirred at room temperature for 20 minutes. Then, the reaction mixture was made weakly acidic by an addition of dilute hydrochloric acid, the solvent was removed from the mixture by distillation, and the residue was crystallized from ethyl acetate/diethyl ether/hexane to obtain 2.6 g (yield=90%) of 1-(2-carboxymethoxy-4,6-dimethoxy-3-isopentylphenyl)-3-(3-hydroxy-4-methoxyphenyl)-1-propanone in the form of a colorless transparent plate.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O.Cl.[CH2:21]([S:25]([C:28]1[S:32][C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:30][CH:29]=1)(=[O:27])=[O:26])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([S:25]([C:28]1[S:32][C:31]([N:33]2[CH2:38][CH2:37][N:36]([C:7]([C:6]3[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=3[O:4][CH2:3][C:2]([CH3:1])([CH3:19])[CH3:18])=[O:9])[CH2:35][CH2:34]2)=[N:30][CH:29]=1)(=[O:27])=[O:26])[CH2:22][CH2:23][CH3:24]
Reactant: CC(C)(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: CCCCS(=O)(=O)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CCCCS(=O)(=O)c1cnc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OCC(C)(C)C)CC2)s1
Yield: 69 %

Procedure:
Prepared in analogy to example 1 (b) from 2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-benzoic acid (Example A11) and 1-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride (Example 38(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 69%). MS (m/e): 558.4 (M+H+, 20%), 575.4 (M+NH4+, 100%).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[F:17][C:18]1[CH:37]=[CH:36][C:21]([C:22]([N:24]2[CH2:30][CH2:29][C:28]3[O:31][C:32]([CH2:34][OH:35])=[N:33][C:27]=3[CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1.[C:38]1(O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([N:24]2[CH2:30][CH2:29][C:28]3[O:31][C:32]([CH2:34][O:35][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[N:33][C:27]=3[CH2:26][CH2:25]2)=[O:23])=[CH:36][CH:37]=1
Reactant: O=C(c1ccc(F)cc1)N1CCc2nc(CO)oc2CC1
Reactant: Oc1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)N1CCc2nc(COc3ccccc3)oc2CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 8.2 %

Procedure:
Di-tert-butyl azodicarboxylate (0.024 g, 0.10 mmol) was added portionwise to a stirred solution of 6-(4-fluorobenzoyl)-5,6,7,8-tetrahydro-4H-oxazolo[4,5-d]azepine-2-methanol (0.02 g, 0.069 mmol), phenol (0.01 g, 0.10 mmol) and triphenylphosphine (0.027 g, 0.10 mmol) in DCM (0.5 mL) at 0° C. The mixture was stirred at room temperature for 10 minutes and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 40/60). The desired fractions were collected and concentrated in vacuo. The product was further purified by flash column chromatography (silica; AcOEt in heptane 50/50 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo and purified by reverse phase HPLC performed on a C18 XBridge 30×100 mm, 5 μm column (0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 in ethyl acetate 80/20 to 0/100) to yield 6-(4-fluorobenzoyl)-5,6,7,8-tetrahydro-2-(phenoxymethyl)-4H-oxazolo[4,5-d]azepine (2.07 mg, 8% yield) as an oil. C21H19FN2O3. (Mixture of rotamers ˜60:40) 1H NMR (400 MHz, CDCl3) δ ppm 2.66 (br. s., 1.2 H), 2.78 (br. s., 0.8 H), 3.00 (br. s., 0.8 H), 3.12 (br. s., 1.2 H), 3.62 (br. s., 2.1 H), 3.93 (br. s., 1.9 H), 5.05 (s, 2 H), 6.97-7.04 (m, 1 H), 7.02 (d, J=7.4 Hz, 2 H), 7.12 (t, J=8.7 Hz, 2 H), 7.31 (dd, J=9.1, 7.1 Hz, 2 H), 7.39 (dd, J=8.8, 5.3 Hz, 2 H).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7](=[O:19])[NH:8][C:9]3[CH:10]=[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]4=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].[C:33]([O:37][C:38](=[O:44])[NH:39][CH2:40][CH2:41][CH2:42]Br)([CH3:36])([CH3:35])[CH3:34]>CN(C=O)C>[C:33]([O:37][C:38]([NH:39][CH2:40][CH2:41][CH2:42][N:8]1[C:9]2[CH:10]=[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]3=[CH:13][C:14]=2[C:5]2=[N:4][N:3]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:2](=[O:1])[N:6]2[C:7]1=[O:19])=[O:44])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: CC(C)(C)OC(=O)n1nc2c3cc4ccccc4cc3[nH]c(=O)n2c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCn1c(=O)n2c(=O)n(C(=O)OC(C)(C)C)nc2c2cc3ccccc3cc21
Temperature: 23 °C
Reaction time: 16 h

Procedure:
A mixture of tert-butyl 3,5-dioxo-5,6-dihydrobenzo[g][1,2,4]triazolo[4,3-c]quinazoline-2(3H)-carboxylate (8-6, 28 mg, 0.079 mmol, 1 equiv), cesium carbonate (100 mg, 0.31 mmol, 3.8 equiv), and N-(3-bromopropyl)carbamic acid tert-butyl ester (50 mg, 0.21 mmol, 2.6 equiv) in DMF (3 mL) was stirred at 23° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated and purified by reverse phase liquid chromatography (H2O/CH3CN gradient w/0.1% TFA present) to yield tert-butyl 6-{3-[(tert-butoxycarbonyl)amino]propyl}-3,5-dioxo-5,6-dihydrobenzo[g][1,2,4]triazolo[4,3-c]quinazoline-2(3H)-carboxylate (8-7).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:24][CH3:25])[C:15]2[C:20]([NH:21][CH2:22][CH3:23])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[CH2:24]([N:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:15]1[C:20]([NH:21][CH2:22][CH3:23])=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:25]
Reactant: CCNc1cccnc1N(CC)C1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCNc1cccnc1N(CC)C1CCNCC1
Reaction time: 24 h

Procedure:
1-Benzyl-4-[N-ethyl-N-(3-(ethylamino)-2-pyridinyl)amino]piperidine (EXAMPLE 205, 0.41 g, 1.2 mmol) is dissolved in 20 ml of ethanol and 0.20 g of palladium hydroxide is added. The reaction is placed on a Parr hydrogenator under 40 psi for 24 hrs. Then it is filtered through diatomaceous earth and concentrated under reduced pressure to give the title compound, NMR (300 MHz, CDCl3) 7.60, 6.80, 6.67, 4.53, 3.76, 3.76, 3.15-2.95, 2.56, 1.76, 1.54, 1.12 and 0.73δ.
Reaction SMILES: I.[CH:2]12[CH2:13][CH2:12][CH:5]([CH2:6][CH:7]1[C:8]([O:10]C)=[O:9])[CH2:4][NH:3]2.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21]>>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:3]1[CH2:4][C@H:5]2[CH2:12][CH2:13][C@@H:2]1[C@H:7]([C:8]([OH:10])=[O:9])[CH2:6]2)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: COC(=O)C1CC2CCC1NC2
Agent: I
Product: O=C(O)[C@@H]1C[C@@H]2CC[C@H]1N(S(=O)(=O)c1ccccn1)C2

Procedure:
The title compound was synthesized as in Production Example 1, using methyl 2-azabicyclo[2.2.2]octane-6-carboxylate hydroiodide and pyridine-2-sulfonyl chloride as the raw material.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(#N)C>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][N:28]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:27][CH2:26]4)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=3)=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCC4CCNCC4)n3)cc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCC4CCN(S(C)(=O)=O)CC4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
To a solution of 2-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(piperidin-4-ylmethylamino)pyrimidine-5-carboxamide (22 mg, 0.049 mmol) and triethylamine (0.040 mL, 0.29 mmol) in acetonitrile (2 mL) at room temperature, methanesulfonyl chloride (0.020 mL, 0.26 mmol) was added. The solution was stirred at room temperature for 1 h. The mixture was then purified by HPLC to give the titled compound (14 mg). MS 531.36 (M+H).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:32])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([C:22]4[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=4)=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.N1C=CC=CC=1.[C:39]1([O:45]C(Cl)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>ClCCl.C(#N)C>[F:29][C:28]([F:31])([F:30])[C:25]1[N:24]=[CH:23][C:22]([C:18]2[CH:17]=[C:16]3[C:21](=[CH:20][CH:19]=2)[N:13]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]4[NH:32][C:39](=[O:45])[O:1][N:2]=4)=[CH:9][CH:8]=2)(=[O:11])=[O:12])[CH2:14][CH2:15]3)=[CH:27][CH:26]=1
Reactant: N=C(NO)c1ccc(S(=O)(=O)N2CCc3cc(-c4ccc(C(F)(F)F)nc4)ccc32)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=c1[nH]c(-c2ccc(S(=O)(=O)N3CCc4cc(-c5ccc(C(F)(F)F)nc5)ccc43)cc2)no1
Temperature: 25 °C

Procedure:
550 mg crude N-Hydroxy-4-[5-(6-trifluoromethyl-pyridin-3-yl)-2,3-dihydro-indole-1-sulfonyl]-benzamidine were dissolved in 20 ml dichloromethane. 0.17 ml pyridine and 0.18 ml phenylchloroformate were added and the mixture stirred at room temperature for ten minutes. The mixture was diluted by the addition of 20 ml acetonitrile and 0.89 ml 1,8-diazabicyclo[5.4.0]undec-7-ene were added. The mixture was stirred at room temperature for 15 minutes. The mixture was evaporated in vacuo and the resulting crude material was purified by reversed phase HPLC to obtain 175 mg 3-{4-[5-(6-Trifluoromethyl-pyridin-3-yl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([Sn](C)(C)C)[N:7]=[C:6]([C:14]#[N:15])[N:5]=1)[CH2:2][CH3:3].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:8]2[CH:9]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]=[C:6]([C:14]#[N:15])[N:7]=2)=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26]
Reactant: CCCc1cc([Sn](C)(C)C)nc(C#N)n1
Reactant: COc1ccc(Br)cc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCCc1cc(-c2ccc(OC)c(C(F)(F)F)c2)nc(C#N)n1
Temperature: 80 °C
Yield: 11.7 %

Procedure:
Bis(triphenylphosphine)palladium dichloride (34 mg, 0.05 mmol) was added under a nitrogen atmosphere to a mixture of 4-propyl-6-trimethylstannanyl-pyrimidine-2-carbonitrile (150 mg, 0.48 mmol) and 4-methoxy-3-trifluoromethyl-bromobenzene (148 mg, 0.58 mmol) in dimethylformamide (3 mL). The mixture was heated for 5 hours at 80° C. then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent Cyclohexane/DCM 7/3) to afford a solid which was triturated in pentane. After filtration, 4-(4-methoxy-3-trifluoromethyl-phenyl)-6-propyl-pyrimidine-2-carbonitrile (18 mg, 11%) was obtained as an off white solid.