Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:49])[CH2:10][C@H:11]([NH:29][C:30](=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:12](=[O:28])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])C1C=CC=CC=1>O1CCCC1.CO.[Pd]>[C:37]([NH:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C:30]([NH:29][C@H:11]([C:12](=[O:28])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:10][C:9]([OH:49])=[O:8])=[O:48])(=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCCCCCCCNC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCNC(=O)CCCCCCCCC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCCCCCNC(=O)[C@H](CC(=O)O)NC(=O)CCCCCNC(=O)CCCCCCCCC
Yield: 77.1 %

Procedure:
Precipitates thus formed were removed by filtration, the filtrate was washed with water, dried over anhydrous magnesium sulfate, concentrated, and subjected to silica gel column chromatography. The product was eluted with ethyl acetate-chloroform (1:9--1:1 by v/v ratio) to provide 600 mg of (S)-3-(6-decanamidohexanamido)-3-tetradecylcarbamoylpropionic acid benzyl ester. 1.00 g of the ester compound obtained was dissolved in a mixture of 30 ml of tetrahydrofuran and 10 ml of methanol and after carrying out catalytic reduction by using 100 mg of 10% Pd-C and removing the catalyst by filtration, the solvent was distilled off to provide 670 mg of (S)-3-(6-decanamidohexanamido)-3-tetradecylcarbamoylpropionic acid.
Reaction SMILES: C([NH:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1)=CC.[CH2:18]([Li])CCC.CI.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:18][C:11]1[CH:10]=[C:9]([O:12][C:13]([F:14])([F:15])[F:16])[CH:8]=[CH:7][C:6]=1[C:5]([NH2:4])=[O:17]
Reactant: CC=CNC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: [Li]CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc(OC(F)(F)F)ccc1C(N)=O
Temperature: -30 °C
Yield: 75 %

Procedure:
To a solution of N-Propenyl-4-trifluoromethoxy-benzamide 12 (8.0 g, 33 mmol) in THF (100 mL) at −78° C. was added n-butyllithium (29 mL, 72 mmol of a 2.5 M solution in hexanes). The reaction mixture was warmed to −30° C. for 10 min and cooled back to −78° C. A solution of MeI (2.24 mL, 33 mmol) in THF (5 mL) was slowly added to the reaction mixture. The cooling bath was removed and once the reaction temperature warmed to 0° C., 3 N HCl (10 mL) was added and the resulting two phase mixture heated to 60° C. for 1 h. Upon completion of reaction, the solution was neutralized with aqueous sodium bicarbonate and extracted with ether. The combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by ether/hexane triturated to provide the title compound (colorless solid 75%). 1H NMR (400 MHz,CDCl3) δ7.50 (d, J=8.4 Hz, 1 H, Ar), 7.09 (m, 2 H, Ar), 5.74 (broad s, 2 H, NH2), 2.52 (s, 3 H, CH3)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[O:12][C:13]2[CH:20]=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:18]=[CH:17][C:14]=2[C:15]=1[CH3:16])=O.Br[C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([NH2:36])=[O:35].ClCCl.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:11]1[O:12][C:13]2[CH:20]=[C:19]([C:32]3[CH:31]=[CH:39][CH:38]=[CH:37][C:33]=3[C:34]([NH2:36])=[O:35])[CH:18]=[CH:17][C:14]=2[C:15]=1[CH3:16]
Reactant: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: NC(=O)c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1c(Cc2ccc(Cl)cc2Cl)oc2cc(-c3ccccc3C(N)=O)ccc12
Yield: 43.8 %

Procedure:
To a solution of (2,4-dichlorophenyl)-[3-methyl-6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-benzofuran-2-yl]-methanone (100 mg, 0.23 mmol) in toluene (4 mL) and ethanol (4 mL) was added 3-bromobenzamide (56 mg, 0.28 mmol) followed by [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium (II), complex with dichloromethane (1:1) (17 mg, 0.02 mmol) and 2M aqueous Na2CO3 (0.29 mL, 0.58 mmol). The mixture was degassed under vacuum, then heated to 85 C for 2 h. The reaction mixture was concentrated in vacuo, diluted in methanol, and filtered through a syringe filter. Purification by prep-HPLC provided the desired material as a white solid (41.3 mg, 42%). 1H-NMR (CDCl3) δ 8.02 (t, J=1.9 Hz, 1H), 7.71-7.67 (m, 3H), 7.61 (m, 1H), 7.52 (dd, J=1.4, 8.4 Hz, 1H), 7.46 (t, J=7.7 Hz, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.39 (m, 1H), 7.31 (ddd, J=8.1, 1.9, 0.2 Hz, 1H), 2.54 (s, 3H).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][C:17](O)=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][CH2:17][OH:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC1c2ccccc2CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCC1c2ccccc2CCc2ccccc21

Procedure:
A solution of 237 g of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-acetic acid in 1 l of dry tetrahydrofuran is added dropwise over a period of 90 minutes to a suspension of 35.6 g of lithium aluminum hydride in 1.5 l of dry tetrahydrofuran stirred at 0° under argon. The mixture is subsequently heated to boiling under reflux for 90 minutes, cooled and successively treated dropwise with 35.6 ml of water, 35.6 ml of 15 percent sodium hydroxide and 106.8 ml of water. The resulting suspension is filtered with repeated back-washing with 2 l of tetrahydrofuran. After removal of the solvent in vacuo, the residue is taken up three times in 500 ml of toluene each time, the solutions obtained being in each case again evaporated. There is obtained pure 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ethanol in the form of an oil, which crystallizes slowly.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[C:8]([CH2:9][CH:10]([CH:19]([C:24]([O:26][CH3:27])=[O:25])[C:20]([O:22][CH3:23])=[O:21])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:7]([N+:28]([O-])=O)[CH:6]=[CH:5][CH:4]=1>C(OCC)(=O)C.CCCCCC>[F:1][C:2]([F:31])([F:32])[C:3]1[C:8]([CH2:9][CH:10]([CH:19]([C:24]([O:26][CH3:27])=[O:25])[C:20]([O:22][CH3:23])=[O:21])[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[C:7]([NH2:28])[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)C(C(=O)OC)C(Cc1c([N+](=O)[O-])cccc1C(F)(F)F)c1ccc(OC)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)C(C(=O)OC)C(Cc1c(N)cccc1C(F)(F)F)c1ccc(OC)cc1

Procedure:
Catalytic reduction of 40.4 g (0.088 mol) of [2-(6-trifluoromethyl-2-nitrophenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (in two portions) following the procedure of Example 28 part B gave 36.9 g of nearly colorless solid, melting point 111°-113° C. Rf 0.62 (1:1 ethyl acetate-hexane). A sample crystallized from methanol melted at 112°-114° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:25])[C@H:12]([CH2:14][S:15][CH2:16][C:17](=[O:24])[NH:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[NH2:13])[CH3:9].[C:26]([O:30][C:31](=[O:35])[CH:32](Br)[CH3:33])([CH3:29])([CH3:28])[CH3:27]>CN(P(N(C)C)(N(C)C)=O)C>[C:26]([O:30][C:31](=[O:35])[C@H:32]([CH3:33])[NH:13][C@H:12]([C:11]([O:10][CH2:8][CH3:9])=[O:25])[CH2:14][S:15][CH2:16][C:17](=[O:24])[NH:18][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)[C@@H](N)CSCC(=O)NC1CCCC1
Reactant: CC(Br)C(=O)OC(C)(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CSCC(=O)NC1CCCC1)N[C@@H](C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A 2.8 ml of triethylamine was added to a solution of 5.5 g of S-cyclopentylcarbamoylmethyl-L-cysteine ethyl ester and 4.2 g of 2-bromopropionic acid t-butyl ester in 10 ml of HMPA. The mixture was stirred at room temperature for 30 hours. The reaction mixture was poured into ice water and the mixture was extracted with ethyl acetate. The extract was sufficiently washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (a 10:1 mixture of ether and n-hexane as an eluent), producing the α-isomer of the title compound from the first eluate as a colorless oil. Yield 1.36 g.
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[C:4](=[O:31])[CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7])[CH3:2].C(N[C:37]1[CH:42]=CC=[CH:39][CH:38]=1)C>>[CH2:32]([N:3]([C:1]1[CH:39]=[CH:38][CH:37]=[CH:42][CH:2]=1)[C:4](=[O:31])[CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:10])=[O:11])=[O:7])[CH3:33]
Reactant: CCNc1ccccc1
Reactant: CCN(CC)C(=O)C(Cc1ccc(OC)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Product: CCN(C(=O)C(Cc1ccc(OC)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Yield: 75.2 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (550 mg) obtained in Example 112 (4) and N-ethylaniline (161 mg). This was purified by silica gel column chromatography to give the title compound (456 mg) as a white powder.
Reaction SMILES: CS(C)=O.[NH2:5][C:6]1[N:15]=[C:14]([NH2:16])[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:17]3[C:25]4[O:24][C:23]([CH3:27])([CH3:26])[CH:22]([OH:28])[C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:12]=2)[N:7]=1.C(N(CC)CC)C.O>C(Cl)Cl>[NH2:5][C:6]1[N:15]=[C:14]([NH2:16])[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:17]3[C:25]4[O:24][C:23]([CH3:26])([CH3:27])[C:22](=[O:28])[C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:12]=2)[N:7]=1
Reactant: CC1(C)Oc2c(-c3cnc4nc(N)nc(N)c4n3)cccc2C1O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC1(C)Oc2c(cccc2-c2cnc3nc(N)nc(N)c3n2)C1=O
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
A stirring solution of 1.8 grams (0.011 mole) of pyridine-sulfur trioxide complex [prepared by the method of E. E. Gilbert, Chem. Rev., 62, 551-555 (1962)] in 25 mL of methylene chloride is cooled to -60° C., and a solution of 2.0 grams (0.024 mole) of dimethyl sulfoxide in 5 mL of methylene chloride is added dropwise during a 5 minute period. Upon completion of addition, the reaction mixture is stirred at -60° C. for about 10 minutes. After this time a solution of 3.2 grams (0.10 mole) of 2,4-diamino-6-(2,3-dihydro-3-hydroxy-2,2-dimethylbenzofuran-7-yl)pteridine in 10 mL of methylene chloride is added dropwise during a 5 minute period. Upon completion of addition, the reaction mixture is again stirred at -60° C. for about 10 minutes, and then 5.1 grams (0.050 mole) of triethylamine is added dropwise during a 5 minute period. The reaction mixture is then allowed to warm to ambient temperature. After this time 30 mL of water is added, and the mixture is stirred for about 10 minutes. The aqueous layer is separated and extracted with about 20 mL of methylene chloride. The extract is combined with the organic layer, and the combination is concentrated under reduced pressure, yielding 2,4-diamino-6-(2,3-dihydro-2,2-dimethyl-3-benzofuranon-7-yl)pteridine.
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][CH2:22][O:23][CH3:24])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C:4]=2[CH:3]=1.Cl.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]2[C:33](=[O:42])[NH:34][C:35]3[C:40]([CH:41]=2)=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:28][CH2:27]1.ClC1C2NN=CC=2C2CN(CC(C)(C)C)C(=O)[C@@H](CC(=O)N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)CC=2C=1>>[Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][CH2:22][O:23][CH3:24])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:18])[N:26]3[CH2:27][CH2:28][CH:29]([C:32]4[C:33](=[O:42])[NH:34][C:35]5[C:40]([CH:41]=4)=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH2:30][CH2:31]3)[CH2:15][C:4]=2[CH:3]=1
Reactant: COCCN1Cc2c(cc(Br)c3[nH]ncc23)C[C@@H](CC(=O)O)C1=O
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Agent: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: COCCN1Cc2c(cc(Br)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C1=O
Yield: 35 %

Procedure:
[(S)-4-Bromo-9-(2-methoxy-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-acetic acid (100 mg, 0.25 mmol) and 3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (80 mg, 0.30 mmol) were combined in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as white solid in 35% yield. High resolution MS m/e (M+H)+=606.1730.
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[CH2:3][C:4](=[O:9])[CH2:5][C:6](=[O:8])[CH3:7].[H-].[Na+].[CH2:13]([O:15][C:16](=[O:19])[CH2:17]Br)[CH3:14]>O1CCCC1>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][CH:5]([C:6](=[O:8])[CH3:7])[C:4](=[O:9])[CH2:3][CH:2]([CH3:10])[CH3:1])[CH3:14]
Reactant: CC(=O)CC(=O)CC(C)C
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C(C)=O)C(=O)CC(C)C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
Add a solution of 6-methylheptane-2,4-dione (5.0 g, 35.16 mmol) in tetrahydrofuran (50 mL) dropwise to a cooled suspension (0° C.) of sodium hydride (1.69 g, 42.2 mmol, 60% dispersion in oil) in tetrahydrofuran (50 mL). After 1 hr., add bromoacetic acid ethyl ester (4.28 mL, 38.68 mmol) dropwise and stir at 0° C. to room temperature over 88 hr. Partition the reaction mixture between ethyl acetate (200 mL) and saturated aqueous ammonium chloride solution (100 mL). Separate the organic layer, dry (sodium sulfate), filter and concentrate. Purify using silica gel chromatography (95:5 hexanes:ethyl acetate) to give 3-acetyl-6-methyl-4-oxoheptanoic acid ethyl ester (5.81 g, 73%). 1H-NMR (400 MHz, CDCl3) δ 4.10 (m, 4H), 2.81 (d, 2H), 2.41 (t, 1H), 2.22 (s, 3H), 1.23 (m, 4H), 0.92 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:25]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1.CC1C=CC(S(O)(=O)=O)=CC=1.CN(C)C=O>O1CCOCC1.C(OCC)(=O)C>[F:32][C:31]([F:34])([F:33])[C:29]1[CH:28]=[CH:27][N:26]=[C:25]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[S:12][C:11]([N:13]4[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]4)=[N:10][CH:9]=3)[CH:5]=[CH:6][CH:7]=2)[N:30]=1
Reactant: CCOC(=O)C1CCN(c2ncc(-c3cccc(N)c3)s2)CC1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2ncc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Temperature: 100 °C
Yield: 35.4 %

Procedure:
To a solution of ethyl 1-[5-(3-aminophenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylate (42 mg, 0.13 mmol) in dioxane (1.3 mL) was added 2-chloro-4-(trifluoromethyl)pyrimidine (23 mg, 1.3 mmol) and 4-methylbenzenesulfonic acid (24 mg, 0.127 mmol), resulting in the instant formation of a suspension. The mixture was heated to 100° C. and N,N-dimethylformamide (0.5 mL) was added to afford a homogenous mixture. The solution was heated at 100° C. for an additional 2 hours. Thus the mixture was the cooled to room temperature, diluted with ethyl acetate (30 mL), and washed with saturated aqueous sodium bicarbonate (30 mL) and brine (30 mL). The aqueous fractions were further extracted with ethyl acetate (30 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. Purification by CombiFlash (30-100% ethyl acetate:hexanes) provided 22 mg (0.046 mmol, 36% yield) of ethyl 1-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylate as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:32])([CH3:31])[C@@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:13])(=[O:7])=[O:6].[N-:33]=[N+:34]=[N-:35].[Na+]>CS(C)=O>[N:33]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:32])([CH3:31])[C@@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:13])(=[O:7])=[O:6])=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)OCCN1CCOCC1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(COS(=O)(=O)CCCN=[N+]=[N-])[C@@H](OCc1ccccc1)C(=O)OCCN1CCOCC1

Procedure:
Following the general procedure for the preparation of azides of Description 16, 2-morpholin-4-ylethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (26a) (0.41 g, 0.83 mmol) dissolved in 5 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 0.12 g (1.7 mmol) of sodium azide (NaN3). After work-up, the crude material (26b) was used in the next step without further purification. MS (ESI) m/z 499.12 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][CH:11]([F:41])[C:12]1[N:16]([C:17]2[N:22]=[C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:20]=[C:19]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:18]=2)[C:15]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:14]=2[N:13]=1.[Cl-].Cl[S:44]([CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][NH+:50]=1)(=[O:46])=[O:45].O>C(Cl)Cl>[F:41][CH:11]([F:10])[C:12]1[N:16]([C:17]2[N:22]=[C:21]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:20]=[C:19]([N:29]3[CH2:34][CH2:33][N:32]([S:44]([CH2:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=4)(=[O:45])=[O:46])[CH2:31][CH2:30]3)[N:18]=2)[C:15]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:14]=2[N:13]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Reactant: O=S(=O)(Cl)CCc1cccc[nH+]1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCc3ccccn3)CC2)n1
Reaction time: 4 h
Yield: 71.5 %

Procedure:
DIPEA (0.29 mL, 1.66 mmol) was added to a suspension of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (Example 2) (150 mg, 0.336 mmol) and 2-[2-(chlorosulfonyl)ethyl]pyridinium chloride (122 mg, 0.504 mmol) in CH2Cl2 (10 mL) at room temperature under nitrogen, and the mixture was stirred for 4 hrs. Additional 2-[2-(chlorosulfonyl)ethyl]pyridinium chloride (41 mg, 0.169 mmol) was added and the reaction mixture was stirred for another 20 hrs. Water was added and the phases were separated. The aqueous phase was extracted with CH2Cl2, the combined organic extracts were dried (Na2SO4), and the solvent was removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 98.5:1.5), gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(2-pyridinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (148 mg, 71%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([NH:23][C:24]3[N:25]=[C:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[S:27][CH:28]=3)=[O:22])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:32]1[CH:31]=[CH:30][C:29]([C:26]2[S:27][CH:28]=[C:24]([NH:23][C:21]([NH:20][C:16]3[N:15]=[C:14]([C:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=4)[CH:19]=[CH:18][CH:17]=3)=[O:22])[N:25]=2)=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(NC(=O)Nc3csc(-c4ccncc4)n3)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc(C2=CCNCC2)n1)Nc1csc(-c2ccncc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-3′,6′-dihydro-2′H-[2,4]bipyridinyl-1′-carboxylic acid tert-butyl ester was suspended in CH2Cl2 (10 mL) and treated with TFA (5 mL). Stirred at RT for 30 min. Quenched with saturated NaHCO3 and filtered yellow solid. Washed solid with H2O and MeOH to give 1-(2-pyridin-4-yl-thiazol-4-yl)-3-(1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-yl)-urea as a yellow solid. MS m/z: 379.1 (M+H). Calc'd for C19H18N6OS-378.45.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:12][O:13][C:14](=[O:29])[C:15]([CH3:28])([CH3:27])[CH2:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([CH:24]=O)=[C:19]([CH3:26])[CH:18]=1.OOS([O-])=O.[K+].O>CN(C=O)C>[CH3:12][O:13][C:14]([C:15]([CH3:28])([CH3:27])[CH2:16][C:17]1[CH:18]=[C:19]([CH3:26])[C:20]([C:24]2[NH:1][C:2]3[CH:3]=[C:4]([C:9]([OH:11])=[O:10])[CH:5]=[CH:6][C:7]=3[N:8]=2)=[C:21]([CH3:23])[CH:22]=1)=[O:29]
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(C=O)c(C)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)Cc1cc(C)c(-c2nc3ccc(C(=O)O)cc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7.6 g of 3,4-diaminobenzenoic acid was stirred in 120 ml of DMF at room temperature. It was treated with 12.4 g of 3-(4-formyl-3,5-dimethyl-phenyl)-2,2-dimethyl-propionic acid methyl ester (the intermediate A in Example 1-62) followed by an addition of a slurry of 15 g of Oxone in 60 ml of DMF. The reaction was stirred at room temperature for 3 h and 60 mL of water was added and the pH was adjusted to 6. Additional 150 mL of water was added and the resulting precipitates were collected by filtration. The collected precipitates were washed with water and dried under vacuum to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:4][C:3]=1[C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20].ClC1C=C(C=CC=1)C(OO)=[O:31]>ClCCl>[C:13]1([S:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([OH:1])=[C:3]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[N:4]=2)=[O:31])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)CNC(=O)c1nc(Sc2ccccc2)c2ccccc2c1O
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1nc(S(=O)c2ccccc2)c2ccccc2c1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The title compound was prepared as follows: 50 mg of [(4-hydroxy-1-phenylsulfanyl-isoquinoline-3-carbonyl)-amino]-acetic acid, Example D-110, was dissolved in 0.3 ml 1-methyl-2-pyrolydinone and 0.7 ml dichloromethane. The solution was cooled to 0° C. and 26 mg of 75% 3-chloroperoxybenzoic acid was added. The solution was stirred for 2 hours at room temperature, then concentrated under high vacuum. The resultant residue was triturated with ethyl acetate to provide 32 mg of the product as a white solid; MS (−) m/z 369.08 (M−1)
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.Cl.[F:10][C:11]1[C:12]([NH2:17])=[N:13][CH:14]=[CH:15][CH:16]=1>C(#N)C>[Br:8][C:15]1[CH:16]=[C:11]([F:10])[C:12]([NH2:17])=[N:13][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncccc1F
Agent: Cl
Solvent: CC#N
Product: Nc1ncc(Br)cc1F
Reaction time: 1 h
Yield: 157.1 %

Procedure:
Solid NBS (750 mg, 4.2 mmol) was added to a solution of 3-fluoropyridin-2-amine HCl salt (1.66 g, 7.18 mmol) in ACN (30 mL) at RT with stirring. The reaction was shielded from light and stirred under nitrogen. After 1 h, an additional amount of NBS (250 mg, 1.4 mmol) was added to the reaction. After 1 h, the solvent was removed under reduced pressure and the residue purified by silica gel flash chromatography eluting with 70% EtOAc/hexane followed by 100% EtOAc to afford 5-bromo-3-fluoropyridin-2-amine as a yellow-brown solid (1.26 g, 92% yield). LC/MS (m/z): 191.0/193.0 (MH+), Rt 1.18 minutes.