Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](NC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:36]1([C@@H:42]([NH2:44])[CH3:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:44][C@H:42]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH3:43])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](N)c1ccccc1
Reactant: CNc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)c(F)cc3C)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: Cc1cc(F)c(NC(=O)Nc2cnn(C(C)(C)C)c2)cc1-c1cc2cnc(N[C@@H](C)c3ccccc3)nc2n(C)c1=O
Yield: 56.3 %

Procedure:
Using a procedure analogous to Example A1, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 109 (0.075 g, 0.15 mmol) and (S)-1-phenylethanamine (0.053 g, 0.44 mmol) were combined in THF (1 mL) to afford (S)-1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-7-oxo-2-(1-phenylethylamino)-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea as a white solid (0.048 g, 58% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.62 (s, 1H), 8.60 (s, 1H), 8.48 (d, J=8.0 Hz, 1H), 8.39 (brs, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 7.62 (s, 1H), 7.44-7.35 (m, 3H), 7.31-7.27 (m, 2H), 7.18 (t, J=7.2 Hz, 1H), 7.09 (d, J=12.4 Hz, 1H), 5.12 (t, J=6.8 Hz, 1H), 3.55-3.46 (m, 3H), 2.01 (s, 3H), 1.44 (s, 9H); (ESI) m/z: 569.3 (M+H+).
Reaction SMILES: [C:1]([N:4]1[CH2:10][C@H:9]([NH2:11])[C:8](=[O:12])[N:7]([CH2:13][CH3:14])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)(=[O:3])[CH3:2].[CH3:19][CH:20]([C:24]([NH:26][CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[O:25])[C:21](O)=[O:22]>>[C:1]([N:4]1[CH2:10][C@H:9]([NH:11][C:21](=[O:22])[CH:20]([CH3:19])[C:24]([NH:26][CH2:27][C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32])=[O:25])[C:8](=[O:12])[N:7]([CH2:13][CH3:14])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Reactant: CCN1C(=O)[C@@H](N)CN(C(C)=O)c2ccccc21
Product: CCN1C(=O)[C@@H](NC(=O)C(C)C(=O)NCC(F)(F)C(F)(F)F)CN(C(C)=O)c2ccccc21

Procedure:
In an analogous manner to that described in Example 20 d) and 27, the condensation of (S)-5-acetyl-3-amino-1-ethyl-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one and (2RS)-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid [see Example 25 b)] yielded the title compound as a white solid;
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[CH:26][C:25]=1[F:39]>>[C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[C:9]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]([F:37])([F:38])[C:33]([F:36])([F:35])[F:34])=[CH:26][C:25]=1[F:39])=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Reactant: Fc1cc(OCC(F)(F)C(F)(F)F)ccc1Br
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OCC(F)(F)C(F)(F)F)cc1F)c1ccc(Cl)cc1

Procedure:
The title compound was prepared from rac-[(4-chloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 8) and 1-bromo-2-fluoro-4-(2,2,3,3,3-pentafluoro-propoxy)-benzene (Intermediate 34) in analogy to Example 1a): MS (ISN): 510.3 (M−H)−.
Reaction SMILES: CS([C:5]1[N:12]=[C:11]([CH2:13][O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])(=O)=O.[CH3:25][Mg]Br.[Cl-].[NH4+].O>CCOCC>[CH3:25][C:5]1[N:12]=[C:11]([CH2:13][O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: C[Mg]Br
Reactant: CC(C)[Si](OCc1ccc(C#N)c(S(C)(=O)=O)n1)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: Cc1nc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1C#N
Yield: 95 %

Procedure:
To a solution of 2-(methylsulfonyl)-6-{[(triisopropylsilyl)oxy]methyl}nicotinonitrile (0.80 g, 2.2 mmol) that was obtained in Example 24 (24b) in ether (10 ml) was added a 3.0 M solution of methylmagnesium bromide in ether (1.5 ml, 4.4 mmol) at −78° C. with stirring, and the resulting mixture was stirred at the same temperature for 1 hour. After stirring, a saturated aqueous solution of ammonium chloride (1 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was poured into water (20 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:10 to 1:9) as the eluent to afford the title compound (0.64 g) in a yield of 95% as a white crystalline solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:25][C:26](O)=[O:27])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.CC(C)(C)C(Cl)=O.[CH2:43]([C@@H:50]1[CH2:54][O:53][C:52](=[O:55])[NH:51]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[Li]CCCC>C1COCC1>[CH2:43]([CH:50]1[CH2:54][O:53][C:52](=[O:55])[N:51]1[C:26](=[O:27])[CH2:25][C:11]1[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=2)[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: O=C(O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1)N1C(=O)OCC1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a mechanically stirred solution of (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid from the previous step (20 g, 52 mmol) in THF (104 mL) at −78° C. was added N-methyl morpholine (NMM) (6.3 mL, 57 mmol) and trimethylacetyl chloride (7.0 mL, 57 mmol) maintaining the internal temperature below −70° C. This mixture was stirred at −78° C. for 15 minutes and at 0° C. for 1 h. The white solid was filtered off and the filtrate containing the mixed anhydride cooled back to −78° C. for the subsequent reaction. In a separate flask, to a solution of (R)-(+)-4-benzyl-2-oxazolidinone (9.6 g, 54.4 mmol) in THF (109 mL) at −78° C. was added nBuLi (1.6M in hexanes, 34 mL, 54.4 mol), drop-wise, maintaining the internal temperature below −70° C. and stirred for 45 min. This metalated chiral auxiliary was cannulated to add to a reaction flask containing the anhydride solution at −78° C. The reaction was stirred and allowed to warm to 0° C. over 1.5 h. The resulting mixture was stirred further at 0° C. for 30 minute and quenched by adding excess saturated aqueous NH4Cl solution. The solution was diluted with EtOAc (200 mL) and the organic phase was washed with saturated aqueous NaHCO3 solution (3×100 mL) and brine (2×100 mL). The solution was dried over MgSO4 and the solvent was removed in vacuo. The crude material was purified by ISCO silica gel column chromatography to yield 20.3 g (72%) of 4-benzyl-3-[2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetyl]-oxazolidin-2-one as a white solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C)C=O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH:21]([O:27][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:19]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(O)Cc1ccc(OCCN2CCOc3ccccc32)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCCN2CCOc3ccccc32)cc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
A solution of ethyl 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate (0.5 g, 1.34 mmol) obtained in example 13 in dry dimethyl formamide (5 mL) was added to a stirred ice cooled suspension of sodium hydride (60% dispension in oil) (0.08 g, 1.66 mmol) in dry dimethyl formamide (3 mL) under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 30 minutes followed by the addition of benzyl bromide (0.46 g, 2.69 mmol). The mixture was allowed to warm to 25° C. and stirring was continued for further 18 h. Water (25 mL) was added and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with water (50 mL), brine (50 mL) and dried Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (2:8) as eluent to afford the title compound (0.3 g) along with benzyl 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4yl)ethoxy]phenyl]-2-benzyloxypropanoate. This mixture (1:1) is used in example 47 without any separation.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[NH2:26][CH2:27][CH2:28][SH:29].B(F)(F)F>O1CCCC1>[S:29]1[C:2]2([CH2:7][CH2:6][N:5]([C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]4=[O:24])=[CH:10][C:9]=3[F:25])[CH2:4][CH2:3]2)[NH:26][CH2:27][CH2:28]1
Reactant: NCCS
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Agent: FB(F)F
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)NCCS4)c(F)c2)C(=O)O1
Yield: 68 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol), 2-aminoethanethiol (1.0 mmol) and BF3. etherate (2.0 mmol) in tetrahydrofuran (10 ml) at a temperature 65° C. for 12 hours in 68% yield.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:32][CH2:33][CH3:34])[C:13]2[C:22]3[CH:21]=[CH:20][C:19]([O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:18][C:17]=3[N:16]=[C:15]([NH2:30])[C:14]=2[N:31]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(Cl)(Cl)Cl>[C:1]([N:27]1[CH2:26][CH2:25][CH:24]([O:23][C:19]2[CH:20]=[CH:21][C:22]3[C:13]4[N:12]([CH2:32][CH2:33][CH3:34])[C:11]([CH2:10][CH2:9][O:8][CH3:7])=[N:31][C:14]=4[C:15]([NH2:30])=[N:16][C:17]=3[CH:18]=2)[CH2:29][CH2:28]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CCCn1c(CCOC)nc2c(N)nc3cc(OC4CCNCC4)ccc3c21
Reactant: CC(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCn1c(CCOC)nc2c(N)nc3cc(OC4CCN(C(=O)C(C)C)CC4)ccc3c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isobutyryl chloride (0.273 mL, 2.61 mmol) was added dropwise to a stirred solution of 2-(2-methoxyethyl)-7-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-ylamine (prepared as described in Part A of Example 388, 1.00 g, 2.61 mmol) in chloroform at 0° C. After 2 hours, the solution was allowed to warm to ambient temperature for 1 hour. Saturated aqueous sodium carbonate (15 mL) and water (10 mL) were added and the mixture was allowed to stir for 16 hours. The mixture was transferred to a separatory funnel, the layers were separated, and the aqueous layer was extracted with dichloromethane (2×30 mL). The organic layers were combined, washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Recrystallization from acetonitrile afforded 1.00 g of 7-[(1-isobutyrylpiperidin-4-yl)oxy]-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as a flocculent white solid, mp 165-166° C.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[CH:5]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:25])=O>[Cl-].C([N+](CC)(CC)CC)C.C(#N)C>[NH2:1][C:2]1[N:7]=[C:6]([Cl:25])[CH:5]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1
Reactant: Nc1nc(C2CCCC2)cc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: Nc1nc(Cl)cc(C2CCCC2)n1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 120.5 %

Procedure:
A suspension of 2-amino-6-cyclopentyl-3H-pyrimidin-4-one (1.52 g, 8.4 mmol), tetraethyl ammonium chloride (2.8 g 16.9 mmol) and dimethylaniline (1.1 mL, 8.4 mmol) in acetonitrile (16 mL) was treated with phosphorous oxychloride (4.7 mL, 51 mmol) and heated at 110° C. for 20 min. The resulting solution was cooled to rt and concentrated to minimum volume then diluted with CHCl3 and ice and stirred for 30 min. The layers were separated and the organic layer was washed with water (3×50 mL) and 5% NaHCO3, dried, and concentrated to yield 2.0 g of crude product that was used without purification.
Reaction SMILES: [C:1]1([C:7](=[O:17])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18]Br>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[C:1]1([C:7](=[O:17])[CH:8]([Br:18])[C:9]2[CH:10]=[CH:11][C:12]([S:15][CH3:16])=[CH:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: CSc1ccc(CC(=O)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CSc1ccc(C(Br)C(=O)c2ccccc2)cc1
Reaction time: 20 h
Yield: 74.7 %

Procedure:
To a solution of the product of step 1 (60 g, 246 mmol) in CCl4 (900 mL) and CHCl3 (900 mL) was added dropwise a solution of Br2 (43.2 g, 270 mmol) in CCl4 (50 mL). After addition was completed, the mixture was concentrated to about 1/3 of its original volume. The mixture was washed with saturated NaHCO3 (500 mL) and Na2S2O8 (2×250 mL). The pale yellow solution was dried over Na2SO4 and concentrated to dryness. The residue was stirred in 10 % EtO2 /hexane for 20 h and filtered to give 59 g of the title compound.
Reaction SMILES: COC1C=CC([CH2:7][N:8](C)[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:22]4[CH:27]=[C:26]([NH2:28])[C:25]([F:29])=[CH:24][C:23]=4[Cl:30])[C:15](=[O:21])[N:16]3[CH2:19][CH3:20])=[CH:11][N:10]=2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C:26]1[C:25]([F:29])=[CH:24][C:23]([Cl:30])=[C:22]([C:14]2[C:15](=[O:21])[N:16]([CH2:19][CH3:20])[C:17]3[C:12]([CH:13]=2)=[CH:11][N:10]=[C:9]([NH:8][CH3:7])[CH:18]=3)[CH:27]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NC)cc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.5 %

Procedure:
To a solution of Example A4 (3 g, 6.2 mmol) in DCM (100 mL) was added TFA (20 mL) at RT, and the resulting mixture was stirred at RT for 6 h. The mixture was extracted with water (2×) and the combined aqueous layers were neutralized with NH3.H2O. The resulting precipitate was collected by filtration and dried to give 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (1 g, 44% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.46 (s, 1H), 7.75 (s, 1H), 7.1 (d, J=11.2 Hz, 1H), 7.0 (m, 1H), 6.73 (d, J=9.6 Hz, 1H), 6.43 (s, 1H), 4.95 (br s, 2H), 4.14 (m, 2H), 2.92 (s, 3H), 1.14 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 347.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=1.S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12]([Cl:17])=[O:14])=[CH:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-c2ccccn2)s1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(-c2ccccn2)s1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
A suspension of 5-(pyrid-2-yl)thiophene-2-carboxylic acid (48 mg) in dry toluene (10 mL) was treated with thionyl chloride (269 μL). After stirring at 100° C. for 2.5 hours the reaction mixture was allowed to cool to room temperature and then evaporated. The residue was azeotroped with toluene to give the title compound (61 mg), which was used without further purification.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[C:21]([CH:27]=O)[NH:22]2.N1CCCCC1>C(O)C>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:27][C:21]1[NH:22][C:23]2[C:19]([CH:20]=1)=[C:18]([O:17][CH3:16])[CH:26]=[CH:25][CH:24]=2)(=[O:5])=[O:4]
Reactant: COc1cccc2[nH]c(C=O)cc12
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1cc3c(OC)cccc3[nH]1)C(=O)N2
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (194 mg, 0.86 mmol), 4-methoxy-1H-indole-2-carbaldehyde (150 mg, 0.86 mmol) and piperidine (36 mg, 0.43 mmol) in ethanol (0.2 M) was stirred at room temperature for a total of 5 days. The reaction was concentrated to ¼ of its volume and the precipitate was collected by vacuum filtration to give the title compound as a pale orangish-red solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:18][CH2:19][O:20]S(C1C=CC(C)=CC=1)(=O)=O.C([O:33][C:34](=[O:55])[C:35]([CH3:54])([O:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:36][C:37]1[CH:42]=[CH:41][C:40](O)=[C:39]([CH2:44][CH2:45][CH3:46])[CH:38]=1)C>C(O)C>[CH3:54][C:35]([O:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:20][CH2:19][CH2:18][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[C:39]([CH2:44][CH2:45][CH3:46])[CH:38]=1)[C:34]([OH:55])=[O:33]
Reactant: CCCc1cc(CC(C)(Oc2ccccc2)C(=O)OCC)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4cccs4)cc3)oc2C)cc1
Solvent: CCO
Product: CCCc1cc(CC(C)(Oc2ccccc2)C(=O)O)ccc1OCCc1nc(-c2ccc(-c3cccs3)cc2)oc1C
Temperature: 55 °C

Procedure:
Toluene-4-sulfonic acid 2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)ethyl ester (see Ex. 3, Part B) (0.132 mmol) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 3-(4-hydroxy-3-propylphenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) (see Ex. 10, Part C) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55 ° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by mass-directed HPLC to provide analytically pure material. MS (EI) 582.1 (M+H)+; LC RT=3.56 min (>99% pure).
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([O:8][CH2:9][C:10]1[C:11]([CH3:33])=[N:12][C:13]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:15]=1)([CH3:7])[CH3:6])C.[Li+].[OH-].Cl>C1COCC1.O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[CH:15]=[C:10]([CH2:9][O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:34])=[O:3])[C:11]([CH3:33])=[N:12][C:13]=2[C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)(C)OCc1cc(-c2ccc(Cl)cc2)c(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)c(-c2ccc(Cl)cc2)cc1COC(C)(C)C(=O)O
Reaction time: 16 h

Procedure:
To a solution of 400 mg of 2-[5-(4-Chloro-phenyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-2-methyl-propionic acid ethyl ester in 2 ml THF was added a solution of 39 mg of LiOH in 2 ml water at room temperature. After 16 h, the mixture was brought to pH 2 by addition of 1 M hydrochloric acid. The reaction mixture was concentrated under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 280 mg.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([CH2:9][O:10][C:11]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:12]=3[CH:13]=[C:14]([C:20](O)=[O:21])[NH:15]4)=[CH:7][O:8][C:4]=2[CH:3]=1.[ClH:25].Cl.Cl.[C@H:28]1([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]2)[C@@H:37]2[N:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30][CH2:29]1>>[ClH:25].[ClH:25].[C@H:28]1([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([NH:45][C:20]([C:14]3[NH:15][C:16]4[C:12]([CH:13]=3)=[C:11]([O:10][CH2:9][C:6]3[C:5]5[CH:23]=[CH:24][C:2]([F:1])=[CH:3][C:4]=5[O:8][CH:7]=3)[CH:19]=[CH:18][CH:17]=4)=[O:21])[CH2:41][CH2:40]2)[C@@H:37]2[N:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Reactant: O=C(O)c1cc2c(OCc3coc4cc(F)ccc34)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cc(F)ccc34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(6-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (106) (preparation see below) and amine 61 analogously to the method described in example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([NH:11][C:12]1[CH:40]=[CH:39][C:15]([CH2:16][C@@H:17]([C:36]([OH:38])=[O:37])[NH:18]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=[CH:14][CH:13]=1)=[O:10].N1CCCCC1>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([NH:11][C:12]1[CH:40]=[CH:39][C:15]([CH2:16][C@@H:17]([C:36]([OH:38])=[O:37])[NH2:18])=[CH:14][CH:13]=1)=[O:10]
Reactant: O=C(N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Solvent: CN1CCCC1=O
Solvent: C1CCNCC1
Product: N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To the 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-phenylalanine on Wang resin prepared above (12.1 mmol, 17.4 g) was added 20% of piperidine in NMP at room temperature. The mixture was shaken for 1.5 h at room temperature and the resin was filtered and washed with DMF (2×20 mL). Then, the resin was suspended in 20% piperidine in NMP (100 mL) and the solvent was decanted. The resin was washed with dichloromethane (2×20 mL) and dried under high vacuum to obtain 13.5 g of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine on Wang resin.