Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.Cl.[CH2:31]([O:33][C:34](=[O:38])[CH2:35][CH2:36][NH2:37])[CH3:32].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl>[CH2:31]([O:33][C:34](=[O:38])[CH2:35][CH2:36][NH:37][C:16]([C:13]1[CH:12]=[C:11]([CH3:19])[C:10]([CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:21])=[O:22])=[CH:15][N:14]=1)=[O:17])[CH3:32]
Reactant: CCOC(=O)CCN
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)CCNC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (106 mg, 0.252 mmol) obtained in Example 12 in methylene chloride (3 ml), β-alanine ethyl ester hydrochloride (46 mg, 0.302 mmol), 1-hydroxybenzotriazole (34 mg, 0.252 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride mg, 0.302 mmol) and 4-methylmorpholine (66 μl, 0.604 mmol) were added. The reaction solution was stirred for 15 hours at room temperature, and was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with hexane:ethyl acetate (=1:1) was concentrated under reduced pressure, to obtain the title compound (126 mg, 0.242 mmol, 96%) as an amorphous substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[O:18])[C@@H:9]2[CH2:19][CH2:20][C@H:21]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:4]([OH:37])[CH:3]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>ClCCl.CN(C)C1C=CN=CC=1>[C:38]([O:37][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[C@@H:8]1[C@@H:9]([CH2:19][CH2:20][C@H:21]([O:29][Si:30]([C:33]([CH3:34])([CH3:36])[CH3:35])([CH3:32])[CH3:31])[C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:10](=[O:18])[N:11]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:40])[CH3:39]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CC[C@H]1C(=O)N(c2ccccc2)[C@@H]1c1ccc(Br)cc1O)c1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1cc(Br)ccc1[C@@H]1[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(F)cc2)C(=O)N1c1ccccc1
Yield: 78.2 %

Procedure:
(3R,4S)-4-(4-Bromo-2-hydroxyphenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (293 mg, 0.50 mmol) was dissolved in anhydrous dichloromethane (3 mL). 4-Dimethylaminopyridine (183 mg, 1.5 mmol) was added followed by acetic anhydride (280 μL, 302 mg, 3.0 mmol). After 1 h the reaction was filtered through a plug of silica gel and eluted with dichloromethane. The solvent was concentrated, azeotroped with toluene and purified by chromatography (40 g silica gel, 1% to 85% ethyl acetate-hexane) to afford 5-bromo-2-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}phenyl acetate (245 mg, 78% yield); Rf 0.47 (1:4 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.38-7.16 (m, 9H), 7.14-6.94 (m, 3H), 4.69 (t, J=5.4 Hz, 1H), 4.64 (d, J=2.3 Hz, 1H), 3.06 (ddd, J=4.7, 2.3, 2.2 Hz, 1H), 2.30 (s, 3H), 1.97-1.78 (m, 4H), 0.89 (s, 9H), 0.032 (s, 3H), −0.14 (s, 3H) ppm; MS [M−OSi(CH3)2C(CH3)3]+ 493.8.
Reaction SMILES: [N:1]1([CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH3:7])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:15]([O-])=[O:16].[Na+].C(OC(=O)C)(=O)C>C(O)=O>[N:1]1([CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]=[O:16])=[CH:10][CH:9]=2)[CH3:7])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C[O-]
Reactant: CC(c1ccc(N)cc1)n1ccnc1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: CC(c1ccc(NC=O)cc1)n1ccnc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
(a-4) To a stirred solution of 15 parts of 4-[1-(1H-imidazol-1-yl)ethyl]-benzenamine and 2.7 parts of sodium formate in 60 parts of formic acid is added dropwise a solution of 9 parts of acetic acid anhydride in 24 parts of formic acid at 50° C. The reaction mixture was stirred for 1 hour at 100° C. and the solvent was evaporated. The residue was dissolved in a small amount of ice water and the solution was treated with ammonium hydroxide while cooling. The product was extracted twice with dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was crystallized twice from tetrahydrofuran, yielding 13.8 parts (80%) of N-[4-[1-(1H-imidazol-1-yl)ethyl]phenyl]-formamide; mp. 129.4° C. (int. 115).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[NH2:23]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=1)[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1cc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-methoxy-5-trifluoromethylaniline (55 mg, 0.290 mmol) similar to Example 117 and isolated as a yellow solid (27 mg, 34%). 1H NMR (CDCl3): 9.65-9.64 (m, 1H), 8.75-8.70 (m, 2H), 7.46-7.41 (m, 2H), 7.36 (s, 1H), 7.31 (s, 1H), 7.00 (s, 1H), 6.93 (s, 1H), 3.91 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([NH2:11])[CH:5]=1)=[O:3].[CH:12]1([C:15](O)=[O:16])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([NH:11][C:15]([CH:12]2[CH2:14][CH2:13]2)=[O:16])[CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(F)c(N)c1
Reactant: O=C(O)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(F)c(NC(=O)C2CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.7 %

Procedure:
To a round, bottom flask was added 3-amino-4-fluoroacetophenone (Method 64, 1 g, 6.54 mmol), cyclopropyl carboxylic acid (0.62 ml, 7.84 mmol), HATu (2.5 g (6.57 mmol), and DIEA (2.3 ml, 13.08 mmol) in DMF (15 ml). The reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was quenched with water and partitioned with EtOAc. The layers were cut, followed by an additional wash of the aqueous with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue obtained was then purified by silica gel chromatography (Biotage Horizon System) using a gradient elution of 5-15% EtOAc in DCM to give 458 mg of the title compound (32% isolated yield). 1H NMR: 10.16 (s, 1H) 8.53 (dd, J=7.91, 2.26 Hz, 1H) 7.67-7.82 (m, 1H) 7.40 (dd, J=10.55, 8.67 Hz, 1H) 2.54 (s, 3H) 1.95-2.09 (m, 1H) 0.78-0.88 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2[C:10](=[N:11][NH:12][C:13]=2[NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][CH:18]([CH:21]=O)[CH:19]=O>CC(O)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2=[C:13]3[N:12]([N:11]=[C:10]2[CH2:9]1)[CH:21]=[C:18]([Cl:17])[CH:19]=[N:16]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Reactant: O=CC(Cl)C=O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1Cc2nn3cc(Cl)cnc3c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.2 %

Procedure:
A mixture of 3-amino-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (2 g; 8.92 mmol; 1 eq.) and 2-chloromalonaldehyde (1.04 g; 9.81 mmol; 1.1 eq.) in AcOH was stirred at room temperature for 18 hours then diluted with water (30 mL). The precipitate was filtered off and purified by column chromatography (DCM/EA, from 95/5 to 80/20) to afford the title compound (1.24 g, 47%) as a white solid. 1H NMR (DMSO-d6) δ 9.57 (d, J=2.3 Hz, 1H), 8.59 (d, J=2.3 Hz, 1H), 4.63-4.57 (m, 4H), 1.47 (s, 9H). HPLC (max plot) 99.1%; Rt 3.75 min.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH:11]1[CH2:16][OH:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].[N+](C1C=CC([O:27][C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[CH2:32][CH2:31]2)=O)=CC=1)([O-])=O.C([O-])(O)=O.[Na+]>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH:11]1[CH2:16][O:17][C:28]([N:30]1[CH2:31][CH2:32][N:33]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:27])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCOCC1CO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOCC1COC(=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: -10 °C
Yield: 67.9 %

Procedure:
NaH (60% in oil, prewashed with hexane; 1.30 g, 31.7 mmol) was suspended in anhydrous THF (50 mL) under nitrogen and the reaction mixture was cooled to −10° C. with stirring. A solution of 3-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (Intermediate 7; 2.30 g, 10.6 mmol) in THF (50 mL) was added dropwise. The reaction mixture was stirred for 20 min at 0° C. 4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 6; 4.38 g, 12.7 mmol) was added and the reaction mixture was stirred overnight at room temperature. Sat aq NaHCO3 solution (10 mL) was added and the solvents were removed in vacuo. The residue was partitioned between water and EtOAc and the aqueous phase extracted with EtOAc. The combined organic extracts were washed with sat aq NaHCO3 (3×100 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash normal column chromatography (Apollo silica, 40-63 μm, 60 A) eluting with EtOAc/hexane. Impure material was further purified by flash normal phase chromatography using 1% MeOH in DCM to give 3-[4-(4-fluorophenyl)-piperazine-1-carbonyloxymethyl]-morpholine-4-carboxylic acid tert-butyl ester (3.05 g, 68%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4([F:27])[CH2:26][O:25][CH2:24]4)=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[Si]([O:48][CH:49]1[CH2:52][NH:51][CH2:50]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[F:27][C:23]1([C:20]2[CH:21]=[CH:22][C:17]([C:14]3[N:13]=[C:12]([C:8]4[CH:9]=[C:10]([CH3:11])[N:6]([CH2:5][C:4]5[CH:3]=[C:2]([N:51]6[CH2:52][CH:49]([OH:48])[CH2:50]6)[CH:30]=[CH:29][CH:28]=5)[N:7]=4)[O:16][N:15]=3)=[CH:18][CH:19]=2)[CH2:26][O:25][CH2:24]1
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(-c2nc(-c3ccc(C4(F)COC4)cc3)no2)nn1Cc1cccc(Br)c1
Product: Cc1cc(-c2nc(-c3ccc(C4(F)COC4)cc3)no2)nn1Cc1cccc(N2CC(O)C2)c1

Procedure:
Analogously to the process described in Example 3, 150 mg (0.320 mmol) of the compound from Example 6A and 149 mg (0.479 mmol) of the compound from Example 8A were used to obtain 60 mg (39% of theory) of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)C(C)C)(C)C.C([O:23][C:24](=O)[CH:25]=[C:26]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[F:37])[CH2:27]Br)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=2[F:37])=[CH:25][C:24]1=[O:23])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)C=C(CBr)Oc1cccc(Cl)c1F
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(Cl)c2F)=CC1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.94 g, 5.17 mmol) in acetonitrile (11 mL) was treated with N,N-diisopropylethylamine (0.84 mL, 5.08 mmol). After addition was complete, the mixture was stirred at 60° C. for 1 h. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (0.84 mL, 5.08 mmol) and acetonitrile (11 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(3-chloro-2-fluoro-phenoxy)-but-2-enoic acid ethyl ester (1.59 g, 4.71 mmol) in acetonitrile (11 mL). After the addition was complete the reaction mixture was heated to 100° C. and stirred overnight. At this time, the reaction mixture was cooled to 25° C. and concentrated in vacuo. The residue was diluted with dichloromethane (100 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes) afforded (S)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.87 g, 52%) as a red/orange oil: HR-ES-MS m/z calculated for C17H19NO4FCl [M+H]+ 356.1060, observed 356.1060; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), 1.36-1.54 (m, 1H), 1.62 (ddd, J=14.0, 9.6, 4.6 Hz, 1H), 1.81 (ddd, J=14.0, 11.4, 4.6 Hz, 1H), 3.66 (s, 3H), 4.22 (d, J=18.3 Hz, 1H), 4.28 (d, J=18.3 Hz, 1H), 4.74 (dd, J=11.4, 4.6 Hz, 1H), 5.07 (s, 1H), 7.33 (td, J=8.1, 1.4 Hz, 1H), 7.48-7.55 (m, 1H), 7.58 (ddd, J=8.1, 6.7, 1.4 Hz, 1H).
Reaction SMILES: COC(=O)C.C[O:7][C:8](=[O:20])[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[CH3:19].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.Br[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([CH3:50])(=[O:49])=[O:48])=[C:43]([C:51]([F:54])([F:53])[F:52])[CH:42]=1>CN(C=O)C>[CH3:50][S:47]([C:44]1[CH:45]=[CH:46][C:41]([CH2:40][N:12]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:18]3[C:10]([CH2:9][C:8]([OH:7])=[O:20])=[C:11]2[CH3:19])=[CH:42][C:43]=1[C:51]([F:52])([F:54])[F:53])(=[O:49])=[O:48]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1C(F)(F)F
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Solvent: COC(C)=O
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-Methanesulfonyl-3-trifluoromethyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester: To a stirred solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((12.8 g, 62.8 mmol) in dry DMF (200 ml) under an inert atmosphere of Argon is added dropwise, BEMP (19.9 ml, 69.1 mmol) over five minutes. After stirring at room temperature for 1 hour, the resulting solution is added dropwise to a stirred solution of 1-bromomethyl-4-methanesulfonyl-3-trifluoromethyl-benzene (23.9 g, 75.4 mmol) and stirred for 18 hours. The reaction is concentrated in vacuo with toluene and the resulting oil is purified by chromatography on silica eluting with iso-hexane/acetone (15:1). The crude is further purified by dissolving in hot ethyl acetate and refluxing in the presence of charcoal for 5 minutes. The solution is filtered and the solvent is removed in vacuo. The resulting solid is re-crystallized from ethyl acetate/iso-hexane to yield the titled product as a white solid. (MH+ 441).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:19]=4[S:20][C:16]=3[CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)=[CH:4][CH:3]=1.Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:31][O:30][C:28](=[O:29])[CH2:27][O:25][C:22]1[CH:23]=[CH:24][C:18]2[C:17]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)=[C:9]4[C:14](=[CH:15][C:16]=3[S:20][C:19]=2[CH:21]=1)[CH:13]=[CH:12][CH:11]=[CH:10]4
Reactant: COC(=O)CBr
Reactant: Oc1ccc(-c2c3ccccc3cc3sc4cc(O)ccc4c23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc2c(c1)sc1cc3ccccc3c(-c3ccc(O)cc3)c12
Reaction time: 2.5 h
Yield: 58.1 %

Procedure:
11-(4-Hydroxy-phenyl)-benzo[b]naphtho[2,3-d]thiophen-3-ol (1.36 g, 3.96 mmol), methyl bromoacetate (0.38 mL, 4.01 mmol), potassium carbonate (0.548 g, 3.97 mmol) and N,N-dimethylformamide (21 mL) were combined and stirred at ambient temperatures for 2.5 h. The reaction mixture was added to water and extracted with ethyl acetate and THF. Silica gel was added to the organic phase and the solvent was removed. The adsorbate was flash chromatographed (eluent:gradient dichloromethane to 98:2 dichloromethane:acetonitrile) to provide the title compound as a white solid (0.953 g, 58%): mp: 229-231° C: NMR (DMSO-d6); δ9.78 (s, 1 H), 8.51 (s, 1 H), 8.00 (d, J=8 Hz, 1 H), 7.56-7.39 (m, 4 H), 7.18 (d, J=9 Hz, 2 H), 7.05 (d, J=9 Hz, 2 H), 6.79 (dd, J=9, 2 Hz, 1 H), 6.66 (d, J=9 Hz, 1 H), 4.86 (s, 2 H), 3.68 (s, 3 H); MS (EI): 414 (100%, M+); Anal. Calc. for C25 H18O4S: C, 72.45, H, 4.38, N, 0.00. Found: C, 71.78, H, 4.41, N, 0.13.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4].[CH3:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C@@H:31]([OH:39])[CH2:32][N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:25][C:23]=2[N:24]=1.C(N(C(C)C)CC)(C)C>C(O)C>[OH:39][C@H:31]([CH2:30][O:29][C:26]1[CH:27]=[CH:28][C:22]2[S:21][C:20]([CH3:19])=[N:24][C:23]=2[CH:25]=1)[CH2:32][N:33]1[CH2:34][CH2:35][N:36]([CH2:2][C:3]([NH:5][C@@H:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4])[CH2:37][CH2:38]1
Reactant: CCOC(=O)[C@@H](NC(=O)CCl)c1ccc(F)cc1
Reactant: Cc1nc2cc(OC[C@@H](O)CN3CCNCC3)ccc2s1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H](NC(=O)CN1CCN(C[C@H](O)COc2ccc3sc(C)nc3c2)CC1)c1ccc(F)cc1

Procedure:
Ethyl (2S)-2-(2-chloroacetylamino)-2-(4-fluorophenyl)acetate (400 mg, 1.46 mmol), (2S)-3-(2-methylbenzothiazol-5-yloxy)-1-piperazinylpropan-2-ol (560 mg, 1.46 mmol), and 1.26 ml diisopropylethylamine (7.3 mmol) was refluxed in ethanol for 24 hours. Solvent was removed under reduced pressure, and the residue purified by Prep TLC, to provide ethyl (2S)-2-(2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}acetylamino)-2-(4-fluorophenyl)acetate.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])[C:28]=4[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])[CH:19]=3)[C:14](O)=[O:15])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:49][NH:50][CH3:51]>>[C:44]([CH2:43][CH2:42][C:28]1[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:18]2[CH:17]=[C:13]([C:14](=[O:15])[N:50]([CH3:51])[CH3:49])[CH:12]=[C:11]([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)[CH:19]=2)=[CH:32][CH:31]=[CH:30][C:29]=1[O:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])([OH:46])=[O:45]
Reactant: CNC
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)OCC
Product: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)OCCO3)c1

Procedure:
The title compound was prepared according to the general procedure described in Example 74 starting from 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoic acid and dimethylamine.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[Cl:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[N:14]=C(S(C)(=O)=O)[N:12]=1.Cl>O1CCCC1.O>[NH:3]([C:1]1[N:12]=[C:11]([Cl:10])[CH:16]=[C:15]([O:17][CH3:18])[N:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1cc(Cl)nc(S(C)(=O)=O)n1
Reactant: O=CNc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)nc(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
1.8 g of formanilide was dissolved in 50 ml of tetrahydrofuran, and 0.4 g of sodium hydride from which the oily matter had been removed beforehand with n-hexane was slowly added to the resulting solution at 10° to 20° C. while cooling with ice water. To the suspension thus obtained was added 3 3 g of 4-chloro-2-methanesulfonyl-6-methoxypyrimidine, and the mixture was stirred for 1 hour at room temperature. Then, 15 ml of 4N hydrochloric acid was added, and reaction was effected for 1 hour under reflux. The reaction liquid was poured in water, extracted with ether, and the ether layer was washed with water, dried over magnesium sulfate, and then the ether was stripped by concentration The residual crystals were recrystallized from n-hexane, and 4.0 g of 2-anilino-4-chloro-6-methoxypyrimidine was obtained (yield 87%). Melting point: 101°-103° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1.[CH2:26]([OH:28])[CH3:27].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:28][CH2:26][CH3:27])[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1
Reactant: COc1cc(-c2nc(N)nc(S(C)(=O)=O)c2C#N)cc(OC)c1OC
Reactant: CCO
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CCOc1nc(N)nc(-c2cc(OC)c(OC)c(OC)c2)c1C#N

Procedure:
From 2-amino-4-methanesulfonyl-6-(3,4,5-trimethoxy-phenyl)-pyrimidine-5-carbonitrile, ethanol and DBU in DME. ES-MS m/e (%): 331 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:9]2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(C3CCCNC3)cnc2N)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc(C3CCCN(S(C)(=O)=O)C3)cnc2N)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of crude methyl 4-(3-amino-6-(piperidin-3-yl)pyrazin-2-yl)-2-fluorobenzoate (38 mg, 0.114 mmol) in DCM (2 mL) in an ice bath was added DIEA (79 μL, 0.454 mmol) followed by methanesulfonyl chloride (9.73 μL, 0.125 mmol). The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was partitioned between DCM and water. The DCM layer was separated and washed with brine. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude product (50% purity) was proceeded to next step. LCMS (m/z): 409.1 (MH+), 0.721 min.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7](=[O:14])[C:8]3[CH:9]=[CH:10][CH:11]=[N:12][C:13]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)(=O)=O>C(#N)C.CN(C)C=O>[O:14]=[C:7]1[NH:6][C:5]2[CH:15]=[CH:16][C:2]([O:1][CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)=[CH:3][C:4]=2[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: O=c1[nH]c2ccc(O)cc2c2ncccc12
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3[nH]c(=O)c4cccnc4c3c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 58.7 %

Procedure:
The compound (60 mg, 0.28 mmol) prepared in step 2 and potassium carbonate (120 mg, 0.85 mmol) were dissolved in acetonitrile (6 ml)/N,N-dimethylformamide (3 ml), added with t-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (240 mg, 0.85 mmol). The resulting mixture was stirred for 3 days at 100˜110° C. and cooled to room temperature. After extraction with chloroform, the reaction mixture was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (chloroform:methanol=10:1) to obtain the title compound (65 mg, yield: 58%, white solid).