Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]3[CH3:24])=[O:17])=[CH:12][N:11]=2)=[CH:5][C:4](B(O)O)=[CH:3]1.[C:28]([C:32]1[CH:33]=[C:34]2[C:39](=[C:40]([F:42])[CH:41]=1)[C:38](=[O:43])[N:37]([C:44]1[N:51]=[CH:50][CH:49]=[C:48](Cl)[C:45]=1[CH:46]=[O:47])[N:36]=[CH:35]2)([CH3:31])([CH3:30])[CH3:29].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>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].C(#N)C.O>[C:28]([C:32]1[CH:33]=[C:34]2[C:39](=[C:40]([F:42])[CH:41]=1)[C:38](=[O:43])[N:37]([C:44]1[N:51]=[CH:50][CH:49]=[C:48]([C:4]3[CH:5]=[C:6]([NH:9][C:10]4[CH:15]=[CH:14][C:13]([C:16]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]5[CH3:24])=[O:17])=[CH:12][N:11]=4)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=3)[C:45]=1[CH:46]=[O:47])[N:36]=[CH:35]2)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3C=O)ncc2c1
Reactant: C[C@H]1COCCN1C(=O)c1ccc(Nc2cc(B(O)O)cn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: C[C@H]1COCCN1C(=O)c1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 43 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 136c (260 mg, 0.70 mmol), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehyde 103b (180 mg, 0.50 mmol), K3PO4 (297 mg, 1.4 mmol), sodium acetate (114 mg, 1.4 mmol), 1,1′-bis(diphenylphosphino) ferrocenedichloropalladium(II) (57 mg, 0.07 mmol), and acetonitrile/water (10/0.2 mL). After three cycles of vacuum/N2 flush, the mixture was heated at 100° C. for 1.5 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with dichloromethane (20 mL) and water (10 mL). The aqueous layer was separated and extracted with dichloromethane (3×20 mL). The combined organic layers was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with 60:1 dichloromethane/methanol to afford 136d (140 mg, 43%) as a yellow solid. MS-ESI: [M+H]+ 652.3
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH2:17](I)[CH3:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH3:18])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2cccc(OCC)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
4-Hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (200 mg) was mixed with ethyl iodide (0.5 mL), K2CO3 (200 mg) and 2 mL of DMF. The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine. Removal of the solvent under vacuum gave the crude product, which was purified by column chromatography to give 175 mg (77% yield) of 4-ethoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)=[C:5]([CH3:17])[C:4]([C:18]([OH:20])=O)=[N:3]1.[N:21]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=2)=[C:5]([CH3:17])[C:4]([C:18]([N:29]2[CH2:30][CH2:31][CH:26]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:27][CH2:28]2)=[O:20])=[N:3]1
Reactant: Cc1c(C(=O)O)nn(C)c1-c1cccc(C(F)(F)F)c1
Reactant: C1CCN(C2CCNCC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(C(=O)N2CCC(N3CCCC3)CC2)nn(C)c1-c1cccc(C(F)(F)F)c1

Procedure:
In analogy to the procedure described for Example 1, 1,4-dimethyl-5-(3-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid and 4-pyrrolidine-1-yl-piperidine with HATU/iPr2Net gave the title compound as yellow oil. MS: 421.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][N:5]([CH3:38])[C:6]=1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)[CH2:18][N:19]1C(=O)C3C(=CC=CC=3)C1=O)[CH2:10]2.NN>CO.O1CCCC1>[NH2:19][CH2:18][C@@H:17]([N:11]1[CH2:10][C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:6]3[N:5]([CH3:38])[N:4]=[CH:3][C:2]=3[F:1])[CH:8]=2)[C:12]1=[O:16])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1
Reactant: Cn1ncc(F)c1-c1ccc2c(c1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Cn1ncc(F)c1-c1ccc2c(c1)CN([C@H](CN)Cc1cccc(F)c1)C2=O
Yield: 36.5 %

Procedure:
A solution of 2-[(2S)-2-[5-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (30.0 mg, 0.058 mmol) and hydrazine (0.2 mL, 6 mmol) in methanol (1.0 mL) and tetrahydrofuran (1.0 mL) was stirred at room temperature overnight. Direct purification on prep.—HPLC (pH=10) gave 8.1 mg of the desired product as white solid. LC/MS found: 383.0 (M+1)+; 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.73 (d, J=7.8 Hz, 1H), 7.71 (s, 1H), 7.61 (d, J=4.9 Hz, 1H), 7.57 (d, J=7.9 Hz, 1H), 7.23 (ddd, J1=8.2 Hz, J2=7.8 Hz, J3=6.4 Hz, 1H), 7.03 (m, 2H), 6.93 (dddd, J1=8.6 Hz, J2=8.4 Hz, J3=2.6 Hz, J4=0.8 Hz, 1H), 4.48 (s, 2H), 4.42 (m, 1H), 3.79 (s, 3H), 3.05 (dd, J1=14.40 Hz, J2=5.20 Hz, 1H), 2.88 (dd, J1=14.40 Hz, J2=10.00 Hz, 1H), 2.81 (d, J=6.70 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]([C:17]2[N:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][C:25]=1[F:33]>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]([NH:14][C:15]([C:17]3[N:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:16])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:26][C:25]=1[F:33]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cccnn1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1)c1cccnn1

Procedure:
The title compound was synthesized in analogy to Example 39, using pyridazine-3-carboxylic acid[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 62 a) and B-(4-chloro-3-fluorophenyl)-boronic acid (CAN 137504-86-0) as starting materials; LC-MS (UV peak area/ESI) 100%, 425.0438 (M−H)−.
Reaction SMILES: C(=O)([O-])OC.[Mg+2].COC(=O)[O-].[CH3:12][C:13](=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:14]=[CH:15][C:16](=[O:18])[CH3:17].[N:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=1>CO>[CH3:12][C:13](=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:14]=[CH:15][C:16](=[O:18])[CH2:17][CH:31]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1
Reactant: CC(=O)C=CC(C)=Cc1ccccc1
Reactant: C1=NCCCC1
Agent: COC(=O)[O-]
Agent: [Mg+2]
Solvent: CO
Product: CC(C=CC(=O)CC1CCCCN1)=Cc1ccccc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
Magnesium methyl carbonate (1.2 moles, 2 N in dimethylformamide) is heated to 120°C. under an atmosphere of carbon dioxide. The compound 5-methyl-6-phenyl-3,5-hexadien-2-one, 53.0 g (0.285 mole) is added and the mixture is stirred at 120°C. for a period of 4 hours under a stream of nitrogen while permitting the methanol that forms to escape. The mixture is allowed to cool under an atmosphere of carbon dioxide and 57.0 g (0.68 mole) of 2,3,4,5-tetrahydropyridine (as α-tripiperidein) is added and stirred at room temperature under an atmosphere of carbon dioxide for a period of 70 hours. The reaction mixture is poured into a concentrated HCl-ice mixture and extracted with methylene dichloride. The extracts are combined, washed with water, dried over anhydrous sodium sulfate, and the solvent removed. The crude 5-methyl-6-phenyl-1-(2-piperidyl)-3,5-hexadein-2-one which remains is recrystallized twice from isopropyl alcohol as the hydrochloride salt and is obtained in 48% yield (41.6 g) and has a M.P. of 179-80°C.
Reaction SMILES: [F:1][CH:2]([F:16])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]([F:15])[F:14])[C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Li+]>CO>[F:1][CH:2]([F:16])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]([F:15])[F:14])[C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1c(C(F)F)cccc1C(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c(C(F)F)cccc1C(F)F
Temperature: 21 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a solution of methyl 2,6-bis(difluoromethyl)benzoate (205 mg) in methanol (3 ml) was added a solution of lithium hydroxide (48 mg) in methanol (3 ml). It was stirred at 21° C. and the initial oily suspension slowly cleared over ca. 2 hours but insoluble material remained. It was stirred for a total of 20 hours and then evaporated to dryness. It was partitioned between ethyl acetate (10 ml) and water (10 ml), washed with ether (10 ml), acidified with 2M hydrochloric acid and extracted with ethyl acetate (2×10 ml). This was washed with water (10 ml) and saturated brine (10 ml), dried over sodium sulphate and evaporated to give the title compound (146 mg).
Reaction SMILES: Cl/[CH:2]=[CH:3]/[C:4]([C:6]1([CH3:12])[CH2:9][CH:8]([CH2:10][CH3:11])[CH2:7]1)=[O:5].[I-:13].[Na+].OS(O)(=O)=O>CC(C)=O>[I:13]/[CH:2]=[CH:3]/[C:4]([C:6]1([CH3:12])[CH2:9][CH:8]([CH2:10][CH3:11])[CH2:7]1)=[O:5]
Reactant: CCC1CC(C)(C(=O)/C=C/Cl)C1
Reactant: [I-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCC1CC(C)(C(=O)/C=C/I)C1
Yield: 108.7 %

Procedure:
A solution of 4.2 g of trans-1-chloro-3-(3-ethyl-1-methylcyclobutyl)-prop-1-en-3-one (prepared in Example 5A) and 10 g of anhydrous sodium iodide in 60 ml of acetone was refluxed with about 0.5 ml H2SO4 for 4 hr under an argon atmosphere. The solvent was removed by evaporation in vacuo. The residue was diluted with water and the aqueous mixture was extracted several times with ether. The combined ether extract was washed with aqueous sodium thiosulfate solution and then dried over anhydrous magnesium sulfate and evaporated in vacuo to yield 6.8 g of the title compound having the following physical characteristics:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].FC1C(C)=C(C2C=CC(C(O)=O)=CC=2COC)C=CC=1.[F:35][C:36]1[CH:37]=[CH:38][C:39]([CH3:45])=[C:40](B(O)O)[CH:41]=1.[F-].[Cs+]>O1CCOCC1.CC(OC)(C)C.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.O>[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH3:45])=[C:38]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[CH2:12][O:13][CH3:14])[CH:37]=1
Reactant: COCc1cc(C(=O)OC)ccc1Br
Reactant: Cc1ccc(F)cc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: COCc1cc(C(=O)O)ccc1-c1cccc(F)c1C
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: COCc1cc(C(=O)OC)ccc1-c1cc(F)ccc1C
Temperature: 90 °C

Procedure:
A mixture of methyl 4-bromo-3-(methoxymethyl)benzoate (Intermediate 1, Step 2, 3.00 g, 11.6 mmol), 5-fluoro-2-methylphenylboronic acid (2.67 g, 17.4 mmol), bis(triphenylphosphine)palladium(II) chloride (162 mg, 0.23 mmol) and cesium fluoride (5.28 g, 34.7 mmol) was prepared in dioxane (30 mL) and water (12 mL) under nitrogen atmosphere. The reaction mixture was heated at 90° C. for 3 hours. The reaction mixture was cooled at RT, diluted with MTBE (150 mL) and the layers were separated. The organic layer was washed with brine (50 mL). The aqueous layers were extracted with MTBE (100 mL). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure. After purification by flash chromatography (silica, EtOAc/heptane), the title compound was obtained as a colorless oil (2.88 g, 86%). HPLC (Method A), Rt 5.0 min (purity: 98.7%). LC/MS (Method B): 288.9 (M+H)+.
Reaction SMILES: COC1C=CC(C)=CC=1C(N[C@H]1CCC[C@@H]1NC1C=NC(C(F)(F)F)=CN=1)=O.Cl.[F:30][C:31]([F:46])([F:45])[C:32]1[N:33]=[CH:34][C:35]([NH:38][C@H:39]2[CH2:43][CH2:42][CH2:41][C@@H:40]2[NH2:44])=[N:36][CH:37]=1.[F:47][C:48]1[C:56]([F:57])=[CH:55][CH:54]=[C:53]([N:58]2[N:62]=[CH:61][CH:60]=[N:59]2)[C:49]=1[C:50](O)=[O:51]>>[F:47][C:48]1[C:56]([F:57])=[CH:55][CH:54]=[C:53]([N:58]2[N:62]=[CH:61][CH:60]=[N:59]2)[C:49]=1[C:50]([NH:44][C@H:40]1[CH2:41][CH2:42][CH2:43][C@@H:39]1[NH:38][C:35]1[CH:34]=[N:33][C:32]([C:31]([F:30])([F:45])[F:46])=[CH:37][N:36]=1)=[O:51]
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(O)c1c(-n2nccn2)ccc(F)c1F
Agent: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1c(-n2nccn2)ccc(F)c1F

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 126 mg, 0.45 mmol) and 2,3-difluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 39a; 120 mg, 0.535 mmol) except this was purified by column chromatography (silica, 40-100% ethyl acetate/petrol) and then further purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:43]([CH3:44])=[CH:42][C:15]2[N:16]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:21]([C:32]4[CH:33]=[C:34]5[C:38](=[CH:39][CH:40]=4)[N:37]([CH3:41])[N:36]=[CH:35]5)[CH2:20]3)[S:18][C:14]=2[C:13]=1[C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)C>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:43]([CH3:44])=[CH:42][C:15]2[N:16]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH:21]([C:32]4[CH:33]=[C:34]5[C:38](=[CH:39][CH:40]=4)[N:37]([CH3:41])[N:36]=[CH:35]5)[CH2:20]3)[S:18][C:14]=2[C:13]=1[C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCN(C(=O)OC(C)(C)C)C(c4ccc5c(cnn5C)c4)C3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc2nc(N3CCN(C(=O)OC(C)(C)C)C(c4ccc5c(cnn5C)c4)C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
To the solution of tert-butyl 4-(6-((S)-1-tert-butoxy-2-ethoxy-2-oxoethyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-2-yl)-2-(1-methyl-1H-indazol-5-yl)piperazine-1-carboxylate (5 mg) in THF/MeOH (0.5 mL/0.5 mL) was added sodium hydroxide solution (0.4 mL, 1.0 N). The mixture was heated at 50° C. for 16 hours. The mixture was cooled, and was acidified with acetic acid (60 μL). Concentration and purification with reverse phase HPLC gave (2S)-2-tert-butoxy-2-(2-(4-(tert-butoxycarbonyl)-3-(1-methyl-1H-indazol-5-yl)piperazin-1-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)acetic acid. LCMS-ESI+: calc'd for C37H43ClN5O5S: 704.3 (M+H+); Found: 704.1 (M+H+). 1H-NMR 400 MHz, (CD3OD) δ 7.96 (s, 1H), 7.64 (m, 2H), 7.49 (m, 3H), 7.38 (m, 3H), 5.46 (m, 1H), 5.19 (s, 1H), 4.4 (m, 1H), 4.2 (m, 1H), 4.07 (s, 3H), 4.0-3.7 (m, 2H), 3.5 (m, 2H), 2.5 (s, 3H), 1.40 (s, 9H), 0.98 (s, 9H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][C@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]1[C:37](ON1C(=O)CCC1=O)=[O:38]>CN(C)C=O>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]1[C:37]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][C@H:3]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:38]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)[C@H](c2ccccc2)Sc2ccccc21
Reactant: O=C(ON1C(=O)CCC1=O)c1cc2ccccc2[nH]1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)c2cc3ccccc3[nH]2)[C@H](c2ccccc2)Sc2ccccc21
Temperature: 60 °C
Reaction time: 33.5 h
Yield: 89.7 %

Procedure:
In 300 ml of dimethylformamide are dissolved 18 g of tert-butyl trans-3-amino-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 12 g of succinimido indolecarboxylate as synthesized by a known method, and the solution is stirred at 60° C. for 33.5 hours. The reaction mixture is poured to ice-water, and the mixture is stirred to separate crystals, which are collected by filtration and washed with water and dried to give 22 g of tert-butyl trans-3-(2-indolecarboxamido)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, m.p. 196°-200° C. (decomposition).
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:20])[CH2:16][C:17]([CH3:19])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH3:21]>>[O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:20])/[CH:16]=[C:17](\[NH2:21])/[CH3:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: N
Reactant: CC(=O)CC(=O)Nc1ccc(C2=NNC(=O)CC2)cc1
Product: C/C(N)=C/C(=O)Nc1ccc(C2=NNC(=O)CC2)cc1

Procedure:
12.5 g (45.7 mmoles) of acetoacetic acid N-[4-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-phenyl]-amide in 225 ml of aqueous concentrated ammonia are heated under reflux for 2 hours. After cooling, the product if filtered off with suction and washed with water until it is neutral.
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:44][O:45][C:46]1[C:47]2[N:60]=[C:59]([NH2:61])[S:58][C:48]=2[C:49]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[N:50][CH:51]=1>C1COCC1>[CH3:44][O:45][C:46]1[C:47]2[N:60]=[C:59]([NH:61][C:1]([C:2]3[CH:10]=[CH:9][C:8]4[O:7][CH2:6][O:5][C:4]=4[CH:3]=3)=[O:12])[S:58][C:48]=2[C:49]([N:52]2[CH2:53][CH2:54][O:55][CH2:56][CH2:57]2)=[N:50][CH:51]=1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccc4c(c3)OCO4)nc12

Procedure:
From piperonylic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 415 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:38])[CH2:20][NH:21][C:22](=[O:37])[NH:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)[O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>CO.O>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:38])[CH2:20][NH:21][C:22](=[O:37])[NH:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)[O:27][CH2:28][C:29]([OH:31])=[O:30])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)COc1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CCC2c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(OCC(=O)O)c1
Yield: 40 %

Procedure:
By proceeding in a fashion similar to that described in Example 9, but starting from 3.7 g of ethyl (2RS,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenoxyacetate in solution in 80 cm3 of methanol and 0.4 g of potassium hydroxide dissolved in 40 cm3 of water. After treatment and recrystallization in isopropyl acetate, 1.4 g of (2RS,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenoxyacetic acid, melting at 192° C., are obtained.
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([O:36][CH3:37])[CH:30]=3)(=[O:28])=[O:27])[CH2:21][CH2:20]2)=[O:18])[CH3:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[C:31]([O:36][CH3:37])[CH:30]=3)(=[O:28])=[O:27])[CH2:21][CH2:20]2)=[O:18])[CH3:15])=[CH:10][CH:9]=1
Reactant: COc1cc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)N[C@H](C)c3ccc(F)cc3)CC2)ccc1O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)N[C@H](C)c3ccc(F)cc3)CC2)ccc1OC1CCCC1
Temperature: 50 °C

Procedure:
Cyclopentylbromide (10.45 mg, 0.07 mmol) was added to solution of trans-4-(4-hydroxy-3-methoxy-benzenesulfonylamino)-cyclohexanecarboxylic acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide (Example 2, 31.6 mg, 0.07 mmol) and potassium carbonate (19.4 mg, 0.14 mmol) in dimethylformamide (700 ul). The reaction was heated 50° C. for 16 h, cooled to room temperature, diluted with ethyl acetate and rinsed with 1:1 water:brine. The organic layer was concentrated and purified by reverse-phase chromatography followed by lyophilization to yield title compound (18 mg, 0.035 mmol). MS MH+ 519.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][C:13]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[N:12][C:11]=2[CH:26]([CH3:28])[CH3:27])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:29](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:29])[C:13]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[N:12][C:11]=2[CH:26]([CH3:28])[CH3:27])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)[nH]2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
(5)In 25 ml of dry N,N-dimethylformamide was dissolved 11.0 g (25.1 mmol)of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (16b), followed by addition of 5.2 g (38 mmol)of potassium carbonate powder. Then, 3.90 g (27.7 mmol)of methyl iodide was further added and the mixture was stirred at room temperature for 8 hours. This reaction mixture was concentrated under reduced pressure and the residue was diluted with water and extracted with diethyl ether. The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was fractionated by silica gel chromatography (ethyl acetate:methylene chloride=1:9). From the first fraction, 1.7 g (yield 15%)of the objective position isomer (17b')was obtained as oil. From the subsequent fraction, 9.14 g (yield 80%)of the objective 5-(3,5-dichlorophenylthio)-1-methyl-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (17b)was obtained. mp 79-80° C.