Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:25][C:26](=[O:28])[CH3:27].O1C2C=CC=CC=2C=C1>CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>[CH2:1]([O:8][C:9]1[C:10]2[CH:11]=[C:25]([C:26](=[O:28])[CH3:27])[O:17][C:13]=2[CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1c(O)cccc1OCc1ccccc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc2occc2c1
Solvent: CN(C)C=O
Product: CC(=O)c1cc2c(OCc3ccccc3)cccc2o1
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 90.1 %

Procedure:
A solution of 2-(benzyloxy)-6-hydroxybenzaldehyde (Example 38B, 11.10 g, 48.63 mmole) in N,N-dimethylformamide (120 mL) was treated with powdered anhydrous cesium carbonate (15.8 g, 48.63 mmol) added all at once. The resulting mixture was stirred in vacuo for 10 min and then flushed with nitrogen. The reaction flask was placed in a water bath (22° C.) and treated with chloroacetone (4.65 mL, 58.4 mmol) added dropwise over 10 min. The resulting mixture was then stirred at 22° C. for 18 h (no starting aldehyde left by tlc and formation of the intermediate alkylated aldehyde). The reaction mixture was then maintained under vacuum (10 mbar) for 15 min to remove any un-reacted chloroacetone and then flushed with nitrogen. Then anhydrous cesium carbonate (1.0 g, 3.1 mmol) was added and the mixture was heated at 55° C. and stirred for 40 h (more cesium carbonate, 1 g, was added after 24 h and 32 h) till complete conversion of the intermediate alkylated aldehyde into the benzofuran as monitored by TLC. The solid was filtered and washed with N,N-dimethylformamide. The filtrate was evaporated in vacuo and the residual oil was diluted with ethyl acetate (400 mL), washed with cold 0.1 N hydrochloric acid, saturated sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, evaporation of the solvent gave a thick syrup. Chromatography on silica gel (4.5×12 cm, elution toluene-ethyl acetate 2-4%) gave 11.67 g (90% yield) of the title benzofuran as a light yellow solid. Recrystallization from a mixture of ethyl acetate (40 mL) and hexane (40 mL) gave colorless prisms (10.50 g). LC (Method A): 2.162 min. HRMS (ESI) calcd for C17H15O3 [M+H]+ m/z 267.1016, found 267.1022. 1H NMR (CDCl3, 600 MHz) δ ppm: 2.56 (s, 3H), 5.20 (s, 2H), 6.73 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.3-7.5 (m, 6H), 7.63 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([OH:7])=O)[CH3:2].CCOC(OC(OCC)=O)=O.[O:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[C:40]([CH2:42][NH2:43])[CH:39]=[C:38]([C:44]3[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][CH:45]=3)[N:37]=2)[CH2:32][CH2:31]1>C1COCC1>[CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([NH:43][CH2:42][C:40]1[CH:39]=[C:38]([C:44]2[CH:45]=[CH:46][C:47]([C:50]([F:53])([F:51])[F:52])=[CH:48][CH:49]=2)[N:37]=[C:36]([N:33]2[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)[CH:41]=1)=[O:7])[CH3:2]
Reactant: C=C(C(=O)O)N(CC)S(=O)(=O)c1ccc(F)cc1
Reactant: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCOCC2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCOCC2)c1)N(CC)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 11 %

Procedure:
A solution of acid 4B (0.40 g, 1.46 mmol) in THF (20 mL) was added with DEPC (0.28 mL, 1.3 mol eq) and the mixture was stirred at room temperature several minutes. Then [2-morpholino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27B (530 mg, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, water was added to the residue that is extracted with EtOAc (3×30 mL) and washed with brine (1×40 mL). The separated organic phase was dried over Na2SO4, evaporated to dryness and the residue was purified by flash chromatography (6/4 EtOAc/Petroleum ether) to afford a white solid (95 mg) after crystallization from ethyl ether. Yield=12%. 1HNMR (DMSO, 200 MHz) δ 1.087 (t, 3H, J=7.8), 3.39 (q, 2H, J=7.6), 3.55 (m, 4H), 3.71 (m, 4H), 4.42 (d, 2H, J=6.2), 5.13 (s, 1H), 6.12 (s, 1H), 6.85 (s, 1H), 7.35 (s, 1H), 7.47 (t, 2H, J=8), 7.83-7.90 (m, 4H), 8.26 (d, 2H, J=8), 8.80 (bt, 1H). [M+1] 592.33 (C28H28F4N4O4S requires 592.60).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[OH:32][CH2:33][C@H:34]1[CH2:39][NH:38][CH2:37][CH2:36][N:35]1C(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][N:38]3[CH2:37][CH2:36][NH:35][C@@H:34]([CH2:33][OH:32])[CH2:39]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CO
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCN[C@@H](CO)C3)c2c1
Reaction time: 16 h

Procedure:
A mixture of the product of Example 75 step i) (300 mg), (R)-2-(hydroxymethyl)piperazine-1-carboxylic acid, tert-butyl ester (465 mg) and sodium triacetoxyborohydride (608 mg) in dichloromethane (20 mL) was stirred under nitrogen for 16 hours. The reaction was partitioned between dichloromethane and water, the organics were then collected and concentrated to dryness. The residue was purified by HPLC to give the title compound (230 mg) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22](CC3C=CC=CC=3)[C:21]3[C:20](=[O:30])[N:19]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:18](=[O:37])[N:17]([CH3:38])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:22][C:21]3[C:20](=[O:30])[N:19]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:18](=[O:37])[N:17]([CH3:38])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2Cc2ccccc2)n(C)c1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)Cn1c(=O)c2[nH]c(N3CCN(C(=O)OC(C)(C)C)CC3)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[7-Benzyl-1-(ethoxycarbonylmethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester was dissolved in acetic acid, and palladium hydroxide (ca. 10 mg) was added thereto. The reaction mixture was stirred at room temperature under hydrogen atmosphere overnight, filtered, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, and washed with saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 111 mg of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:32][C:33]1[C:38]([CH3:39])=[CH:37][C:36]([C:40](=[O:42])[NH2:41])=[CH:35][C:34]=1[CH3:43])[C:9](=[O:31])[N:10]1[CH:19]([C:20]2[NH:21][CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:7][CH:8]([C:9](=[O:31])[N:10]1[CH:19]([C:20]2[NH:21][CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)[CH2:32][C:33]1[C:34]([CH3:43])=[CH:35][C:36]([C:40]([NH2:41])=[O:42])=[CH:37][C:38]=1[CH3:39]
Reactant: Cc1cc(C(N)=O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)N1Cc2ccccc2CC1c1nc(-c2ccccc2)c[nH]1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(N)=O)cc(C)c1CC(N)C(=O)N1Cc2ccccc2CC1c1nc(-c2ccccc2)c[nH]1
Reaction time: 3 h
Yield: 28 %

Procedure:
To 0.8 mmol of {1-(4-carbamoyl-2,6-dimethyl-benzyl)-2-oxo-2-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamic acid tert-butyl ester cooled in an ice bath under argon, was added 3 mL of trifluoroacetic acid. After stirring for 3 hours, the reaction mixture was concentrated and purified on a Gilson prep LC system. Obtained 79 mg (0.13 mmol) of the pure S,S isomer of 4-{2-amino-3-oxo-3-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3,5-dimethyl-benzamide and 58 mg (0.09 mmol) of a mix of diastereomers for a total of 137 mg (0.22 mmol, 28% yield). Data for “pure” isomer (may contain a trace of other isomer as evident by tlc): 1H NMR (300 MHz, CD3OD): δ 1.85 (0.5H, dd), 2.13-2.51 (6H, m), 2.91 (0.4H, dd), 3.18-3.52 (4H, m), 3.70 (0.5H, d), 4.28-4.47 (1H, m), 4.60-5.06 (2.5H, m), 5.62 (0.5H, t), 6.95-7.90 (13H, m).
Reaction SMILES: C(N(CC)CC)C.[ClH:8].Cl.[NH2:10][CH2:11][CH2:12][C:13]1[CH:45]=[CH:44][C:16]([O:17][C:18]2[CH:19]=[CH:20][C:21]3[N:25]=[C:24]([CH2:26][O:27][C:28]4[CH:41]=[CH:40][C:31]([CH2:32][CH:33]5[S:37][C:36](=[O:38])[NH:35][C:34]5=[O:39])=[CH:30][CH:29]=4)[N:23]([CH3:42])[C:22]=3[CH:43]=2)=[CH:15][CH:14]=1.[C:46]([C:50]1[CH:51]=[C:52]([CH:56]=[C:57]([C:60]([CH3:63])([CH3:62])[CH3:61])[C:58]=1[OH:59])[C:53](O)=[O:54])([CH3:49])([CH3:48])[CH3:47].CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[ClH:8].[C:60]([C:57]1[CH:56]=[C:52]([CH:51]=[C:50]([C:46]([CH3:49])([CH3:48])[CH3:47])[C:58]=1[OH:59])[C:53]([NH:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:19]=[CH:20][C:21]3[N:25]=[C:24]([CH2:26][O:27][C:28]4[CH:41]=[CH:40][C:31]([CH2:32][CH:33]5[S:37][C:36](=[O:38])[NH:35][C:34]5=[O:39])=[CH:30][CH:29]=4)[N:23]([CH3:42])[C:22]=3[CH:43]=2)=[CH:44][CH:45]=1)=[O:54])([CH3:63])([CH3:62])[CH3:61]
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCN)cc3)cc21
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCNC(=O)c4cc(C(C)(C)C)c(O)c(C(C)(C)C)c4)cc3)cc21
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 42.4 %

Procedure:
A mixture of anhydrous triethylamine (0.106 g), 5-[4-[6-[4-(2-aminoethyl)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (0.3 g), anhydrous N,N-dimethylformamide (10 ml), 3,5-di-t-butyl-4-hydroxybenzoic acid (0.13 g) and 1-ethyl-3-[(3′-dimethylamino)propyl]carbodiimide hydrochloride (WSC.HCl, 0.13 g) was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by liquid chromatography on a silica gel column using ethyl acetate:n-hexane=4:1 as the eluant. To a solution of the glassy product in ethyl acetate (15 ml) was added 4N hydrogen chloride in 1,4-dioxane (2 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the residue was crystallized in acetone to afford the title compound (0.17 g, pale yellow powder, mp 164-168° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([O:34][CH3:35])=[C:19]([CH2:24][CH2:25][N:26]4[CH2:29][CH:28]([C:30]([O:32]C)=[O:31])[CH2:27]4)[CH:20]=[C:21]([F:23])[CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([O:34][CH3:35])=[C:19]([CH2:24][CH2:25][N:26]4[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]4)[CH:20]=[C:21]([F:23])[CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: COC(=O)C1CN(CCc2cc(F)cc(-c3cnc(-c4ccc(OC(C)C)c(Cl)c4)s3)c2OC)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: COc1c(CCN2CC(C(=O)O)C2)cc(F)cc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.6 %

Procedure:
To a solution of methyl 1-{2-[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-5-fluoro-2-(methyloxy)phenyl]ethyl}-3-azetidinecarboxylate (D82) (100 mg) in isopropanol (15 mL) and water (5 mL) stirred under nitrogen at room temperature was added 2 M NaOH (0.193 mL) in one charge. The reaction mixture was stirred at room temperature overnight. Isopropanol was removed in vacuo. The residue was dissolved in water and acidified with 1N HCl to pH=5. The solvent was removed in vacuo, the residue was dissolved in THF, and filtered. The filtrate was purified by Mass Directed AutoPrep to give 1-{2-[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-5-fluoro-2-(methyloxy)phenyl]ethyl}-3-azetidinecarboxylic acid (E33) (21 mg) as a TFA salt. δH (DMSO-d6, 400 MHz): 1.34 (6H, d), 2.90 (2H, t), 3.47 (2H, br. s.), 3.66 (4H, m), 4.28 (4H, m), 4.80 (1H, m), 7.26 (1H, d), 7.32 (1H, d), 7.73 (1H, dd), 7.90 (1H, dd), 8.01 (1H, d), 8.46 (1H, s), 10.12 (1H, br s), 13.13 (1H, br s). δF (DMSO-d6, 376 MHz): −117.4, −73.9. MS (ES): C25H26ClFN2O4S requires 504. found 505.2 (M+H+).
Reaction SMILES: [C:1]([C:9]1[CH:21]=[CH:20][C:12]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])=[CH:11][CH:10]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>C(O)=O.[Pd].CO>[CH2:1]([C:9]1[CH:21]=[CH:20][C:12]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC#Cc1ccc(CC2CCCC2=O)cc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CCCCCCCCc1ccc(CC2CCCC2=O)cc1
Reaction time: 48 h
Yield: 91.1 %

Procedure:
Several drops of formic acid and catalytic amount 5% Pd/C was added to a 25 mL flask charged with 10 mL methanol and 1.25 g (4.75 mmol) of 2-(4′-(oct-1-ynyl)benzyl)cyclopentanone (4). The reaction vessel was flushed with H2, three times, and then mounted with a H2 balloon. After two days under the hydrogen atmosphere, the reaction mixture was exposed to nitrogen, and then filtered through a pad of silica gel. The silica gel plug was washed with ethyl ether (2×25 mL) and the combined organic layers were concentrated to a crude product providing a light yellow oil (1.24 g, 98%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1.[NH4+].[Cl-]>C1COCC1>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]([OH:29])[CH2:20][C:19]([C:16]2[CH:15]=[CH:14][C:13]([C:9]([CH3:12])([CH3:10])[CH3:11])=[CH:18][CH:17]=2)=[O:21])=[CH:26][CH:25]=1
Reactant: CC(=O)c1ccc(C(C)(C)C)cc1
Reactant: COc1ccc(C=O)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)CC(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
3.4 ml of LDA (lithium diisopropylamide) 1M in THF (3.4 mmol) are added under nitrogen to a solution of p-tert-butylacetophenone (500 mg, 2.8 mmol) in THF (15 ml) at −78° C. The mixture is stirred for 1 h before 5 ml of a THF solution of p-methoxybenzaldehyde (425 mg, 3.1 mmol) are added. The reaction is allowed to reach -400C over the course of 1 h. A cold aqueous solution of NH4Cl 1N is subsequently added to the reaction mixture. The resultant mixture is partitioned between water (30 ml) and dichloromethane (30 ml). The resultant aqueous phase is subsequently extracted with dichloromethane (2×30 ml). The combined organic phases are dried over MgSO4. Removal of the solvent gives 3-(4-methoxyphenyl)-3-hydroxy-1-(4-tert-butylphenyl)propan-1-one.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21](/[CH:23]=[CH:24]/[C:25](OCC)=[O:26])=[CH:20][C:19]=2[CH:30]=1.[H-].C([Al+]CC(C)C)C(C)C>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21](/[CH:23]=[CH:24]/[CH2:25][OH:26])=[CH:20][C:19]=2[CH:30]=1
Reactant: CCOC(=O)/C=C/c1cc2cc(OCc3nc(-c4ccccc4)oc3C)ccc2o1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2oc(/C=C/CO)cc2c1
Yield: 90 %

Procedure:
In the same manner as in Reference Example 11, (E)-ethyl 3-[5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-benzofuranyl]acrylate was reduced with diisobutylaluminum hydride to yield (E)-3-[5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-benzofuranyl]-2-propen-1-ol (yield 90%), which was then recrystallized from ethyl acetate-hexane to yield colorless prisms having a melting point of 145° to 146° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:14])[CH:11]([CH3:13])[CH3:12])=[CH:6][CH:5]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[Br:47][C:48]1[C:53]([CH3:54])=[CH:52][C:51](O)=[CH:50][C:49]=1[CH3:56]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:14][C:51]2[CH:52]=[C:53]([CH3:54])[C:48]([Br:47])=[C:49]([CH3:56])[CH:50]=2)[CH:11]([CH3:12])[CH3:13])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(O)C(C)C)cc1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(Oc2cc(C)c(Br)c(C)c2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-hydroxy-2-methyl-propyl)-benzoic acid methyl ester (5000 mg, 24.04 mmol) in toluene (240 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 9098 mg, 36.06 mmol) at 0° C., followed by the additions of tributylphosphine (8.98 mL, 36.06 mmol) and 4-bromo-3,5-dimethyl-phenol (5798 mg, 28.85 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving the titled compound (5540 mg).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[CH2:18][CH3:19])[C:5]1=[O:23])(=O)C.[NH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH2:31])=[O:30])=[CH:27][CH:26]=1>>[NH2:31][C:29]([C:28]1[CH:32]=[CH:33][C:25]([NH:24]/[C:17](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[CH2:18][CH3:19])=[CH:26][CH:27]=1)=[O:30]
Reactant: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21
Reactant: NC(=O)c1ccc(N)cc1
Product: CC/C(Nc1ccc(C(N)=O)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone and 4-aminobenzamide
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[CH:8][C:7]=1[O:17][CH3:18]>C(O)(=O)C>[OH:5][C:6]1[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:9]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[CH:8][C:7]=1[O:17][CH3:18]
Reactant: O=[N+]([O-])O
Reactant: CCCC(=O)c1ccc(O)c(OC)c1
Solvent: CC(=O)O
Product: CCCC(=O)c1cc(OC)c(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
6.5 ml of 11.2N nitric acid are added dropwise to a solution of 12.7 g of 4'-hydroxy-3'-methoxybutyrophenone in 250 ml of glacial acetic acid while stirring within 10 minutes. The reaction mixture is subsequently stirred for 15 minutes, poured into ice-water, the separated precipitate is filtered under suction, washed with ice-water and taken up in methylene chloride. The methylene chloride solution is filtered over 50 g of silica gel. The material obtained is recrystallized from methylene chloride/n-hexane. There is obtained 4'-hydroxy-3'-methoxy-5'-nitrobutyrophenone in the form of yellow crystals of m.p. 92°-93°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:22]([NH:24][CH3:25])=[O:23])[CH2:10][NH:11]C(=O)OCC1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:11][CH2:10][C@@H:9]([C:22]([NH:24][CH3:25])=[O:23])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CNC(=O)C(CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CNC(=O)[C@H](CN)NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of benzyl {2-[(tert-butoxycarbonyl)amino]-3-(methylamino)-3-oxopropyl}carbamate (2.5 g, 7.4 mmol) in methanol (40 mL) was added palladium on carbon (0.25 g, 10% w/w). The mixture was stirred under a hydrogen atmosphere (50 psi) at 50° C. After 4 hours, the reaction mixture was filtered and concentrated under reduced pressure to afford 3-amino-N2-(tert-butoxycarbonyl)-N-methylalaninamide. MS ESI calc'd. for C9H20N3O3 [M+H]+ 218. found 218. 1H NMR (400 MHz, CD3OD) δ 4.06-4.02 (m, 1H), 2.93-2.82 (m, 2H), 2.76 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: CS(C1C=CC([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].N1CCCC1>>[CH3:33][CH:32]([S:29]([C:26]1[CH:27]=[CH:28][C:20]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:21]([CH:25]=1)[C:22]([OH:24])=[O:23])(=[O:31])=[O:30])[CH3:34]
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Reactant: CC(C)S(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Solvent: C1CCNC1
Product: CC(C)S(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Yield: 72 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-(propane-2-sulfonyl)-benzoic acid and pyrrolidine and obtained in 72% yield. MS (m/e): 296.2 (MH−, 100%).
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([I:10])[N:4]2[N:3]=1.[NH2:11][C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)=[O:13].C([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>O1CCOCC1.O.C(Cl)Cl.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>[I:10][C:9]1[N:4]2[C:5]([S:6][C:2]([C:18]3[CH:19]=[C:14]([CH:15]=[CH:16][CH:17]=3)[C:12]([NH2:11])=[O:13])=[N:3]2)=[N:7][CH:8]=1
Reactant: Brc1nn2c(I)cnc2s1
Reactant: NC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)c1cccc(-c2nn3c(I)cnc3s2)c1
Temperature: 90 °C
Yield: 43.8 %

Procedure:
A mixture of 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (150 mg, 0.45 mmol), 3-aminocarbonylphenylboronic acid (85 mg, 0.50 mmol), PdCl2(PPh3)2 (32 mg, 0.045 mmol) and Na2CO3 (145 mg, 1.4 mmol) in dioxane (1.5 mL) and water (0.3 mL) was heated at 90° C. for 2 h. The reaction mixture was cooled and diluted with DCM (35 mL) and sat NaHCO3 (20 mL). The organic layer was washed with sat. NaHCO3 (3×20 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with diethylether and filtered to give the desired product (73 mg, 42%). HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=3.59 min, [M+H]+ m/z 371.1.
Reaction SMILES: CC1N=C(C2C=CC=CC=2C([NH:11][C@H:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)=O)ON=1.[F:32][C:33]1[CH:34]=[CH:35][C:36]([N:42]2[N:46]=[CH:45][CH:44]=[N:43]2)=[C:37]([CH:41]=1)[C:38]([OH:40])=O.Cl.FC(F)(F)C1C=CC(N[C@H]2CCC[C@@H]2N)=NC=1>>[F:32][C:33]1[CH:34]=[CH:35][C:36]([N:42]2[N:46]=[CH:45][CH:44]=[N:43]2)=[C:37]([CH:41]=1)[C:38]([NH:11][C@H:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][N:19]=1)=[O:40]
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: Cc1noc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2ccc(C(F)(F)F)cn2)n1
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1cc(F)ccc1-n1nccn1

Procedure:
Prepared according to the procedure for 2-(3-methyl-1,2,4-oxadiazol-5-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide (Example 8) from 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 8; 72 mg, 0.26 mmol) and (1S,2S)-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 1; 61 mg, 0.28 mmol) to afford the title compound.