Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[CH2:14]1[CH2:20][CH:19](Cl)[C:17](=[O:18])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[O:1][CH:16]1[CH2:15][CH2:14][CH2:20][CH2:19][C:17]1=[O:18]
Reactant: O=C1CCCCC1Cl
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(OC2CCCCC2=O)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 3-hydroxy-4-methoxybenzoate (2.47 g), α-chlorocyclohexanone (2.33 ml), potassium carbonate (3.76 g), and DMF (25 ml) was stirred at 90° C. for 2 hours. α-Chlorocyclohexanone (2.0 ml) was further added to the mixture, followed by stirring at 90° C. for one hour. After being allowed to stand for cooling, water was added to the mixture followed by extraction with ether. The organic layer was washed with a 1N aqueous solution of sodium hydroxide and then with a saturated saline, and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (silica gel, hexane:ethyl acetate=2:1) to give Compound IIm-a (3.16 g, 83%) as an oily substance.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.[Cl:24][CH2:25][C:26](Cl)=[O:27].N1C=CC=CC=1>CN(C=O)C>[Cl:24][CH2:25][C:26]([NH:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1)=[O:27]
Reactant: O=C(Cl)CCl
Reactant: Cc1nc(N)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)CCl)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of [4-(2-amino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine (0.33 g, 1.0 mmol,) in dry DMF (3 mL) was cooled on an ice-water bath. Chloroacetyl chloride (0.22 g, 2.0 mmol) and pyridine (80 μL) were added. After stirring at room temperature for 18 h, the reaction mixture was concentrated, poured into ice water and extracted with CH2Cl2. The organic phases were combined, washed with brine, dried on MgSO4 and evaporated to dryness. The resulting greenish residue was purified by SiO2 chromatography (1:1 EtOAc/PE) to afford the title compound as a gray solid. Anal. RP-HPLC: tR=20.6 min (0-60% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity >97%). 1H-NMR (DMSO-d6) δ: 2.45 (s, 3H, CH3), 4.12 (s, 2H, CH2), 7.03 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 7.42 (m, 1H, Ph-H), 7.63 (m, 1H, Ph-H), 8.01 (m, 1H, Ph-H), 8.41 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 8.64 (s, 1H, Ph-H).
Reaction SMILES: C(N1[C:8](=[O:9])[C:7]2=[C:10]([F:17])[C:11]([F:16])=[C:12]([F:15])[C:13]([F:14])=[C:6]2[C:5]1=[O:18])(C)C.S(=O)(=O)(O)[OH:20].C(O)(=O)C>O>[F:17][C:10]1[C:11]([F:16])=[C:12]([F:15])[C:13]([F:14])=[C:6]2[C:5](=[O:18])[O:9][C:8](=[O:20])[C:7]=12
Reactant: O=S(=O)(O)O
Reactant: CC(C)N1C(=O)c2c(F)c(F)c(F)c(F)c2C1=O
Solvent: O
Solvent: CC(=O)O
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Yield: 66.4 %

Procedure:
In a 500 ml three neck distillation flask were placed 47 g (0.18 mol) of N-isopropyl-tetrafluorophthalimide, 71 ml of concentrated sulfuric acid, 43 ml of acetic acid, and 13 ml of water, and the mixture was reacted for 5 hours at 140° to 150° C. with stirring. After cooling, the reaction mixture was extracted three times with 200 ml of toluene, and the toluene layers thus formed were collected and concentrated by distillation under a reduced pressure to provide 26.3 g (yield 66.4%) of tetrafluorophthalic anhydride as white crystals.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:12]([CH3:13])[C:11]2[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:10]=2[N:9]=1.[CH3:22][O-:23].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:22][O:23][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:12]([CH3:13])[C:11]2[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:10]=2[N:9]=1
Reactant: C[O-]
Reactant: Cn1c(-c2ccncc2F)nc2cc(C(F)(F)F)ccc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cnccc1-c1nc2cc(C(F)(F)F)ccc2n1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.7 %

Procedure:
To a mixture of 0.30 g of 2-(3-fluoropyridin-4-yl)-1-methyl-5-trifluoromethyl-1H-benzimidazole and 10 ml of DMF was added 0.16 g of sodium methoxide under ice cool, then, the mixture was heated up to room temperature and stirred for 1.5 hours. A saturated ammonium chloride aqueous solution was poured, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.28 g of 2-(3-methoxypyridin-4-yl)-1-methyl-5-trifluoromethyl-1H-benzimidazole (hereinafter, referred to as present active compound 8).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]([O:15][C@@H:16]1[C@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@@H:20]([O:26][C:27](=[O:29])[CH3:28])[C@H:19]([CH3:30])[O:18][C@H:17]1[O:31][C@@H:32]1[C@@H:38]([OH:39])[C@H:37]([CH3:40])[O:36][C@@:34]([C@H:41]2[O:70][C@H:69]([CH2:71][O:72][CH2:73][C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=3)[C@@H:60]([O:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C@H:51]([O:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C@H:42]2[O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([OH:35])[C@@H:33]1[O:80][C:81](=[O:88])[C:82]1[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=1)(=[O:14])[CH3:13].[Cl:89][C:90]([Cl:94])([Cl:93])[C:91]#[N:92]>C(Cl)Cl>[Cl:89][C:90]([Cl:94])([Cl:93])[C:91](=[NH:92])[OH:14].[C:12]([O:15][C@@H:16]1[C@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@@H:20]([O:26][C:27](=[O:29])[CH3:28])[C@H:19]([CH3:30])[O:18][C@H:17]1[O:31][C@@H:32]1[C@@H:38]([OH:39])[C@H:37]([CH3:40])[O:36][C@@:34]([C@H:41]2[O:70][C@H:69]([CH2:71][O:72][CH2:73][C:74]3[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=3)[C@@H:60]([O:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C@H:51]([O:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C@H:42]2[O:43][CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)([OH:35])[C@@H:33]1[O:80][C:81](=[O:88])[C:82]1[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=1)(=[O:14])[CH3:13]
Reactant: N#CC(Cl)(Cl)Cl
Agent: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](C)O[C@@H](O[C@@H]2[C@@H](O)[C@H](C)O[C@](O)([C@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)[C@@H]2OC(=O)c2ccccc2)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: N=C(O)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
DBU (100 μL) was added at 0° C. to a solution of the hemiacetal 522 (3.8 g, 3.58 mmol) in DCM (40 mL) containing trichloroacetonitrile (4 mL). The mixture was stirred for 30 min at 0° C., and volatiles were evaporated. Flash chromatography (solvent B, 7:3+0.2% Et3N) of the crude material gave the donor 505 (3.9 g, 90%) as a white solid; 1H NMR (a anomer): δ 8.75 (s, 1H, NH), 8.13-7.12 (m, 25H, Ph), 6.40 (d, 1H, J1,2=2.4 Hz, H-1C), 5.54 (br s, 1H, H-2B), 5.49 (dd, 1H, J2,3=2.9 Hz, H-2C), 5.26 (d, 1H, J1,2=2.8 Hz, H-1E), 5.20 (dd, 1H, J2,3=J3,4=10.0 Hz, H-3B), 5.17 (br s, 1H, H-1B), 4.96 (dd, 1H, H-4B), 4.99-4.41 (m, 8H, OCH2), 4.34 (m, 1H, H-3C), 4.14-4.02 (m, 3H, H-3E, 5E, 5C), 3.87 (m, 1H, H-4C), 3.78 (dq, 1H, J4,5=9.5, J5,6=6.1 Hz, H-5B), 3.70 (m, 2H, H-6aE, 6bE), 3.65 (dd, 1H, J2,3=3.4, J3,4=9.8 Hz, H-2E), 3.57 (pt, 1H, J2,3=J3,4=9.4 Hz, H-4E), 1.86, 1.83 (2s, 9H, CH3CO), 1.42 (d, 3H, J5,6=6.2 Hz, H-6C), 0.98 (d, 3H, H-6B); 13C NMR (α anomer): δ 170.3, 170.1, 169.9, 166.1 (4C, C═O), 160.7 (C═NH), 139.2-127.8 (Ph), 100.2 (C-1B), 98.1 (C-1E), 94.8 (C-1C), 91.2 (CCl3), 82.4 (C-4C), 82.0 (C-3E), 81.2 (br s, C-2E), 78.5 (br s, C-3C), 78.3 (C-4E), 75.9, 75.4, 74.3, 73.3 (4C, CH2Ph), 71.8 (C-5E), 71.7 (C-2C), 71.3 (C-4B), 70.8 (br s, C-5C), 70.0 (C-2B), 69.3 (C-3B), 69.2 (C-6E), 67.6 (C-5B), 21.3, 21.0, 20.9 (3C, CH3CO), 18.9 (C-6C), 17.1 (C-6B). Anal. Calcd. for C61H66Cl3NO18: C, 60.67; H, 5.51; N, 1.16%. Found: C, 60.53; H, 5.48; N, 1.38%.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH:4]=O.Cl.[CH3:9][C@@H:10]([NH2:14])[CH2:11][CH2:12][CH3:13].C(N(CC)CC)C>CO.[Pd]>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:14][C@@H:10]([CH2:11][CH2:12][CH3:13])[CH3:9]
Reactant: COC(C=O)OC
Reactant: CCC[C@@H](C)N
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCC[C@@H](C)NCC(OC)OC
Reaction time: 2 h

Procedure:
2,2-Dimethoxyacetaldehyde (0.59 mL) was added to a solution of (R)-pentan-2-amine hydrochloride (0.48 g) and triethylamine (0.54 mL) in methanol (4 mL) and the mixture stirred for 2 h. A slurry of palladium on carbon (10%, 20 mg) in methanol (1 mL) was added and the mixture hydrogenated at 5 bar for 20 h. The mixture was then filtered and in vacuo. The resulting residue was triturated with diethyl ether (5 mL) and the resulting white solid extracted with further diethyl ether (2×5 mL). The combined ether fractions were concentrated in vacuo to afford (R)—N-(2,2-dimethoxyethyl)pentan-2-amine (0.745 g) as an oil. 1H NMR (400 MHz, CDCl3) δ 4.92 (t, J=5.4 Hz, 1H), 3.47 (s, 3H), 3.47 (s, 3H), 3.25-3.15 (m, 1H), 2.99 (ddd, J=27.9, 12.7, 5.5 Hz, 2H), 1.86-1.77 (m, 1H), 1.64-1.54 (m, 1H), 1.49-1.32 (m, 5H), 0.95 (t, J=7.3 Hz, 3H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH:31]1[CH2:34][CH:33]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH2:32]1.C(N(CC)CC)C>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:31]3[CH2:34][CH:33]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[CH2:32]3)=[O:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: C1CN(C2CNC2)CCO1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CC(N3CCOCC3)C2)no1
Yield: 105.9 %

Procedure:
A solution of ethyl 5-{(1R)-1 -[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (1.00 g, 2.54 mmol) in ethanol (10 ml) was treated with 4-(3-azetidinyl)morpholine dihydrochloride (2.72 g, 12.6 mmol) and triethylamine (2.56 g, 25 mmol) and the resulting mixture was heated under reflux under a nitrogen atmosphere for 24 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed sequentially with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (97:3) gradually changing to dichloromethane:methanol (95:5) to afford the title compound as a colourless oil (1.32 g).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[O:24][CH:25]=[C:26]([C:28]([O:30]C)=[O:29])[N:27]=1.[OH-].[Na+].Cl>O1CCCC1.O>[O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[O:24][CH:25]=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1
Reactant: COC(=O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)n1
Temperature: 25 °C
Yield: 57.3 %

Procedure:
To a solution of methyl 2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylate (1.17 g, 2.79 mmol) in tetrahydrofuran (20 mL) was added a solution of sodium hydroxide (0.45 g, 11.1 mmol) in water (5 mL). The mixture was stirred at reflux for 16 h. After cooling down to ambient temperature, the mixture was acidified with concentrated hydrochloric acid (2 mL). The reaction mixture was concentrated in vacuo to remove most of tetrahydrofuran and extracted with ethyl acetate (3×25 mL). The combined organic solution was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was triturated with diethyl ether and ethyl acetate to afford 2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylic acid (0.65 g, 58%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 13.07 (br, 1H), 8.74 (s, 1H), 7.29 (t, J=7.7 Hz, 1H), 7.17 (d, J=6.6 Hz, 1H), 7.10 (d, J=7.8 Hz, 1H), 7.04 (t, J=7.5 Hz, 1H), 6.66 (s, 1H), 6.34 (s, 1H), 6.04 (s, 2H), 5.20-5.08 (m, 2H), 4.73 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.1, 162.2, 159.9, 155.7, 148.8, 146.4, 142.2, 142.1, 133.8, 132.2, 129.4, 124.1, 123.9, 120.3, 109.7, 103.8, 101.9, 93.7, 80.0, 57.8, 31.2; MS (ES+) m/z 407.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[O:5][CH2:6][C:7](=O)[CH3:8].S(O)(O)(=O)=O.[NH2:19][OH:20].C(=O)([O-])O.[Na+].O>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[O:5][CH2:6][C:7](=[N:19][OH:20])[CH3:8]
Reactant: CC(=O)COc1cc(C)cc(C)c1
Reactant: NO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(COc1cc(C)cc(C)c1)=NO
Yield: 155.2 %

Procedure:
10.0 Grams (56 mmol) of 1-(3,5-dimethylphenoxy)-2-propanone was dissolved in 50 ml of ethanol, and 5.53 g (34 mmol) of hydroxylamine sulfate and 5.66 g (67 mmol) of sodium hydrogencarbonate were added. And, the resultant mixture was stirred at room temperature for 4 hours, and 50 ml of water was added. Ethanol was distilled off under reduced pressure, and the resultant solid precipitate was recovered by filtration, washed with water and dried to give 10.2 g of 1-(3,5-dimethylphenoxy)-2-propanone oxime (yield 92%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[N:14]=[N:13][CH:12]=[N:11]2)=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>C(O)C.[Pd]>[N:11]1[N:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[N:14]=[N:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(-n2ncnn2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(-n2ncnn2)cc1
Reaction time: 2 h

Procedure:
2-(4-Nitrophenyl)-2H-tetrazole (200 mg, 1.05 mmol) was suspended in ethanol (1 mL). Ethyl acetate (1 mL) was added to improved solubility. The solution was degassed and purged with nitrogen 3 times before palladium on carbon (10% w/w, 223 mg, 0.2 mmol) was added. The mixture was degassed and purged with hydrogen 3 times and stirred under a hydrogen balloon for 2 hours. The reaction was diluted with acetone and passed through a plug of silica gel, which was washed thoroughly with acetone. The filtrated was concentrated to give the crude product which was used as isolated.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([F:28])[CH:19]=3)[CH2:10][C:11](O)([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[C:20]([F:28])[CH:19]=3)[CH:10]=[C:11]([C:13]([F:15])([F:14])[F:16])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(Br)cc2)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(Br)cc2)cc1F
Yield: 51.7 %

Procedure:
A mixture of 2-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-hydroxy-4-trifluoromethyl-4,5-dihydro-1H-imidazole (3.05 g, 6.33 mmol) and p-toluenesulfonic acid monohydrate (0.300 g) in toluene (250 mL) was heated to reflux for 21 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude residue was redissolved in methylene chloride (150 mL) and the whole washed with water, aqueous NaHCO3 (50 mL), and brine. After dried over MgSO4, and concentrated in vacuo. The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (3/1) to give the subtitle compound (1.517 g, 51.8% yield).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[OH:31])[CH:26]=O>>[ClH:1].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[OH:31])[CH2:26][N:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH3:2])[CH:5]=3)[O:10][C:9](=[O:14])[CH:8]=2)[CH2:17][CH2:18]1
Reactant: COc1ccc2oc(=O)cc(NC3CCNCC3)c2c1
Reactant: O=Cc1ccc(O)c(F)c1
Agent: Cl
Product: COc1ccc2oc(=O)cc(NC3CCN(Cc4ccc(O)c(F)c4)CC3)c2c1
Yield: 95.4 %

Procedure:
According to Procedure C above, (I) (0.0223 g; 0.081 mmol) and 3-fluoro-4-hydroxy-benzaldehyde were allowed to react to give after the purification the corresponding mono-TFA salt. The product was then suspended in MeOH and hydrochloride salt was precipitated by addition of 4 N HCl solution in dioxane. The resulting white solid was triturated with Et2O/MeOH (2:1), washed with Et2O and dried under high vacuum to afford 33.6 mg (95.4%) of the title compound. MS (DCI/NH3)(+)Q1MS m/z 399 (M+H)+; 1H NMR (500 MHz, pyridine-d5) δ ppm 1.94 (m, 2H), 2.10 (m, 2H), 2.27 (m, 2H), 3.06 (m, 2H), 3.42 (s, 3H), 3.61 (m, 1H), 3.65 (s, 2H), 5.71 (s, 1H), 7.15 (m, 2H), 7.24 (m, 1H), 7.33 (d, J=9.05 Hz, 1H), 7.39 (m, 1H), 7.69 (m, 1H+1N H).
Reaction SMILES: C[O:2]C(=O)CCCCC(O)=O.[CH2:12]1[CH2:17][CH2:16][CH:15]([N:18]=[C:19]=[N:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:14][CH2:13]1.ON1C(=O)CCC1=O>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:19]([NH:18][CH:15]1[CH2:14][CH2:13][CH2:12][CH2:17][CH2:16]1)([NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:2]
Reactant: COC(=O)CCCCC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Step 1, Compound 4: Adipic acid monomethyl ester is treated with one molar equivalent of DCC, DMAP and N-hydroxysuccinimide in DMF for 30 min. To this a molar equivalent of the compound obtained from Step 3a (Example 1) is added and stirred at ambient temperature for 8 h. Dicylcohexylurea formed during the course of the reaction is filtered off and the product is extracted into ethyl acetate, washed with sodium bicarbonate solution followed by standard workup. The methyl ester thus obtained is treated with LiOH in THF/water to obtain compound 4.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([OH:23])=O)[C:8]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.Cl>[CH:1]1([C:7]2[C:15]3[CH:10]=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][C:14]=3[N:9]3[CH2:20][C:21](=[O:23])[N:31]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH2:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[C:8]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CNCCN(C)C)n(CC(=O)O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)N(CCN(C)C)Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [3-cyclohexyl-2-[2-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-6-(methoxycarbonyl)-1H-indol-1-yl]acetic acid in DCM (0.08 M), DIPEA (3.5 eq) and HATU (2.5 eq) were added and the mixture stirred at RT overnight. The solution was diluted with DCM and HCl (1N) and the 2 phases separated. The aqueous phase was extracted with DCM (2×). The combined organic phases were then washed with a saturated aqueous solution of NaHCO3 and brine before being dried over Na2SO4, filtered and concentrated in vacuo. The crude was then used in the next step without further purification; MS (ES+) m/z 474 (M+H)+
Reaction SMILES: C([Li])CCC.C(OP([CH2:14][C:15]([OH:17])=[O:16])(OCC)=O)C.[CH3:18][N:19]([CH3:30])[C:20]1[CH:29]=[CH:28][C:23]([CH:24]=[CH:25][CH:26]=O)=[CH:22][CH:21]=1>O1CCCC1>[CH3:18][N:19]([CH3:30])[C:20]1[CH:29]=[CH:28][C:23]([CH:24]=[CH:25][CH:26]=[CH:14][C:15]([OH:17])=[O:16])=[CH:22][CH:21]=1
Reactant: CN(C)c1ccc(C=CC=O)cc1
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)c1ccc(C=CC=CC(=O)O)cc1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
Butyllithium (24 mL of 2.5 N solution) was added to 120 mL of anhydrous tetrahydrofuran (THF) at −65° C. A solution of diethylphosphonoacetic acid (5.5 g) in 45 mL of anhydrous THF was added dropwise to the stirred solution at −65° C. over a period of one hour. The resulting solution was stirred at −65° C. for an additional 30 minutes and then a solution of p-dimethylaminocinnamaldehyde (5.0 g) in 80 mL of anhydrous THF was added to the reaction at −65° C. over a period of 30 minutes. The reaction was stirred for one hour, allowed to warm to room temperature and then stirred overnight. The reaction was then quenched with 400 mL of water and extracted with 300 mL of ethyl acetate three times. The aqueous layer was acidified with 5% hydrochloric acid (11 mL) to a pH of 6.1. The solid formed was filtered, washed with 75 mL of water and dried to yield 3.83 g of the desired 5-(p-dimethylaminophenyl)-2,4-pentadienoic acid. 1H NMR (DMSO-d6, 300 MHz), δ(ppm) 7.34 (m, 3H), 6.82 (m, 2H), 6.70 (d, 2H), 5.84 (d, 1H), 2.94 (s, 6H).
Reaction SMILES: [OH:1][C@H:2]([CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1O>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[O:1][C@@H:2]([CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: COC(=O)[C@H](O)C(C)C
Product: COC(=O)[C@@H](Oc1cc(C)ccc1Cl)C(C)C

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 42, using the (R)-methyl 2-hydroxy-3-methylbutanoate instead of the (S)-methyl 2-hydroxypropanoate and the 2-chloro-5-methylphenol instead of the m-cresol.
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH2:1][C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])=[CH:14][CH:13]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=C(CBr)c1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(CSc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.1 %

Procedure:
To a solution of phenacyl bromide (1 g), 4-chlorothiophenol (1.37 g), and benzyl triethyl ammonium chloride (78 mg) in dichloromethane (20 ml) NaOH (0.61 g) in water (2 ml) was added. The mixture was stirred vigorously at rt for 16 h. After dilution with water (50 ml) the organic layer was separated, washed with brine (20 ml), dried (MgSO4), and evaporated. The crude was purified by column chromatography on silica gel (petrol ether/ethyl acetate 12:1) to provide 2-(4-chlorophenylthio)-1-phenylethanone (0.74 g) as pale yellow solid.