Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][CH:37]=[CH:36][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:35])[CH2:12][NH:13][C:14]([C:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27]CC3C=CC=CC=3)[O:18][N:17]=2)=[O:15])[CH2:7][CH2:6]1>CO.[Pd]>[Cl:1][C:2]1[CH:39]=[CH:38][CH:37]=[CH:36][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:35])[CH2:12][NH:13][C:14]([C:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[OH:27])[O:18][N:17]=2)=[O:15])[CH2:7][CH2:6]1
Reactant: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cc(-c2ccccc2OCc2ccccc2)on1
Agent: [Pd]
Solvent: CO
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cc(-c2ccccc2O)on1
Reaction time: 3 h
Yield: 43.1 %

Procedure:
To a stirred solution of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide (0.153 g, 0.00028 mole) in methanol (50 mL) was added 10% Pd/C (0.03 g) and the resulting mixture was stirred under an atmosphere of hydrogen for 3 hours. The mixture was then filtered through celite, the celite was washed with methanol and the organic layers were concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to afford 0.055 g (43%) of 5-(2-hydroxy-phenyl)-isoxazole-3-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 456.12 (M+1)+, 98.75%. 1H NMR (DMSO-d6): δ 10.8 (s, 1H), 8.7 (t, 1H), 7.8 (d, 1H), 7.4 (d, 1H), 7.24 (m, 3H), 7.12 (s, 1H), 7.04 (d, 1H), 6.92 (t, 2H), 4.7 (m, 1H), 4.2 (d, 2H), 3.7 (m, 2H), 3.4 (m, 2H), 1.9 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH3:10])[CH:3]([N+:6]([O-:8])=[O:7])[CH2:4][CH3:5].[C:11](OC(=O)C)(=[O:13])[CH3:12]>S(=O)(=O)(O)O.C(Cl)(Cl)Cl>[C:11]([O:1][CH:2]([CH2:9][CH3:10])[CH:3]([N+:6]([O-:8])=[O:7])[CH2:4][CH3:5])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(O)C(CC)[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCC(OC(C)=O)C(CC)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h
Yield: 86.1 %

Procedure:
A reaction vessel was charged with 4-hydroxy-3-nitrohexane (14.7 g, 100 mmol), acetic anhydride (14.8 ml, 157.3 mmol), chloroform (50 ml) and a few drops of concentrated sulfuric acid, then stirred for 10 hours at room temperature. After the reaction was finished, chloroform (50 ml) was added, and the resulting solution was washed with water, 5% aqueous sodium bicarbonate solution and saturated saline. The obtained organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, whereby 4-acetoxy-3-nitrohexane (16.3 g, yield 86%) was obtained.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[OH:10][C:11]1[CH:12]=[CH:13][C:14]2[C:18]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:23][CH:22]=3)=[O:20])=[C:17]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3O)[S:16][C:15]=2[CH:44]=1>C1COCC1>[N:30]1([CH2:29][CH2:28][O:27][C:24]2[CH:23]=[CH:22][C:21]([CH:19]3[C:18]4[C:14]5[CH:13]=[CH:12][C:11]([OH:10])=[CH:44][C:15]=5[S:16][C:17]=4[CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=4[O:20]3)=[CH:26][CH:25]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(Cc2ccccc2O)sc2cc(O)ccc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Oc1ccc2c3c(sc2c1)Cc1ccccc1OC3c1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
Add DIBAL solution (5 mL, 1M/THF) dropwise to [6-hydroxy-2-(2-hydroxy-benzyl)-benzo[b]thiophen-3-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (300 mg, 0.6 mmol) in THF (5 mL) at −78° C. Stir for 30 min and quench with water, followed by TFA (5 mL). Stir the mixture for 3 h while warming to r.t. Remove the solvent in vacuo and dissolve the residue in i-PrOH/CH2Cl2 (1:3). Wash the organic phase with water and brine, dry over MgSO4, filter and concentrate. Purify by flash chromatography (0-5% (2M NH3 in MeOH)/CH2Cl2) to afford 5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,11-dihydro-6-oxa-12-thia-dibenzo[a,f]azulen-2-ol (180 mg, 62%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([O:13][C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][C:22]=2[O:29][CH3:30])=[C:18]([CH3:31])[N:17]=[C:16]([NH2:32])[N:15]=1)(=[O:12])=[O:11].[NH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[NH2:32][C:16]1[N:15]=[C:14]([O:13][S:10]([C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])(=[O:12])=[O:11])[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][NH:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:23][C:22]=2[O:29][CH3:30])=[C:18]([CH3:31])[N:17]=1
Reactant: COc1cc(CCl)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Reactant: CCOC(=O)CN
Product: CCOC(=O)CNCc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1

Procedure:
The sub-title compound was synthesized by the method of example 1 step (vii) from the product of example 1 step (v) (100 mg) and ethyl glycinate. The sub-title compound (23 mg) was obtained as a colourless amorphous solid; 1H NMR (300 MHz, CDCl3); 6.92 (2H, s), 6.84 (1H, s), 6.76-6.70 (2H, m), 4.68 (2H, br s), 4.18 (2H, q), 3.81 (3H, s), 3.79 (2H, s), 3.77 (2H, s), 3.39 (2H, s), 2.56 (6H, s), 2.28 (3H, s), 2.22 (3H, s), 1.26 (3H, t); LC-MS: m/z=543.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:43]=[CH:42][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31](/[CH:35]=[CH:36]/[C:37]([O:39]CC)=[O:38])[O:32][C:33]=4[CH3:34])=[C:25]([O:44][CH3:45])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:43]=[CH:42][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31](/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38])[O:32][C:33]=4[CH3:34])=[C:25]([O:44][CH3:45])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1nc(COc2ccc(COc3nn(-c4ccccc4)cc3/C=C/c3csc(CC)n3)cc2OC)c(C)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(/C=C/C(=O)O)oc3C)c(OC)c2)cs1
Temperature: 50 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a mixture of ethyl (2E)-3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]-2-propenoate (0.25 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at 50° C. for 2 hrs. 1N hydrochloric acid and water were added to the reaction mixture to acidify the solution, and the precipitated crystals were collected by filtration to give (2E)-3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]-2-propenoic acid as colorless crystals (0.21 g, yield 88%). Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 125-126° C.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[O:7]1[CH2:11][CH2:10][O:9][CH:8]1[CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH:19]([C:18]1[CH:21]=[CH:22][C:15]([O:14][CH2:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][O:7]2)=[CH:16][CH:17]=1)=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccc(OCCC2OCCO2)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: C=Cc1ccc(OCCC2OCCO2)cc1
Yield: 88.5 %

Procedure:
In another 2 liter flask, 57.2 g of methyl triphenylphosphonium bromide was placed. 500 ml of anhydrous ether was poured and then, stirred. To the resulting solution was slowly added 18.0 g of potassium tert-butoxide and reacted at room temperature for 3 hrs. 23.7 g of the above 4-(2-[1,3]-dioxolan-2-yl-ethoxy)benzaldehyde was dissolved in 200 ml of anhydrous ether and was slowly added to the reaction mixture and then subjected to reaction at room temperature for 4 hrs. After completion of the reaction, the produced solid by-product was filtered off and washed with distilled water and saturated saline. The organic phase washed was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The reaction mixture was purified by Silica gel column chromatography to obtain 20.8 g of 2-[2-(4-vinylphenoxy)ethyl]-[1,3]-dioxolan, represented by the following formula: ##STR10##
Reaction SMILES: CC([O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:18]3([O:27][C:25](=[O:26])[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]3=4)[C:17]3[CH:16]=[CH:15][C:14]([O:28]C(C)=O)=[CH:13][C:12]=3[O:11][C:9]=2[CH:10]=1)=O>CS(C)=O>[CH:21]1[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[C:19]([C:18]2[C:8]3[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][C:9]=3[O:11][C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([CH:13]=3)=[O:28])[CH:20]=1
Reactant: CC(=O)Oc1ccc2c(c1)Oc1cc(OC(C)=O)ccc1C21OC(=O)c2ccccc21
Solvent: CS(C)=O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Temperature: -20 °C

Procedure:
Fluorescein diacetate (FDA) (Sigma Chemical Co., St. Louis, Mo.), or 2′,7′-bis-(2-carboxyethyl)-5(and-6) carboxyfluorescein, acetoxymethyl ester (BCECF-AM) (Molecular Probes, Inc., Eugene, Oreg.) was dissolved in dimethyl sulfoxide (DMSO) to produce a 1 mg/ml stock solution. The stock was filtered through 0.8 μm nylon, aliquoted into 1.5 ml microfuge tubes and stored frozen at −20° C. in the dark. For individual assays, an intermediate stock was prepared by thawing and diluting an aliquot with RPMI-1640+10% Fetal Calf Serum (FCS) such that adding 50 μl of dye solution to a well would produce a final concentration of 8 μg/ml. To minimize reaction with endogenous enzymes in the FCS (which could increase the background fluorescence by cleaving ester groups to form free fluorescein), intermediate dilutions were prepared immediately prior to loading each individual plate.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:11]=3[N:12]=2)[CH2:4]1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][N:2]([CH3:18])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([NH:17][C:30]([C:29]4[CH:28]=[CH:27][C:26]([C:23]5[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=5)=[CH:34][CH:33]=4)=[O:31])=[CH:13][C:11]=3[N:12]=2)[CH2:4]1
Reactant: CN(C)C1CCN(c2nc3cc(N)ccc3o2)C1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(c2nc3cc(NC(=O)c4ccc(-c5ccc(F)cc5)cc4)ccc3o2)C1
Reaction time: 72 h
Yield: 77.2 %

Procedure:
Combine 2-(3-dimethylamino-pyrrolidin-1-yl)-benzooxazol-5-ylamine (0.100 g, 0.406 mmol), 4-(4-fluorophenyl)benzoic acid (0.073 g, 0.338 mmol), and HATU (0.129 g, 0.338 mmol) in CH2Cl2 and add DIEA (0.18 mL, 1.01 mmol). Shake the mixture in a shaker block at 40° C. for 72 h. Dilute the reaction mixture with CH2Cl2 (30 mL), and wash with saturated NaHCO3 (aqueous) (2×25 mL). Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate in vacuo. Subject the crude product to flash column chromatography (40 g column) eluting with 8% MeOH/CH2Cl2, to yield the title compound as a bluish-white solid (0.116 g, 65%). mass spectrum (m/e): 445.3 [M+1], 443.3 [M−1]. 1H NMR (400 MHz, DMSO-d6): δ 10.23 (s, 1H), 8.05 (d, 2H, J=8.4 Hz), 7.85-7.79 (m, 4H), 7.75 (d, 1H, J=2.2 Hz), 7.41-7.30 (m, 4H), 3.79 (dd, 1H, J=9.9, 7.1 Hz), 3.72 (m, 1H), 3.54 (m, 1H), 3.31 (m, 1H), 2.86 (m, 1H), 2.25-2.12 (m, 7H), 1.86 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[OH-].[Na+].[Na:9][C:10]1[CH:21]=[CH:20][C:13]([CH:14](Br)[S:15]([OH:18])(=[O:17])=[O:16])=[CH:12][CH:11]=1.O>C(O)(C)C.C(O)C.CO>[Na:9][C:10]1[CH:21]=[CH:20][C:13]([CH:14]([S:15]([OH:18])(=[O:16])=[O:17])[O:1][CH2:2][CH:3]([OH:4])[CH2:5][OH:6])=[CH:12][CH:11]=1
Reactant: O=S(=O)(O)C(Br)c1ccc([Na])cc1
Reactant: OCC(O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CO
Product: O=S(=O)(O)C(OCC(O)CO)c1ccc([Na])cc1
Temperature: 95 °C

Procedure:
A 300-ml. beaker is charged with 18.4 parts of glycerin and 1.7 parts of sodium hydroxide. The mixture is heated to 95° C. while being stirred magnetically. To the beaker then is added 13.7 parts of 4-sodiosulfobenzyl bromide and the temperature is maintained at 95° C. for 3 hours. The viscous reaction solution then is added to 300 parts of water. The aqueous solution is concentrated to about one-tenth of its original volume and 250 parts of dimethyl sulfoxide added; isopropanol, about 200 parts, is then added resulting in a white, fluffy precipitate which is isolated by centrifugation. The solid is taken up in about 320 parts of an ethanol-methanol mixture, the volume reduced by about 25%, and isopropanol added. The product was isolated by centrifugation and dried at 60° C. under reduced pressure. The product, 3-(p-sodiosulfobenzyloxy)-1,2-propanediol, is obtained in a yield of 3 parts and has the following analysis:
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)#[CH:25]>>[F:33][C:32]([F:34])([F:35])[C:29]1[CH:28]=[CH:27][C:26]([C:24]2[N:3]=[N:2][N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[CH:25]=2)=[CH:31][CH:30]=1
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1cc(-c3ccc(C(F)(F)F)cc3)nn1)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 1-ethynyl-4-(trifluoromethyl)benzene. MS (+ESI) m/z: 441.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22](OC)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:26][CH3:27])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][OH:23])=[CH:19][CH:20]=3)[CH:11]=[C:10]([CH2:26][CH3:27])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(Cc2ccc(CC(=O)OC)cc2)nc(-c2cccc(Cl)c2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cc(Cc2ccc(CCO)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 37.1 %

Procedure:
A 25-mL flask, with stirrer bar, was charged with methyl 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetate (52 mg, 0.13 mmol, 1.0 eq.) and THF (3 mL). The flask was cooled to 0° C. under nitrogen. A solution of 1M LiAlH4 in THF (0.31 mL, 0.31 mmol, 2.3 eq.) was added and the reaction was allowed to slowly warm to room temperature. After 4.5 hrs, the reaction mixture was quenched with methanol, diluted with water (10 mL), and acidified with 2N HCl to pH˜3. The mixture was extracted with ethyl acetate (3×12 mL). The organic extract was washed with sat. sodium chloride (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue (49 mg) was purified by chromatography on silica gel using hexanes/ethyl acetate (1:0 to 1:1) as eluent to afford 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)ethanol (17 mg, 36% yield) as a colorless oil. MW=352.86. 1H NMR (DMSO-d6, 500 MHz) δ 8.38-8.33 (m, 2H), 7.61-7.53 (m, 2H), 7.28-7.25 (m, 3H), 7.16 (d, J=8.0 Hz, 2H), 4.58 (t, J=5.5 Hz, 4.08 (s, 2H), 3.60-3.53 (m, 2H), 2.77 (q, J=7.5 Hz, 2H), 2.67 (t, J=7.0 Hz, 2H), 1.26 (t, J=7.5 Hz, 3H).
Reaction SMILES: [N:1]1([C:7]([C:9]2[N:10]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18](O)=[O:19])=[CH:13][CH:12]=3)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([N:32]2[CH2:37][CH2:36][N:35]([C:18]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[N:10]([CH2:21][C:22]([F:24])([F:23])[F:25])[C:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])=[CH:17]4)=[O:19])[CH2:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(O)c1ccc2c(c1)cc(C(=O)N1CCOCC1)n2CC(F)(F)F
Reactant: C1CCC(N2CCNCC2)CC1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCOCC1)n2CC(F)(F)F)N1CCN(C2CCCCC2)CC1
Yield: 65 %

Procedure:
The title compound was synthesized in analogy to example 46, intermediate e), from 2-(morpholine-4-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indole-5-carboxylic acid and 1-cyclohexylpiperazine (commercially available), to give the desired product as a white solid (65%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([F:15])=[C:4]([CH:10]=[C:11]([F:14])[C:12]=1[F:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.BrCC1C(F)=[C:40](C=C(F)C=1F)[C:41]([O:43]CC)=[O:42].C([O-])(=O)C.[Na+]>C1C=CC=CC=1.CN(C=O)C.C(OCC)(=O)C>[C:41]([O:43][CH2:1][C:2]1[C:3]([F:15])=[C:4]([CH:10]=[C:11]([F:14])[C:12]=1[F:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:42])[CH3:40]
Reactant: CCOC(=O)c1cc(F)c(F)c(C)c1F
Reactant: CCOC(=O)c1cc(F)c(F)c(CBr)c1F
Agent: CC(=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(F)c(F)c(COC(C)=O)c1F
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Ethyl 3-methyl-2,4,5-trifluorobenzoate (61.0 g, 279 mmol) was dissolved in benzene (1,000 mL). N-Bromosuccinimide (76.2 g, 428 mmol) and 2,2′-azobisisobutyronitrile (100 mg) were added thereto, and the mixture was refluxed for 3 days. The reaction mixture was left to cool, and the solid matter that precipitated was separated through filtration and washed with benzene. Subsequently, the filtrate and the wash solution were combined. The mixture was concentrated under reduced pressure. The residue was subjected to silica gel chromatography (eluent; n-hexane:ethyl acetate=20:1 to 10:1), to thereby yield a mixture of the starting material and ethyl 3-bromomethyl-2,4,5-trifluorobenzoate (about 1:1, 57.8 g). The mixture was dissolved in DMF (290 mL), and sodium acetate (22.1 g, 269 mmol) was added thereto, followed by stirring for 30 minutes at 90° C. The reaction mixture was left to cool, and ethyl acetate (1,000 mL) was added thereto. The mixture was washed with water (500 mL×2) and saturated brine (500 mL), and dried with sodium sulfate anhydrate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography (eluent; n-hexane:ethyl acetate=20:1), whereby the starting material was recovered in an amount of 27.4 g (45%) and the title compound was obtained as a pale yellow oily substance (26.5 g, 34%).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][CH:14]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:28](N(CC)CC)C.CI>CO>[CH3:28][N:11]([CH2:12][CH2:13][CH:14]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:10][CH2:9][CH2:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc(C(CCNCCCSc2ccccc2)c2ccccc2)cc1
Reactant: CCN(CC)CC
Solvent: CO
Solvent: CI
Product: CN(CCCSc1ccccc1)CCC(c1ccccc1)c1ccc(O)cc1

Procedure:
To a solution of 0.8 g (0.0021 moles) of N-(3-phenylthiopropyl)-3-p-hydroxyphenyl-3-phenylpropylamine in 20 ml methanol and containing 0.3 ml triethylamine are added gradually 0.13 ml (0.0021 moles) methyl iodide.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[CH3:8][O:9][C:10](=[O:42])[CH2:11][C@H:12]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][C@H:22]3[C:30]4[C:25](=[C:26]([CH2:35][N:36]5[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]5)[C:27]([C:31]([F:34])([F:33])[F:32])=[CH:28][CH:29]=4)[CH2:24][CH2:23]3)=[CH:20][C:15]=2[O:14][CH2:13]1>>[CH3:8][O:9][C:10](=[O:42])[CH2:11][C@H:12]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][C@H:22]3[C:30]4[C:25](=[C:26]([CH2:35][N:36]5[CH2:37][CH2:38][N:39]([C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3])[CH2:40][CH2:41]5)[C:27]([C:31]([F:32])([F:33])[F:34])=[CH:28][CH:29]=4)[CH2:24][CH2:23]3)=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCNCC3)ccc21
Reactant: CC(C)OC(=O)Cl
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCN(C(=O)OC(C)C)CC3)ccc21

Procedure:
The title compound is prepared from isopropyl chloroformate and {(S)-6-[(R)-4-piperazin-1-ylmethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester following a procedure analogous to that described for Intermediate 27. LC (method 4): tR=1.05 min; Mass spectrum (ESI+): m/z=577 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]([SH:24])([CH3:23])[CH3:22].O>CN(C=O)C>[Br:1][C:2]1[C:3]([S:24][C:21]([CH3:23])([CH3:22])[CH3:20])=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH:5]=[O:6]
Reactant: CC(C)(C)S
Reactant: O=Cc1cc([N+](=O)[O-])cc(Br)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)Sc1c(Br)cc([N+](=O)[O-])cc1C=O
Temperature: 110 °C
Yield: 104.8 %

Procedure:
A mixture of 3-bromo-2-fluoro-5-nitro-benzaldehyde (1.0 g, 4 mmol), potassium carbonate (667 mg, 4.8 mmol) and 2-methyl-2-propanethiol (326 mg, 0.40 mL, 3.6 mmol) in dry DMF (5 mL) was heated at 110° C. in a sealed tube for 16 h. The reaction was cooled to RT, water was added, and the mixture extracted with dichloromethane (2×30 mL). The combined organic fractions were washed with water (3×15 mL), dried over sodium sulfate, filtered and concentrated to afford 1.2 g of the crude title compound, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:15][N:14]([C:16]3[S:17][C:18]([C:22]([O:24]CC)=[O:23])=[C:19]([CH3:21])[N:20]=3)[CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].C1COCC1.O>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:13][N:14]([C:16]3[S:17][C:18]([C:22]([OH:24])=[O:23])=[C:19]([CH3:21])[N:20]=3)[CH2:15]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC(NC(=O)c3nc(Cl)c(CC)[nH]3)C2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)NC2CN(c3nc(C)c(C(=O)O)s3)C2)nc1Cl
Temperature: 25 °C
Reaction time: 27 h
Yield: 92.4 %

Procedure:
Ethyl 2-(3-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}azetidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (218c) (145 mg, 0.36 mmol) was dissolved in methanol (3.6 mL). A 2 N aqueous lithium hydroxide solution (1.82 mL, 3.64 mmol) was added, and the mixture was stirred at room temperature for 27 hours. THF (2 mL) was added, followed by further stirring for 22 hours. Water was added to the reaction solution, and then the mixture was washed with ethyl acetate. A 1 N aqueous hydrochloric acid solution (4 mL) was added to the aqueous layer, followed by extraction with a chloroform/methanol mixed solvent. The combined organic layers were dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The resulting solid was suspended and washed in diethyl ether to obtain 123 mg of the title compound as a white solid (91%).