Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]1>O1CCOCC1.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: CC(C)(O)C1CCNCC1
Solvent: CS(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC(C(C)(C)O)CC3)n3nccc3n2)cc1
Temperature: 25 °C
Yield: 39.7 %

Procedure:
A solution of N-(7-chloro-pyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 200 mg, 0.604 mmol) and 2-(piperidin-4-yl)propan-2-ol (130 mg, 0.906 mmol) in Dioxane (6 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 5-95% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (105 mg, 41%). 1H NMR (METHANOL-d4) δ: 8.00 (d, J=2.3 Hz, 1H), 7.95 (d, 2H), 7.66 (d, J=8.3 Hz, 2H), 7.39 (s, 1H), 6.33 (d, J=1.5 Hz, 1H), 4.59 (d, J=11.6 Hz, 2H), 2.97 (t, 2H), 1.95 (d, J=9.1 Hz, 2H), 1.61-1.69 (m, 3H), 1.56 (s, 6H), 1.21 (s, 6H). ESI-MS: m/z 438.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][C:15]([F:18])([F:17])[F:16])[CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[NH4+:20]>C(O)C>[NH2:20][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][C:15]([F:18])([F:17])[F:16])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1c(OC(F)(F)F)ccc2nc(Cl)sc12
Agent: [OH-]
Solvent: CCO
Product: Nc1nc2ccc(OC(F)(F)F)c([N+](=O)[O-])c2s1
Temperature: 110 °C

Procedure:
A mixture of 0.4 g of 2-chloro-7-nitro-6-trifluoromethoxybenzothiazole and 10 cm3 of 33% aqueous ammonium hydroxide solution in 30 cm3 of ethanol is heated at 110° C. in an autoclave for 5 hours. The mixture is cooled and the solvent is evaporated off under reduced pressure (2.7 kPa). After purification by flash chromatography on silica with a cyclohexane/ethyl acetate mixture (4/6 by volume) as eluent, 0.22 g of 2-amino-7-nitro-6-trifluoromethoxybenzothiazole is obtained, melting at 180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)=[O:8].[H-].[Na+].[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:11]=1)=[O:8]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Oc1ccc(Cl)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.08 h
Yield: 80.2 %

Procedure:
A solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]-benzamide(0.20 g, 0.52 mmol) in tetrahydrofuran(3 mL) was added to a suspension of 60% sodium hydride(21.8 mg, 0.55 mmol) in tetrahydrofuran (3 mL) under ice bath, and the mixture was stirred for 5 minutes. Then, pivaloyl chloride(71 μ L, 0.57 mmol) was added and the mixture was stirred for 10 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was washed with isopropyl ether/n-hexane under suspension to give the title compound (195 mg, 80.2%) as a white crystal.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]3[N:11]([CH:13]=[N:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)=O>[C:1]1([C:7]2[CH:8]=[N:9][C:10]3[N:15]([N:14]=[CH:13][N:11]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2cnc3nncn3c2)cc1
Solvent: O=CO
Product: c1ccc(-c2cnc3ncnn3c2)cc1

Procedure:
A mixture of 1.0 g. of 6-(phenyl)-1,2,4-triazolo[4,3-a]pyrimidine and 10 ml. of 97% formic acid is refluxed for 5 hours and the excess formic acid is removed under reduced pressure. The solid residue is collected, washed with hexane and recrystallized from glacial acetic acid to give the product as crystals, m.p. 164°-167° C.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[N:5](COCC[Si](C)(C)C)[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:26]4[N:27]=[CH:28][CH:29]=[C:30]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[C:25]4=[N:24][C:23]=3[CH2:37][CH2:38][C:39]3[CH:48]=[CH:47][C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:40]=3)=[CH:18][CH:17]=2)=[N:3]1.CCOCC>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][N:2]1[C:6](=[O:7])[NH:5][C:4]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[N:26]4[N:27]=[CH:28][CH:29]=[C:30]([N:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)[C:25]4=[N:24][C:23]=3[CH2:37][CH2:38][C:39]3[CH:48]=[CH:47][C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:40]=3)=[CH:20][CH:21]=2)=[N:3]1
Reactant: Cn1nc(-c2ccc(-c3c(CCc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cc2)n(COCC[Si](C)(C)C)c1=O
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2ccc(-c3c(CCc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cc2)[nH]c1=O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A solution of compound 51e (0.20 g, 0.29 mmol) in TFA/DCM (1:3 v/v, 5 mL) was stirred overnight at rt. The mixture was concentrated under reduced pressure, and the residue obtained was treated with Et2O (10 mL). The solids formed were collected by filtration, washed with Et2O (2×20 mL), and treated with MeOH (5 mL) and DIEA (0.5 mL). The resulting solution was stirred at 70° C. for 30 min and allowed to cool to rt. The solids formed were collected by filtration and washed with Et2O (2×20 mL) to obtain the title compound 78 as a white solid. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 12.30 (s, 1H), 8.21 (d, J=8.7 Hz, 1H), 8.08 (d, J=5.4 Hz, 1H), 7.85-7.92 (m, 4H), 7.76-7.67 (m, 3H), 7.55-7.50 (m, 1H), 7.41 (d, J=8.4 Hz, 1H), 6.34 (d, J=5.7 Hz, 1H), 3.92-3.85 (m, 4H), 3.78-3.70 (m, 4H), 3.39-3.34 (m, 7H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C30H28N8O2: 533.2 (M+H). Found: 533.3.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23]O)[CH2:18][CH2:17]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([O:12][CH2:23][CH2:22][N:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CN1CCN(CCO)CC1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Product: COc1cc2ncnc(Cl)c2cc1OCCN1CCN(C)CC1

Procedure:
The compound was synthesised according to GP 4 from 4-chloro-6-hydroxy-7-methoxy-quinazoline and 2-(4-Methyl-piperazin-1-yl)-ethanol. LC/ESI-MS: m/z=337 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13](Br)[CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)=[CH2:26].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)C(C)C)(C)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13](/[CH:26]=[CH:25]/[C:27]4[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=4)[CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=[N+]([O-])c1cc(Br)c2nc(Nc3ccc(Cl)c(Cl)c3)nc(O)c2c1
Reactant: C=Cc1ccc(C(=O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(/C=C/c2cc([N+](=O)[O-])cc3c(O)nc(Nc4ccc(Cl)c(Cl)c4)nc23)cc1
Temperature: 120 °C
Yield: 62.3 %

Procedure:
To a solution of 2-((3,4-dichlorophenyl)amino)-8-bromo-6-nitroquinazolin-4-ol (50 mg) in N,N-dimethylformamide (2 mL) was added 4-vinylbenzoic acid (35 mg), followed by palladium acetate (2.6 mg), tri-o-tolylphosphine (7.1 mg) and N,N-diisopropylethylamine (0.24 mL). The reaction mixture was heated at 120° C. for 24 h, then was cooled to room temperature and concentrated in vacuo. The residue was triturated with 50% (v/v) methanol/dichloromethane (2 mL). The resulting solid was isolated by filtration, washed sequentially with diethyl ether and water, then was dried in vacuo to give the title compound (36 mg). 1H NMR (300 MHz, DMSO-d6/CF3CO2H) δ8.75 (d, J=2.7 Hz, 1H), 8.60 (d, J=2.7 Hz, 1H), 8.43 (d, J=4.5 Hz, 1H), 7.99-7.88 (m, 3H), 7.74 (d, J=8.4 Hz, 1H), 7.67-7.51 (m, 2H), 7.38 (dd, J=8.7, 2.6 Hz, 1H). HPLC Method B 8.26 min. MS (APCI−) m/z 496, 498.
Reaction SMILES: [O:1]=[C:2]([CH3:35])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:18]2[CH2:22][CH2:21][C@H:20]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)[O:19]2)[CH:10]=[C:11]([OH:17])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].Br[CH2:37][CH2:38][CH2:39][OH:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)C>[O:1]=[C:2]([CH3:35])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:18]2[CH2:22][CH2:21][C@H:20]([C:23]3[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=3)[O:19]2)[CH:10]=[C:11]([O:17][CH2:37][CH2:38][CH2:39][OH:40])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:5])=[O:6]
Reactant: OCCCBr
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCOc1c(OCCCO)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of trans-2-[3-(2-oxopropylsulfonyl)-4-propoxy-5-hydroxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (30 mg, 0.059 mmol), 3-bromo-1-propanol (12 uL, 0.13 mmol) and potassium carbonate (17 mg, 0.12 mmol) in DMF (0.5 mL) was heated at 80° C. with stirring under nitrogen for 1 h. The reaction mixture was cooled and diluted with ethyl ether. It was washed with water (2x), brine, dried, filtered, and evaporated to a residue, which was purified by preparative TLC (hexane-ethyl acetate; 7:3, v/v) to give the title compound: Rf 0.3; NMR (CDCl3) δ 2.38 (s, SO2CH2COCH3), 4.15 & 4.24 (2 t, OCH2CH2), 4.48 (s, SO2CH2), 5.22 (m, H-2 & H-5).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)=[O:5])C>C(O)C.O1CCCC1.[OH-].[Na+]>[CH3:12][O:11][C:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[S:7][CH:8]=1
Reactant: CCOC(=O)c1cc(OC)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1csc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Methoxythiophene (4.0 ml) was dissolved in tetrahydrofuran (50 ml), and the mixture was cooled to -78° C. n-Butyllithium (1.6M in hexane, 19.5 ml) was slowly added dropwise, and the mixture was stirred at the same temperature for 1 hour. The mixture was poured into a mixture of dry ice and diethyl ether, and warmed to room temperature with stirring. The solvent was distilled off, and the residue was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a mixture of 3-methoxy-2-thiophenecarboxylic acid and 4-methoxy-2-thiophenecarboxylic acid (6.0 g). This mixture was dissolved in N,N-dimethylformamide (50 ml), and iodothane (3.0 ml) and potassium carbonate (5.25 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 4-methoxy-2-thiophenecarboxylic acid ethyl ester (2.69 g) and 3-methoxy-2-thiophenecarboxylic acid ethyl ester (3.98 g). 4-Methoxy-2-thiophenecarboxylic acid ethyl ester (2.69 g) was dissolved in a mixture of ethanol (25 ml) and tetrahydrofuran (25 ml), and 1N aqueous sodium hydroxide (22 ml) was added. The mixture was stirred at room temperature for 3 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-methoxy-2-thiophenecarboxylaic acid (2.11 g) as crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1cnc2[nH]ccc2c1N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
tert-Butyl 4-(5-bromo-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazine-1-carboxylate (0.40 g, 1.05 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.3 mL) was then added. The reaction was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was dissolved in minimal DCM and added to a stirring solution of 1M HCl in ether. The resulting solid was collected by filtration, washed with ether, and dried to give 5-bromo-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.28 g, 94.9% yield) as the dihydrochloride salt.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.O.[H][H].[OH-].[K+]>[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH:10]([OH:12])[CH3:11]
Reactant: [H][H]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(O)c1cccc(N)c1
Yield: 75 %

Procedure:
m-Nitroacetophenone (66.0 g., 0.40 mole), water containing 0.70 mole phosphoric acid (300 ml.), and 5% palladium on carbon (2.0 g.) were hydrogenated as in Example II until hydrogen absorption ceased (2 hours). Work-up after neutralization with 1.40 moles potassium hydroxide gave m-amino-α-methylbenzyl alcohol in 75% yield which was 99% pure by GLC and contained 0.8% m-ethylaniline.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7].[H-].[Na+].[CH2:10]([O:12][C:13](=[O:16])[CH2:14][CH3:15])[CH3:11]>C1COCC1>[CH2:10]([O:12][C:13](=[O:16])[C@@H:14]([N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7])[CH3:15])[CH3:11]
Reactant: CCOC(=O)CC
Reactant: O=c1cccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)n1ccccc1=O
Reaction time: 0.17 h
Yield: 46.7 %

Procedure:
A stirred solution of 1H-Pyridin-2-one (500 mg, 5.26 mmol) in anhydrous THF (50 ml) at room temperature was treated portionwise with 60% NaH (231 mg, 5.78 mmol). The reaction mixture was kept for 10 min then added over 5 min to a solution of (R)-2-trifluoromethanesulfonyloxy)-propionic acid ethyl ester (1315 mg, 5.26 mmol) in anhydrous THF (2.5 ml) at room temperature. The resulting mixture was stirred for 2 h, then concentrated. The residue was dissolved in ethyl acetate, and the resulting solution was washed with ice cold dilute HCl. The organic layer was removed and the aqueous layer re-extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (20% up to 80% ethyl acetate in hexane) to afford the title compound as a yellow oil (480 mg, 46%): [α]27D=−56.40° (c=0.275, CH2Cl2) 1H NMR (400 MHz CDCl3) δ 1.3 3H, t), 1.65 3H, d), 4.2 2H, q), 5.6 1H, q), 6.2 1H, t), 6.4 1H, d), 7.2-7.3 2H, m).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH:12]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>O1CCCC1>[CH2:3]([O:10][CH2:11][CH:12]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[O:13][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(O)COCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COC(COCc1ccccc1)CO[Si](C)(C)C(C)(C)C
Temperature: 5 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
Dried tetrahydrofuran (600 ml) was added to 60% sodium hydride (5.8 g), and the solution cooled to 5° C. A solution (100 ml) of 1-O-benzyl-3-O-t-butyldimethylsilylglycerol (35.9 g) in tetrahydrofuran was added thereto, and the resultant mixture stirred at the same temperature for 2 hours. Then, ethyl bromoacetate (24.3 g) was added dropwise thereto, and the mixture stirred at the same temperature for 2 hours and then room temperature overnight. Upon concentrating the reaction mixture under reduced pressure, water was added to the residue, and the mixture was acidified with 5% hydrochloric acid. After extracting the aqueous layer with ethyl acetate, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. Upon concentrating thereof under reduced pressure, the residue was purified on a silica gel column (eluent: n-hexane/ethyl acetate=6/1) to obtain the desired product (28.7 g) as oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][N:16]=1)=O)(C)(C)C.[ClH:28]>C(OCC)C>[ClH:28].[CH2:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[N:16][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccccc2)cn1
Agent: Cl
Solvent: CCOCC
Product: c1ccc(Cc2ccc(OC[C@H]3CCCN3)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To the product from step 2 (10 mg, 0.027 mmol) was added 3 ml of 2N HCl in diethyl ether. The resulting mixture was stirred at rt for 2 h. The solvent was removed to give the title compound (8 mg, 96%). MS; m/z 269 (M+H)>90% 1H NMR (DMSO-d6, 400 MHz) δ 1.59-2.12 (4H, m), 3.21 (2H, m), 3.90 (2H, s), 4.31 (1H, m), 4.46 (1H, dd, J1=4.0 Hz, J2=11.6 Hz), 6.80 (1H, d, J=8.4 Hz), 7.17-7.31 (5H, m), 7.57 (1H, dd, J1=2.4 Hz, J2=8.4 Hz), 8.09 (1H, d, J=2.4 Hz), 8.93 (1NH, s), 9.48 (1NH, s)
Reaction SMILES: [Cl:1][C:2]1[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]([CH2:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([N+:17]([O-])=O)[CH:11]=1>[Pd].Cl.CCOCC>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:4][C:3]2[CH:34]=[CH:35][CH:36]=[C:37]([C:38]([F:40])([F:41])[F:39])[C:2]=2[Cl:1])[CH2:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:11][C:12]=1[NH2:17]
Reactant: O=[N+]([O-])c1cc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)ccc1Cl
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Product: Nc1cc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)ccc1Cl
Reaction time: 24 h

Procedure:
(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(4-chloro-3-nitro-phenoxy)-propyl]-amine (400 mg, 0.66 mmol) was hydrogenated over 10% Pd/C (40 mg) at 60 psi at room temperature in the presence of 1N HCl-Et2O (10 ml). After 24 h, the reaction mixture was filtered and concentrated in vacuo to give a heavy oil. HPLC purification of the crude amine (Phenomonex Luna Combi HTS, 5 micron C18, 275 mm×30 mm, 10% CH3CN— water gradient to 95% CH3CN) afforded the title compound as an oil. Treatment of the free base with 1N HCl-Et2O (excess), followed by filtration and isolation of the resulting precipitate gave the title compound as a brown solid, 18.5 mg (4.3%). MS (ESI) 572.5 (M+).
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:18])=O>ClCCl>[Cl:18][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: COCCCOc1ccnc(CO)c1C
Solvent: ClCCl
Product: COCCCOc1ccnc(CCl)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
450 mg of the 2-hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine prepared above was dissolved in 20 ml of dichloromethane to obtain a solution. 760 mg of thionyl chloride was dropwise added to this solution at 0° C. The obtained mixture was stirred at a room temperature for 2 hours. After the completion of the reaction, the reaction mixture was distilled to remove the dichloromethane and the thionyl chloride. A saturated aqueous solution of sodium hydrogencarbonate was added to the obtained residue. The obtained mixture was extracted with chloroform. The obtained chloroform layer was concentrated to obtain 470 mg of 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine as a brown crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:15][CH3:16])[C:13]=1[OH:14])[CH:6]=[CH:7][C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>O>[CH3:16][O:15][C:12]1[CH:11]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:13]=1[OH:14])[CH:6]=[CH:7][C:8]([O:10][CH2:22][CH3:23])=[O:9]
Reactant: CCO
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C=Cc1cc(OC)c(O)c(OC)c1

Procedure:
In an argon atmosphere, 3.00 g (13.4 mmol) of 3,5-dimethoxy-4-hydroxycinnamic acid was suspended in a sulfuric acid - ethanol (1 : 115, 50 ml) solution. The suspension was refluxed for 5.5 hours. Water was added to the reaction solution, and the mixture was extracted with methylene chloride. The organic layer was washed with an aqueous solution of sodium hydrogen carbonate and concentrated under reduced pressure to give 3.34 g (13.24 mmol) of ethyl 3,5-dimethoxy-4-hydroxycinnamate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]2[C:11]=1[NH:10][CH:9]=[C:8]([C:12]([O:14]CC)=[O:13])[C:7]2=[O:17].CC(O)C.[OH-].[Na+].C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]([F:21])([F:19])[F:20])=[C:6]2[C:11]=1[NH:10][CH:9]=[C:8]([C:12]([OH:14])=[O:13])[C:7]2=[O:17]
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ccc(C(F)(F)F)c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1c[nH]c2c(Cl)ccc(C(F)(F)F)c2c1=O
Temperature: 25 °C
Yield: 88.5 %

Procedure:
Ethyl 8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylate (15) (1200 g, 3.754 mol) was charged into a reaction vessel followed by the addition of 2-propanol (1.200 L) and water (7.200 L) and stirred. Sodium hydroxide (600.6 g, 7.508 mol) and water (1.200 L) were mixed and allowed to cool to room temperature. The resulting mixture was charged into the reaction vessel and then was heated to 80° C. and stirred for 3.5 h to generate a dark, homogenous mixture. After an additional hour, acetic acid (9.599 L of 20% w/v, 31.97 mol) was added via dropping funnel over 45 min. The reaction mixture was cooled with stirring to 22° C. at a rate of 6° C./h. The resulting solid was filtered and washed with water (3 L) to generate a wet cake (1436 g). The filtrate was dried in a vacuum oven with a nitrogen bleed over Drierite® to generate 8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid as a brown solid (1069 g). The 8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid was purified by slurrying in 1.5 L methanol and stirring for 6 h. It was then filtered and dried to furnish 968.8 g of purified 8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid.