Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[C:4](=O)[CH2:5]Br.[C:13]([NH2:21])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CC1C=CC=CC=1C>[C:14]1([C:13]2[O:20][CH:5]=[C:4]([C:3]3[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:8]=3[F:12])[N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CBr)c1c(F)cccc1F
Reactant: NC(=O)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1C
Product: Fc1cccc(F)c1-c1coc(-c2ccccc2)n1
Yield: 121.8 %

Procedure:
5.7 g 2,6-difluorophenacyl bromide and 3.63 g benzamide were suspended in 20 ml o-xylene, and the suspension was subjected to reflux under heating for 1.5 hours. After completing the reaction, the suspension reacted was added with water, then extracted with ethyl acetate and further washed with saturated saline solution. The organic layer obtained was dried with anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduced pressure. Out of 7.6 g residue obtained, 1.0 g thereof was purified by using silica gel column chromatography, affording the objective substance in an amount of 0.6 g.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(N(CC)CC)C.[O:21]1[CH:25]=[CH:24][CH2:23][CH2:22]1>CN(C)C=O>[O:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: C1=COCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Reaction time: 6 h
Yield: 60 %

Procedure:
In 30 ml of dimethylformamide were dissolved 2.6 g of 5-fluorouracil, 2.66 g of anhydrous aluminum chloride and 7.0 ml of triethylamine. The reaction was carried out at 130° C. for 6 hours while adding 3.0 ml of 2,3-dihydrofuran to the solution. The reaction liquid was treated in the same manner as described in Example 13 to obtain 2.4 g of (1-(2-tetrahydrofuryl)-5-fluorouracil. The yield was 60%.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH:15]1([CH2:18]Br)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[CH:15]1([CH2:18][N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:17][CH2:16]1
Reactant: BrCC1CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(CC3CC3)c2)OC1(C)C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.1 g, 0.5 mmol), cyclopropylmethyl bromide (60.0 uL, 0.62 mmol, Aldrich, Cat. No. 242403), and cesium carbonate (500.0 mg, 1.5 mmol) in acetonitrile (1 mL) was stirred at 90° C. overnight. After cooling it was diluted with ethyl acetate. Then the organic solution was washed with water, brine; dried over Na2SO4. After filtration the filtrate was concentrated to yield 120 mg of the product which was directly used in the next step reaction without further purification.
Reaction SMILES: C([O:3][C:4](=[O:10])[CH:5]([CH:8]=O)[CH:6]=O)C.Cl.[C:12]([NH:16][NH2:17])([CH3:15])([CH3:14])[CH3:13].C(NN)(C)(C)C.[OH-].[Na+].Cl>C(O)C>[C:12]([N:16]1[CH:6]=[C:5]([C:4]([OH:3])=[O:10])[CH:8]=[N:17]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)NN
Reactant: CCOC(=O)C(C=O)C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)n1cc(C(=O)O)cn1
Temperature: 32 °C
Reaction time: 3 h

Procedure:
Formyl-3-oxo-propionic acid ethyl ester (75.85 g, 525.6 mmol) was dissolved in ethanol (1 L) at room temp. Tert-butylhydrazine hydrochloride (65.5 g, 525.6 mmol) was added at room temp and the reaction temperature gradually increased to 32° C. The flask was then placed in an ice-bath to cool it back to 20° C. It took ca. 1 h for t-butylhydrazine to fully dissolve. The solution was stirred at room temp. for 3 h. The reaction mixture was cooled in an ice-bath. Sodium hydroxide (4N, 152.4 g) was added to neutralize the hydrochloric acid. Most of the ethanol was then removed in vacuo and methanol (300 ml) was added followed by additional sodium hydroxide (4N, 304.8 g, 1.05 mol). The internal temperature gradually rose to 32° C. The reaction flask was then placed in a water bath to cool it back to room temp. and the reaction was allowed to stir at room temp. for 18 h. Methanol (300 ml) was then removed in vacuo with the water bath temperature kept below 30° C. The reaction mixture was then cooled to 0° C. and hydrochloric acid (6N, 190 ml) was added slowly to keep internal temperature below 15° C. The solution was adjusted to pH=2. The resulting suspension was allowed to stir in the ice-bath for 2 h, and the solid was filtered. After drying at 60° C. in vacuo for 2.5 days, 1-tert-butyl-1H-pyrazole-4-carboxylic acid (56.06 g) of off-white solid was collected. The mother liquor was extracted 3 times with dichloromethane (200 ml×3). The combined organic layer was washed once with brine (100 ml) and dried over magnesium sulfate. After concentrating in vacuo and drying, 16.5 g of yellowish solid was collected. The crude material was crystallized in hot iso-propyl acetate (25 ml) and heptane (25 ml). After cooling to room temp, the solid was filtered off and the cake was washed with mixed solvent of isopropyl acetate and heptane (1/1 (v/v, 14 ml) and dried in oven at 60° C. in vacuo for 5 h. A second crop of 1-tert-butyl-1H-pyrazole-4-carboxylic acid (7 g) was collected as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:4]=1.Br.[OH-].[Na+]>C(O)(=O)C.O>[C:10]1([NH:9][C:5]2[NH:4][C:3](=[O:2])[CH:8]=[CH:7][N:6]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccnc(Nc2ccccc2)n1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1ccnc(Nc2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
To a solution of 4-methoxy-N-phenylpyrimidin-2-amine (0.632 g, 3.14 mmol) in acetic acid (20 mL) was added HBr (2.132 ml, 18.84 mmol; 48 wt % in H2O). The reaction mixture was heated at a temperature ranging from about 90° C. to about 95° C. for 3 hours. The reaction mixture was cooled to room temperature and diluted with H2O. The pH of the reaction mixture was adjusted to about 5 to about 6 with 6M aqueous NaOH which resulted in the formation of a solid precipitate. The solid was filtered, washed with H2O, collected and dried under vacuum to yield the desired product (0.553 g, 94%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 10.74 (br s, 1H), 8.81 (br s, 1H), 7.76 (s, 1H), 7.60 (d, 2H), 7.31 (t, 2H), 7.02 (t, 1H), 5.81 (s, 1H). LRMS (ESI pos) m/e 188 (M+1).
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[CH:6](=O)[CH:7]([CH3:9])[CH3:8]>O>[CH2:3]([C:2](=[CH:6][CH:7]([CH3:9])[CH3:8])[CH:1]=[O:5])[CH3:4]
Reactant: CCCC=O
Reactant: CC(C)C=O
Solvent: O
Product: CCC(C=O)=CC(C)C

Procedure:
Accordingly, it has been discovered that if water is added to the n-butyraldehyde feed to the distillation column in an amount effective to hydrolyze the isobutyraldehyde oligomers to the monomeric form during distillation, they can be stripped from the n-butyraldehyde, thereby reducing the amount of isobutyraldehyde which reacts to form 2-ethyl-4-methyl-pentenal during aldol condensation and subsequent hydrogenation of the 2-ethyl-4-methyl-pentenal to 2-ethyl-4-methyl pentanol during the hydrogenation stage. By this method the content of 2-ethyl-4-methyl-pentanol in the final product can be substantially reduced; typically from a range of from about 0.2 to about 0.4 wt. % without the water addition to less than 0.2 wt. %, preferably to within a range of from about 0.08 to about 0.1 wt. % with the water addition, based on 2-ethylhexanol. The degree of improvement will vary with the amount of water added, with increasing amounts of water tending to give increasing reductions in the amount of 2-ethyl-4-methyl-pentanol in the 2-ethylhexanol.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([OH:19])(=[O:18])/[C:14](=[CH:16]/[CH3:17])/[CH3:15].[CH3:20][C:21]([CH3:23])=[O:22]>O1CCCC1>[OH:22][C:21]([C:14]([CH3:15])([CH:16]=[CH2:17])[C:13]([OH:19])=[O:18])([CH3:23])[CH3:20]
Reactant: C/C=C(\C)C(=O)O
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=CC(C)(C(=O)O)C(C)(C)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
A cooled (−78° C.) solution of N,N-diisopropylamine (12.5 g, 123 mmol) in anhydrous tetrahydrofuran (100 mL) was treated with n-butyllithium (2.5 M solution in hexanes, 49 mL, 123 mmol). Temperature was raised to 0° C. for 30 minutes, then re-cooled down to −78° C. Tiglic acid (5.00 g, 49.4 mmol) in anhydrous tetrahydrofuran (100 mL) was added dropwise. Temperature was raised to room temperature for 1 h then re-cooled down to −78° C. Acetone (2.86 g, 49.4 mmol) in anhydrous tetrahydrofuran (100 mL) was added dropwise. After stirring for 3 h, the reaction was quenched with a saturated solution of ammonium chloride and allowed to warm up to room temperature. The pH was adjusted to pH 2 by addition of concentrated hydrochloric acid and diethyl ether (400 mL) was added. The organic layer was separated, and the volatiles removed in vacuo. The residue was partitioned between diethyl ether (200 mL) and a saturated solution of sodium bicarbonate (300 mL). The aqueous layer was acidified to pH 1 with concentrated hydrochloric acid, then re-extracted with diethyl ether (2×100 mL). The organics were combined and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Biotage cartridge eluted with a continuous gradient of iso-hexanes/acetone 1:0 to 3:2 to afford the title compound (5.129 g, 66%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 1.27 (s, 3H), 1.31 (s, 3H), 1.38 (s, 3H), 5.28 (d, J=17.6 Hz, 1H), 5.34 (d, J=10.9 Hz, 1H), 6.25 (dd, J=17.6, 10.9 Hz, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:9](=[O:28])[N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1)(C)(C)C.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[NH2:7][C@@H:8]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:9]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:16]=1)=[O:28].[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1c1cccc(Oc2ccccc2)c1)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](C(=O)N1CCC[C@H]1c1cccc(Oc2ccccc2)c1)C1CCCCC1
Reaction time: 0.5 h

Procedure:
To a solution of {(S)-1-cyclohexyl-2-oxo-2-[(S)-2-(3-phenoxy-phenyl)-pyrrolidine-1-yl]-ethyl}-carbamic acid tert-butyl ester in CH2Cl2 (20 mL) is added TFA (10 mL) and the mixture is stirred for 30 minutes. The mixture is concentrated under reduced pressures to give (S)-2-amino-2-cyclohexyl-1-[(S)-2-(3-phenoxy-phenyl)-pyrrolidin-1-yl]-ethanone as a TFA salt quantitavely (1.65 g). LCMS m/z 379 (M+1).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[N:14]([CH2:15][CH2:16][CH:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[OH:18])[C:13](=[O:25])[NH:12][C:11]1=[O:26])([OH:3])=[O:2].[CH2:27](O)[CH3:28]>S(=O)(=O)(O)O>[CH2:27]([O:2][C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[N:14]([CH2:15][CH2:16][CH:17]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[OH:18])[C:13](=[O:25])[NH:12][C:11]1=[O:26])=[O:3])[CH3:28]
Reactant: O=C(O)CCCCCCC1C(=O)NC(=O)N1CCC(O)C1CCCCC1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCCCCCC1C(=O)NC(=O)N1CCC(O)C1CCCCC1
Reaction time: 18 h

Procedure:
A solution of 5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin (diastereomer of m.p. 96°-98°) (Example 14c) (4 g) in ethanol (60 ml) and concentrated sulphuric acid (1.6 ml) was allowed to stand at room temperature for 18 hours. The alcohol was evaporated, water was added, and the precipitated oil was extracted with ether. The ether solution was washed with sodium bicarbonate solution and with water, dried (MgSO4) and evaporated to give a single diastereomer of 5-(6-ethoxycarbonylhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin as a colourless oil, soon solidifying, and crystallising from cyclohexane in small colourless plates, m.p. 62°-63°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:41])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([NH:16][C@@H:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]([F:40])([F:39])[F:38])[CH2:18][N:19]2C(=O)C3C(=CC=CC=3)C2=O)=[O:15])[S:10][C:11]=1[CH2:12][CH3:13].NN>O1CCCC1.CO>[NH2:19][CH2:18][C@@H:17]([NH:16][C:14]([C:9]1[S:10][C:11]([CH2:12][CH3:13])=[C:7]([C:6]2[N:5]([CH3:41])[N:4]=[CH:3][C:2]=2[Cl:1])[CH:8]=1)=[O:15])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:40])([F:39])[F:38]
Reactant: CCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: CCc1sc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)cc1-c1c(Cl)cnn1C
Reaction time: 12 h
Yield: 56.6 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide (316 mg, 0.53 mmol) in tetrahydrofuran (1.314 ml) and methanol (1.3 ml) at 25° C. was added hydrazine (0.16 ml, 5.26 mmol) dropwise. After 12 h, the solution was concentrated, purified via column chromatography (silica, 5% MeOH in DCM (1% NH4OH)) and converted to the HCl salt by adding excess 2M HCl in Et2O (2 ml) to the residue in MeOH (5 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide (163 mg, 0.30 mmol, 57% yield) as a white solid: LCMS (ES) m/z=471, 473 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.82 (br. s., 1H) 8.04 (bs, 3H) 7.85 (s, 1H) 7.65-7.72 (m, 2H) 7.52-7.59 (m, 2H) 7.39-7.46 (m, 1H) 4.41-4.47 (m, 1H) 3.71 (s, 3H) 2.98-3.07 (m, 4H) 2.67 (q, J=7.58 Hz, 2H) 1.16 (t, J=7.58 Hz, 3H).
Reaction SMILES: [I:1][CH2:2][C:3]([O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:17]([CH2:18][CH2:19][C@@H:20]2[C:21](=[O:23])[CH3:22])[C@H:16]2[C@H:7]1[C@:8]1([CH3:32])[C@@H:13]([CH2:14][CH2:15]2)[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:4].O>C(O)(C)(C)C>[I:1][CH2:2][C:3]([O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:17]([CH2:18][CH2:19][C@@H:20]2[C:21](=[O:23])[CH3:22])[C@H:16]2[C@H:7]1[C@:8]1([CH3:32])[C@@H:13]([CH2:14][CH2:15]2)[CH2:12][CH:11]=[CH:10][CH2:9]1)=[O:4]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OS(C)(=O)=O)CC[C@]4(C)[C@H]3[C@@H](OC(=O)CI)C[C@]12C
Solvent: O
Solvent: CC(C)(C)O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3[C@@H](OC(=O)CI)C[C@]12C
Reaction time: 1.25 h
Yield: 68.9 %

Procedure:
A solution of 11β-iodoacetoxy-3α-methanesulphonyloxy-5α-pregnan-20-one (22.2 g) in t-butanol (950 ml) containing water (500 ml) was treated with powdered silica gel (44 g) and refluxed with stirring for 75 minutes. The cooled mixture was filtered and the filtrate was evaporated to small bulk and diluted with water. The precipitated solid was collected by filtration and recrystallized from aqueous methanol to afford title compound (12.77 g). A sample recrystallized from acetone-petroleum ether had m.p. 127°-129°, [α]D +100.5°.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]([CH3:26])([CH3:25])[C:9]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[CH3:25][C:8]1([CH3:26])[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:9]1=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)C(C)(C)c2nccnc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)c3nccnc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
A mixture of tert-butyl 4-(2-(3-chloropyrazin-2-yl)-2-methylpropanamido)piperidine-1-carboxylate (2.8 g, 7.31 mmol) and cesium carbonate (7.15 g, 21.94 mmol) in DMSO (25 mL) was stirred at RT overnight. H2O was added, extracted with EtOAc (3×). The extracts were dried over MgSO4, concentrated, purified by ISCO (30% EtOAc/Hexanes) to give the title compound (2.15 g, 85%). MS (M+1): 347.1
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10](=[O:22])[C:11]3[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]([OH:21])=[O:20])=[CH:13][CH:12]=3)=[C:8]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[S:7][C:6]=2[CH:30]=1>CCO.CCOC(C)=O.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10](=[O:22])[C:11]3[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:16]=3)=[C:8]([C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)[S:7][C:6]=2[CH:30]=1
Reactant: O=C(O)C=Cc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)CCc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Yield: 72.7 %

Procedure:
6-hydroxy-3-[4-(2-carboxyvinyl)benzoyl]-2-(4-hydroxyphenyl)benzo[b]thiophene (310 mg, 0.74 mmol) was dissolved in 50 mL of a 1:1 mixture of EtOH and EtOAc. This solution was hydrogenated at 40 psi in the presence of 10% Pd/C (200 mg). When the reaction was judged complete by TLC analysis, the mixture was filtered through Celite to remove the catalyst. The filtrated was concentrated in vacuo to a yellow oil that was triturated from hexanes/EtOAc. Filtration provided 225 mg (72%) of 6-hydroxy-3-[4-(2-carboxyethyl)benzoyl]-2-(4-hydroxyphenyl)benzo[b]thiophene as a yellow solid. mp 244-248° C. 1H NMR (DMSO-d6) δ12.15 (bs, 1H), 9.74 (s, 1H), 9.68 (s, 1H), 7.56 (d, J=8.1 Hz, 2H), 7.30 (d, J=2.0 Hz, 1H), 7.23-7.19 (m, 3H), 7.12 (d, J=8.5 Hz, 2H), 6.82 (dd, J=9.0, 2.0 Hz, 1H), 6.62 (d, J=8.5 Hz, 2H), 2.77 (t, J=7.0 Hz, 2H), 2.45 (t, J=7.0 Hz, 2). FD mass spec: 418. Anal. Calcd. for C24H18O5S.20 H20: C, 68.89; H, 4.34. Found: C, 68.35; H, 4.72.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Cl-].[Al+3].[CH3:17][CH:18]([CH2:23][CH3:24])[CH2:19][C:20](Cl)=[O:21].Cl>[N+](C1C=CC=CC=1)([O-])=O.O>[CH3:17][CH:18]([CH2:23][CH3:24])[CH2:19][C:20]([C:4]1[CH:5]=[CH:6][C:1]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:2][CH:3]=1)=[O:21]
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: CCC(C)CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: CCC(C)CC(=O)c1ccc(-c2ccccc2)cc1
Temperature: -7 °C
Reaction time: 18 h

Procedure:
To commercially available biphenyl (0.08 mole) and anhydrous aluminium trichloride (0.1 mole) dissolved in dry nitrobenzene (90ml), (+)-3-methylpentanoylchloride (0.1mole) the preparation of which is known and described in United Kingdom Patent Application No. 36211/75), is added in drops, the temperature being maintained at about -7° C. during the addition. The mixture is then stirred for about 18 hr. with cooling in an ice bath. It is then poured onto a mixture of ice, water and concentrated hydrochloric acid and stirred for 0.5 hr., and the nitrobenzene layer is separated. The nitrobenzene is removed by steam distillation and the residue is crystallised from a small volume of ethanol to constant melting point.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].C(Cl)(=O)C([Cl:19])=O.CN(C=O)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:19])=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(C(=O)O)cc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Cl)cc1C(F)(F)F

Procedure:
The title compound was prepared from 4-methoxy-3-trifluoromethylbenzoic acid with oxalyl chloride and DMF in chloroform at room temperature [D. Levin, Chem. Br., 1977, 20] followed by evaporation in vacuo.
Reaction SMILES: [C:1]1(=[O:21])[N:5]([CH2:6][CH2:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12.[BH4-].[Na+].C(O)C.C(OCC)(=O)C>C(O)C>[OH:21][CH:1]1[C:2]2[C:3](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:4](=[O:16])[N:5]1[CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCSc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1c2ccccc2C(O)N1CCCSc1ccncc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.4 %

Procedure:
To a solution of 5.97 g (20.0 mmol) of 4-(3-phthalimidopropylthio)pyridine in 300 ml of ethanol, 1.51 g (40 mmol) of sodium borohydride was added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off and saturated saline was added to the residue. The mixture was extracted with chloroform and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethanol/ethyl acetate =1:10 to give 3.27 g of the desired compound (54.4% yield, colorless crystals), mp. 132°-134° C. NMR (200 MHz, CDCl3) δ: 2.11 (2H, m), 2.97 (2H, m), 3.72 (2H, m), 5.83 (1H, s), 6.98 (2H, d, J=5.4 Hz), 7.47-7.67 (3H, m), 7.77 (1H, dd, J=7.6, 1.2 Hz), 8.02 (2H, m).
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[N+:17]([O-])([OH:19])=[O:18]>C(O)(=O)C>[N+:17]([C:14]1[CH:15]=[C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:11]=[CH:12][C:13]=1[OH:16])([O-:19])=[O:18]
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCCCCCCCCc1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
10 g of 4-nonylphenol (manufactured by Tokyo Kasei K.K., containing 10% of ortho compound) was dissolved in 30 ml of acetic acid and to the resulting solution was added 20 ml of 30% solution of nitric acid at 5°-10° C. for 2 hours. After 10 minutes, the resulting solution was treated with 50 g of ice water and then extracted with three 50-ml portions of ether. The ether was distilled off and then the residue was isolated using a silica gel column to obtain 9.33 g of the desired product in a 78% yield.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH2:17]([NH2:19])[CH3:18]>C1COCC1>[Br:1][C:2]1[C:7]([NH:19][CH2:17][CH3:18])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: CCN
Solvent: C1CCOC1
Product: CCNc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine and ethylamine in THF. ES-MS m/e (%): 285 (M{81Br}+H+, 100), 283 (M{79Br}+H+, 95).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:6]=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25])=[CH:18][CH:17]=2)[N:4]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:25][N:24]([CH3:26])[C:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]3[CH3:15])[CH:8]=[C:3]([CH2:2][O:1][S:36]([CH3:35])(=[O:38])=[O:37])[N:4]=2)=[CH:17][CH:18]=1)=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1COCCN1c1cc(CO)nc(-c2ccc(NC(=O)N(C)C)cc2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-[4-[4-(Hydroxymethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-1,1-dimethyl-urea (384 mg) was dissolved in DCM (12 mL) and triethylamine (0.216 mL) and the solution was cooled to 0° C. Methane sulfonyl chloride was added (0.121 mL) and the reaction was stirred for 15 minutes at RT before being concentrated in vacuo to give the desired material.