Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[Br-:20].S([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C>CC(C)=O.O.OOS([O-])=O.[K+]>[CH2:1]([O:8][C:9]1[C:14]([Br:20])=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([CH3:18])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1C
Reactant: [Br-]
Agent: O=S([O-])OO
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(=O)c1cc(Br)c(OCc2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97.8 %

Procedure:
To a solution of 1-[4-(benzyloxy)-2-methylphenyl]ethanone (20.9 g, 87.1 mmol) in acetone (300 mL), a solution of NaBr (9.86 g, 95.9 mmol) in water (100 mL), water (200 mL) and Oxone® (oxone monopersulfate compound, Aldrich) (59.0 g, 95.9 mmol) were added and stirred at room temperature for 2.5 hours. The reaction mixture was mixed with a solution of sodium sulfite (20 g) in water (50 mL) under ice cooling, followed by addition of water and ethyl acetate to separate the organic layer. The organic layer was washed with 20 wt. % aqueous sodium sulfite and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure to give a mixture (27.2 g) of 1-[4-(benzyloxy)-5-bromo-2-methylphenyl]ethanone and 1-[4-(benzyloxy)-3-bromo-2-methylphenyl]ethanone. To this mixture, a 5% solution of sodium hypochlorite (300 mL, 255 mmol) and a solution of potassium hydroxide (4.80 g, 85.3 mmol) in water (10 mL) were added and stirred at 120° C. for 1 hour. The reaction mixture was cooled to room temperature and filtered to collect the precipitated insoluble product, to which 2N hydrochloric acid was then added. After extraction with ethyl acetate, the organic layer was washed with 2N hydrochloric acid and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure and the resulting residue was washed with methanol to give the titled compound (16.6 g, 59%, 2 steps) as a colorless powder.
Reaction SMILES: [CH2:1]([C:4]1([C:19]#[N:20])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3].[BH4-].[Na+]>[Co](Cl)Cl.C(O)C>[CH2:1]([C:4]1([CH2:19][NH2:20])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2)[CH2:2][CH3:3]
Reactant: C=CCC1(C#N)c2ccccc2CCc2ccccc21
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCC1(CN)c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.3 %

Procedure:
Dissolved 10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-nitrile (4.68 g, 0.018 mol) is 150 mL of absolute ethanol, and added sodium borohydride (1.70 g, 0.045 mol). Stirred at room temperature for 15 mins then cooled to 0° C. Added cobalt (II) chloride (4.29 g, 0.018 mol) portionwise. Stirred at room temperature for 30 mins then added additional sodium borohydride (1.70 g, 0.045 mol). Stirred at room temperature for 16 hours. Evaporated, and added 0.5N HCl. Washed with ethyl acetate, and extracted organic solution with 1.0N HCl. Combined acidic aqueous extracts, and made basic with 25 weight % NaOH. Extracted basic solution with dichloromethane. Dried combined organic extracts with MgSO4, filtered, and evaporated. Purified by flash chromatography on silica gel eluting with ethyl acetate. Combined appropriate fractions, and evaporated to give 1.4 g (30% yield) of 10,11-dihydro-5-propyl-5H-dibenzo[a,d]cycloheptene-5-methanamine as an oil. Dissolved free base in ethyl acetate, and added one equivalent of maleic acid dissolved in ethanol. Added ether to precipitate maleate salt.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:32]=[CH:33][C:34]([NH2:37])=[N:35][CH:36]=1)(=[O:24])=[O:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15](=[O:17])[NH:37][C:34]3[CH:33]=[CH:32][C:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[S:22]([CH3:21])(=[O:24])=[O:23])=[CH:36][N:35]=3)[N:13]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Reactant: CS(=O)(=O)c1ccccc1-c1ccc(N)nc1
Agent: Cl
Product: CS(=O)(=O)c1ccccc1-c1ccc(NC(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)nc1

Procedure:
In analogy to example 1.3, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) was coupled with 5-(2-methanesulfonyl-phenyl)-pyridin-2-ylamine, hydrochloride (CAS 209959-31-9) to give 4-chloro-N-(4-{[5-(2-methanesulfonyl-phenyl)-pyridin-2-ylcarbamoyl]-methyl}-thiazol-2-yl)-benzamide, using general procedure C. White solid. MS 527.2 ([M+H]+)
Reaction SMILES: [OH:1][C@@H:2]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)[C@H:3]([CH3:16])[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].CS(O[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)(=O)=O>>[CH:30]1([CH2:29][O:23][C:19]2[CH:18]=[C:17]([C@H:2]([OH:1])[C@H:3]([CH3:16])[CH2:4][N:5]3[C:13](=[O:14])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6]3=[O:15])[CH:22]=[CH:21][CH:20]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: C[C@H](CN1C(=O)c2ccccc2C1=O)[C@@H](O)c1cccc(O)c1
Reactant: CS(=O)(=O)OCC1CCCC1
Product: C[C@H](CN1C(=O)c2ccccc2C1=O)[C@@H](O)c1cccc(OCC2CCCC2)c1

Procedure:
2-((2R,3R)-3-Hydroxy-3-(3-hydroxyphenyl)-2-methylpropyl)isoindoline-1,3-dione (82) was reacted with cyclopentylmethyl methanesulfonate following the method described for Example 72 to give 2-((2R,3R)-3-(3-(cyclopentylmethoxy)phenyl)-3-hydroxy-2-methylpropyl)isoindoline-1,3-dione as a colorless oil. Yield (0.295 g, 61%). 1H NMR (400 MHz, DMSO-d6) δ 7.75-7.80 (m, 4H), 7.13 (t, J=7.8 Hz, 1H), 6.83-6.88 (m, 2H), 6.66-6.69 (m, 1H), 5.30 (d, J=4.5 Hz, 1H), 4.38-4.41 (m, 1H), 3.77 (d, J=7.0 Hz, 2H), 3.70 (dd, J=5.5, 13.7 Hz, 1H), 3.40 (dd, J=9.4, 13.7 Hz, 1H), 2.20-2.30 (m, 2H), 1.70-1.78 (m, 2H), 1.46-1.62 (m, 4H), 1.26-1.34 (m, 2H), 0.65 (d, J=6.85 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:17][CH:18]=[CH:19][N:20]=3)[C@@H:14]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:13][C@@:12]2([CH2:34][CH:35]([CH3:37])[CH3:36])[C:27]([O:29]C(C)(C)C)=[O:28])=[O:10])=[CH:7][C:6]=1[CH3:40])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:17][CH:18]=[CH:19][N:20]=3)[C@@H:14]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:13][C@@:12]2([CH2:34][CH:35]([CH3:36])[CH3:37])[C:27]([OH:29])=[O:28])=[O:10])=[CH:7][C:6]=1[CH3:40])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C(=O)N2[C@@H](c3nccs3)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)OC(C)(C)C)ccc1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2[C@@H](c3nccs3)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)O)ccc1C(C)(C)C

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1. The compound was purified by SPE (C18) eluting with water followed by acetonitrile to afford the title compound as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([OH:11])[NH:8][N:7]=1)=[O:5])[CH3:2].[C:12](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH3:12])[NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(O)[nH]n1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OC)[nH]n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 38 %

Procedure:
5-Hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester (300 mg, 1.92 mmol) was dissolved in anhydrous N,N-dimethylformamide (DMF) (35 ml) and cesium carbonate (626 mg, 1.92 mmol) was added. The resulting suspension was treated with iodomethane (120 μl, 273 mg, 1.92 mmol) and stirred for 12 h at room temperature. The reaction mixture was quenched with saturated potassium hydrogen sulfate solution and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml). The extract was dried over sodium sulfate, evaporated and the crude product was purified by column chromatography on silica gel. Elution with ethyl acetate/n-heptane (1:3) yielded 124 mg (38%) of a white solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.CN(C=O)C>C1(C)C=CC=CC=1.[Cu]>[C:3]1([C:4]2[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:2]=1
Reactant: O=Cc1ccccc1Br
Agent: [Cu]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
2-bromo benzaldehyde (266 g, 1.35 mol) was heated to 185° C. and then copper powder (201.16 g, 3.17 mmol) was added portion wise to the liquid. After 30 mins, DMF (100 mL) was added to the solution and heating maintained for a further 8 h. After cooling to room temperature the product was dissolved in toluene and filtered through celite. Purification via column chromatography eluting with Hexane:EtOAc (6:1) gave a foam. Recrystallisation from Et2O/hexane gave 73.27 g (50% yield); 1H NMR (CDCl3) 9.81 (2H, s), 8.04 (2H, d, J 7.6), 7.65 (2H, dt, J 1.2, 7.2), 7.58 (2H, t, J 7.2), 7.34 (2H, d, J 7.6); 13C NMR 114.05, 119.97, 121.68, 123.54, 140.54.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH:2]=1.[Mg+].[C:18]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:23])[CH2:19]C([O-])=O>O1CCCC1>[O:14]=[C:12]([C:11]1[CH:10]=[CH:9][C:8]([O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:16][CH:15]=1)[CH2:19][C:18]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]
Reactant: O=C(O)c1ccc(Oc2cccnc2)cc1
Reactant: O=C([O-])CC(=O)OCc1ccccc1
Agent: [Mg+]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1ccc(Oc2cccnc2)cc1)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 4-(pyridin-3-yloxy)benzoic acid (11.2 g, 52.0 mmol) in tetrahydrofuran (160 ml) was added N,N′-carbonyldiimidazole (9.28 g, 57.3 mmol), and the mixture was heated under reflux for 3 hrs. After cooling the reaction solution to room temperature, monobenzyl malonate magnesium salt (11.7 g, 28.6 mmol) was added, and the mixture was heated under reflux for 2 hrs. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the objective substance (14.1 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].[I:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1>>[I:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[N:6]([C@@H:11]3[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[CH:5]=2)=[O:40])=[CH:37][CH:36]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(Cl)c1ccc(I)cc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc(I)cc3)c3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole obtained in Example 1-(3) and 4-iodobenzoyl chloride were treated in a manner similar to Example 2-(4) to give 4-chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indol-3-yl 4-iodophenyl ketone as a colorless powder. APCI-Mass m/Z 711/713 (M+H). 1H-NMR (DMSO-d6) δ 1.69 (s, 3H), 1.97 (s, 3H), 1.98 (s, 3H), 2.04 (s, 3H), 4.10 (d, J=4.0 Hz, 2H), 4.29 (m, 1H), 5.28 (t, J=9.8 Hz, 1H), 5.53 (t, J=9.6 Hz, 1H), 5.73 (t, J=9.2 Hz, 1H), 6.33 (d, J=9.0 Hz, 1H), 7.29 (d, J=7.7 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.57 (d, J=8.3 Hz, 2H), 7.79 (d, J=8.4 Hz, 1H), 7.94 (d, J=8.3 Hz, 2H), 8.17 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH2:12]O)=[C:7]([CH3:14])[C:6]([O:15][CH3:16])=[C:5]([O:17][CH3:18])[C:4]=1[O:19][CH3:20].C(N(CC)CC)C.CS(Cl)(=O)=O.[I-:33].[Na+]>C(Cl)Cl.CC(C)=O>[CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][I:33])=[C:7]([CH3:14])[C:6]([O:15][CH3:16])=[C:5]([O:17][CH3:18])[C:4]=1[O:19][CH3:20]
Reactant: COc1c(C)c(CCCCO)c(OC)c(OC)c1OC
Reactant: [I-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COc1c(C)c(CCCCI)c(OC)c(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
In anhydrous methylene chloride (300 ml) were 1,2,3,4-tetramethoxy-5-methyl-6-(4-hydroxybutyl)benzene (28.2 g, 0.1 mole) as obtained in Reference Example 59 and triethylamine (16 g, 0.15 mole), and the solution was cooled to 0° C. A solution of methanesulfonyl chloride (14.3 g, 0.12 mole) in methylene chloride (30 ml) was added dropwise to the solution, followed by stirring for 30 minutes. The reaction solution was washed with water, dilute aqueous phosphoric acid and water, successively, and the organic layer was dried (over MgSO4) and freed of the solvent. Acetone (300 ml) and sodium iodide (39.0 g, 0.26 mole) were added to the residue, and the mixture was warmed at 50° C. for 2 hours. After the completion of the reaction, acetone was distilled off under reduced pressure, and isopropyl ether (300 ml) and water (200 ml) were added to the residue for extraction of the product. The organic layer was washed with 5% aqueous sodium hydrosulfite and water, successively, and dried (over MgSO4), followed by distilling off the solvent under reduced pressure. The residue was chromatographed on a column of silica gel, and developing with isopropyl ether-hexane (1:1) yielded 1,2,3,4-tetramethoxy-5-methyl-6-(4-iodobutyl)benzene (37.0 g, 94%).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21]O)[CH:16]=[CH:17][CH:18]=3)[CH:10]=[C:9]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:39]([N:41](CC)[CH2:42]C)C.CS(Cl)(=O)=O>C(Cl)Cl>[CH3:39][N:41]([CH3:42])[CH2:21][CH2:20][CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11]2[CH:10]=[C:9]([N:23]3[CH2:24][CH2:25][N:26]([C:29]4[C:34]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:27][CH2:28]3)[N:8]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:12]=2)[CH:14]=1
Reactant: CCN(CC)CC
Reactant: OCCCc1cccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(N3CCOCC3)n2)c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CN(C)CCCc1cccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(N3CCOCC3)n2)c1
Reaction time: 2 h

Procedure:
Dissolve 3-(3-{2-morpholin-4-yl-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-4-yl}-phenyl)-propan-1-ol (104 mg, 0.197 mmol) in methylene chloride and add triethylamine (55 μL, 0.394 mmol). Bring the solution to 0° C. with an ice bath and add methanesulfonyl chloride (23 μL, 0.394 mmol) dropwise. After 2 hours, dilute the reaction with additional methylene chloride and wash the mixture with brine (1×) in a separatory funnel. Dry the organic layer (Na2SO4) and concentrate under reduced pressure to give the title compound, which was used without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH3:4].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(O)(=O)C>CN(C=O)C>[CH2:3]([O:5][C:6](=[O:16])[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])=[CH:10][CH:9]=1)[CH3:4]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)C(=O)OCC)cc1
Temperature: 25 °C
Yield: 84 %

Procedure:
To 0.325 g (8.1 mmol) of a 60% oil dispersion of NaH suspended in 15 ml of anhydrous DMF and stirred under an argon atmosphere at room temperature was added 1.5 g (7.73 mmol) of 4-hydroxyalpha-oxobenzeneacetic acid ethyl ester. The reaction mixture was stirred at room temperature for 20 minutes and a solution of 3.2 g (9.66 mmol) of 1-bromooctadecane in 20 ml of anhydrous DMF was added dropwise over 15 minutes. After stirring at reflux for 16 hours, 5 ml of acetic acid was added and the solvent was removed at reduced pressure. Water was added to the residue and the product was extracted with methylene chloride. The dried extract was concentrated at reduced pressure and the solid residue was purified by HPLC using 50% methylene chloride-hexane to give 2.9 g (84% yield, mp 46°-48°) of 4-(octadecyloxy)-alpha-oxobenzeneacetic acid ethyl ester.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]2[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:24](OC)([O:27]C)[O:25][CH3:26])=O)(C)(C)C.[ClH:31]>CO>[ClH:31].[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]2[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:24]([O:25][CH3:26])=[O:27]
Reactant: COC(OC)(OC)c1nc2ccc(C(=O)O)cc2n1CCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)c1nc2ccc(C(=O)O)cc2n1CCCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 1-{3-[(tert-Butoxycarbonyl)amino]propyl}-2-(trimethoxymethyl)-1H-benzimidazole-6-carboxylic acid (Intermediate A, 20 g, 68.7 mmol) in methanol (200 mL) is added conc. HCl (5 mL) and the reaction mixture is stirred at room temperature for 1 h. The solvent is evaporated to afford the title compound as a solid (20 g, 92%) which is used in the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[NH:16][C:15]([CH3:20])([CH3:19])[NH:14]1.C(O)(=O)C(C)=[O:23].O>O1CCOCC1.S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[NH:16][C:19](=[O:23])[C:15]([CH3:20])=[N:14]1
Reactant: CC(=O)C(=O)O
Reactant: CC(C)Oc1cc(N2NC(C)(C)NC2=O)c(Cl)cc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: Cc1nn(-c2cc(OC(C)C)c(Cl)cc2Cl)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
To a stirred mixture of 1.0 g (0.0031 mole) of 1-[2,4-dichloro-5-(1-methylethoxy)phenyl]-3,3-dimethyl-1,2,4-triazolidin-5-one in 10 mL of p-dioxane was added 0.29 g (0.0031 mole) of pyruvic acid and one drop of concentrated sulfuric acid. The mixture was stirred at room temperature for one hour, then an additional 0.25 g (0.0029 mole) of pyruvic acid was added. The mixture was heated at 90° C. for three hours, then poured into water. The mixture was extracted with ethyl acetate, and the solvent was evaporated from the extract under reduced pressure to give an oil. The oil was purified by thin-layer preparative chromatography on silica gel, eluting with ethyl acetate:heptane (1:1). Extraction of the appropriate bands gave 0.6 g of 2-[2,4-dichloro-5-(1-methylethoxy)phenyl]-6-methyl-1,2,4-triazine-3,5(2H,4H)-dione as a solid (mp 163°-164° C.), Compound 10 in the tables.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:15]([CH3:21])=[N:16][O:17][C:18]=2[CH:19]=O)=[O:7])=[CH:4][CH:3]=1.[C:24]1([CH:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[CH:30](/[N:31]=[CH:19]/[C:18]1[O:17][N:16]=[C:15]([CH3:21])[C:14]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]([C:5]1[CH:22]=[CH:23][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:7])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: Cc1noc(C=O)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1noc(/C=N/C(c2ccccc2)c2ccccc2)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a round bottomed flask was added 4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazole-5-carbaldehyde (3.86 g, 11.85 mmol), DCM (50 mL), diphenylmethanamine (2.143 mL, 12.44 mmol), and Na2SO4 (5.05 g, 35.5 mmol). The reaction was stirred at room temperature overnight before being filtered and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford the titled compound (5.61 g, 11.43 mmol) as pale yellow foam. LC/MS m/z 491 [M+H]+.
Reaction SMILES: S([N:11]1[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]1)(C1C=CC(C)=CC=1)(=O)=O.[C:17]1(=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])O1>CN(C=O)C.C(#N)C.O>[NH:11]1[CH:15]=[C:14]([N:16]2[C:19](=[O:26])[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]2=[O:27])[CH:13]=[N:12]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(N)cn2)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1cn[nH]c1
Yield: 92.3 %

Procedure:
1-tosyl-1H-pyrazol-4-amine (example 9-1b) (3 g, 12.7 mmol) and isobenzofuran-1,3-dione (1.9 g, 13 mmol) were stirred in DMF/Acetonitrile (1/1) (20 mL) at 100° C. for 1 hour. The mixture was cooled and diluted with H2O. The precipitate was collected by filtration, washed with additional water followed by ethyl acetate and hexanes. The solid product was dried under high vacuum to afford 2-(1H-pyrazol-4-yl)isoindoline-1,3-dione (2.5 g, 92%) as a yellow solid. MS M+H calculated 214.1. found 214.1. 1H NMR (CDCl3, 400 MHz), δ 7.93-8.10 (m, 6H), 13.03 (bs, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[F:18][C:17]([F:19])([F:20])[CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1
Reactant: FC(F)(F)COc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: Oc1ccc(OCC(F)(F)F)cc1

Procedure:
A solution of 1-benzyloxy-4-(2,2,2-trifluoroethoxy)benzene (Description 18, 5 g) and palladium (10% on carbon; 0.1 g) in methanol (50 ml) was hydrogenated at 50 psi for 12 h. The solution was filtered and the solvent removed in vacuo to give the title compound as a colourless solid m.p. 60-64° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([S-:10])=[N:2]1.[K+].[OH-].[K+].Cl[CH:15]([F:17])[F:16]>O1CCOCC1.O>[F:16][CH:15]([F:17])[S:10][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][N:2]=1
Reactant: FC(F)Cl
Reactant: [S-]c1nsc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)Sc1nsc2ccccc12
Temperature: 0 °C

Procedure:
4.1 g (0.02 mol) Potassium 1,2-benzoisothiazole-3-thiolate was suspended in 25 ml dioxane and treated with a solution of 5.6 g (0.10 mol) potassium hydroxide in 9 ml water. At a temperature of 60°-70° C., a slow stream of chlorodifluoromethane was passed through over 30 minutes. The mixture was added to 500 ml ice/water and extracted several times with ethyl acetate. The organic phase was dried over magnesium sulphate, filtered and concentrated. The residual oil was purified by silica gel column chromatography (eluent: hexane/diethyl ether 9:1).