Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH:3]=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)([O-:16])=[O:15].C(OCC)(=O)C.[OH-].[Na+]>ClC1C=CC=CC=1>[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH:3]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)OC(=O)c1cc(Cl)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: CC(C)OC(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Temperature: 120 °C
Reaction time: 23 h
Yield: 45.3 %

Procedure:
2-Propyl 4-chloropyridine-2-carboxylate (3.13 g) was dissolved in chlorobenzene (9.5 ml). 4-Nitrophenol (3.28 g) was added thereto, followed by stirring at 120° C. for 23 hr. 4-Nitrophenol (1.09 g) was added thereto, followed by stirring at 120° C. for 3 hr. The reaction mixture was allowed to cool down to room temperature. Ethyl acetate (50 ml) and a 1N aqueous solution of sodium hydroxide (50 ml) were added to the reaction mixture and stirred. Insoluble matter was precipitated, which was dissolved by addition of THF (50 ml). The organic layer was separated, washed with a 1N aqueous solution of sodium hydroxide (50 ml×3) and brine (50 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:1 to 1:1). Fractions containing the target compound were concentrated under reduced pressure, and dried under reduced pressure to provide the titled compound as pale brown crystals (2.147 g, 45%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[N+:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1)([O-:26])=[O:25]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][N:13]([CH2:31][C:30]4[CH:33]=[CH:34][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][CH:29]=4)[CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c3c(c(=O)oc2c1)CN(Cc1ccc([N+](=O)[O-])cc1)CC3
Temperature: 90 °C
Yield: 46.6 %

Procedure:
A mixture of 8-methoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one (1.2 g, 5.2 mmol), potassium carbonate (0.69 g, 5.0 mmol), and 4-nitrobenzyl bromide (1.1 g, 5.1 mmol) in 15 mL of N,N-dimethylformamide is heated at 90° C. for 4 hours. The cooled reaction mixture is evaporated, and the residue partitioned between ethyl acetate and brine. The organic layer is dried (anhydrous magnesium sulfate) and evaporated. Recrystallization of the residue from ethyl acetate gives 0.87 g (47%) of product; mp 176°-178° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][C@@H:13]([CH2:12][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc2c(c1)O[C@H](CN1CCCCC1)CO2
Temperature: 120 °C

Procedure:
A mixture of [(2S)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.5 g, 1.1 mmol), piperidine (1 ml) and ACN (3 ml) was heated under microwave radiation at 120° C. for 20 min. Purification on SCX-3 column (TEA/MeOH) and by flash chromatography, first with (DCM/MeOH) as eluent and then (EtOAc/MeOH) as eluent. Yield: 0.2 g, 72%. The amine was converted to the hydrochloric acid salt and crystallized from EtOH/Et2O. M.p. 226° C. MS m/z (rel. intensity, 70 eV) 311 (M+, 1), 310 (M+, 1), 99 (7), 98 (bp), 79 (2), 55 (4). [α]=+62° (MeOH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:9][Si:10]([CH3:12])([CH3:11])[C:13]1[CH:3]=[CH:4][C:5]([CH3:8])=[C:6]([C:7]#[CH:2])[CH:14]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Product: C#Cc1cc([Si](C)(C)C)ccc1C
Temperature: 80 °C
Yield: 96.3 %

Procedure:
Under an argon atmosphere, 33 g (0.193 mol) of 4-bromotoluene, 2.7 g (3.85 mmol) of bis(triphenylphosphine)palladium(II) dichloride and 0.735 mg (3.85 mmol) of copper Iodide were put into a 1 L 3-necked flask equipped with a stirrer, thermometer and reflux condenser, and dissolved in 500 ml of diisopropylamine. 37.9 g (0.385 mol) of trimethylsilyl acetylene was slowly dropped into the resluting solution at room temperature. The reaction mixture was slowly heated to 80° C. and refluxed for 12 hours. After the reaction was completed, the reaction mixture was cooled down to room temperature. The precipitated salt was filtered off, and then the solvent was removed under a reduced pressure. The residue was dissolved in methylene chloride. The organic solution was washed with water several times and then dried with anhydrous magnesium sulfate. The solvent was removed to obtain liquid, which was purified by silica gel column chromatography using hexane as an eluent, to give 35 g (99.3% yield) of pale brown viscous liquid.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:13]=[O:14])[C:9](F)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1.[CH3:15][C@H:16]1[O:21][C@H:20]([CH3:22])[CH2:19][NH:18][CH2:17]1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:13]=[O:14])[C:9]([N:18]3[CH2:17][C@@H:16]([CH3:15])[O:21][C@H:20]([CH3:22])[CH2:19]3)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1
Reactant: C[C@@H]1CNC[C@@H](C)O1
Reactant: O=Cc1cc2c(Cl)noc2c(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H]1CN(c2c(C=O)cc3c(Cl)noc3c2F)C[C@@H](C)O1
Temperature: 25 °C

Procedure:
A solution of 3-chloro-6,7-difluorobenzo[d]isoxazole-5-carbaldehyde (Intermediate 532, 3.32 g, 10.6 mmol), (2R,6R)-2,6-dimethylmorpholine (Purchased from BASF®, 2.64 g, 22.9 mmol) and DIEA (4 ml, 22.9 mmol) in acetonitrile (20 ml) was heated at reflux for 3 hours. The mixture was cooled to room temperature before being partitioned between EtOAc and 1N HCl. The EtOAc was separated and washed with brine. The combined aqueous layers were extracted with EtOAc, which was washed with brine. The combined EtOAc was dried (MgSO4) and concentrated to give an oil that was chromatographed on silica gel (50% hexanes in CH2Cl2 followed by gradient elution to 100% CH2Cl2 followed by gradient elution to 5% EtOAc in CH2Cl2) to give 2 materials in order of elution: the first material (265 mg) is consistent with starting material and the second (3.33 g) with desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@H:20](OS(C)(=O)=O)[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C@@H:29]([CH2:39][CH3:40])[C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:52][C:53]([CH3:59])([CH3:58])[CH2:54][CH2:55][CH2:56][SH:57].O>CC#N>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([S:57][CH2:56][CH2:55][CH2:54][C:53]([OH:52])([CH3:59])[CH3:58])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C@@H:29]([CH2:39][CH3:40])[C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])=[O:31])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC[C@@H](C(=O)OCC[Si](C)(C)C)c1ccccc1CC[C@@H](OS(C)(=O)=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: CC(C)(O)CCCS
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CC[C@@H](C(=O)OCC[Si](C)(C)C)c1ccccc1CC[C@H](SCCCC(C)(C)O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 9.2 %

Procedure:
A suspension of mesylate of Step 6 (4.4 g, 66 mmol) and Cs2CO3 (4.3 g, 132 mmol) in CH3CN (44 mL) was degassed and then purged with N2. The suspension was then cooled to 0° C. and 4-hydroxy-4-methyl-1-pentanethiol (Step 7, 1.8 mL, 132 mmol) was added. The reaction was stirred for 30 min at 0° C. followed by 3 h at r.t. Water (50 mL) was then added and the product was extracted with EtOAc. The organic layer was washed with H2O and saturated NaCl solution. The solvent was removed under vacuum and the crude product was purified by flash chromatography (1:20 and 1:10 EtOAc:toluene) to give the title compound as an off-white foam (4.25 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]2)[C:5]1=[O:24].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.C(N(CC)CC)C>C1COCC1>[N:1]1([CH2:2][CH2:3][N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]3([C:16]4=[CH:17][C:18]5[O:22][CH2:21][O:20][C:19]=5[CH:23]=[C:15]4[O:14][CH2:13]3)[C:5]2=[O:24])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Reactant: BrCCCCCBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1N(CCN2CCCCC2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
A mixture of 1′-(2-aminoethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.20 g, 0.62 mmol), 1,5-dibromopentane (0.08 mL, 0.62 mmol) and triethyl amine (0.17 mL, 1.23 mmol) in THF (10.0 mL) was refluxed for 15 hrs and concentrated in vacuo to dryness. The residue was subjected to flash chromatography eluting with 10% methanol in ethyl acetate to give 1′-(2-piperidin-1-ylethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, which was treated with 4.0 M HCl in dioxane to give the title compound (28%): mp >240° C.; 1H NMR (300 MHz, CD3OD) δ 7.40 (t, 1H), 7.27-7.11 (m, 3H), 6.51 (s, 1H), 6.17 (s, 1H), 5.86 (s, 2H), 4.91 (d, 1H), 4.71 (d, 1H), 4.40-4.13 (m, 2H), 3.95-3.84 (m, 1H), 3.66-3.37 (m, 3H), 3.14-2.96 (m, 2H), 2.06-1.45 (m, 6H); 13C NMR (75 MHz, CD3OD) δ 180.4, 157.5, 150.5, 143.8, 142.5, 133.9, 130.3, 125.3, 125.1, 120.6, 110.2, 103.9, 102.9, 94.2, 81.4, 59.7, 55.4, 54.9, 53.9, 36.4, 24.2, 22.6; MS (ES+) m/z 393 (M+1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[N:4]=1.[ClH:12].[H][H]>C(O)(C)C.[Pd]>[ClH:12].[F:11][C:2]([F:1])([F:10])[CH:3]1[NH:4][C:5]([NH2:9])=[N:6][CH2:7][CH2:8]1
Reactant: Nc1nccc(C(F)(F)F)n1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: NC1=NCCC(C(F)(F)F)N1

Procedure:
To a solution of 10 g (45.11 mmol) of 4-trifluoromethyl-pyrimidin-2-ylamine and 0.065 g of palladium 10 wt. % on activated carbon in 5 ml of isopropanol was added 45 ml of a solution of hydrochloric acid in isopropanol (5–6 N). The mixture was shaken at 40° C. under hydrogen pressure of 4 atmospheres until hydrogen uptake ceased. The catalyst was removed by filtration and washed with isopropanol. The filtrate was evaporated to dryness to afford 12.14 g of pure product as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH:12]1[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:25]O>>[N:11]1([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:16][CH2:15][O:14][CH2:13][CH:12]1[C:17]([O:19][CH3:25])=[O:18]
Reactant: CO
Reactant: O=C(O)C1COCCN1C(=O)OCc1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)C1COCCN1C(=O)OCc1ccccc1
Temperature: 50 °C

Procedure:
4-(Benzyloxycarbonyl)morpholine-3-carboxylic acid (crude material, 21.2 g, about 75 mmol) was dissolved in methanol (250 ml). Sulfuric acid (12.01 ml, 225 mmol) was added slowly with vigorous stirring. An exotherm was noticed and the temperature rose to 34° C. after the addition. Once the addition was complete, reaction solution was heated to 50° C. for 18 hours. The reaction mixture was cooled to room temperature and concentrated to remove most of the methanol. EtOAc (500 ml) was added and the organic solution was washed with water (150 ml), saturated sodium bicarbonate solution (100 ml) and water (150 ml). The organic solution was then concentrated to give a residue which was purified by silica gel column (330 g silica gel, hexanes/EtOAc 5:1) to afford 15.9 gram of 4-benzyl 3-methyl morpholine-3,4-dicarboxylate as clear oil. 1H NMR (400 MHz, CDCl3) δ=3.28-3.57 (m, 2H), 3.67 (m, 1H), 3.57-3.96 (m, 5H), 4.4 (dd, 1H), 4.61 (dd, 1H), 5.19 (m, 2H), 7.32-7.4 (m, 5H)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[F:9][C:5]1[CH:4]=[C:3]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[C:2]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[C:27]([O:28][CH3:29])[CH:26]=2)=[CH:7][C:6]=1[F:8]
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2cc(F)c(F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1OC

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene (Example 18, Step 2) was reacted with 3,4-dimethoxyphenyboronic acid (step 1) to give 1,2-difluoro-4-(3,4-dimethoxypheny)-5-[4(methylsulfonyl)phenyl]benzene as a colorless solid: mp 140.0-141.0° C.; NMR (CDCl3) δ 3.04 (s, 3H), 3.61 (s, 3H), 3.86 (S, 3H), 6.48 (d, J=2 Hz, 1H), 6.65 (dd, J=2, 8 Hz, 1H), 6.75 (d, J=8 Hz, 1H), 7.17-7.29 (m, 2H), 7.31 (d, J=8 Hz, 2H), 7.81 (d, J=8 Hz, 2H); MS (FAB) m/z 411 (M+Li)+; HRMS calc'd for M+ 404.0894, found 404.0893. Anal. Calc'd for C21H18F2O4S (0.24 H2O): C, 61.70; H, 4.51. Found: C, 61.69; H, 4.56.
Reaction SMILES: Cl.[CH3:2][NH2:3].C[Al](C)C.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]([NH:3][CH3:2])=[NH:15])=[CH:12][CH:11]=1
Reactant: COc1ccc(C#N)cc1
Reactant: CN
Agent: C[Al](C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CNC(=N)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methylamine hydrochloride (2.28 g, 33.8 mmol) was suspended in toluene (16 ml). After cooling the resulting mixture to 0° C., trimethylaluminum (2M in toluene) was added drop-wise under Ar, followed by warming the mixture to r.t and stirring for 2 h. To this mixture was then added a solution of 4-methoxybenzonitrile in toluene (16 ml), followed by stirring at 80° C. for 24 h. The reaction mixture was cooled to r.t. and slowly poured in to a slurry of silica gel (10 g) in CHCl3 (75 ml). The slurry was stirred at r.t for 15 minutes and filtered using MeOH. The filtrate was concentrated. The isolated residue was dissolved in water (50 ml) and extracted with CHCl3. The combined organic phase was washed with brine, dried (Na2SO4), filtered and concentrated in-vacuo, to isolate the title compound (1.25 g). 1H-NMR (DMSO-d6): 7.68 (d, 2H), 6.91 (dd, 2H), 6.33 (br. s, 2H), 3.77 (s, 3H), 2.77 (s, 3H)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:7][C:6]=1[NH:18][C:19](=[O:37])[CH2:20][CH:21]([C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1[O:35][CH3:36])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.CCCCCC>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][C:6]=1[NH:18][C:19](=[O:37])[CH2:20][CH:21]([C:27]1[C:28]([O:35][CH3:36])=[CH:29][CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(CCC(=O)OCC)ccc1C(C)(C)C)c1c(OC)cccc1OC
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCC(CC(=O)Nc1cc(CCC(=O)O)ccc1C(C)(C)C)c1c(OC)cccc1OC

Procedure:
Following a similar procedure to that described in Preparation 77, but using N-[2-t-butyl-5-(2-carboethoxyethyl)phenyl]-3-(2,6-dimethoxyphenyl)octanamide (prepared as described in Preparation 86), the title compound was obtained as colorless crystals, melting at 52°-53° C. (from methylene chloride-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C:8]2[O:12][N:11]=[C:10]([CH2:13][S:14][C:15]3[N:19]([CH2:20][CH2:21][OH:22])[C:18]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[N:17][N:16]=3)[N:9]=2)[CH:7]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>CN(C=O)C.N1C=CC=CC=1>[CH3:29][S:30]([O:22][CH2:21][CH2:20][N:19]1[C:18]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[N:17][N:16]=[C:15]1[S:14][CH2:13][C:10]1[N:9]=[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:28])[O:12][N:11]=1)(=[O:32])=[O:31]
Reactant: OCCn1c(SCc2noc(-c3cc(Cl)ccc3F)n2)nnc1-c1cccs1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCn1c(SCc2noc(-c3cc(Cl)ccc3F)n2)nnc1-c1cccs1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-[3-({[5-(5-chloro-2-fluorophenyl)-1,2,4-oxadiazol-3-yl]methyl}thio)-5-(2-thienyl)-4H-1,2,4-triazol-4-yl]ethanol in a mixture of DMF (1 ml) and pyridine (0.5 ml) was added methanesulfonyl chloride (20 uL). The mixture was stirred at r.t. for 24 h before poured onto water (10 ml). The crude product was filtered off and purified by chromatography on silica gel using 0-5% MeOH in DCM as eluent to give 43 mg of the title compound, which was used directly in the next step.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:24](OC)[N:25]([CH3:27])[CH3:26].O>CN(C)C=O>[CH3:24][N:25]([CH3:27])/[CH:26]=[CH:2]/[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(C)=O)cc2)CC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)/C=C/N(C)C)cc2)CC1
Temperature: 25 °C

Procedure:
The product from Example 26A (2.14 g, 7.42 mmol) and N,N-dimethylformamide dimethylacetal (1.42 g, 11.9 mmol) in N,N-dimethylformamide (20 mL) were heated at 100° C. for 16 h. The solution was cooled to room temperature, and water (20 mL) was added over a period of 10 min. The precipitate was collected by filtration, washed with water (3×20 mL), and dried in vacuo at 50° C. for 24 h to give crude product. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.11-1.21 (m, 5H), 1.43-1.55 (m, 2H), 1.63-1.82 (m, 5H), 2.22 (d, J=6.76 Hz, 2H), 2.43-2.47 (m, 1H), 2.90 (s, 3H), 3.12 (s, 3H), 4.07 (q, J=7.06 Hz, 2H), 5.79 (d, J=12.27 Hz, 1H), 7.27 (d, J=8.59 Hz, 2H), 7.67 (d, J=12.27 Hz, 1H), 7.79 (d, J=8.59 Hz, 2H); MS (ESI) m/z 344.1.0 [M+H]+.
Reaction SMILES: C1([CH:7]([S:12]C(C2C=CC=CC=2)C=C(C)C)[CH:8]=[C:9]([CH3:11])[CH3:10])C=CC=CC=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)O.[CH:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH3:10][C:9]1([CH3:11])[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[S:12][CH2:7][CH2:8]1
Reactant: CC(C)=CC(SC(C=C(C)C)c1ccccc1)c1ccccc1
Reactant: c1ccccc1
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1(C)CCSc2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 15.48 g (86.824 mmol) of phenyl-3-methylbut-2-enylsulfide (from Example 1) in 160 ml benzene were added successively 12.6 g (88.767 mmol) of phosphorus pentoxide and 11 ml of 85% phosphoric acid. This solution was refluxed with vigorous stirring under argon for 20 hours, then cooled to room temperature. The supernatant organic layer was decanted and the syrupy residue extracted with 3×50 ml ether. Organic fractions were combined and washed with water, saturated NaHCO3 and saturated NaCl solution and then dried (MgSO4). Solvent was removed in vacuo and the residue purified by kugelrohr distillation (80° C., 0.5 mm) to give the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][OH:14])[C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:35]1[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[CH:37][CH:36]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][N:2]([CH2:12][CH2:13][O:14][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[CH:37][CH:36]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CN(CCO)c1nc2ccccc2o1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(CCOc1ccc(C=O)cc1)c1nc2ccccc2o1
Temperature: 25 °C

Procedure:
To a solution of 2-[N-methyl-N-(2-benzoxazolyl)amino]ethanol (9.6 g), triphenylphosphine (13.1 g) and 4-hydroxybenzaldehyde (6.1 g) in dry tetrahydrofuran (150 ml) was added dropwise a solution of diethyl azodicarboxylate (9.0 g) in dry tetrahydrofuran (30 ml), under a blanket of nitrogen with stirring at room temperature. The solution was stirred overnight at room temperature following which the solvent was removed under reduced pressure. The residue was dissolved in diethyl ether (300 ml), filtered and the ether solution was washed with dilute sodium hydroxide solution (200 ml), saturated brine (200 ml), dried (MgSO4), filtered and the solvent evaporated. The title compound (mp 97°-98° C.) was obtained after chromatography on silica-gel, eluting with dichloromethane.
Reaction SMILES: CC(OC1CCCCO1)(C)C#C[C:5](=[O:11])[C:6]([O:8]CC)=[O:7].[C:20]1([CH:26]2[CH2:30][S:29][C:28](=[S:31])[S:27]2)[CH:25]=CC=C[CH:21]=1.C(Cl)Cl>C1(C)C(C)=CC=CC=1>[CH3:25][C:20]1([CH3:21])[C:26]2[S:27][C:28](=[S:31])[S:29][C:30]=2[C:5](=[O:11])[C:6](=[O:7])[O:8]1
Reactant: S=C1SCC(c2ccccc2)S1
Reactant: CCOC(=O)C(=O)C#CC(C)(C)OC1CCCCO1
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: CC1(C)OC(=O)C(=O)c2sc(=S)sc21
Temperature: 130 °C

Procedure:
Ethyl 5-methyl-2-oxo-5-(tetrahydro-2H-pyran-2-yloxy)hex-3-ynoate (2) (1.0 g, 3.7 mmol) and 4-phenyl-1,3-dithiolane-thione (2.0 g, 9.3 mmol) were dissolved in xylene (15 mL). The deep yellow solution was heated to 130° C. for ca. 4 h under Ar (the reaction was followed by TLC, eluent: CH2Cl2). The solvent was removed under reduced pressure and purification of the residue by chromatography (silica gel, CH2Cl2) provided 4,4-dimethyl-2-thioxo-4H-[1,3]dithiolo[4,5-c]pyran-6,7-dione (4) as a yellow solid. Yield: 0.44 g (48%). 1H-NMR spectrum in CDCl3 (ppm): 1.88 (s, 6H). 13C-NMR spectrum in CDCl3 (ppm): 205.3, 167.7, 162.6, 157.8, 153.6, 83.2, 31.9. Selected IR (neat, cm−1): 1747, 1681, 1557, 1460. MS-ESI calculated for C7H8O4S2Na [M+Na]+ 268.96; found 268.79.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].[H-].[Na+].[Cl:9][C:10]1[C:11]([N:16]2[CH2:25][CH2:24][C:23]3[C:22]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)=[N:21][C:20](S(C)(=O)=O)=[N:19][C:18]=3[CH2:17]2)=[N:12][CH:13]=[CH:14][CH:15]=1>CN(C=O)C>[F:36][C:33]([F:34])([F:35])[C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:22]2[C:23]3[CH2:24][CH2:25][N:16]([C:11]4[C:10]([Cl:9])=[CH:15][CH:14]=[CH:13][N:12]=4)[CH2:17][C:18]=3[N:19]=[C:20]([O:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[N:21]=2)=[CH:28][CH:29]=1
Reactant: COC(=O)CO
Reactant: CS(=O)(=O)c1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1Cl)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1Cl)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.3 %

Procedure:
Methyl glycolate (31 mg, 0.33 mmol) was dissolved in DMF (dry), NaH (8 mg, 0.31 mmol) was added and stirred at room temperature under an atmosphere of Nitrogen for 30 min. 7-(3-Chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-4-amine (120.0 mg, 0.22 mol) (in 4 mL DMF, dry) was added to the above mixture. The reaction was heated via microwave at 180° C. for 15 minutes. Solvent was removed and the residue was purified by flash chromatography over silica gel to obtain the product as a white solid (25 mg).