Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[O:9][N:8]=1)([CH3:6])[CH2:4][F:5].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[N:30]=[CH:29][N:28]=[C:27]2[O:36][C:37]1[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=1)[NH2:40].C(N(CC)C(C)C)(C)C>C1COCC1>[F:5][CH2:4][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13]([NH:40][C:39]2[CH:41]=[CH:42][CH:43]=[C:37]([O:36][C:27]3[C:26]4[C:31](=[CH:32][C:33]([O:34][CH3:35])=[C:24]([O:23][CH3:22])[CH:25]=4)[N:30]=[CH:29][N:28]=3)[CH:38]=2)=[O:21])[O:9][N:8]=1)([CH3:6])[CH2:2][F:1]
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)no4)c3)c2cc1OC
Temperature: 50 °C
Yield: 57.6 %

Procedure:
A mixture of phenyl 3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-ylcarbamate (0.158 g, 0.5 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.119 g, 0.4 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) was heated at 50° C. for 5 hours. It was quenched with saturated NaHCO3 and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. It was purified by silica gel chromatography with 40-95% EtOAc/hexane as eluants to afford 1-[3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-yl]-3-[3-(6,7-dimethoxyquinazolin-4-yloxy]phenyl)urea as solid (0.115 g, 58%). 1H NMR (300 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.00 (s, 1H), 8.55 (s, 1H), 7.56 (m, 3H), 7.39 (s, 1H), 7.27 (s and d, 2H), 6.24 (s, 1H), 4.73 (m, 2H), 4.56 (m, 2H), 3.99 (s, 3H), 3.98 (s, 3H), 1.30 (s, 3H); LC-MS (ESI) m/z 500 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9])[CH2:2][CH3:3].C(OC)(OC)OC.[C:20]([O:24][C:25](=[O:36])[NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=1)([CH3:23])([CH3:22])[CH3:21].[BH4-].[Na+]>CO>[C:20]([O:24][C:25](=[O:36])[NH:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][NH:9][CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:10][CH2:11][CH3:12])=[CH:32][CH:33]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Reactant: CCCN(CCC)CCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CCCN(CCC)CCCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
The compound (9.25 g) obtained in Example 1-2 was dissolved in anhydrous methanol (200 ml) and then added with trimethyl orthoformate (8.81 ml) and the compound (12.6 g) obtained in Example 23-3. The whole was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. Then, sodium borohydride (2.03 g) was added thereto in an ice bath and the whole was stirred at room temperature for 2 hours. After completion of the reaction, distilled water was added thereto and the whole was stirred for a while. The solution was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (19.3 g) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.[CH3:29][CH:30]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[O:32][CH2:31]1.C(N(C(C)C)CC)(C)C>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:11]([C:4]2[C:5]([C:8]([N:35]3[C:34]4[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=4[O:32][CH2:31][CH:30]3[CH3:29])=[O:9])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:12][O:13][CH3:14])(=[O:17])=[O:16])=[CH:19][C:20]=1[C:25]([F:26])([F:27])[F:28]
Reactant: CC1COc2ccccc2N1
Reactant: COCN(c1cc(Cl)cnc1C(=O)Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Product: COCN(c1cc(Cl)cnc1C(=O)N1c2ccccc2OCC1C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl chloride (50 mg, 0.11 mmol), 3-methyl-3,4-dihydro-2H-benzo[1,4]oxazine (60 mg, 0.40 mmol) and di-isopropylethylamine (DIEA, 0.07 mL, 0.40 mmol) in CH2CL2 (1.5 mL) was stirred at room temperature overnight. The mixture was concentrated to provide 4-chloro -N[5-chloro-2-(3-methyl-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide, which was directly used in the next step without any purification.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.Br[CH:16]=[CH:17][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][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O.O>[CH2:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: CCCCCCCCCCCCCCC=CBr
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C=CC(=O)OCC)cc1
Temperature: 60 °C

Procedure:
A mixture of ethyl p-aminocinnamate, one equivalent of 1-bromohexadecene, one equivalent of anhydrous potassium carbonate in hexamethylphosphoramide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated to provide ethyl 4-hexadecylaminocinnamate. The ester is hydrolyzed with sodium hydroxide in a 1:1 water:ethanol solution at steam bath temperature for 10 hours. The hot solution is then acidified with acetic acid, cooled, filtered and the precipitate is washed with water. Recrystallization from chloroform yields 4-hexadecylaminocinnamic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[I:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>>[I:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:27]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Reactant: Ic1c[nH]cn1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidine (example A.2) (1.31 g, 4.0 mmol) and commercially available 4-iodo-imidazole (0.85 g, 4.4 mmol) according to the general procedure IVa. Obtained as a pink solid (1.88 g, 97%). MS (ISP) 485.3 [(M+H)+]; mp 194° C.
Reaction SMILES: I[CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[N:10]=[N:11][N:12]3[C:17]=2[C:16]2[CH:18]=[CH:19][NH:20][C:15]=2[N:14]=[CH:13]3)[CH2:5][CH2:4]1.[F:21][C:22]([S:25]([O-:27])=[O:26])([F:24])[F:23].[Na+].O>CN(C)C=O>[F:21][C:22]([F:24])([F:23])[S:25]([CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[N:10]=[N:11][N:12]3[C:17]=2[C:16]2[CH:18]=[CH:19][NH:20][C:15]=2[N:14]=[CH:13]3)[CH2:5][CH2:4]1)(=[O:27])=[O:26]
Reactant: O=S([O-])C(F)(F)F
Reactant: IC[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(C[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1)C(F)(F)F

Procedure:
1-[trans-4-(Iodomethyl)cyclohexyl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine (50.0 mg, 0.131 mmol) and sodium trifluoromethylsulfinate (205 mg, 1.31 mmol) in N,N-dimethylformamide (3 mL) were stirred at 100° C. for 26 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2→1/1 (v/v)) and preparative HPLC (Waters XBridge Prep C18 μm ODS, 19×100 mm, acetonitrile/0.1% aqueous formic acid solution=20/80→80/20(v/v)) to give the title compound as a colorless solid (6.30 mg, yield 12%).
Reaction SMILES: [OH2:1].[NH2:2][CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5].[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1.[ClH:26]>O1CCOCC1>[OH2:5].[OH2:1].[ClH:15].[ClH:26].[NH2:2][CH:3]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(CC(N)C(=O)O)cc1
Reactant: Clc1ccnc2ccccc12
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: NC(Cc1ccc(Nc2ccnc3ccccc23)cc1)C(=O)O
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 129.7 %

Procedure:
A mixture of 2-amino-3-(4-aminophenyl)-propionic acid hydrate (0.27 g, 1.5 mmol), 4-chloro-quinoline (0.245 g, 1.5 mmol) and conc. HCl (0.43 g) in dioxane (3 mL) is stirred at 120° C. temperature for 30 min in a tightly closed Pierce glass reaction vial. After cooling the liquid phase is separated and the solid residue is washed with acetonitrile (3×3 mL) and diethyl ether (5 mL) to give the title compound (0.405 g, 65%) as yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]([C:5](=[N:11][O:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:4].[SH:14][CH2:15][CH2:16]O.Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[O:4]1[C:3]([C:5](=[N:11][O:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:2][S:14][CH2:15][CH2:16]1
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Reactant: OCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=NOC)C1=CSCCO1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 29 %

Procedure:
A solution of ethyl 2-chloroacetyl-2-methoxyiminoacetate (65 g.) in dry chloroform (130 ml.) was added to a stirred mixture of 2-mercaptoethanol (25 g.), triethylamino (35 g.) and dry chloroform (70 ml.) at 20° C. over 30 minutes, and stirred at the same temperature for 2.5 hours. After the solution was adjusted to pH 1.0 with 10% hydrochloric acid under ice cooling, the chloroform layer was separated, washed with water twice and dried over magnesium sulfate. The solution was concentrated in vacuo at 40° C. to give yellow oil. The oil was dissolved in toluene (600 ml.), and then p-toluenesulfonic acid (5.5 g.) was added to the toluene solution. The solution was heated under reflux for 2 hours while removing the produced water. The resultant solution was allowed to cool at room temperature and filtered. The filtrate was washed with water (100 ml.) three times, a saturated aqueous solution of sodium bicarbonate (100 ml.) twice and water (100 ml.) twice in turn, and then dried over magnesium sulfate. The solution was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel "Kieselgel 60" [Trademark: manufactured by E. Merck] (1 kg.) and eluted with benzene. After the eluate was concentrated under reduced pressure, the residue was washed with diisopropyl ether and dried to give ethyl 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetate (syn isomer, 21 g.), pale yellow crystals, mp. 64° to 66° C.
Reaction SMILES: [Na].[K].[C:3]1(=[O:18])[N:7]([CH2:8][S:9](O)(=[O:11])=[O:10])[C:6](=[O:13])[C:5]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:4]12.P(Cl)(Cl)(Cl)(Cl)[Cl:20]>C1C=CC=CC=1>[C:3]1(=[O:18])[N:7]([CH2:8][S:9]([Cl:20])(=[O:11])=[O:10])[C:6](=[O:13])[C:5]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:4]12
Reactant: O=C1c2ccccc2C(=O)N1CS(=O)(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [K]
Agent: [Na]
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)N1CS(=O)(=O)Cl
Reaction time: 1.5 h

Procedure:
To 41.7 g. (0.15 mol.) of phthalimidomethanesulfonic acid potassium sodium 220 ml. of dry benzene is added 22.5 g. (0.132 mol.) of phosphorus pentachloride. The reaction mixture is refluxed on a steam bath for one hour, then an additional 22.5 g. of phosphorus pentachloride is added and heating is continued for 1.5 hours. The reaction mixture is evaporated to dryness, crushed ice is added to the residue and the slurry is filtered. The product is washed with water to give phthalimidomethanesulfonyl chloride.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[Mg+].[Br-].[CH3:22]COCC>C1COCC1>[OH:1][C@@:2]1([CH3:22])[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOCC
Reactant: O=C(NC1CCCCC1=O)OCc1ccccc1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: C[C@]1(O)CCCC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.9 %

Procedure:
Benzyl 2-oxocyclohexylcarbamate (173 mg, 0.7 mmol) in THF (3 mL) was cooled to −78° C. and added MeMgBr in ether (0.7 mL, 2.1 mmol) dropwise via syringe. The ice bath was removed and the reaction was allowed to stir at rt for 3 h. The reaction was quenched with sat. aqueous NH4Cl (1 mL) and partitioned between ethyl acetate and water. The layers were separated and the organic layer washed with brine, dried (Na2SO4), filtered and concentrated. The product was subjected to flash chromatography on silica gel (10% to 70% ethyl acetate/hexanes) to afford the title compound (81 mg, 88% yield) as a single diastereomer. This material was used as is in the next transformation.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([S:11][CH2:12][C:13](=O)[CH3:14])[CH:8]=[C:7]([F:16])[CH:6]=1)[CH3:2].Cl.[Cl:19][C:20]1[C:21]([F:28])=[C:22]([NH:26]N)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:6]=[C:7]([F:16])[CH:8]=[C:9]([S:11][C:12]2[C:23]3[C:22](=[C:21]([F:28])[C:20]([Cl:19])=[CH:25][CH:24]=3)[NH:26][C:13]=2[CH3:14])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(F)cc(SCC(C)=O)c1
Reactant: NNc1cccc(Cl)c1F
Agent: Cl
Product: CCOC(=O)c1cc(F)cc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 3-fluoro-5-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and (3-chloro-2-fluoro-phenyl) hydrazine hydrochloride
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[NH:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:12]([O:14][CH2:15][CH3:16])=[O:13].[C:27](Cl)(=O)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>C(Cl)(Cl)Cl>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][CH2:21][N:20]1[C:19]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]=2[N:8]=[C:44]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH3:27]
Reactant: CCOC(=O)c1ccc(NCCCN(C)C)c(N)c1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCc1nc2cc(C(=O)OCC)ccc2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
Triethylamine (1.05 ml) was added to a solution containing ethyl 3-amino-4-{[3-(dimethylamino)propyl]amino}benzoate (1.83 g) in chloroform (20 ml), and then stearoyl chloride (2.07 g) was added thereto while being cooled with ice. After being stirred for 4 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (5.00 ml) was added to a solution containing the residue (3.95 g) in ethanol (30 ml). After being stirred for 3 hours at 90° C., the reaction mixture was neutralized with 5N sodium hydroxide aqueous solution (12 ml) and concentrated. The residue, with ethyl acetate added thereto, was washed with water and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (3.28 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=20:1-10:1), thereby yielding the entitled compound (2.99 g) as orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:16][Si:17]([CH2:20][CH2:21][O:22][CH2:23]Cl)([CH3:19])[CH3:18].[H-].[Na+]>CN(C=O)C>[CH2:14]([O:13][C:11]([C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[N:8]([CH2:23][O:22][CH2:21][CH2:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:9]=1)=[O:12])[CH3:15]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c[nH]c2ncnc(Cl)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(Cl)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of ethyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (4.00 g, 17.7 mmol) and SEMCl (4.71 mL, 26.6 mmol) in DMF (90 mL) was added sodium hydride (0.851 g, 21.3 mmol) portion-wise at 0° C. The resulting yellow suspension was stirred at 0° C. for one hour and then allowed to warm to room temperature over one hour. The reaction was quenched with water slowly then extracted with ethyl acetate (×3). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica eluting with 0-50% ethyl acetatehexane to afford ethyl-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C15H23ClN3O3Si [M+H]+: 356; found 356.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:23])=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[CH3:25][S:26][CH2:27][CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:23])=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:28][CH2:27][S:26][CH3:25])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: C/C(=C\c1ccc(O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CSCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCCOc1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 74.4 %

Procedure:
A mixture of 6 g of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenol, 4.8 g of 2-chloroethyl methyl sulphide and 10.5 g finely powdered potassium carbonate in 100 ml of dimethylformamide is heated to 100° for 20 hours. The cooled reaction mixture is diluted with water and extracted several times with ethyl acetate. The crystalline residue obtained after drying and evaporating the organic phase is recrystallized from hexane and gives 5.5 g of methyl 2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]phenoxy]ethyl sulphide in colourless crystals, melting point 94°-96°.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10].[Mg].[O:12]1[C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1.[Cl-].[NH4+]>O1CCCC1>[F:10][C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[C:19]1([OH:22])[CH2:20][CH2:21][C:16]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:17][CH2:18]1
Reactant: Fc1cc(F)c(Br)cc1F
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2cc(F)c(F)cc2F)CCC2(CC1)OCCO2
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A three neck flask (2 L) under an atmosphere of nitrogen with Mg turnings (9.8 g) was stirred for 15 rain and tetrahydrofuran (90 m1L) was added and stirring continued for an additional 15 min. 1-Bromo-2,4,5-trifluorobenzene (85 g) was dissolved in tetrahydrofuran (340 mL). A portion of this solution (75 mL) was added to the stirred magnesium turnings and then heated to 50° C. The rest of the solution was added and stirring continued at the same temperature for an additional 1 h. The reaction mixture was cooled to 40° C., a solution of 1,4-dioxaspiro[4.5]decan-8-one (57.3 g) in tetrahydrofuran (275 mL) was added, and stirring continued for 10 h. The reaction mixture was poured into saturated aqueous ammonium chloride solution (970 mL) and extracted with toluene (700 mL). The organic layer was washed with water (3×700 mL), dried over anhydrous sodium sulfate, filtered and evaporated to yield the title compound as a red-orange oil which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:6]=1)([CH3:4])[CH3:3].[CH2:16]([Mg]Cl)[CH:17]=C.Cl>O1CCOCC1.O1CCCC1.[Cu]I>[OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH:10]([CH:11]([C:12]#[N:13])[C:14]#[N:15])[CH:16]=[CH2:17])[CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(O)c1cc(C=C(C#N)C#N)no1
Reactant: C=CC[Mg]Cl
Agent: [Cu]I
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C=CC(c1cc(C(C)(C)O)on1)C(C#N)C#N
Reaction time: 1 h

Procedure:
2.26 g of {[5-(1-hydroxy-1-methylethyl)-isoxazol-3-yl]methylidene}malononitrile was dissolved in 50 ml of 1,4-dioxane. Thereto, 0.08 g of copper(I) iodide was added and 18.6 ml of a 1.4 M solution of allylmagnesium chloride in tetrahydrofuran was then added under ice-cooling. The mixture was stirred for 1 hour under ice-cooling. The reaction mixture was added to 0.1 M hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.56 g of {1-[5-(1-hydroxy-1-methylethyl)-isoxazol-3-yl]allyl}malononitrile.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:10])[CH:9]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([NH:20][CH2:21][CH:22]=[CH2:23])[CH:18]=[CH2:19].O>C(#N)C>[Br:10][C:8]1[CH:9]=[C:5]([C:3](=[O:4])[CH2:2][N:20]([CH2:21][CH:22]=[CH2:23])[CH2:17][CH:18]=[CH2:19])[S:6][CH:7]=1
Reactant: O=C(CBr)c1cc(Br)cs1
Reactant: C=CCNCC=C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C=CCN(CC=C)CC(=O)c1cc(Br)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1-(4-bromothiophen-2-yl)ethanone (10 g, 48.8 mmol) in methanol (98 mL) and dichloromethane (163 mL) is added tetra-n-butylammonium tribromide (28.8 g, 58.5 mmol). The reaction mixture is concentrated under reduced pressure at 50° C. to give a residue which is purified by silica gel chromatography, eluting with dichloromethane to give crude 2-bromo-1-(4-bromo-2-thienyl)ethanone. To a solution of the crude 2-bromo-1-(4-bromo-2-thienyl)ethanone in acetonitrile (200 ml) is added potassium carbonate (20.2 g, 146 mmol) and diallylamine (9.48 g, 97.5 mmol). The reaction is stirred at room temperature for 2 hours. Water is added and the solution is extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title compound. ES/MS (m/e): (79Br/81Br) 300/302 (M+H).