Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2([CH3:18])[NH:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:7][CH:6]=1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([N:29]1[CH2:34][C@H:33]([CH3:35])[N:32]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([O:51]COC)([C:47]([F:50])([F:49])[F:48])[C:43]([F:46])([F:45])[F:44])=[CH:38][C:37]=2/[CH:55]=[CH:56]\[CH3:57])[CH2:31][C@H:30]1[CH3:58])=[O:28].O>CN(C)C=O>[F:45][C:43]([F:44])([F:46])[C:42]([C:39]1[CH:40]=[CH:41][C:36]([N:32]2[CH:33]([CH3:35])[CH2:34][N:29]([C:27](=[O:28])[CH2:26][N:13]3[C:12](=[O:17])[C@@:11]([C:8]4[CH:7]=[CH:6][C:5]([O:4][CH:2]([CH3:1])[CH3:3])=[CH:10][CH:9]=4)([CH3:18])[NH:15][C:14]3=[O:16])[C@H:30]([CH3:58])[CH2:31]2)=[C:37](/[CH:55]=[CH:56]\[CH3:57])[CH:38]=1)([OH:51])[C:47]([F:50])([F:49])[F:48]
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)cc1
Reactant: C/C=C\c1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1C[C@@H](C)N(C(=O)CBr)C[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C/C=C\c1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1C[C@@H](C)N(C(=O)CN2C(=O)N[C@@](C)(c3ccc(OC(C)C)cc3)C2=O)CC1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.7 %

Procedure:
5-[4-(1-Methylethoxy)phenyl]-5-methylimidazolidine-2,4-dione (7.7 mg, 0.0311 mmol) was dissolved in N,N-dimethylformamide (500 μL), added potassium carbonate (8.6 mg, 0.0622 mmol) under ice-cold conditions, and the mixture was stirred at room temperature for 5 minutes. Then, under ice-cold conditions, (2R,5S,Z)-2-bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-(prop-1-en-1-yl)phenyl}-2,5-dimethylpiperazin-1-yl)ethanone (17 mg, 0.0311 mmol) was added and stirred at room temperature for 18 hours. Under ice-cold conditions, the reaction solution was added water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was dissolved in ethyl acetate (1.0 mL), added a solution of 4N-hydrochloric acid-ethyl acetate (1.0 mg), and the mixture was stirred at room temperature for 1 hour. Under ice-cold conditions, the reaction solution was added water and a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (17.4 mg (yield 83%)) was obtained as a yellow oil.
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH2:10][NH:11][C:12]([NH2:14])=[S:13].[NH4+].[OH-]>O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]2[S:13][C:12]([NH2:14])=[N:11][N:10]=2)[CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: NNC(N)=S
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Nc1nnc(-c2cccnc2)s1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 50.7 %

Procedure:
5-pyridin-3-yl-[1,3,4]thiadiazol-2-ylamine was prepared as described by Turner et al. J. Med. Chem. 1988, 31, 898. Nicotinic acid (30 g, 0.24 mol) was added in portions to polyphosphoric acid (60 mL) under mechanical stirring. After stirring for 5 minutes, thiosemicarbazide (22.2 g, 0.24 mol) was added in portions. The reaction mixture was heated to 90° C. for 6 hours, cooled to room temperature over 14 hours, and re-heated to 40° C. to melt the solid yellow cake. Water was added (50 mL) dropwise via Pasteur pipette while stirring. The solution was cooled to 0° C., NH4OH (29% solution, approx 250 mL) was added dropwise over 2.5 hours to bring the pH to 14. The solids were collected by filtration, washed with water (150 mL) and dried in vacuo at 65° C. for 16 hours to afford the title compound as a beige-colored solid (21.7 g, 50%): mp 201-211° C.; IR (KBr thin film) 1508 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 8.95 (d, J=2.1 Hz, 1H), 8.62 (dd, J=4.5, 0.9 Hz, 1H), 8.14 (dt, J=8.4, 1.5 Hz, 1H), 7.51 (dd, J=8.1, 1.5 Hz, 1H); ESIMS m/z 179 ([M+H]+).
Reaction SMILES: [CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[ClH:21].O1CCOCC1>C(Cl)Cl>[ClH:21].[NH2:13][C@@H:10]1[CH2:9][CH2:8][C@H:7]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:12][CH2:11]1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl cis-4-(isopropylcarbamoyl)cyclohexylcarbamate (39.11 g, 138 mmol) in DCM (400 mL) was added 4 M HCl in dioxane (138 mL, 550 mmol), and 0.5 mL concentrated HCl. The reaction was stirred vigorously overnight at RT. A large amount of white precipitate had formed in the flask and it was collected by vacuum filtration, washed with DCM, and dried in vacuo, to generate cis-4-amino-N-isopropylcyclohexanecarboxamide hydrochloride as a white powder (31.08 g, 102% yield).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=2)O1.[OH-:23].[Na+].OO>C1COCC1>[CH3:19][Si:18]([CH3:21])([CH3:20])[CH2:17][CH2:16][O:15][CH2:14][N:12]1[CH:13]=[C:9]([OH:23])[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (compound 280.1, 9.7 g, 30.0 mmol) in THF (100 mL) was added 2M sodium hydroxide (aq.) (30 mL) dropwise. To this was added H2O2 (30%) (22.7 mL) dropwise at 0° C. The reaction mixture was stirred for 2 h at room temperature, then quenched with 50 mL of water. The aqueous phase was extracted with 2×150 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 4.3 g (67%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH3:18])=[C:12]([O:19][CH3:20])[C:11]=2[O:21][CH3:22])=[O:9])=[C:6]([O:23]C(=O)C(C)(C)C)[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CO>O>[CH3:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH3:18])=[C:12]([O:19][CH3:20])[C:11]=2[O:21][CH3:22])=[O:9])=[C:6]([OH:23])[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C)c(C(=O)c2c(C)cccc2OC(=O)C(C)(C)C)c(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cc(C)c(C(=O)c2c(C)cccc2O)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3B (1.42 g, 3.6 mmol), potassium carbonate (1.5 g), methanol (30 ml) and water (10 ml) is stirred at room temperature for 16 hours. The reaction mixture is poured into water, acidified and extracted with diisopropylether. The organic phase is separated and concentrated. The pure product is obtained as a yellow solid, 0.75 g (65.8%), mp. 82-84° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][C:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(-c2cc3ccccc3s2)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2sc3ccccc3c2Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A slurry of 5.0 g (20.8 mmol) of 2-(4-methoxyphenyl)benzo[b]thiophene (Example 3, Part A) in 400 mL of CHCl3 at 0° C. was treated slowly with 1.6 mL of Br2, resulting in a yellow solution. The reaction was stirred at 0° C. for 1 h and then washed sequentially with 200 mL of 1.0 N aq Na2S2O3, 200 mL of 1.0 N aq NaHCO3, and 200 mL of H2O. After drying over Na2SO4, evaporation of the solvent in vacuo gave 6.24 g (19.5 mmol; 94%) of an off-white solid which was clean by thin layer chromatography.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:17].[BH4-].[Na+].O>C(O)(C)C>[OH:2][CH2:3][CH2:4][CH:5]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[OH:17]
Reactant: COC(=O)CC1CCCCCCCCCCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: OCCC1CCCCCCCCCCC1O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
The crude ketoester (IX) from step 4 (approximately 180 gm; 0.7 mol) was refluxed for 8 hours with agitation under nitrogen with 74 gm (1.96 mol) of sodium borohydride in 1250 ml of isopropanol. After addition of 150 ml of water, the mixture was agitated for 30 minutes at 60° C., and any sodium borohydride remaining was destroyed by the addition of 100 ml of acetone with good cooling. After agitation for another 30 minutes, the isopropanol was distilled off with the simultaneous addition of 200 ml water. After cooling to approximately 30° to 35° C., the residue was neutralized with half-concentrated sulfuric acid and mixed with 700 ml of toluene. The aqueous phase was separated. The toluene phase contained approximately 135 gm of 1,4-diol (IV) (85% yield) and was used further without evaporation.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]([OH:21])([CH3:20])[CH3:19])=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][N:23]([CH3:51])[C:24](=[O:50])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)=[O:33])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)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.O>[OH:21][C:18]([C:6]1[CH:5]=[C:4]2[C:9]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:11][C:2]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:32](=[O:33])[NH:31][C:28]4[CH:27]=[CH:26][C:25]([C:24]([N:23]([CH3:51])[CH3:22])=[O:50])=[CH:30][CH:29]=4)=[CH:40][CH:39]=3)=[N:3]2)=[CH:8][CH:7]=1)([CH3:20])[CH3:19]
Reactant: CC(C)(O)c1ccc2c(N3CCOCC3)nc(Cl)nc2c1
Reactant: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)c4ccc(C(C)(C)O)cc4n3)cc2)cc1
Temperature: 95 °C
Reaction time: 5 h
Yield: 4.9 %

Procedure:
To a 50 mL round bottom flask, 2-(2-chloro-4-morpholino-quinazolin-7-yl) propan-2-ol (0.08 g, 0.00026 mol), N,N-dimethyl-4-{3-{4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido}-benzamide (0.128 g, 0.000312 mol), cesium carbonate (0.169 g, 0.00052 mol), DMF (3 mL) and water (1 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (0.009 g, 0.000013 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 5 h. To the cooled reaction mixture, water was added and extracted with ethyl acetate. The organic layer was separated, washed with water, brine and dried over anhydrous sodium sulfate. The organic layer was evaporated under reduced pressure to afford the crude product. The crude product was purified by column chromatography using 60-120 silica gel and 10% MeOH in chloroform. The compound was further purified by prep TLC using 10% MeOH in chloroform to obtain the title compound [0.007 g, 5%]. 1H NMR (400 MHz, DMSO-d6): δ 9.02 (s, 1H), 8.97 (s, 1H), 8.44 (d, J=8.8 Hz, 2H), 7.97 (d, J=8.8 Hz, 1H), 7.91 (d, J=1.6 Hz, 1H), 7.97 (d, J=8.8 Hz, 3H), 7.54 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 5.30 (s, 1H), 3.83 (brs, 4H), 3.81 (brs, 4H), 2.96 (s, 6H), 1.52 (s, 6H). LC-MS (ESI): Calculated mass: 554.2; Observed mass: 555.1 (RT: 0.17 min).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:14][O:15][CH2:16][CH3:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:18][S:19][CH2:20][CH2:21]Br>[OH-].[K+].C(O)C>[CH3:18][S:19][CH2:20][CH2:21][O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[CH2:14][O:15][CH2:16][CH3:17])=[CH:8][CH:9]=1
Reactant: CSCCBr
Reactant: CCOCC(COc1ccc(O)cc1)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOCC(COc1ccc(OCCSC)cc1)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.9 %

Procedure:
A 2.40 g quantity of 4-(2,3-diethoxypropoxy)phenol was dissolved in 0.56 g of potassium hydroxide and 10 ml of 90% ethanol. To the solution was added 1.55 g of 2-methylmercaptoethyl bromide. The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and the residue was extracted with chloroform. The chloroform layer was washed with water, dewatered with Glauber's salt and concentrated. The residue was distilled at reduced pressure, giving 2.95 g of 2-{4-(2,3-diethoxypropoxy)phenoxy}ethyl methyl sulfide in 93.9% yield, b.p. 176° to 177° C./l to 2 mmHg.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:9][C:10]1[CH:15]=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[CH:12][C:11]=1[C@:25]1([CH2:36][F:37])[CH2:30][C@@H:29]([C:31]([F:34])([F:33])[F:32])[O:28][C:27]([NH2:35])=[N:26]1.Br[C:39]1[CH:40]=[CH:41][C:42]([C:45]#[C:46][Si:47]([CH3:50])([CH3:49])[CH3:48])=[N:43][CH:44]=1.CCCCCC>O1CCOCC1.O.O.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:39]2[CH:44]=[N:43][C:42]([C:45]#[C:46][Si:47]([CH3:48])([CH3:50])[CH3:49])=[CH:41][CH:40]=2)=[CH:12][C:11]=1[C@:25]1([CH2:36][F:37])[CH2:30][C@@H:29]([C:31]([F:33])([F:32])[F:34])[O:28][C:27]([NH2:35])=[N:26]1
Reactant: C[Si](C)(C)C#Cc1ccc(Br)cn1
Reactant: CC1(C)OB(c2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)OC1(C)C
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)C#Cc1ccc(-c2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)cn1
Reaction time: 0.25 h
Yield: 44.3 %

Procedure:
A mixture of potassium phosphate (0.676 g, 3.19 mmol), (4S,6S)-4-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (8b, 1.428 g, 3.40 mmol), 5-bromo-2-((trimethylsilyl)ethynyl)pyridine (0.270 g, 1.062 mmol) and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (0.038 g, 0.053 mmol) in dioxane/water (5.0/1.2 mL) was heated in microwave reactor at 110° C. for 35 min. The reaction mixture was diluted with water and extracted with DCM three times. The combined organic layers were washed with brine, dried on sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography: 0-100% EtOAc/hexane in 15 min. The product was obtained as an off-white solid. Trituration with hexane afforded the pure product as a white solid (0.22 g, 44% yield). MS m/z=468 [M+H]+. Calculated for C22H22F5N3OSi: 467.5.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH3:8][O:9][C:10]1[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=1.[CH2:17]=O>C(O)C>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][CH2:17][N:3]1[C:4](=[O:6])[CH2:5][S:1][C:2]1=[O:7]
Reactant: C=O
Reactant: O=C1CSC(=O)N1
Reactant: COc1ccccc1N
Solvent: CCO
Product: COc1ccccc1NCN1C(=O)CSC1=O
Temperature: 30 °C
Reaction time: 8 h

Procedure:
A mixture of 13.3 g of 2,4-thiazolidinedione and 12.3 g of o-anisidine was dissolved in 100 ml of warm ethanol at 55° to 70° C. The solution was cooled to about 30° C, and 9.1 ml of 37% formaldehyde solution was added and stirred overnight. The resulting precipitate was filtered to give 22.5 g of N-(2-methoxyphenylaminomethyl)-2,4-thiazolidinedione, mp 88.5°-91° C; identified by IR and NMR.
Reaction SMILES: [Cl:1]Cl.[Cl:3][Si:4]([Cl:11])([Cl:10])[CH2:5][Si:6]([Cl:9])([CH3:8])[CH3:7].N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Cl:3][Si:4]([Cl:11])([Cl:10])[CH2:5][Si:6]([Cl:9])([CH3:8])[CH2:7][Cl:1]
Reactant: C[Si](C)(Cl)C[Si](Cl)(Cl)Cl
Reactant: ClCl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](Cl)(CCl)C[Si](Cl)(Cl)Cl
Reaction time: 5 h

Procedure:
A stirrer was added to a 250 ml, round bottomed flask, which was equipped with a bubbling column linked to a dry ice/aceton condenser and a chlorine gas cylinder. To the flask were added 100 g (0.41 mole) of 1,1,1,3-tetrachloro-3-methyl-1,3-disilabutane and 1 g of a reaction initiator, azobisisobutyronitrile, using carbon tetrachloride as a solvent. The obtained mixture was photoreacted for 5 hrs using a sun lamp, while bubbling chlorine gas and refluxing carbon tetrachloride. After confirming the degree of the reaction process by gas chromatography, the reaction mixture was distilled under vacuum to obtain 38 g of 1,1,1,3,4-pentachloro-3-methyl-1,3-disilabutane.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.Br[CH2:26][CH2:27][OH:28].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:24][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[N:14][C:13]([NH:16][C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[O:23][CH2:26][CH2:27][OH:28])=[N:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: OCCBr
Reactant: Oc1cccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: OCCOc1cccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)c1
Temperature: 25 °C

Procedure:
A solution of 3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenol 39 (1.2 mmol), 2-bromoethanol (1.4 mmol) and cesium carbonate (1.6 mmol) in acetonitrile (10 mL) is heated to 85° C. for 12 h then cooled to rt. The reaction is evaporated to dryness then re-dissolved in DCM. The organic mixture is washed with water and brine then dried over magnesium sulfate, filtered and reduced to dryness. Purification by silica gel chromatography with hexane:EtOAc=1:1 as eluant affords 2-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenoxy)ethanol 40a as white solid. MS (m/z) (M+1)+: 373.8.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:12][C:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([NH:35][CH3:36])=[O:34])[CH:28]=2)(=[O:26])=[O:25])[CH:14]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].I[CH3:38].O>O1CCCC1.CN(C)C=O>[CH3:36][N:35]([CH3:38])[C:33]([C:29]1[CH:28]=[C:27]([S:24]([N:15]2[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:17][C:13]([CH2:12][N:4]([CH3:3])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:14]2)(=[O:26])=[O:25])[CH:32]=[CH:31][CH:30]=1)=[O:34]
Reactant: CI
Reactant: CNC(=O)c1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2)c1
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To a suspension (3 mL) of sodium hydride (60% in oil, 36 mg) in tetrahydrofuran was added a solution (2 mL) of tert-butyl methyl{[1-({3-[(methylamino)carbonyl]phenyl}sulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}carbamate (240 mg) in N,N-dimethylformamide at room temperature. After stirring at the same temperature for 15 min, iodomethane (106 mg) was added, and the mixture was stirred for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1) to give the title compound as a colorless oil (yield 168 mg, 68%).
Reaction SMILES: [S:1]1(=[O:8])(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1.Br[C:10]1[CH:11]=[CH:12][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[N:14][CH:15]=1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:13]3[CH:12]=[CH:11][C:10]([N:2]4[CH2:3][CH2:4][CH2:5][CH2:6][S:1]4(=[O:8])=[O:7])=[CH:15][N:14]=3)=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Reactant: O=S1(=O)CCCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)cn3)CC2)c(C)c1
Yield: 71.9 %

Procedure:
Using [1,2]thiazinane 1,1-dioxide (94 mg) and (5-bromopyridin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (260 mg) described in Preparation Example 134 and by the reaction and treatment in the same manner as in Example 1, the title compound (214 mg) was obtained.
Reaction SMILES: C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.[NH2:16][C:17]1[S:18][CH:19]=[C:20]([C:22](=[N:52][O:53][C:54]([C:57]([OH:59])=[O:58])(C)C)[C:23]([NH:25][CH:26]2[C:50](=[O:51])[N:28]3[C:29]([C:47]([OH:49])=[O:48])=[C:30]([CH:33]=[CH:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:36]=4[N+:44]([O-:46])=[O:45])[CH2:31][S:32][C@H:27]23)=[O:24])[N:21]=1>>[NH2:16][C:17]1[S:18][CH:19]=[C:20]([C:22](=[N:52][O:53][CH2:54][C:57]([OH:59])=[O:58])[C:23]([NH:25][CH:26]2[C:50](=[O:51])[N:28]3[C:29]([C:47]([OH:49])=[O:48])=[C:30]([CH:33]=[CH:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:36]=4[N+:44]([O-:46])=[O:45])[CH2:31][S:32][C@H:27]23)=[O:24])[N:21]=1
Reactant: CC(C)(ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=Cc3ccc([N+](=O)[O-])cc3[N+](=O)[O-])CS[C@H]12)c1csc(N)n1)C(=O)O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(C(=NOCC(=O)O)C(=O)NC2C(=O)N3C(C(=O)O)=C(C=Cc4ccc([N+](=O)[O-])cc4[N+](=O)[O-])CS[C@H]23)cs1
Yield: 73 %

Procedure:
This compound (238 mg, 0.22 mmol), anisole (0.5 ml, 4.5 mmol) and trifluoro acetic acid (2.5 ml, 33.8 mmol) were used to conduct the procedure similar to that shown in (2) of Example 1 to obtain 120 mg (yield: 73%) of the titled compound as yellow powder.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CCO>[CH3:1][S:2][C:3]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: C1CCNCC1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: CSC(=C[N+](=O)[O-])N1CCCCC1
Yield: 39.6 %

Procedure:
In 20 ml of EtOH was dissolved 1.7 g (0.01 mole) of 1,1-bis(methylthio)-2-nitroethylene under heating and 0.9 g (0.01 mole) of piperidine dissolved in 10 ml of EtOH was added dropwise in 3 portions at 30-minutes intervals under reflux. After 2 hours of reflux, the solvent was distilled off and the residue was chromatographed on a silica gel column and eluted with AcOEt-toluene (2:3). The above procedure yielded 0.8 g of the title compound as yellow prisms.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=1B(O)O>>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: COc1cccc(F)c1B(O)O
Product: COc1cccc(F)c1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 58, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-fluoro-6-methoxy-phenylboronic acid (CAS RN 78495-63-3) and using preparative HPLC for the chromatographic purification. Off-white solid (36%). MS (ESI): m/z=473.2 [M+H]+.