Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][SiH:2]([CH3:4])[CH3:3].[CH:5]([Si:7]([CH:12]=[CH2:13])([CH:10]=[CH2:11])[CH:8]=[CH2:9])=[CH2:6]>CC(OC)(C)C>[Si:7]([CH2:12][CH2:13][Si:2]([Cl:1])([CH3:4])[CH3:3])([CH2:10][CH2:11][Si:2]([Cl:1])([CH3:4])[CH3:3])([CH2:8][CH2:9][Si:2]([Cl:1])([CH3:4])[CH3:3])[CH2:5][CH2:6][Si:2]([Cl:1])([CH3:4])[CH3:3]
Reactant: C[SiH](C)Cl
Reactant: C=C[Si](C=C)(C=C)C=C
Solvent: COC(C)(C)C
Product: C[Si](C)(Cl)CC[Si](CC[Si](C)(C)Cl)(CC[Si](C)(C)Cl)CC[Si](C)(C)Cl
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
Under argon, 234.2 g (2.475 mol) chlorodimethyl silane, 500 ml TBME and 1.5 g catalyst 1 were added to 75 g (0.550 mol) tetravinyl silane. The reaction mixture was heated, with vigorous stirring, to 45° C. until an exothermic reaction set in and the temperature rose to 51° C. A mixture comprising 525 g (3.853 mol) tetravinyl silane, 1639.4 g (17.327 mol) chlorodimethyl silane and 940 ml TBME was then added slowly dropwise, wherein care was taken that the reaction temperature did not fall below 50° C. Stirring was then continued for 1.5 hours under reflux, the reaction mixture was cooled to room temperature, the catalyst was filtered off over a frit, and volatile constituents were removed from the colourless solution under vacuum. The product took the form of a white solid. Yield: 2120.8 g (94% of theoretical yield).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1)=[O:6])#[N:2].[Br:16][C:17]1[C:18](I)=[N:19][C:20]([I:23])=[N:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:16][C:17]1[C:18]([C:10]2[CH:11]=[CH:12][C:7]([C:5]([NH:4][CH2:3][C:1]#[N:2])=[O:6])=[CH:8][CH:9]=2)=[N:19][C:20]([I:23])=[N:21][CH:22]=1
Reactant: Brc1cnc(I)nc1I
Reactant: N#CCNC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: N#CCNC(=O)c1ccc(-c2nc(I)ncc2Br)cc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 50.2 %

Procedure:
To a mixture of 4-(cyanomethylcarbamoyl)phenylboronic acid (see example 3) (185 mg, 0.9 mmol) and 5-bromo-2,4-diiodopyrimidine (410 mg, 1.0 mmol) in 1,4-dioxane (10 mL), was added 2M aqueous potassium carbonate (100 μL). The resulting mixture was stirred under nitrogen for 5 minutes then tetrakis(triphenylphosphine)palladium(0) (52 mg, 0.045 mmol) was added under a nitrogen atmosphere. The mixture was heated at 80° C. overnight. The cooled reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with water then brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product as a brown solid. The crude material was purified by flash chromatography, eluting with 50% ethyl acetate/petroleum spirit to give 4-(5-bromo-2-iodopyrimidine-4-yl)-N-(cyanomethyl)benzamide (200 mg, 35% over 2 steps). LC-ESI-MS (method B): rt 6.2 min.; m/z 443.0/445.0 [M+H]+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[C:11]1([NH:17]N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C.C(O)(=O)C>[CH:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH2:1][C:2]1[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:17][C:3]=12
Reactant: O=C1Cc2ccccc2C1
Reactant: NNc1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: c1ccc2c(c1)Cc1c-2[nH]c2ccccc12
Temperature: 85 °C

Procedure:
A modified version of the method reported by Okamoto, et al. was employed. Okamoto, T. A.; Kobayashi, S. M.; Yamamoto, H. N., DE1952019, 1970. To a solution of 2-indanone (16.3 g, 123 mmol) in ethanol (80 mL) was added phenyl hydrazine (12.1 mL, 123 mmol) followed by acetic acid (12 drops) at room temperature. While stirring, the solution was warmed to reflux (oil bath at 85° C.) for 15 minutes at which point it was removed from the oil bath and allowed to cool to room temperature. Light yellow needle-like crystals precipitated from the solution. Upon cooling to room temperature, the solution was cooled to 0° C. for 30 minutes. The crystals were filtered via vacuum filtration and used without further purification.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:17])[N:5]([CH3:16])[C:6](=[O:15])[N:7]([CH3:14])[C:8]=1[N:9]=[CH:10][N:11](C)C)#[N:2].Cl.ON.C(N(CC)CC)C.C([OH:30])C>O>[NH2:2][C:1]1[N+:11]([O-:30])=[CH:10][N:9]=[C:8]2[N:7]([CH3:14])[C:6](=[O:15])[N:5]([CH3:16])[C:4](=[O:17])[C:3]=12
Reactant: CCO
Reactant: CN(C)C=Nc1c(C#N)c(=O)n(C)c(=O)n1C
Agent: Cl
Agent: NO
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1c(=O)c2c(N)[n+]([O-])cnc2n(C)c1=O
Yield: 85 %

Procedure:
0.235 g (1 mmol) of the compound 15, 0.138 g (2 mmol) of hydroxyamine hydrochloride and 0.243 g (2.4 mmol) of triethylamine were added to 3 ml of ethanol, and then the reaction mixture was refluxed for 3 hours. After cooling, 5 ml of water was added thereto, and the crystalline precipitate was filtered off and recrystallized from ethanol to give 0.223 g of 5-amino-1,3-dimethylpyrimido[4,5-d]pyrimidine-2,4-dione-6-oxide in a 85% yield.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.O>O1CCCC1>[O:8]1[CH2:9][CH2:10][CH:5]([O:4][CH2:3][CH2:2][OH:1])[CH2:6][CH2:7]1
Reactant: C1CC2(CCO1)OCCO2
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: OCCOC1CCOCC1
Temperature: -50 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
1,4,8-Trioxaspiro[4.5]decane (0.43 g, 3.0 mmol) produced in Reference Example 13 (13a) was dissolved in tetrahydrofuran (1.0 mL), and the resulting mixture was cooled to −50° C. Subsequently, a 1.0M solution of borane-tetrahydrofuran complex in tetrahydrofuran (3.6 mL) and trimethylsilyl trifluoromethanesulfonate (33 mg, 0.15 mmol) were added. The resulting mixture was warmed to room temperature, followed by stirring for 18 hours. A small amount of water was added, and then the resulting mixture was purified by basic silica gel column chromatography (hexane:ethyl acetate, 100:0-0:100, V/V) to give the desired title compound (0.39 g, yield 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[CH:7][CH:6]=[CH:5]2.[CH3:13][O:14][CH2:15][CH2:16]O.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:13][O:14][CH2:15][CH2:16][O:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([NH2:1])=[CH:3]2
Reactant: Nc1ccc2c(O)cccc2c1
Reactant: COCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOc1cccc2cc(N)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 219.2 %

Procedure:
6-Aminonaphthalen-1-ol (100 mg, 0.63 mmol) was dissolved in THF (6 mL), and 2-methoxyethanol (96 mg, 1.26 mmol), DEAD (635 μL, 1.26 mmol), and triphenylphosphine (330 mg, 1.26 mmol) were added thereto. The resulting mixture was stirred at room temperature for 4 hours and then concentrated. The residue was purified by silica-gel column chromatography (n-hexane:ethyl acetate=5:1) to give 5-(2-methoxyethoxy)naphthalen-2-ylamine (300 mg, quantitative) as a wax-like material.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:31]([C:33]1[N:37]([CH3:38])[CH:36]=[N:35][CH:34]=1)#[CH:32]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:4]([N:1]3[CH:32]=[C:31]([C:33]4[N:37]([CH3:38])[CH:36]=[N:35][CH:34]=4)[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: C#Cc1cncn1C
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cncn4C)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 18 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide and 5-ethynyl-1-methyl-1H-imidazole (Aldrich) in the same manner as Example 15. ESI MS m/z 538 [C26H31N7O4S+H]+.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[O:6][C:7]([CH3:11])=[CH:8][C:9]=1[SH:10].Cl[CH:13]([C:16](=[O:20])[CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15].O>CO>[CH2:14]([CH:13]([S:10][C:9]1[CH:8]=[C:7]([CH3:11])[O:6][C:5]=1[CH3:4])[C:16]([CH2:17][CH2:18][CH3:19])=[O:20])[CH3:15]
Reactant: CCCC(=O)C(Cl)CC
Reactant: Cc1cc(S)c(C)o1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCC(=O)C(CC)Sc1cc(C)oc1C
Temperature: 23 °C
Reaction time: 1 h

Procedure:
Into a 25 ml round bottom 3 neck flask equipped with magnetic stirrer, Y tube, nitrogen inlet, reflux condenser and thermometer is placed a solution of 0.27 g (0.005 moles) of sodium methoxide dissolved in 3 ml absolute methanol. The sodium methoxide solution is cooled using a water bath to 25° C. A solution of 0.64 g (0.005 moles) of 2,5-dimethyl-3-furan thiol in 3 ml of absolute methanol is then added to the sodium methoxide solution dropwise from a pipette while maintaining the temperature of the reaction mass between 22° C and 28° C. While maintaining the temperature of the reaction mass at 23° - 35° C, 3-chloro-4-heptanone (0.74 g; 0.005 moles) in 1 ml absolute methanol is added dropwise. The reaction mass is then stirred for a period of 1 hour while maintaining the temperature at 23° C. After this 1 hour period, 15 ml of water is added with stirring and the reaction mass temperature rises to 28° - 30° C. The reaction mass is cooled to 25° C using a water bath and now exists in an aqueous phase and an organic phase. The aqueous phase (pH=6) is extracted with two 6 ml portions of n-hexane; and the hexane extracts and organic phase are combined, washed with a 4 ml portion of saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The resulting material is gravity filtered and concentrated on a rotary evaporator at 25° - 35° C and 15 mm Hg pressure, yielding a crude yellow oil weighing 1.2 g. The desired product is isolated by GLC trapping (8 foot × 1/4 inch SE-30 Column), and NMR, IR and Mass Spectral analyses yield the information that this material has the structure: ##SPC16##
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].CS[C:14](=[N:19][CH3:20])[S:15]([O-:18])(=[O:17])=[O:16]>C(#N)C>[CH3:20][NH:19][C:14]([S:15]([OH:18])(=[O:17])=[O:16])=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[CH3:1]
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CN=C(SC)S(=O)(=O)[O-]
Solvent: CC#N
Product: CNC(=NCCSCc1nc[nH]c1C)S(=O)(=O)O

Procedure:
A solution of 1.43 g (0.0085 mole) of 2-(5-methyl-4-imidazolylmethylthio)ethylamine in dry acetonitrile (150 ml) was added dropwise, with stirring, to a solution of 1.43 g (0.0084 mole) of 1-methylthio-1-methyliminomethanesulphonate in dry acetonitrile (150 ml) at 50°, giving an immediate white precipitation. After further warming at 70° for one hour, the mixture was stripped to dryness, dissolved in methanol and absorbed onto silica gel. Chromatography on a column of silica gel was performed with ethylacetate/methanol (20:1), and the crude product recrystallised from isopropanol to give the title compound, 0.46 g.m.p. 162.5°-163.5° as an almost colourless crystalline solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[OH-].[Na+].[F:10][C:11]([F:24])([F:23])[O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>O1CCCC1>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([S:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]([F:10])([F:23])[F:24])=[CH:18][CH:17]=2)(=[O:21])=[O:20])[CH2:7]1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: C[C@H]1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H]1CN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CCN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.7 %

Procedure:
A mixture of (2S)-2-methylpiperazine (1 g, 9.98 mmol, supplier Aldrich) in tetrahydrofuran (8 mL) and 3M aqueous sodium hydroxide (6.66 mL, 19.97 mmol) was cooled to 0° C. before addition of 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (2.86 g, 10.98 mmol, supplier Aldrich) dropwise via a dropping funnel. After addition, the cool bath was removed and the reaction stirred at room temperature for 4 h before standing at room temperature for 17 h. The mixture was concentrated in vacuo and then the residue was taken up in water (15 mL) and DCM (20 mL) and the mixture stirred for 1 h. The layers were separated and then the organic phase extracted with 1M HCl (40 mL). The acidic aqueous phase was then basified to pH12 with solid NaOH and the mixture extracted with DCM (2×30 mL). The combined organic phase was dried (phase separator) and concentrated under vacuum to give the title compound (2.58 g) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([O:11]C)[O:9]C)=[C:4]([F:13])[C:3]=1[O:14][CH3:15].[OH-:16].[K+:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([B-:8]([OH:16])([OH:11])[OH:9])=[C:4]([F:13])[C:3]=1[O:14][CH3:15].[K+:17]
Reactant: COB(OC)c1ccc(Cl)c(OC)c1F
Reactant: [OH-]
Agent: [K+]
Product: COc1c(Cl)ccc([B-](O)(O)O)c1F

Procedure:
Another embodiment of the present disclosure includes a method of forming 2-(4-chloro-2-fluro-3-methoxylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane that comprises contacting 2-chloro-6-fluoroanisole with n-butyl lithium to form 6-chloro-2-fluoro-3-lithioanisole. The 6-chloro-2-fluoro-3-lithioanisole may be contacted with trimethyl borate to form dimethyl 4-chloro-2-fluoro-3-methoxyphenylboronate. The dimethyl 4-chloro-2-fluoro-3-methoxyphenylboronate may be reacted with aqueous potassium hydroxide to form potassium (4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate. The potassium (4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate then may be reacted with aqueous hydrochloric acid to form 4-chloro-2-fluoro-3-methoxyphenylboronic acid. The 4-chloro-2-fluoro-3-methoxyphenylboronic acid may be reacted with 2,3-dimethyl-2,3-butanediol.
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][C:12](=[N:17][OH:18])[C:13]2=[O:16])=[CH:9][CH:8]=1.N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>O>[Si:24]([O:18][N:17]=[C:12]1[CH2:11][C:10]2[C:14](=[CH:15][C:7]([CH3:6])=[CH:8][CH:9]=2)[C:13]1=[O:16])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc2c(c1)C(=O)C(=NO)C2
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)C(=O)C(=NO[Si](C)(C)C(C)(C)C)C2
Temperature: 95 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To N,N-dimethylformamide (50 ml) were added at room temperature the compound (4.36 g, 24.9 mmol) obtained in step A, imidazole (5.10 g, 74.7 mmol) and tert-butyldimethylsilyl chloride (5.60 g, 37.4 mmol), and the mixture was stirred at 95° C. for 2 hr. After cooling to room temperature, water was added to the reaction solution with stirring and the precipitated solid was filtered, washed with water, and dried under reduced pressure to give the title compound (6.00 g, yield 83%) as a pale-bistered solid.
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][C@H:14]([NH:16][C:17]([O:19][CH2:20][CH:21]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:13][N:12]1[C:34](=[O:56])[C@@H:35]([NH:42][C:43](=[O:55])[C@@H:44]([N:46]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH3:47])[CH3:45])[CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:10])C1C=CC=CC=1>CO.[Pd]>[C:51]([O:50][C:48]([N:46]([CH3:47])[C@@H:44]([CH3:45])[C:43]([NH:42][C@@H:35]([CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C:34]([N:12]1[CH2:13][C@@H:14]([NH:16][C:17]([O:19][CH2:20][CH:21]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])=[O:56])=[O:55])=[O:49])([CH3:54])([CH3:53])[CH3:52]
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)OCc1ccccc1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)O)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
(2S,4S)-1-{(S)-2-[(S)-2-(tert-Butoxycarbonyl-methyl-amino)-propionylamino]-2-cyclohexyl-acetyl}-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-2-carboxylic acid benzyl ester (1.2 g, 1.56 mmol) was dissolved in methanol (15 mL) and 10% Pd—C (200 mg) was added. The mixture was stirred under hydrogen (1 atm) for 1 h, filtered through Celite and concentrated to give the title compound (800 mg, 76%) as a colorless oil which solidified upon standing and was used without purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[F:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>O>[F:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[CH:19][CH:18]=1
Reactant: OCCCCCCBr
Reactant: Oc1ccc(-c2cccc(F)c2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: OCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Yield: 63.8 %

Procedure:
First, 5 g of 6-bromo-1-hexanol, 5.7 g of 2,3difluoro-4'-hydroxybiphenyl, 7.6 g of potassium carbonate, and 70 ml of methyl ethyl ketone were placed in a 100 ml flask. Then, the mixture was stirred under reflux for 20 hours. The reaction mixture was poured into water, and an organic layer was extracted with toluene. The toluene layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was recrystallized from acetone to obtain 5.4 g of 2,3-difluoro-4'-(6-hydroxyhexyl)oxybiphenyl (Y: 63.5%). The compound thus obtained had a purity of 99.9% by GC.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][OH:15])=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccccc1Nc1ccc(CCO)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1Nc1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.2 %

Procedure:
To a stirred solution of 2-[4-(2-nitroanilino)phenyl]ethanol (2.0 g, 7.6 mmol) in methanol (15 mL) was added 10% Pd—C (160 mg). The mixture was stirred at room temperature for 6 h under hydrogen atmosphere. The palladium catalyst was removed by filtration and washed with ethanol (100 mL). The filtrate was concentrated under reduced pressure to afford 1.6 g (92%) of the title compound as pale yellow solids: 1H-NMR (CDCl3)δ2.79 (2H, t, J=6.6 Hz), 3.75 (2H, br), 3.80 (2H, t, J=6.6 Hz), 5.14 (1H, s), 6.82-6.66 (4H, m), 7.15-6.96 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[C:16]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:18][CH:19]=3)[C:11](=[O:24])[N:10]([CH2:25][C:26]([O:28]C)=O)[N:9]=2)=[CH:4][CH:3]=1.O.[NH2:31][NH2:32]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[C:16]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:18][CH:19]=3)[C:11](=[O:24])[N:10]([CH2:25][C:26]([NH:31][NH2:32])=[O:28])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2cccc(C(=O)OC)c2)c1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: COC(=O)c1cccc(Cn2c(-c3ccc(Cl)cc3)nn(CC(=O)NN)c2=O)c1
Reaction time: 18 h

Procedure:
172 mg (0.41 mmol) of the compound from Example 15A were suspended in 1 ml of ethanol, and 40 μl (0.83 mmol) of hydrazine hydrate were added. The mixture was heated under reflux for 4 h and then allowed to stand at room temperature for 18 h. The reaction was concentrated under reduced pressure on a rotary evaporator and the residue was dried under high vacuum. This gave 161 mg (94% of theory) of the target compound as a colorless solid.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][C:14]1[CH:30]=[CH:29][C:17]([CH2:18][C:19]2[CH:28]=[C:27]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=[CH:26]3)[CH:20]=2)=[CH:16][C:15]=1Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:32]([O:39][C@@H:40]1[C@@H:46]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@H:45]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@@H:44]([CH2:63][O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[O:43][C:41]1=[O:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH:20]1[C:21]2[C:27]([CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:28][C:19]=1[CH2:18][C:17]1[CH:29]=[CH:30][C:14]([O:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:15]([C:41]2([O:43][C@H:44]([CH2:63][O:64][CH2:65][C:66]3[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=3)[C@@H:45]([O:55][CH2:56][C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[C@H:46]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C@H:40]2[O:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[OH:42])[CH:16]=1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: Brc1cc(Cc2cc3cccccc-3c2)ccc1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC1(c2cc(Cc3cc4cccccc-4c3)ccc2OCc2ccccc2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 0.17 h
Yield: 468.1 %

Procedure:
A 1.6 M n-hexane solution of n-butyl lithium (0.32 ml) was added dropwise to a solution of 2-[4-(benzyloxy)-3-bromobenzyl]azulene (0.17 g) in THF (3.0 ml) at −55° C. and the mixture was stirred at the same temperature for 10 minutes. A solution of 2,3,4,6-tetra-O-benzyl-glucono-1,5-lactone (0.12 g) in THF (3.0 ml) was added dropwise to the reaction mixture and the mixture was stirred at the same temperature for 30 minutes. Saturated aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-n-hexane) to obtain 1-C-[5-(azulen-2-ylmethyl)-2-(benzyloxy)phenyl]-2,3,4,6-tetra-O-benzyl-D-glucopyranose (0.9 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[C:37]([C:43]([F:46])([F:45])[F:44])=[N:38][C:39]([NH2:42])=[N:40][CH:41]=2)O1>>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:3][C:2]([C:36]4[C:37]([C:43]([F:46])([F:45])[F:44])=[N:38][C:39]([NH2:42])=[N:40][CH:41]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CC1(C)OB(c2cnc(N)nc2C(F)(F)F)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4C(F)(F)F)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (200 mg), prepared via General Procedure B-3, was coupled to 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4-trifluoromethyl-pyrimidin-2-ylamine via General Procedure A to yield 20 mg of 327. MS (Q1) 559.2 (M)+.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=[CH:17][C:4]=2[CH2:3]1.[N+](=[CH2:23])=[N-]>CO.CCOCC>[O:1]=[C:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[C:15]([C:18]([O:20][CH3:23])=[O:19])[CH:16]=[CH:17][C:4]=2[CH2:3]1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1ccc2c(c1)Sc1ccc(F)cc1C(=O)C2
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1ccc2c(c1)Sc1ccc(F)cc1C(=O)C2
Yield: 94 %

Procedure:
10-Oxo-8-fluoro-dibenzo[b,f]thiepin-3-carboxylic acid (2 g; 6.94 mmoles) is partially dissolved in methanol (20 mL) and is treated with excess diazomethane in ether. The resulting solution is evaporated to dryness, triturated in methanol to yield 1.98 g (94%) of methyl 10-Oxo-8-fluoro-dibenzo [b,f]thiepin-3-carboxylate, m.p. 129°-131° C.