Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:14]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.CCOCC>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH:12]=[CH:11][CH:10]=1
Reactant: Oc1cccc(N2CCOCC2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CI
Product: COc1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a stirred mixture of 3-morpholinyl-phenol (3.8 g; 21.2 mmol) and powdered K2CO3 (4.4 g; 31.8 mmol) in dry DMF (15 mL) was added iodomethane (1.45 mL; 23.3 mmol) via syringe at room temperature under nitrogen atmosphere. The resulting mixture was allowed to stir at room temperature for 22 hours. The reaction was diluted with ether (150 mL) and washed successively with water (2×40 mL) and brine (40 mL), then dried (MgSO4), filtered and concentrated in vacuo to provide the desired ether as a yellow oil (2.51 g; 61%).
Reaction SMILES: C([Si](C(C)C)(C(C)C)N1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:15]=2)=[CH:6]1)(C)C.[S:30]1C=CC(B(O)O)=C1>>[S:30]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:15]=2)=[CH:6]1
Reactant: OB(O)c1ccsc1
Reactant: CCOC(=O)c1cn2cc(-c3ccn([Si](C(C)C)(C(C)C)C(C)C)c3)ccc2n1
Product: CCOC(=O)c1cn2cc(-c3ccsc3)ccc2n1

Procedure:
This product is prepared under conditions similar to those described for the preparation of Intermediate 15 (step 15.1), replacing the 1-(triisopropylsilyl)pyrrole-3-boronic acid with thiophene-3-boronic acid (catalyst: dichlorobis(triphenylphosphine)palladium).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[CH:5]2.[O:14]1CCOCC1>>[CH:1]([C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[CH:5]2)=[O:14]
Reactant: Cc1ccc2ncc(C#N)cc2n1
Reactant: C1COCCO1
Product: N#Cc1cnc2ccc(C=O)nc2c1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 6-methyl-[1,5]naphthyridine-3-carbonitrile (220.0 mg, 1.30 mmol) in 1,4-dioxane was added SeO2 (187.6 mg, 1.70 mmol) and the reaction mixture was refluxed for 2 hrs, when the TLC showed no starting material left, then cooled to room temperature and filtered through celite. The solid was washed with hot AcOEt and the filtrate was then concentrated to give 6-formyl-[1,5]naphthyridine-3-carbonitrile as a light yellow solid (238.1 mg, 100.0%). HR-MS-EI (+) m/e calcd for C10H5N3O (M+) 183.0433. found 183.0433
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[C:10]([C:14]#[N:15])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])[CH3:2].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.N1C=CC=CC=1.CS(C)=O>O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[C:10]([C:14]#[N:15])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])[CH3:2]
Reactant: CCOC(=O)CNc1cc(F)c(C#N)cc1[N+](=O)[O-]
Reactant: c1c[nH]cn1
Solvent: c1ccncc1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CNc1cc(-n2ccnc2)c(C#N)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 4 h
Yield: 95.6 %

Procedure:
A mixture of 2.50 g of N-(4-cyano-5-fluoro-2-nitrophenyl)glycine ethyl ester, 0.67 g of imidazole, 7.40 g of pyridine and 40 ml of DMSO was stirred at 80° C. for 4 hours. After the addition of water, the reaction product was extracted with chloroform. The extract was washed successively with water and brine, dried over anhydrous sodium sulfate and then, concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (eluent:chloroform:methanol=95:5) to give 2.82 g (92%) of N-[4-cyano-5-(1H-imidazol-1-yl)-2--nitrophenyl]glycine ethyl ester.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]([O:11][CH2:12][CH2:13][CH2:14][OH:15])(=[O:10])[C:7]([CH3:9])=[CH2:8]>N1C=CC=CC=1>[C:6]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:3](=[O:4])[CH2:2][Cl:1])(=[O:10])[C:7]([CH3:9])=[CH2:8]
Reactant: C=C(C)C(=O)OCCCO
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCCOC(=O)CCl

Procedure:
Chloroacetoxypropyl methacrylate (CAPM) was prepared by condensation of chloroacetyl chloride with hydroxypropyl methacrylate in pyridine (cf Chem. Abs. 68, 105913 g) b.p. 92°-4° C./0.2 mm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+].CCCCCC.C(OCC)(=O)C>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a solution of 4-methylbenzotrifluoride (18.6 g, 116 mmol) in concentrated sulfuric acid (120 ml) was added dropwise a solution of potassium nitrate (12.9 g, 128 mmol) in concentrated sulfuric acid (60 ml) at room temperature over 15 minutes. After stirring for 2 hours at the same temperature, the reaction mixture was poured into ice water, which was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and solvent was distilled off. The residue obtained was submitted to silica gel column chromatography [hexane-ethyl acetate=8:1] to obtain 22.8 g of title compound as pale yellow liquid. Yield 96%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH:36]([C@@H:38]1[CH2:42][CH2:41][CH2:40][N:39]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=O.N1CCCCC1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[C:32]([C:33]#[N:34])=[CH:36][C@@H:38]3[CH2:42][CH2:41][CH2:40][N:39]3[C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 57.7 %

Procedure:
To a sealed tube was added 3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (507 mg, 1.07 mmol), tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (0.2 mL, 1.1 mmol), piperidine (0.05 mL, 0.54 mmol) and ethanol (3 mL). The tube was capped and heated to 100° C. for 16 hrs. The reaction was not complete so an additional amount of tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (732 mg, 3 eq) was added and heating was continued for 4 hrs at 110° C. The reaction was cooled and concentrated then dissolved in DCM (50 mL) and washed with water (50 mL) and brine. The organic layer was dried (MgSO4), filtered and concentrated. The resulting material was purified by Isolera (250 g column; 2%-3% MeOH/DCM) to provide 403 mg (57%) of tert-butyl (2S)-2-[3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-2-cyano-3-oxo-prop-1-enyl]pyrrolidine-1-carboxylate as a solid.
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.Cl.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH2:26])=[NH:25])=[CH:16][CH:15]=1>>[F:11][C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:10])[NH:26][C:24]([CH2:23][CH2:22][CH2:21][CH2:20][C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=3)=[N:25][C:2]=2[N:3]=1
Reactant: N=C(N)CCCCc1ccc(F)cc1
Reactant: O=C(O)c1ccc(F)nc1F
Agent: Cl
Product: O=c1[nH]c(CCCCc2ccc(F)cc2)nc2nc(F)ccc12

Procedure:
The title compound was prepared in analogy to example 85 from 2,6-difluoropyridine-3-carboxylic acid and 5-(4-fluoro-phenyl)-pentanamidine hydrochloride. White solid. MS: m/e=316.1 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].[C:15](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.C(OC(=O)C1C=C(OCCOC)C(OCCOC)=CC=1N)C>[CH3:15][O:9][C:8](=[O:10])[C:7]1[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1N
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)ccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
5-Methoxy-2-nitro-benzoic acid (2.5 g) was dissolved in N,N-dimethylformamide (compound A′) (40 ml). Potassium carbonate (4.5 g) and methyl iodide (2.5 ml) were added to the solution at room temperature, and the mixture was then stirred at that temperature for 30 min. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was then subjected to separatory extraction with ethyl acetate. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a hexane-acetone system to give 5-methoxy-2-nitrobenzoic acid methyl ester (2.7 g, yield 100%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([I:14])=[C:10]2[C:6]=1[CH:7](O)[N:8]([C:16]([CH3:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])[C:9]2=[O:15].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[N+](C)([O-])=O>[OH:4][C:5]1[CH:13]=[CH:12][C:11]([I:14])=[C:10]2[C:6]=1[CH2:7][N:8]([C:16]([CH3:24])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:17])[C:9]2=[O:15].[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([I:14])=[C:10]2[C:6]=1[CH2:7][N:8]([C:16]([CH3:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])[C:9]2=[O:15]
Reactant: COCOc1ccc(I)c2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Product: CC(C)(c1ccccc1)N1Cc2c(O)ccc(I)c2C1=O
Product: COCOc1ccc(I)c2c1CN(C(C)(C)c1ccccc1)C2=O
Yield: 59 %
Yield: 27 %

Procedure:
In a similar manner to Step 4 of Example 16, 4-methoxymethoxy-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (500 mg, 1.10 mmol) was dissolved in nitromethane (25 mL), and the solution was treated with trifluoroacetic acid (0.525 mL, 6.82 mmol) and triethylsilane (0.527 mL, 3.30 mmol), followed by purification by flash column chromatography (chloroform/methanol=100/0, 99/1) to obtain 4-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (257 mg, yield 59%) and 4-methoxymethoxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (131 mg, yield 27%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[N:29]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)[N:28]=[CH:27][CH:26]=2)O1>>[C:11]1([C:8]2[N:6]3[CH:7]=[C:2]([C:25]4[N:29]([C:30]5[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=5)[N:28]=[CH:27][CH:26]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1ccc2ncc(-c3ccccc3)n2c1
Reactant: Cc1ccc(-n2nccc2B2OC(C)(C)C(C)(C)O2)cc1
Product: Cc1ccc(-n2nccc2-c2ccc3ncc(-c4ccccc4)n3c2)cc1

Procedure:
The title compound, off-white solid (53 mg, 41%), MS (ISP) m/z=351.5 [(M+H)+], mp 107° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-phenyl-imidazo[1,2-a]pyridine (intermediate G) (0.1 g, 0.366 mmol) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-p-tolyl-1H-pyrazole (intermediate C) (0.125 g, 0.44 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=[O:6].[CH3:16][Zn]C>O1CCOCC1.C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:16][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=[O:6]
Reactant: C[Zn]C
Reactant: O=C(O)c1ccc(OC(F)(F)F)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(C(=O)O)ccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
A mixture of 3-bromo-4-(trifluoromethoxy)benzoic acid (923 mg, 3.24 mmol) and PdCl2(dppf) (95 mg, 0.13 mmol) were stirred in 1,4-dioxane (9 mL) in a three necked flask under argon atmosphere (a condensor was added to the flask). Dimethylzinc in toluene (3.2 mL of 2.0 M, 6.4 mmol) was added very slowly (caution: the reaction was very exothermic) and the mixture was stirred at room temperature for 1 hour before it was heated at 70° C. for 18 h. The mixture was cooled to room temperature before it was charged with additional dioxane (9 mL) and PdCl2(dppf) (100 mg). The mixture was cooled to 0° C. before additional dimethyl zinc in toluene (3.0 mL, 2.0M) was added. The ice bath was removed and the mixture was heated at 70° C. overnight. The mixture was cooled to room temperature and was quenched with methanol (2 mL) very slowly. The solution was diluted with ethyl acetate and was washed with 1N HCl (3×). The organic layer was washed with brine, dried over sodium sulfate and evaporated to dryness to yield 3-methyl-4-(trifluoromethoxy)benzoic acid (56%).
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:19][CH2:20][CH2:21][S:22][CH3:23])[CH:3]=1.Cl.I([O-])(=O)(=O)=[O:26].[Na+].[OH-].[Na+]>O.C(Cl)Cl>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([O:19][CH2:20][CH2:21][S:22]([CH3:23])=[O:26])[CH:3]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCSC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCS(C)=O
Reaction time: 2 h
Yield: 93.3 %

Procedure:
To a stirred solution of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[2-(methylthio)ethoxy]benzamide (1.0 g, 2.28 mmoles) (prepared in Example 20) and 1.4N HCl solution (3.97 ml, 5.56 mmoles) in 15 ml of H2O at 0°-5°, was added sodium metaperiodate (0.625 g, 2.92 mmoles). The mixture, which soon began to darken, was stirred at 0°-5° to 2 hours. The mixture was then diluted to 50 ml and made alkaline (pH=12) with NaOH solution. Methylene chloride (50 ml) was added, the mixture was shaken well, and the layers were separated. The aqueous layer was extracted with 3 portions of methylene chloride and the combined organic solutions were dried (anhydrous MgSO4) and evaporated. A dark oil (0.96 g) which solidified upon standing was obtained. The crude product was flash chromatographed on silica, eluting with CH2Cl2 :CH3OH:NH4OH, 80:20:0.5. Appropriate fractions were combined and evaporated to give 0.80 g (77%) of the title compound as a yellow resin which crystallized upon standing, mp. 110°-114°.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:27]2[S:28][CH:29]=[C:30]([CH2:32][CH2:33][CH:34]=[O:35])[N:31]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[CH3:16].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:27]2[S:28][CH:29]=[C:30]([CH2:32][CH2:33][CH:34]([C:2]3[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=3)[OH:35])[N:31]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[CH3:16]
Reactant: CCOc1ccc(-c2nc(CCC=O)cs2)cc1OCC
Reactant: COc1cccnc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1ccc(-c2nc(CCC(O)c3ncccc3OC)cs2)cc1OCC
Temperature: -30 °C
Reaction time: 0.75 h
Yield: 25.8 %

Procedure:
A solution of 2-bromo-3-methoxypyridine (1.65 g, 8.78 mmol) in THF was cooled to −78° C., and 5.23 ml (8.16 mmol) of a 1.57 N solution of n-butyllithium in n-hexane was added dropwise. The resulting mixture was stirred at the same temperature for 45 minutes, and a solution (15 ml) of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionaldehyde (1.34 g, 4.39 mmol) in THF was added dropwise. After stirring at the same temperature for 30 minutes, the temperature of the mixture was raised to −30° C. over a period of 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated salt solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2). The solvent was distilled off under reduced pressure, to thereby obtain 470 mg (yield: 26%) of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(3-methoxypyridine-2-yl)-1-propanol as a yellow oil.
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>C(OCC)C>[CH:8]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:21](=[O:24])[CH:22]=[CH2:23])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: C=CC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC(=O)N(C1CCCCC1)C1CCCCC1
Reaction time: 12 h

Procedure:
A solution of dicyclohexylamine (19.92 ml, 0.10 mole) and triethylamine (27.88 ml, 0.20 mole) in ethyl ether (100 ml) was cooled to 0° C. A solution of acryloyl chloride (7.93 ml, 0.1 mole) in ethyl ether (20 ml) was added and the solution was stirred for 12 hours, filtered and concentrated to obtain the product as a solid which was dried in vacuo. The stucture was confirmed by NMR.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[CH2:26][CH2:25][NH:24][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:17]=2)[CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O.C(#N)C>[C:1]([O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[CH2:26][CH2:25][N:24]([C:42]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[O:49])[C:14]=3[N:15]=[C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[N:17]=2)[CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Oc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3)c1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)Oc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 90.2 %

Procedure:
To an acetonitrile solution (2 ml) of 4-(3-t-butoxyphenyl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (36 mg), an acetonitrile solution (1 ml) of pyridine (25 μl, 3 equivalents), dimethylaminopyridine (ca. 2 mg, catalytic amount) and benzoyl chloride (28 mg, 2 equivalents) was added under ice cooling, followed by stirring at room temperature for 10 hours. To the reaction mixture, water (20 ml) was added, followed by extraction with ethyl acetate (10 ml×2). The organic layer was washed with aqueous ammonium chloride solution and brine, and subsequently dried over sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative TLC (n-hexane/ethyl acetate=2/1), to obtain the desired compound as a colorless powder (42 mg, 90%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[F:15][C:16]([F:50])([F:49])[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[N:20]=[C:19]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]3[CH:40]=[C:41]([S:45](Cl)(=[O:47])=[O:46])[CH:42]=[CH:43][CH:44]=3)[CH:34]=2)[N:18]=1>C1COCC1>[F:50][C:16]([F:15])([F:49])[C:17]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=2)[N:20]=[C:19]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]3[CH:40]=[C:41]([S:45]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)(=[O:47])=[O:46])[CH:42]=[CH:43][CH:44]=3)[CH:34]=2)[N:18]=1
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Reactant: C1COCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1)N1CCOCC1
Temperature: 0 °C
Yield: 91.1 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of morpholine (0.063 g, 0.72 mmol), triethylamine (0.07 ml, 0.5 mmol) and THF (1 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.14 g, 0.24 mmol) in THF (2 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane/hexane) yielded the title compound as a white solid (0.13 g, 91%). MS (ISP) 595.2 [(M+H)+]; mp 202° C.
Reaction SMILES: CN(C=O)C.C([O-])(O)=O.[Na+].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[C:21](=O)[C:20](=[CH:23]N(C)C)[CH2:19][C:18](=[O:27])[N:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:16]=2[CH:34]=1.[NH:35]([C:39]1[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=1)[C:36]([NH2:38])=[NH:37]>CCO>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[C:21]3[N:37]=[C:36]([NH:35][C:39]4[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=4)[N:38]=[CH:23][C:20]=3[CH2:19][C:18](=[O:27])[N:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:16]=2[CH:34]=1
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Reactant: CN(C)C=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(O)c1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2N(c2ccccc2)C(=O)C3)cc1

Procedure:
In a manner similar to method I (DMF and NaHCO3 were used in place of EtOH and KCO3), 8-chloro-4-dimethylaminomethylene-1-phenyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-i) and 4-guanidinobenzoic acid were converted to I-10 (61%): HRMS Calcd. for C25H17ClN4O3: 457.1067, Found 457.1076.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH2:17][OH:18])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.C(N(CC)CC)C.[CH2:26]([Si:28](Cl)([CH2:31][CH3:32])[CH2:29][CH3:30])[CH3:27]>ClCCl>[CH3:1][O:2][CH2:3][C:4]1([CH2:17][O:18][Si:28]([CH2:31][CH3:32])([CH2:29][CH3:30])[CH2:26][CH3:27])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: COCC1(CO)c2ccccc2-c2ccccc21
Reactant: CC[Si](Cl)(CC)CC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[Si](CC)(CC)OCC1(COC)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
1 g of 9-methoxymethyl-9-hydroxymethyl-fluorene (4.2 mmol) was dissolved in 20 ml of dichloromethane. The solution was cooled in ice-water bath, and 0.87 ml of triethyl amine (6.2 mmol) was added thereto. After stirring for 5 minutes, 0.91 ml of triethylsilyl chloride (5.4 mmol) was added drop-wise, and the mixture was stirred for further 2 hours, followed by stirring at room temperature for 1 hour. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give 1.24 g of concentrate (yield 84%).