Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])[CH:6]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (3-hydroxy-phenyl)-acetic acid methyl ester (4.26 g, 25.66 mmol) and potassium carbonate (7.1 g, 51.33 mmol) in DMF (60 mL) is added 4-chloromethyl-5-methyl-2-phenyl-oxazole (5.33 g, 25.66 mmol) at RT. The reaction mixture is stirred for 16 h at 40° C. followed by 16 h at 60° C. The reaction mixture is cooled to RT, diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated at reduced pressure. The crude product is purified on a Biotage 40M column using 25% ethyl acetate in hexane to yield [3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-acetic acid methyl ester as a white solid.
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Na+].Cl[Si:8]([CH3:11])([CH3:10])[CH3:9]>O1CCCC1>[CH3:9][Si:8]([C:1]1([Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][CH:3]=[CH:2]1)([CH3:11])[CH3:10].[CH3:9][Si:8]([C:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1)([CH3:11])[CH3:10]
Reactant: c1cc[cH-]c1
Reactant: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)C1([Si](C)(C)C)C=CC=C1
Product: C[Si](C)(C)C1=CC=CC1
Reaction time: 3 h

Procedure:
Trimethylsilylcyclopentadiene and bis(trimethylsilyl)cyclopentadiene are prepared by the procedures of Kraihanzel et al., J. Amer. Chem. Soc., 90, 4701 (1968) and I. M. Pribytkova et al., J. of Organometallic Chem., 30, C57-C60 (1971). Sodium cyclopentadienide (44 g, 0.50 mole) is added to 150 ml of tetrahydrofuran. Chlorotrimethylsilane (54 g, 0.5 mole) is added dropwise slowly to the reaction and the stirring is continued for 3 hours. The reaction mixture is poured into 150 ml of cold, distilled water and trimethylsilylcyclopentadiene is extracted into diethyl ether. The extract is rotary evaporated to remove the ethereal solvent and the residue is vacuum distilled to give trimethylsilylcyclopentadiene, b.p. 41° C.-43° C. (16 mm).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=1I.C(=O)=O.CC(C)=O.C([Mg]Cl)(C)C.[F:32][C:33]([F:41])([F:40])[C:34](N(OC)C)=[O:35]>C1COCC1>[F:32][C:33]([F:41])([F:40])[C:34]([C:12]1[CH:13]=[C:14]([CH:15]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[OH:16])[CH:17]=[CH:18][C:11]=1[F:10])=[O:35]
Reactant: O=Cc1ccc(F)c(I)c1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)C(F)(F)F
Agent: CC(C)[Mg]Cl
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=C(c1cc(C(O)c2ccc(F)cc2)ccc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 4-fluorophenylmagnesium bromide (3.64 mL, 1.1 M in THF, 4.0 mmol) in THF (3.6 mL) was stirred on a dry ice/acetone bath under argon while a solution of 4-fluoro-3-iodobenzaldehyde (1.00 g, 4.00 mmol, Intermediate 35: step a) in THF (6.4 mL) was added rapidly dropwise over 1.5 minutes, and the reaction was then immediately transferred to a room temperature water bath and stirred for 5 minutes. The clear, ˜colorless reaction was then cooled in the dry ice/acetone bath and treated with iPrMgCl (2.04 mL, 2.06 M in THF, 4.20 mmol) rapidly dropwise over 2.5 minutes. The yellow reaction was stirred for 30 minutes, and was then treated with 2,2,2-trifluoro-N-methoxy-N-methylacetamide dropwise over ˜30 seconds. The homogeneous yellow reaction was then immediately removed from the cold bath and allowed to warm to room temperature with stirring. After 2.5 hours, the dark yellow homogeneous reaction was chilled in a dry ice/acetone bath and quenched with 1 M aqueous NaH2PO4 (10 mL) in one portion. The reaction was warmed to room temperature and extracted with MTBE (1×10 mL, 1×5 mL), and the combined organic layers were washed with 5 M NaCl (1×3 mL), dried (Na2SO4), filtered, and concentrated twice from DCM to provide the crude title compound as a clear yellow oil.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[N:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]#[N:20])=[CH:11][CH:10]=2)[C:7]([S:21][C:22]([F:29])([F:28])[C:23]([O:25]CC)=[O:24])=[N:6][CH:5]=1>C1COCC1.C(O)C.O>[Br:3][C:4]1[N:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]#[N:20])=[CH:11][CH:10]=2)[C:7]([S:21][C:22]([F:29])([F:28])[C:23]([OH:25])=[O:24])=[N:6][CH:5]=1
Reactant: CCOC(=O)C(F)(F)Sc1ncc(Br)n1-c1ccc(C#N)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1ccc(-n2c(Br)cnc2SC(F)(F)C(=O)O)c2ccccc12
Reaction time: 4 h

Procedure:
Aqueous lithium hydroxide solution (1M, 2 eq) was added to a solution of ethyl 2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetate (1 eq) in THF, ethanol and water, and stirred for 4 h. After concentrating, the residue was acidified with aqueous HCl solution (1N), diluted with water and filtered to afford 2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetic acid.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[CH:5][C:6]([Cl:11])=[C:7]([O:9][CH3:10])[CH:8]=1.[C:12]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=O)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C1C[O:29]CC1>>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][C:22]([C:3]2[CH:4]=[CH:5][C:6]([Cl:11])=[C:7]([O:9][CH3:10])[CH:8]=2)([OH:29])[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: COc1cc(Br)ccc1Cl
Agent: [Mg]
Product: COc1cc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)ccc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Magnesium turnings (2.60 g) in a flask were stirred vigorously under vacuum at room temperature for 12 h and then the flask was filled with nitrogen gas. THF (20 mL) was added followed by the addition of one crystal of 12. The mixture was cooled to 0° C. and a solution of 5-bromo-2-chloroanisole (6.64 g) in THF (100 mL) was added in a period of 10 min. The mixture was warmed up to room temperature and stirred at room temperature for 15 min before it was heated to 45° C. for 2 h to provide a solution of the Grignard solution. To 24 mL of the Grignard solution obtained from above (at −40° C.) was added N-Boc-piperidone (1.0 g) in one portion. The resultant mixture was warmed up to room temperature, stirred for 1 h and quenched by the addition of sat. aqueous NH4Cl solution (20 mL). The organic layer was separated and the aqueous layer was extracted by EtOAc (3×20 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated in vacuo. The crude residue was purified by flash chromatography to provide 4-(4-Chloro-3-methoxy-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil (502 mg).
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][C:6]1[CH:26]=[CH:25][C:9]([CH2:10][C:11]2[C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[N:13][C:14]([NH2:18])=[N:15][C:16]=2[CH3:17])=[C:8]([F:27])[CH:7]=1>CS(C)=O.CN(C=O)C.CCOC(C)=O>[NH2:18][C:14]1[N:15]=[C:16]([CH3:17])[C:11]([CH2:10][C:9]2[CH:25]=[CH:26][C:6]([CH2:5][C:1]#[N:2])=[CH:7][C:8]=2[F:27])=[C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:13]=1
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CCl)cc1F
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.1 %

Procedure:
Potassium cyanide (0.473 g) was added to a stirred solution of the product from step (vi) (0.85 g) in DMSO (10 mL) and DMF (10 mL). The mixture was stirred at rt for 15 h, diluted with EtOAc, washed with saturated NaHCO3 solution, saturated brine dried, filtered and evaporated. The crude product was purified by chromatography eluting with 0 to 5% MeOH in DCM to afford the subtitle compound as a yellow solid 0.530 g.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[CH:3]([C:30]1[CH:35]=[CH:34][N+:33]([O-])=[CH:32][CH:31]=1)[O:4][C:5]1[C:14]([N:15](COCC[Si](C)(C)C)[S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[N:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.C([NH2:43])(C)(C)C.C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C(F)(F)F)C=CC=CC=1.O>[NH2:43][C:32]1[CH:31]=[C:30]([CH:3]([O:4][C:5]2[C:14]([NH:15][S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[N:13][C:12]3[C:7]([N:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:2]([F:38])([F:37])[F:1])[CH:35]=[CH:34][N:33]=1
Reactant: CC(C)(C)N
Reactant: CCCS(=O)(=O)N(COCC[Si](C)(C)C)c1nc2ccccc2nc1OC(c1cc[n+]([O-])cc1)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: FC(F)(F)c1ccccc1
Solvent: O
Product: CCCS(=O)(=O)Nc1nc2ccccc2nc1OC(c1ccnc(N)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 54 %

Procedure:
Compound B4 (200 mg, 0.349 mmol) obtained in Step 1 of Example 42 was suspended in benzotrifluoride (10 mL). To the suspension were added tert-butylamine (0.19 mL, 1.7 mmol) and p-toluenesulfonic anhydride (228 mg, 0.698 mmol), and the mixture was stirred at room temperature for 18 hours. To the reaction mixture were added tert-butylamine (0.19 mL, 1.7 mmol) and p-toluenesulfonic anhydride (228 mg, 0.698 mmol) and the mixture was further stirred at room temperature for 18 hours. Further, to the reaction mixture were added tert-butylamine (0.19 mL, 1.7 mmol) and p-toluenesulfonic anhydride (228 mg, 0.698 mmol) and the mixture was further stirred at room temperature for 18 hours. A saturated aqueous sodium bicarbonate solution and water were added to the reaction mixture. Extraction with ethyl acetate and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was dissolved in benzotrifluoride (2.0 mL) and trifluoroacetic acid (2.0 mL) and the solution was stirred at 70° C. for 18 hours. The solvent was evaporated under reduced pressure, and a saturated aqueous sodium bicarbonate solution and water were added to the residue. Extraction with ethyl acetate and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=1/10) to give Compound 45 (83.2 mg, 54% yield).
Reaction SMILES: [C:1](=[S:3])=[S:2].[CH2:4]([N:6]([CH2:9][CH3:10])[CH2:7][CH3:8])[CH3:5].[CH:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([OH:18])[CH:12]=1>C(O)C>[OH:18][C:13]1[CH:14]=[CH:15][C:16]([NH:17][C:1](=[S:3])[S-:2])=[CH:11][CH:12]=1.[CH2:4]([NH+:6]([CH2:9][CH3:10])[CH2:7][CH3:8])[CH3:5]
Reactant: Nc1ccc(O)cc1
Reactant: CCN(CC)CC
Reactant: S=C=S
Solvent: CCO
Product: CC[NH+](CC)CC
Product: Oc1ccc(NC(=S)[S-])cc1
Reaction time: 1 h

Procedure:
A solution of carbon disulfide (13.8 g) in absolute ethanol (100 ml) is added to a mixture of triethylamine (18.5 g), p-aminophenol (20 g) and absolute ethanol (400 ml). After the addition is completed, the reaction exotherms from 24° C to 29° C over a period of one hour and a tan solid is formed. The mixture is stirred one additional hour, cooled and filtered. Yield 39.8 g, of a tan solid (76% of theory), melting point 214° C to 217° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O-:12])([O-])=O.[Cs+].[Cs+].[CH3:15][N:16]1[C:21](=O)[N:20]([CH3:23])[CH2:19][CH2:18]C1>CCOC(C)=O.CCCCCC>[CH2:19]([N:20]1[C:23]([CH:9]=[O:12])=[CH:15][N:16]=[C:21]1[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:18]
Reactant: Oc1ccc(F)cc1
Reactant: CN1CCCN(C)C1=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCn1c(C=O)cnc1Oc1ccc(F)cc1
Temperature: 200 °C
Reaction time: 1 h

Procedure:
A suspension of the compound obtained in Example 7-(1) (5.0 g), 4-fluorophenol (2.87 g) and Cs2CO3 (10.4 g) in DMPU (10 ml) was stirred at 200° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted with methanol/chloroform (1/4) and filtered. The filtrate was concentrated, and the resulting residue was purified by column chromatography (OH-type SiO2, AcOEt/hexane=0% to 30%) to give the titled compound (4.16 g) as a light-pink liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[S:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)(=[O:37])=[O:36])[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3cnccn3)cc2)S(=O)(=O)c2ccccn2)c1

Procedure:
The title compound of Step A was prepared from 3-{3-[(4-pyrazin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11x, and pyridine-2-sulfonyl chloride hydrochloride, of Preparation 47, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.98 (d, 1H), 8.69 (m, 1H), 8.62 (m, 1H), 8.50 (d, 1H), 7.99 (m, 1H), 7.86 (m, 3H), 7.48 (m, 1H), 7.26 (m, 2H), 7.11 (m, 1H), 7.01 (d, 1H), 6.94 (d, 1H), 6.89 (s, 1H), 4.56 (s, 2H), 4.48 (s, 2H), 3.65 (s, 3H), 2.80 (t, 2H), 2.49 (t, 2H); MS 503 (M+1).
Reaction SMILES: [C:1]([CH:3]([NH:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH2:13][CH2:14][OH:15])[C:5]=1[F:16])#[N:2].[NH4+]=[S:27].O>O1CCCC1.CO>[C:22]([C:21]1[CH:20]=[CH:19][C:18]([NH:17][CH:3]([C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH2:13][CH2:14][OH:15])[C:5]=2[F:16])[C:1]([NH2:2])=[S:27])=[CH:25][CH:24]=1)#[N:23]
Reactant: COc1cc(OCCO)c(F)c(C(C#N)Nc2ccc(C#N)cc2)c1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C#N)cc2)C(N)=S)c1
Temperature: 25 °C
Yield: 61.4 %

Procedure:
The crude product of 4-({cyano[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}amino)benzonitrile (2.77 g) obtained in Example 30 was dissolved in tetrahydrofuran (4.26 mL) and methanol (4.26 mL), and 20% aqueous ammonium sulfide solution (8.54 mL, 25 mmol) was added dropwise thereto at room temperature, and the resulting mixture was stirred at the same temperature. After completion of the reaction, water (4.26 mL) was added dropwise to the reaction mixture, and the resulting mixture was stirred at the same temperature for 0.5 hours. The precipitated solid was filtered. The filtrate obtained was sequentially washed with water and tert-butyl methyl ether, and dried to obtain the captioned compound (1.87 g) as a pale yellow solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.Cl[C:18]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:21]=[C:20]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:19]=1.CO>CN(C)C=O.O>[Cl:3][C:4]1[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[N:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:21]=[C:20]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:19]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: Clc1cccc2[nH]c3ccccc3c12
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cccc2c1c1ccccc1n2-c1nc(-c2ccccc2)nc(-c2ccccc2)n1
Yield: 64.3 %

Procedure:
In a stream of nitrogen, a 100 mL three-necked flask was charged with 0.53 g (13.4 mmol) of sodium hydride (oily, 60%). 15 mL of dehydrated dimethylformamide was added to the content, and the mixture was stirred. To the thus-obtained slurry, a solution of 2.2 g (11.2 mmol) of 4-chlorocarbazole in 15 mL of dehydrated dimethylformamide was dropwise added, and the mixture was stirred for 30 minutes. To the thus-obtained reaction mixture, a solution of 3.0 g (11.2 mmol) of 2-chloro-4,6-diphenyl-1,3,5-triazine in 40 mL of dehydrated dimethylformamide was dropwise added. The reaction mixture was stirred at room temperature for 2 hours, and, 10 mL of methanol and then 100 mL of pure water were added to terminate the reaction. A white powder deposited upon the addition of pure water was collected, and washed with pure water and then with ethanol. The thus-obtained powder was recrystallized from o-xylene to give 3.1 g (7.2 mmol) of 4-chloro-9-(4,6-diphenyl-1,3,5-triazin-2-yl)carbazole as a white crystal (yield: 64%).
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.Cl[C:7]1[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]>C(O)(C)(C)C.ClCCl>[Cl:16][C:14]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([NH:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:15]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: NCC1CC1
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: O=C(O)c1ccc(Cl)nc1NCC1CC1
Temperature: 170 °C
Yield: 107.1 %

Procedure:
In a sealable tube, 3 g (42 mmol) of cyclopropylmethylamine is added to 3 g (14 mmol) of 2,6-dichloronicotinic acid in solution in tert-butanol (14 ml), the tube is sealed and heated at 170° C. for 30 minutes in a Biotage Initiator microwave. The reaction mixture is cooled to room temperature, diluted in dichloromethane (100 ml) and washed with a 10% aqueous solution of acetic acid (12 ml). The organic phase is dried over Na2SO4, filtered, concentrated and dried under vacuum. 3.4 g of product is obtained in the form of an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([S:20]C#N)([CH:17]([CH3:19])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([C:11]([SH:20])([CH:17]([CH3:19])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:6]=1
Reactant: CCOC(=O)C(SC#N)(c1nc(OC)cc(OC)n1)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(S)(c1nc(OC)cc(OC)n1)C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.9 %

Procedure:
A mixture of the product of Example 16 (0.8 g), trifluoroacetic acid (1 ml) and dichloromethane (10 ml) was stirred at room temperature for 24 hours, and was then washed with water and aqueous sodium bicarbonate. The organic layer was dried, evaporated to dryness under vacuum, and flash chromatographed on silica gel, eluting with ethyl acetate/60°-80° petroleum ether, to give 0.25 g of the desired product which partly solidified.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li].[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([OH:16])=[O:15].[CH3:17][C:18]([CH3:20])=[O:19].C(O)(=O)C(O)=O>O1CCCC1.O>[CH3:1][O:15][C:14]([C:10]1[O:9][C:13]([C:18]([OH:19])([CH3:20])[CH3:17])=[CH:12][CH:11]=1)=[O:16]
Reactant: CC(C)=O
Reactant: CC(C)NC(C)C
Reactant: O=C(O)c1ccco1
Agent: O=C(O)C(=O)O
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(C)(C)O)o1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of diisopropylamine (7.6 ml, 54.0 mmole) in tetrahydrofuran (20 ml) at 0° C. was added 2.5 M nButyl lithium (22 ml, 54.0 mmole). The mixture was cooled to −78° C. and a solution of Furan-2-carboxylic acid (3.0 grams, 27.0 mmole) in tetrahydrofuran (20 ml) was added dropwise and stirred for 20 minutes and acetone (2.4 ml, 32.0 mmole) was added. The mixture was stirred at −78° C. for 10 minutes and allowed to warm to room temperature over 1 hour. The mixture was poured into 200 ml water, acidified with oxalic acid to pH 2 and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to give a solid. (0.580 g). MW 145.22; MS (m/e) 146 (M++1).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][C:14]([C:17](=[S:19])[NH2:18])=[CH:15][N:16]=2)[CH2:8][CH2:7]1.Cl[CH2:27][C:28](=O)[CH2:29][C:30]([O:32][CH3:33])=[O:31]>CO.O>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][C:14]([C:17]3[S:19][CH:27]=[C:28]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[N:18]=3)=[CH:15][N:16]=2)[CH2:8][CH2:7]1
Reactant: COC(=O)CC(=O)CCl
Reactant: NC(=S)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Solvent: O
Solvent: CO
Product: COC(=O)Cc1csc(-c2cnc(N3CCC(Oc4ccccc4C(F)(F)F)CC3)s2)n1
Temperature: 82.5 °C

Procedure:
A mixture of 2-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3-thiazole-5-carbothioamide (240 mg, 0.62 mmol) and methyl 4-chloroacetoacetate (73 μL, 0.62 mmol) in methanol (3 mL) was heated in a sealed tube at 80-85° C. overnight. After cooling, the mixture was diluted with water and extracted with EtOAc. The EtOAc extract was washed twice with water, dried (Na2SO4) and concentrated. The crude material was purified by column chromatography on silica gel (eluting with 30-60% EtOAc/hexanes) to give the title compound as a pale yellow gum.
Reaction SMILES: Br[C:2](=[CH2:12])[CH2:3][C:4]([O:10][CH3:11])([CH3:9])[C:5]([O:7][CH3:8])=[O:6].C(#N)C.BrN1C(=[O:22])CCC1=O.[BrH:24]>ClCCl.O>[Br:24][CH2:12][C:2](=[O:22])[CH2:3][C:4]([O:10][CH3:11])([CH3:9])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: Br
Reactant: C=C(Br)CC(C)(OC)C(=O)OC
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(C)(CC(=O)CBr)OC
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To a 125 mL round-bottom flask, methyl 4-bromo-2-methoxy-2-methylpent-4-enoate (0.525 g, 2.21 mmol) was added acetonitrile (8 mL), water (2 mL) and N-bromosuccinimide (0.493 g, 2.77 mmol). A catalytic amount of 1M HBr was added (0.066 mL, 0.066 mmol). The resulting solution was agitated overnight, diluted with 50 mL of dichloromethane and washed twice with saturated sodium bicarbonate, dried and evaporated. The residue was purified by chromatography on silica gel, eluting with 10% ethyl acetate/hexane to provide the title compound (0.52 g, 92.8% yield) as clear oil.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[F:23])=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:24][CH3:25].[C:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])[CH3:27]>C(Cl)Cl.C(OCC)(=O)C>[ClH:22].[C:26]([N:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=4[F:23])=[N:10][CH:11]=[N:12]3)=[CH:7][C:6]=2[O:24][CH3:25])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCBr
Reactant: CC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN1CCN(C(C)=O)CC1
Product: Cl
Yield: 170.2 %

Procedure:
7-(2-Bromoethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (150 mg, 0.35 mmol) and 1-acetylpiperazine (135 mg, 1 mmol) were heated together at 140° C. for 10 minutes. The mixture was allowed to cool and was dissolved in a mixture of methylene chloride/ethyl acetate. The solution was washed with water, and then brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (9/1). The purified product was dissolved in methylene chloride and 2.9M ethereal hydrogen chloride was added. The precipitate was collected by filtration, washed with ether and dried under vacuum to give 7-(2-(4-acetylpiperazin-1-yl)ethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (152 mg, 79%).