Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:3]=1[C:4]#[N:5].Br[CH:12]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH:13]=O>CCO.CCOC(C)=O>[Br:10][C:6]1[CH:7]=[CH:8][N:9]2[C:12]([CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:13][N:1]=[C:2]2[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(Br)ccnc1N
Reactant: O=CC(Br)CC(F)(F)F
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1c(Br)ccn2c(CC(F)(F)F)cnc12
Temperature: 150 °C
Yield: 48.8 %

Procedure:
A mixture of compounds D8 (2 g, 10.1 mmol) and D4 (2.898 g, 14.14 mmol) in EtOH (10 ml) was subjected to microwave heating at 150° C. for 40 min. After cooling to room temperature, the solvent was evaporated in vacuo. The residue thus obtained was diluted with EtOAc and washed with water. The organic layer was separated and washed with water, then with 1M HCl (aqueous solution), dried (MgSO4) and evaporated in vacuo. The crude product thus obtained was triturated with diethylether to yield compound D9 (1.5 g, 48.8%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].Cl[C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[N:9]=[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:26][CH2:27][CH3:28])[N:7]=1.C(#N)C.C1COCC1>O>[CH2:27]([S:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:8]1[N:7]=[C:6]([NH:4][CH2:1][CH2:2][CH3:3])[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:17])([F:18])[F:19])=[CH:13][CH:14]=2)[N:9]=1)[CH3:28]
Reactant: CCSc1ccccc1-c1nc(Cl)c2ccc(C(F)(F)F)cc2n1
Reactant: CCCN
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: CCCNc1nc(-c2ccccc2SCC)nc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.5 ml of n-propylamine was added to a mixture of 450 mg of 4-chloro-2-(2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline, 3 ml of acetonitrile and 3 ml of THF, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 495 mg of 2-(2-ethylsulfanylphenyl)-4-propylamino-7-trifluoromethylquinazoline (Compound of Present Invention 8).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.Cl.N[C:22]1[C:23]([CH3:29])=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1.C([N:33](C(C)C)CC)(C)C>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([N:8]([C:27]3[CH:22]=[C:23]([CH3:29])[CH:24]=[C:25]([OH:28])[CH:26]=3)[C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH2:33])[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(O)ccc1N
Agent: Cl
Product: Cc1cc(O)cc(N(c2ccc3c(c2)OCCO3)c2nc(N)ncc2F)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 4-amino-m-cresol hydrogenchloride salt, and diisopropylethylamine were reacted to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-(3-hydroxy-5-methylphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.06 (s, 1H), 8.94 (s, 1H), 8.11 (s, 1H), 7.86 (d, 1H, J=3.9 Hz), 7.21-7.15 (m, 2H), 7.03 (d, 1H, J=8.1 Hz), 6.59 (bd, 2H, J=8.7 Hz), 6.52 (dd, 1H, J=3.0 and 8.1 Hz), 4.17 (s, 4H), 2.05 (s, 3H); LCMS: purity: 99%; MS (m/e): 369 (MH+).
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3]([NH2:5])=O.F[B-](F)(F)F.C([O+](CC)CC)C.N[C:20]1[C:21]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[OH:1][C@@H:2]([C:3]1[N:29]([C@H:30]2[CH2:31][CH2:32][C@H:33]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:34][CH2:35]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:5]=1)[CH3:6]
Reactant: C[C@@H](O)C(N)=O
Reactant: CCOC(=O)C[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C[C@H]1CC[C@H](n2c([C@@H](C)O)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2R)-2-hydroxypropanamide (170 mg, 1.9 mmol) and triethyloxonium tetrafluoroborate (0.36 g, 1.9 mmol) in tetrahydrofuran (2 mL) was stirred at room temperature for 1 h and then concentrated. A mixture of ethyl {trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}acetate (150 mg, 0.45 mmol) and the above made reagent in ethanol (4.8 mL) was heated at reflux for 2 h. The mixture was concentrated and purified on silica gel column (eluting with 0-5% MeOH in methylene chloride) to give the desired product (0.15 g, 86%). LCMS calculated for C20H26N3O3S (M+H)+: m/z=388.2. Found: 388.1.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([F:18])[CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)C1C=CC=CC=1>CCO.CO.[OH-].[OH-].[Pd+2]>[F:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][CH:20]=1)[NH:8][CH2:17][CH2:16]2
Reactant: Fc1cccc2c1C(c1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: Fc1cccc2c1C(c1ccc(C(F)(F)F)cc1)NCC2

Procedure:
A solution of 2-benzyl-8-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-isoquinoline (0.7 g, 2.1 mmol) in EtOH (20 mL) was stirred with 20% Pd(OH)2/C (0.20 g) under hydrogen atmosphere at 50 psi and at RT for 3 h. The reaction mixture was filtered through a celite pad and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC [gradient 10-90% MeCN (0.1% TFA)/H2O (0.1% TFA)] to give the pure product which was dissolved in methanol (10 mL) and neutralized by passing the solution through a Polymer Lab-HCO3 Macroporous resin cartridge, and the filtrate was concentrated to give 8-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline as an off-white solid. MS (ESI pos. ion) m/z: 296 (M+1).
Reaction SMILES: [C:1]([CH:8]([CH:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[OH:11])[OH:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClCCl.C(N(CC)CC)C.[CH2:29]([O:31][P:32](Cl)(=[O:36])[O:33][CH2:34][CH3:35])[CH3:30]>O>[CH2:29]([O:31][P:32]([O:11][C@H:10]([C@@H:8]([OH:9])[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([O:33][CH2:34][CH3:35])=[O:36])[CH3:30]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CC(C)(C)OC(=O)C(O)C(O)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOP(=O)(OCC)O[C@@H](C(=O)OC(C)(C)C)[C@@H](O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 33.4 %

Procedure:
(Step 1) To di-tert-butyl tartrate (182 mg, 0.692 mmol), dichloromethane (1.73 mL), triethylamine (0.145 mL, 1.04 mmol), and diethylchlorophosphoric acid (0.050 mL, 0.346 mmol) were added, and the resulting mixture was stirred at room temperature for 20 hours. To the reaction mixture, water was added, and the resulting mixture was extracted with chloroform. The organic layer was dried, over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica, gel column chromatography (ethyl acetate/n-hexane=5/95 to 30/70), whereby di-tert-butyl (2R,3R)-2-(diethoxyphosphoryloxy)-3-hydroxysuccinate (46 mg, 33%) was obtained.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19](F)=[C:20]([F:25])[CH:21]=2)[NH:16][C:15]1=[O:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:20]([F:25])[CH:21]=2)[NH:16][C:15]1=[O:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: O=c1[nH]c2cc(F)c(F)cc2c(=O)n1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=c1[nH]c2cc(N3CCCC3)c(F)cc2c(=O)n1OCc1ccccc1
Yield: 86.6 %

Procedure:
Pyrrolidine (0.065 mL, 0.8 mmol) was added to a solution of 3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example B, 0.2 g, 0.65 mmol) and triethylamine (0.18 mL, 1.2 mmol) in 30 mL of acetonitrile. The solution was warmed to reflux for 18 hours, cooled, and filtered to give 0.2 g of the title compound as a solid, mp>250° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[F:19][C:20]([F:36])([F:35])[C:21]([C:27]1[N:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][CH:28]=1)([OH:26])[C:22]([F:25])([F:24])[F:23].[OH-].[Na+]>CO.O.C(Cl)(Cl)Cl>[F:25][C:22]([F:23])([F:24])[C:21]([C:27]1[N:32]=[C:31](/[CH:33]=[C:8]2/[C:9](=[O:12])[C:10]3[C:6]([CH2:7]/2)=[CH:5][C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[C:3]([O:2][CH3:1])[CH:11]=3)[CH:30]=[CH:29][CH:28]=1)([OH:26])[C:20]([F:36])([F:35])[F:19]
Reactant: O=Cc1cccc(C(O)(C(F)(F)F)C(F)(F)F)n1
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cccc(C(O)(C(F)(F)F)C(F)(F)F)n1)C2=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (0.1 g, 0.40 mmol)) in MeOH/H2O (1:1) was added 6-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)picolinaldehyde 262 (0.132 g, 0.485 mmol), NaOH (0.032 g, 0.80 mmol), and the reaction stirred at RT for 6 h. The reaction mass was diluted with chloroform and washed with water (3×25 ml). The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified through flash chromatography by using 100-200 mesh silica gel. The compound 265 was eluted at 30% ethyl acetate in hexane to afford yellow coloured solid (E)-2-((6-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-2-yl)methylene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 265.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([C:15]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[CH2:20][CH2:19][C:18](=[O:21])[CH:17]=[CH:16]2)[CH:12]=[CH:13][CH:14]=1.C(O[CH2:34][N:35]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:36][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:41]([N:35]1[CH2:36][CH:17]2[CH:16]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([F:8])[CH:10]=3)[CH2:20][CH2:19][C:18]2=[O:21])[CH2:34]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C1C=CC(c2cccc(F)c2)(c2cccc(F)c2)CC1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(c2cccc(F)c2)(c2cccc(F)c2)C2CN(Cc3ccccc3)CC12
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (3 cc) is added to a solution of 4,4-bis(3-fluorophenyl)cyclohexenone (90.3 g) and N-butoxymethyl-N-(trimethylsilylmethyl)benzylamine (123 cc) in dry dichloromethane (1000 cc). The reaction mixture is brought to reflux, then stirred for 2 hours while allowing the temperature to return to 25° C. and for a further 15 minutes after the addition of potassium carbonate (60 g). After filtration and concentration to dryness under reduced pressure (2.7 kPa), the crystallized residue is stirred vigorously with isopropyl ether, drained, washed and recrystallized in cyclohexane (300 cc). The crystals are drained, washed with cyclohexane (2×15 cc) and dried to give (3aRS,7aRS)-2-benzyl-7,7-bis(3-fluorophenyl)perhydro-4-isoindolone (92 g) in the form of white crystals. M.p. 124° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(N(CC)CC)C.[C:21](=S)=[S:22].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[N:13]([CH2:12][CH2:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[C:21]=[S:22]
Reactant: COc1cc(CCN)cc(OC)c1
Reactant: S=C=S
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(CCN=C=S)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.7 %

Procedure:
To a solution of 1.0 mL (1.0 g, 5.5 mmol) of 2-(3,5-dimethoxyphenyl)ethanamine (8) in 30 mL of THF was added dropwise 2.5 mL (1.8 g, 18.2 mmol) of triethylamine at 0° C. After stirring for 5 min, a solution of 420 mg (5.52 mmol) of carbon disulfide in 5 mL of THF was added dropwise at 0° C. The resulting solution was slowly warmed to room temperature, stirred for 1.5 h and then cooled to 0° C. To the reaction mixture was added 1.16 g (6.07 mmol) of tosyl chloride in one portion and solution stirred at room temperature for an additional hour. The reaction was quenched by slowly adding 30 mL of saturated NH4Cl(aq). The layers were separated and the aqueous phase was extracted once with ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was taken up in methylene chloride and filtered through a plug of silica gel (eluted with methylene chloride) and concentrated in vacuo to afford 1.2 g (100%) of 9 as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 6.37 (s, 3H), 3.80 (s, 6H), 3.71 (t, J=7.0 Hz, 2H), 2.92 (t, J=7.0 Hz, 2H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1([CH3:52])[CH2:18][O:17][C:16]2([CH2:23][CH2:22][CH:21]([N:24]3[C:29](=[O:30])[C:28]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=5)=[CH:34][CH:33]=4)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]4[N:49]=[CH:50][N:51]=[C:25]34)[CH2:20][CH2:19]2)[O:15]1>C(OCC)(=O)C>[CH3:52][C:14]1([CH3:13])[CH2:18][O:17][C:16]2([CH2:19][CH2:20][CH:21]([N:24]3[C:29](=[O:30])[C:28]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=5[C:44]5[NH:3][C:4](=[O:7])[O:5][N:45]=5)=[CH:34][CH:33]=4)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]4[N:49]=[CH:50][N:51]=[C:25]34)[CH2:22][CH2:23]2)[O:15]1
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCC(C)(C)O3)c2ncnn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC3(CC2)OCC(C)(C)O3)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 45.1 %

Procedure:
A mixture of hydroxylammonium chloride (0.39 g), sodium hydrogen carbonate (0.63 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-(2,2-dimethyl-1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.2 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.072 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.061 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.1 g, 47%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9](Br)[S:8][CH:7]=1)=[O:5])[CH3:2].[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOCC>O.COCCOC>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)[S:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(Br)c1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOCC
Solvent: COCCOC
Product: CCOC(=O)c1csc(-c2ccncc2)c1
Temperature: 140 °C
Yield: 2.9 %

Procedure:
5-Bromo-thiophene-3-carboxylic acid ethyl ester (5.26 mmol), 4-pyridylboronic acid (5.26 mmol), caesium carbonate (7.9 mmol) and palladium (0) tetrakis-triphenylphosphine (0.53 mmol) were dissolved in a mixture of water (10 mL), IMS (20 mL) and DME (50 mL). The reaction mixture was heated by microwave irradiation to 140° C. for 10 minutes, and then ether (100 mL) and water (20 mL) were added. The organic solution was washed with water, dried with anhydrous magnesium sulfate, filtered and the solvent evaporated to give brown oil. The residue was purified by flash chromatography on silica. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.035 g) as an off-white solid. LCMS m/z 234.04 [M+H]+ R.T.=2.10 min. (Analytical Method 5).
Reaction SMILES: [CH:1]1([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:14][CH:13]=2)[C:9]([OH:11])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(C2C=CC([O:45][CH2:46]C3C=CC4C(=CC=CC=4)N=3)=CC=2)C(O)=O)CCCC1.C1C2C(=CC=CC=2)C=CC=1COC1C=C(C([O:85][N:86]=CC(O)=O)CCCC2C=CC=CC=2)C=CC=1.N>>[OH:85][N:86]([O:45][CH3:46])[C:9](=[O:11])[CH:8]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)=[CH:14][CH:13]=1
Reactant: O=C(O)C=NOC(CCCc1ccccc1)c1cccc(OCc2ccc3ccccc3c2)c1
Reactant: O=C(O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCC1
Reactant: O=C(O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCCC1
Agent: N
Product: CON(O)C(=O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCCC1

Procedure:
The desired material was prepared according to the procedures described in Example 4 substituting 2-cycloheptyl-2-[4-(quinolin-2yl-methoxy)phenyl]acetic acid, prepared according to the procedure described in U.S. Pat. No. 4970215, for 2-cyclopentyl-2-[4-(quinolin-2-yl-methoxy)phenyl]acetic acid and Example 6 substituting 2-cycloheptyl-2-[4-(quinolin-2-yl-methoxy)phenyl]-acetic acid for {[1-(3-[2-naphthylmethoxy]-phenyl)4-phenylbutyl]oximino}acetic acid. 1H NMR (DMSO-d6, 300 MHz) δ 0.93 (m, 1H), 1.22 (m, 3H), 1.48 (m, 8H), 2.1 (m, 1H), 3.02 (s, 3H), 3.94 (d, J=7Hz, 1H), 5.33 (s, 2H), 7.0 (d, J=7Hz, 2H), 7.23 (d, J =7Hz, 2H), 7.62 (d-t, J=8Hz, 2Hz, 1H), 7.68 (d, J=8Hz, 1H), 7.8 (d-t, J=8Hz, 2Hz, 1H), 8.0 (t, J=8Hz, 2H), 8.42 (d, J=8Hz, 1H), 9.82 (s, 1H). IR (CDCl3): 3520, 1610 cm-1. MS (DCI/NH3) m/e 419 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:12]=[C:13]1[CH2:16][CH2:15][CH2:14]1>>[CH3:12][C:13]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: C=C1CCC1
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Product: CC1(c2ccccc2)CCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred mixture of benzene (5.0 ml, 56 mmol) and Sulfuric acid (1.17 ml, 21.9 mmol) was cooled to 0° C. and treated dropwise with a solution of Methylenecyclobutane (1.00 ml, 10.8 mmol) in Benzene (3.0 ml, 34 mmol) over-1 h. Upon completion of the addition, the reaction mixture was stirred an additional 1 h while being warmed to RT. The mixture extracted with 15 ml of hexane. The organic phase was washed with 10 ml H2O and 10 ml sat NaHCO3, dried over Na2SO4, filtered and concentrated to yield a colorless liquid. The liquid was purified by kugelrohr distillation (5-10 torr) to yield the desired compound as a colourless liquid. First fraction was collected at 75-85° C. as a colorless liquid (330 mg) of product as a colorless liquid.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[O:4].[F:6][C:7]([F:14])([F:13])[C:8](=[CH2:12])[C:9](Cl)=[O:10].O>CN(C=O)C>[CH3:1][N:2]1[CH2:12][CH:8]([C:7]([F:14])([F:13])[F:6])[C:9](=[O:10])[NH:5][C:3]1=[O:4].[CH3:1][N:2]1[C:9](=[O:10])[CH:8]([C:7]([F:14])([F:13])[F:6])[CH2:12][NH:5][C:3]1=[O:4]
Reactant: CNC(N)=O
Reactant: C=C(C(=O)Cl)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)NCC(C(F)(F)F)C1=O
Product: CN1CC(C(F)(F)F)C(=O)NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %
Yield: 10 %

Procedure:
A solution of methylurea (148 mg; 2.0 mmoles) in DMF (2 ml) was cooled to 0° C., and α-trifluoromethylacryloyl chloride (317 mg; 2.0 mmoles) was added dropwise. The mixture was stirred at room temperature for 1 hour, and water (20 ml) was added. The mixture was extracted with methylene chloride (20 ml×1, 10 ml×2). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by a column chromatography on silica gel (chloroform:ethyl acetate=3:1) to give 39 mg (yield: 10%) of 1-methyl-5-trifluoromethyl-5,6-dihydrouracil (OF-3) and 117 mg (yield: 30%) of 3-methyl-5-trifluoromethyl-5,6-dihydrouracil (OF-2).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].N(OC(C)(C)C)=O.[Br:19][C:20]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:21]=1N>[Cu](F)F.N1C=CC=CC=1>[Br:19][C:20]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:21]=1[O:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10]
Reactant: Nc1ccc(Br)cc1Br
Reactant: CC1(C)CCCC(C)(C)N1O
Agent: F[Cu]F
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Product: CC1(C)CCCC(C)(C)N1Oc1ccc(Br)cc1Br
Yield: 68.3 %

Procedure:
The procedure of Example 1 is repeated using 1.95 g (12.5 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidine, 3.92 g (38 mmol) of tert-butyl nitrite, 12.5 mg (0.125 mmol) of copper(II) fluoride, 120 mL of pyridine and 6.30 g (25 mmol) of 2,4-dibromoaniline at 70° C. The crude product obtained is purified by vacuum flash chromatography (heptane) to give 3.34 g of the title compound as a light yellow oil in 68.5% yield. The structure is confirmed by 1Hnmr analysis.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[NH:30][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:23])[C:15]=3[CH:14]=2)[CH:8]=1)=[O:4].[CH3:31][NH:32][CH3:33]>O1CCOCC1.C(O)C>[CH3:31][N:32]([CH3:33])[CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[NH:30][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:23])[C:15]=3[CH:14]=2)[CH:8]=1)=[O:4]
Reactant: CNC
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3cccc(CNC(=O)CCl)c3)cc12)c1ccccc1
Solvent: CCO
Solvent: C1COCCO1
Product: C[C@@H](Nc1ncnc2[nH]c(-c3cccc(CNC(=O)CN(C)C)c3)cc12)c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 210 mg (0.5 mmol) 2-chloro-N-{3-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide in 3 ml dry dioxane is treated with 268 μl (1.5 mmol) of a 5.6 N dimethylamine solution in ethanol (Fluka, Buchs, Switzerland) and then heated to 100 ° C. for 6 h. The clear yellow solution is cooled and the solvent evaporated. The residue is purified by flash chromatography using a mixture of dichloromethane/methanol with gradually increasing concentrations of methanol starting with 100:2.5 and ending with 100:5 and then switching to dichloromethane/methanol/conc. ammonia starting with 100:5:0.25 and ending with 100:10:0.5. The title compound is obtained as a colorless foam; Rf (dichloromethane/methanol/conc. ammonia 90:10:1)=0.41; MS-ES+: (M+H)+=429.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9]O)[CH2:4][CH2:3]1.[Na].[CH3:12][O:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][N:21]=2)=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=2)=[CH:30][CH:31]=1.[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH3:9])[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(CCc2ccc(OC)cc2)nc1
Reactant: CN1CCN(CCO)CC1
Agent: [Na]
Product: CCN1CCN(C)CC1
Product: COc1ccc(CCc2ccc(C(=O)O)cn2)cc1
Reaction time: 6 h

Procedure:
The apparatus and procedures of Example 3 were used, employing 2-(N-methyl-N'-piperazinyl)ethan-1-ol (21.35 g.), sodium (0.1 g.), methyl 6-p-methoxyphenethylnicotinate (13.56 g.), and a temperature of 170° C. for 6 hours. The crude ester was treated to give the dimaleate of N-methyl-N'-ethylpiperazine 6-p-methoxyphenethylnicotinate, m.p. 200° C.