Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[CH:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[SH:51][C@@H:52]1[CH2:56][N:55]([C:57]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=2)=[O:58])[C@H:54]([C:70]([N:72]2[CH2:76][CH2:75][C@H:74]([N:77]3[CH:81]=[N:80][CH:79]=[N:78]3)[CH2:73]2)=[O:71])[CH2:53]1>C(#N)C>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[C:8]([S:51][C@@H:52]3[CH2:56][N:55]([C:57]([O:59][CH2:60][C:61]4[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=4)=[O:58])[C@H:54]([C:70]([N:72]4[CH2:76][CH2:75][C@H:74]([N:77]5[CH:81]=[N:80][CH:79]=[N:78]5)[CH2:73]4)=[O:71])[CH2:53]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: O=C([C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](n2cncn2)C1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](n5cncn5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 70.1 %

Procedure:
486 mg of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate were dissolved in 5 ml of dry acetonitrile, and 379 mg of diphenylphosphoryl chloride and 182 mg of diisopropylethylamine were added dropwise, with ice-cooling, to the resulting solution. The mixture was then stirred at the same temperature for 1 hour. At the end of this time, a solution of 173 mg of diisoproylethylamine and 690 mg of (2S,4S)-4-mercapto-2-[(3S)-3-(1-1,2,4-triazolyl)-1-pyrrolidinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 119) in 4 ml of dry acetonitrile was added dropwise with ice-cooling, to the resulting mixture, and the mixture was stirred at the same temperature for 6 hours. The solvent was then removed by distillation under reduced pressure, and the resulting residue was dissolved in ethyl acetate. The resulting solution was then washed with water, with an aqueous solution of sodium hydrogencarbonate, again with water and finally with a saturated aqueous solution of sodium chloride. The aqueous layer was extracted with methylene chloride, and the aqueous layer was combined with the washings and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography, using a 5:1 by volume mixture of ethyl acetate and methanol as the eluent, to obtain 744 mg of the title compound, as a powder.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:12].IC.[C:15](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[C:3]([O:12][CH3:15])=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:11])[F:9]
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(C(F)(F)F)c1F
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccc(C(F)(F)F)c1F
Temperature: 0 °C
Reaction time: 17 h
Yield: 90.7 %

Procedure:
A mixture of 2-fluoro-3-(trifluoromethyl)-phenol (4.87 g, 27.04 mmol) and iodomethane (4.60 g, 32.4 mmol) in acetone (50 mL) is cooled to 0° C. and then 325 mesh potassium carbonate (4.48 g, 32.4 mmol) is added. The reaction is warmed to rt and stirred for 17 hours under N2. The reaction filtered to remove the solids, and the filtrate is acidified with 1 N HCl. The mixture is diluted with water and extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford 4.76 g (91%) of 2-fluoro-3-methoxybenzotrifluoride that is utilized without purification. Rf=0.35 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3).
Reaction SMILES: [CH3:1][NH2:2].Cl[CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=2)[N:6]=1>C1(C)C=CC=CC=1>[CH3:1][NH:2][CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=2)[N:6]=1
Reactant: O=[N+]([O-])c1ccc2nc(CCl)ccc2c1
Reactant: CN
Solvent: Cc1ccccc1
Product: CNCc1ccc2cc([N+](=O)[O-])ccc2n1
Temperature: 20 °C

Procedure:
Methylamine (g) was bubbled through a stirring solution of 2-(chloromethyl)-6-nitroquinoline (5.00 g, 22.47 mmol) in toluene (70 mL) at 0° C. The mixture was slowly warmed to 20° C. over 4 hours, concentrated to 1/2 volume, and partitioned between 10% aqueous K2CO3 /ethyl acetate. The organic phase was dried (MgSO4), decolorized (charcoal) and concentrated. Yield: 4.89 g as a brown solid which was used without purification.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]3[S:16][CH:15]=[C:14]([CH2:17][C:18]4[CH:22]=[CH:21][S:20][CH:19]=4)[C:11]=3[S:12][CH:13]=2)=[CH:4]1.[CH2:23](Br)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].O>C1COCC1>[S:20]1[CH:21]=[CH:22][C:18]([C:17]([C:14]2[C:11]3[S:12][CH:13]=[C:9]([C:8]([C:5]4[CH:6]=[CH:7][S:3][CH:4]=4)([CH2:7][CH2:6][CH2:5][CH2:8][CH2:9][CH2:10][CH2:11][CH3:14])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:10]=3[S:16][CH:15]=2)([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19]1
Reactant: CCCCCCCCBr
Reactant: c1cc(Cc2csc3c(Cc4ccsc4)csc23)cs1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCC(CCCCCCCC)(c1ccsc1)c1csc2c(C(CCCCCCCC)(CCCCCCCC)c3ccsc3)csc12

Procedure:
To a suspension of sodium hydride in THF is added a THF solution of 3,6-bis(thiophen-3-ylmethyl)thieno[3,2-b]thiophene. Octyl bromide is then added and the mixture is refluxed until reaction completion, as determined by TLC. The reaction is then poured into cold water, extracted with MTBE and combined organic phases are washed with water. After drying the organic phase with magnesium sulfate and filtering through Buchner the solvent is evaporated. The resulting product can be purified by column chromatography.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([C:12]1[CH:26]=[CH:25][C:15]([CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH:14][CH:13]=1)=O)#[N:2].[OH:27]O.[OH-].[Na+]>C1COCC1.[Cl-].[Na+].O>[OH:27][C:1]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:9]=[C:10]([C:12]2[CH:26]=[CH:25][C:15]([CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)[N:2]=1
Reactant: CCOP(=O)(Cc1ccc(C(=O)Nc2ccccc2C#N)cc1)OCC
Reactant: OO
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1ccc(-c2nc(O)c3ccccc3n2)cc1)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Diethyl 4-[N-(2-cyanophenyl)carbamoyl]benzylphosphonate (11.2 g) was dissolved in 100 ml of THF and cooled with ice water. After adding 50 ml of a 30% hydrogen peroxide aqueous solution containing 1.2 g of sodium hydroxide dropwise, the reaction mixture was stirred at room temperature for 16 hours. Saturated brine (50 ml) was added, and the reaction mixture was extracted with chloroform. The chloroform layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was dissolved in 150 ml of ethanol and 20 ml of a 2N sodium hydroxide solution and stirred at room temperature for 6 hours. Saturated brine (150 ml) was added, and the reaction mixture was extracted with chloroform. The chloroform layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was recrystallized with methylene chloride-diethyl ether to give 5.9 g of diethyl 4-(4-hydroxyquinazolin-2-yl)benzylphosphonate as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18](=O)[CH2:19]Br)[O:17][C:13]=2[CH:12]=[C:11]([Cl:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:23][C:24]1[S:28][C:27]([NH2:29])=[N:26][N:25]=1.CC(O)C>>[CH2:1]([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18]3[N:29]=[C:27]4[N:26]([CH:19]=3)[N:25]=[C:24]([Br:23])[S:28]4)[O:17][C:13]=2[CH:12]=[C:11]([Cl:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nnc(Br)s1
Reactant: O=C(CBr)c1cc2c(OCc3ccccc3)cc(Cl)cc2o1
Solvent: CC(C)O
Product: Clc1cc(OCc2ccccc2)c2cc(-c3cn4nc(Br)sc4n3)oc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A sealable vessel was charged with 1-(4-(benzyloxy)-6-chlorobenzofuran-2-yl)-2-bromoethanone (Example 37F, 1.48 g, 3.51 mmol), 5-bromo-1,3,4-thiadiazol-2-amine (0.632 g, 3.51 mmol) and IPA (25 mL, 324 mmol). The reaction mixture was heated in an oil bath at 80° C. for 6 hours then heated in the microwave at 150° C. for 1 hour. The reaction mixture was allowed to stand for 1 hour and the insoluble material was filtered off and rinsed with MeOH to give the desired product as a brown solid (1.19 g, 2.58 mmol, 73.6% yield). LC (Method A): 2.549 min. LCMS (APCI) calcd for C19H12BrClN3O2S [M+H]+ m/z 459.95. found 460.0. 1H NMR (CDCl3, 400 MHz) δ ppm: 8.74 (s, 1H), 7.55-7.50 (m, 2H), 7.45-7.34 (m, 4H), 7.17 (d, J=0.8 Hz, 1H), 7.02 (d, J=1.6 Hz, 1H), 5.32 (s, 2H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:23]([O:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[CH2:23]([O:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33][C:13]1([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)C1CCCCC1
Reactant: ClCc1ccccc1OCc1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccccc2OCc2ccccc2)CCCCC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 69.5 %

Procedure:
Under anhydrous conditions and a nitrogen atmoshere a solution of 8.7 g (0.086 mole) diisopropylamine in 250 ml tetrahydrofuran was cooled to -78° C. and 1.6M n-butyllithium (53.75 ml, 0.086 mole) was added dropwise over ten minutes. The mixture was stirred for 45 minutes, allowed to warm to 0° C. and 12.2 g (0.086 mole) methyl cyclohexancarboxylate was added. Stirring was continued for 45 minutes and then 20 g (0.086 mole) 2-benzyloxybenzyl chloride in 20 ml tetrahydrofuran was added dropwise. The resulting mixture was stirred at room temperature for 24 hours, quenched by addition of 150 ml 3M acetic acid and stirred at room temperature for one week. The mixture was diluted with ethyl ether, washed with sodium bicarbonate solution, brine, dried (MgSO4) and concentrated to a yellow oil, 29.3 g. This was distilled to obtain 20.23 g (70%) of viscous oil, b.p. 135°-140° C. (0.4 Torr).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[CH2:4][C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:6]=1[C:15]#[C:16][C:17]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=[C:19]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)[N:18]=1>CCOC(C)=O.C(N(CC)CC)C.[Pd]>[CH3:1][O:2][C:3](=[O:47])[CH2:4][C:5]1[C:10]([C:11]([F:12])([F:13])[F:14])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:15][CH2:16][C:17]1[C:22]([C:23]([F:25])([F:26])[F:24])=[CH:21][N:20]=[C:19]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]3[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH2:39]3)=[CH:30][CH:29]=2)[N:18]=1
Reactant: COC(=O)Cc1c(C#Cc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)cccc1C(F)(F)F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1c(CCc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)cccc1C(F)(F)F
Reaction time: 20 h

Procedure:
A suspension of tert-butyl 4-(4-((4-((2-(2-methoxy-2-oxoethyl)-3-(trifluoromethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A94) (0.127 g, 0.192 mmol) and 10% Pd/C (53% water; 0.234 g) in EtOAc (4.0 mL) and triethylamine (0.2 mL) was stirred under a hydrogen atmosphere for 20 hours. The resulting mixture was filtered through Celite and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15-30% EtOAc in petroleum benzine 40-60° C.) to give the title compound A95 (0.106 g, 83%); 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.56 (m, 3H), 7.46 (d, J=7.3 Hz, 1H), 7.36 (m, 2H), 7.21 (d, J=8.5 Hz, 2H), 4.25 (m, 2H), 3.98 (s, 2H), 3.68 (s, 3H), 3.11 (m, 4H), 2.81 (m, 2H), 2.64 (m, 1H), 1.83 (m, 2H), 1.62 (m, 2H), 1.49 (s, 9H). LCMS-A: rt 7.19 min; m/z 665.1 [M−H]−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[CH3:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]([Cl:22])=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:22].[CH3:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: Cc1ccccc1/C=C/C(=O)Cl
Reactant: Nc1ccccc1Nc1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1ccccc1/C=C/c1nc2ccccc2n1-c1ccccn1

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-2-methylcinnamoyl chloride (Sekiya, T.; Hiranuma, H.; Hata, S.; Mizogami, S.; Hanazuka, M.; Yamada, S. J. Med. Chem., 1983, 26, 411) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound. MW: 347.85; mp: 212.0-215.0° C.; 1H-NMR (CDCl3) δ: 9.26 (1H, d, J=16.1 Hz), 8.89-8.83 (1H, m), 8.24-8.12 (2H, m), 7.72-7.64 (2H, m), 7.59-7.43 (4H, m), 7.43-7.11 (3H, m), 6.92 (1H, d, J=16.1 Hz), 2.70 (3H, s).
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].O.NN>CO.[Ni]>[NH:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CC(=O)Nc1ccc(N)cc1

Procedure:
1.688 g (9.38 mmol) p-acetamino nitrobenzene is dissolved in 10 ml of anhydrous methanol. Suitable amount, i.e., 0.1266 g Raney-Ni and 0.83 g (14.1 mmol, 85%) hydrazine hydrate is added to the solution. The mixture is reacted for 6 hours, and then suction filtered. The filtrate is concentrated to give a product, p-acetamino aniline. The yield reaches the theoretical value.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1.Br.[N+:12]([CH:15]=[C:16](SC)[S:17][CH3:18])([O-:14])=[O:13]>>[N+:12]([CH:15]=[C:16]([S:17][CH3:18])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1)([O-:14])=[O:13]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCSCc1ccon1
Agent: Br
Product: CSC(=C[N+](=O)[O-])NCCSCc1ccon1

Procedure:
By the procedure of Example 8(i), 3-[(2-aminoethyl)thiomethyl]isoxazole (from the hydrobromide (3.7 g)) is reacted with 1-nitro-2,2-bis-methylthioethylene (3.5 g) to give 1-nitro-2-methylthio-2-[2-(3-isoxazolylmethylthio)ethylamino]ethylene (3.6g) which, on reaction with methylamine by the procedure of Example 8(ii) gives the title product (3.0 g).
Reaction SMILES: Br[CH2:2][C@H:3]1[CH2:14][C@H:13]2[C:15]3[C:9]([CH2:10][CH2:11][CH2:12]2)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4]1.[C-:16]#[N:17].[Na+].O>CS(C)=O>[CH2:4]1[C:5]2=[C:15]3[C:9](=[CH:8][CH:7]=[CH:6]2)[CH2:10][CH2:11][CH2:12][C@H:13]3[CH2:14][C@@H:3]1[CH2:2][C:16]#[N:17]
Reactant: [C-]#N
Reactant: BrC[C@@H]1Cc2cccc3c2[C@@H](CCC3)C1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC[C@@H]1Cc2cccc3c2[C@@H](CCC3)C1

Procedure:
A solution of 1.6 g cis-2-bromomethyl-2,3,3a,4,5,6-hexahydro-1H-phenalene 13 and 330 mg NaCN in 7 ml DMSO (dimethylsulphoxide) was heated at 80°-85° C. for 4 hours. The reaction mixture was then poured into 50 ml water and the product extracted with ether. The organic layer was washed with water, dried and evaporated. This yielded 1.2 g of the nitrile 14.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[C@H:11]1[C@@H:18]2[N:14]([C:15](=[O:32])[N:16]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]([C:30]#[N:31])=[CH:22][CH:21]=3)[C:17]2=[O:19])[CH2:13][CH2:12]1>C(Cl)Cl>[F:7][CH:11]1[CH:18]2[N:14]([C:15](=[O:32])[N:16]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]([C:30]#[N:31])=[CH:22][CH:21]=3)[C:17]2=[O:19])[CH2:13][CH2:12]1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2ccccc12
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(N2C(=O)C3C(F)CCN3C2=O)c2ccccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of diethylaminosulfur trifluoride (0.073 mL, 0.45 mmol) in CH2Cl2 (2 mL) cooled at −78° C. in a flame-dried flask under argon was added dropwise a solution of 6C (92 mg, 0.3 mmol) in CH2Cl2 (12 mL). After addition, the reaction mixture was stirred at −78° C. for 30 min, then at 0° C. overnight. The reaction mixture was partitioned between CH2Cl2 and saturated aqueous NaHCO3. The separated aqueous layer was extracted with CH2Cl2 (2×). The combined CH2Cl2 layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was chromatographed (silica gel) eluting with EtOAc/hexane (1:2) to give 52 mg of the title compound (racemate) as a white solid. m.p. 228-230° C.; HPLC: 99% at 5.0 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 641 [2M+Na]+.
Reaction SMILES: [CH:1](OCC)=[O:2].[H-].[Na+].[CH3:8][O:9][C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][CH2:15][C:16]2=[O:19])=[CH:12][CH:11]=1.O>C1C=CC=CC=1>[OH:2][CH:1]=[C:15]1[CH2:14][C:13]2[C:17](=[CH:18][C:10]([O:9][CH3:8])=[CH:11][CH:12]=2)[C:16]1=[O:19]
Reactant: CCOC=O
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc2c(c1)C(=O)C(=CO)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a mixture of ethyl formate (15.75 mL, 0.195 mol) and NaH (60%, 7.80 g, 0.195 mol) in benzene (550 mL) was added a suspension of 6-methoxy-indan-1-one (15.81 g, 0.0974 mol) in benzene (150 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature overnight and treated with water. The solid was filtered, washed with water, and oven dried to give the desired product (16.86 g, 91%). The product may exist in sodium salt form, however, it was carried into the next reaction without further characterization. MS (DCI/NH3) m/z: 191.1 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 3.50 (s, 2H) 3.80 (s, 3H) 7.13-7.20 (m, 2H) 7.47 (d, J=8.14 Hz, 1H) 7.74 (s, brd, 1H).
Reaction SMILES: C[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=S.[Cl-].[Al+3].[Cl-].[Cl-].Cl.[C:18](=S)=[S:19]>>[CH3:18][S:19][C:9]1[CH:10]=[CH:11][CH:12]=[C:2]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:8]
Reactant: S=C=S
Reactant: Cc1ccccc1C=CC(O)=S
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CSc1cccc2c1CCC2=O
Reaction time: 3 h

Procedure:
To a solution of 50 g of o-methylthiocinnamic acid in 500 ml of carbon disulfide was gradually added with stirring 34 g of aluminum chloride, and the resulting mixture was then boiled with stirring for 3 hours. The reaction liquid after reaction was poured into a cooled 1 N aqueous hydrochloric acid solution and extracted with ethyl acetate. The ethyl acetate solution was washed with an aqueous potassium carbonate solution, followed by water-washing and then drying over anhydrous sodium sulfate, to remove the solvent therefrom. The residue was purified by column chromatography to obtain 18 g of the title compound.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3](=[O:9])[CH2:2]2.Cl[C:11]1[O:12][C:13]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:14]=2[N:15]=1>>[OH:20][C:18]1[CH:17]=[CH:16][C:14]2[N:15]=[C:11]([N:8]3[CH:5]4[CH2:6][CH2:7][CH:1]3[CH2:2][C:3](=[O:9])[CH2:4]4)[O:12][C:13]=2[CH:19]=1
Reactant: O=C1CC2CCC(C1)N2
Reactant: Oc1ccc2nc(Cl)oc2c1
Product: O=C1CC2CCC(C1)N2c1nc2ccc(O)cc2o1

Procedure:
By a method similar to Example 1, step F, and using 8-azabicyclo[3.2.1]octan-3-one and 2-chloro-1,3-benzoxazol-6-ol, the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH:8](=[O:11])[CH2:9][CH3:10].C([N-]C(C)C)(C)C.[Li+]>C(OCC)C>[Br:1][C:2]1[C:3]([CH:8]([OH:11])[CH2:9][CH3:10])=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: CCC=O
Reactant: Brc1cncnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Product: CCC(O)c1ncncc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
To 5-bromopyrimidine (2.39 g, 15.0 mmol) and propionaldehyde (1.05 g, 18.0 mmol) in diethyl ether (80 mL), lithium diisopropylamide (18 mmol) in diethyl ether (20 mL) was gradually added dropwise at 0° C. After the dropwise addition, the reaction mixture was warmed to room temperature and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was extracted by adding water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=2.5/1) to give a mixture (colorless oil) containing the desired product, which was used for the next step (427 mg, 13% yield). 2-[1-(5-Bromopyrimidin-4-yl)propyl]isoindoline-1,3-dione
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]([OH:22])[CH3:21])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[CH2:28].CC([O-])=O.[Na+]>CN(C=O)C.CS(C)=O>[C:24]1([CH3:23])[CH:31]=[CH:30][CH:29]=[C:26]([CH:27]=[CH:28][C:2]2[S:6][C:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]4[CH:15]=[C:16]([CH:20]([OH:22])[CH3:21])[CH:17]=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=2)[CH:25]=1
Reactant: CC(O)c1cccc(Nc2nccc(-c3ccc(Br)s3)n2)c1
Reactant: C=Cc1cccc(C)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: Cc1cccc(C=Cc2ccc(-c3ccnc(Nc4cccc(C(C)O)c4)n3)s2)c1
Temperature: 100 °C
Yield: 4.3 %

Procedure:
1-{3-[4-(5-Bromothiophen-2-yl)pyrimidin-2-ylamino]-phenyl}-ethanol (20 mg, 0.056 mmol), 3-methylstyrene (22 uL, 0.168 mmol), FibreCat1001 (12 mg, 0.0056 mmol), and NaOAc (9.2 mg, 0.112 mmol) were combined in degassed DMF (0.5 mL) in an 8-mL glass vial. The reaction was heated at 100° C. for 18 hours. The mixture was diluted with DMSO, filtered and purified by preparative LCMS to afford 1-(3-{4-[5-(2-m-tolyl-vinyl)-thiophen-2-yl]-pyrimidin-2-ylamino}-phenyl)-ethanol (1.0 mg, 4.3%). 1H NMR (500 MHz, DMSO-d6) δ 1.35 (d, J=6 Hz, 3H), 2.27 (s, 3H), 4.68 (q, J=6 Hz, 1H), 5.12 (br s, 1H), 6.90 (d, J=7.5 Hz, 1H), 6.98 (d, J=16.5 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H), 7.18-7.26 (m, 3H), 7.32 (d, J=8 Hz, 1H), 7.38 (Br s, 1H), 7.41 (d, J=16 Hz, 1H), 7.50 (dd, J=1.5 Hz, J=8.5 Hz, 1H), 7.87 (d, J=4 Hz, 1H), 7.92 (br s, 1H), 8.34 (s, 1H), 8.40 (d, J=5 Hz, 1H), 9.57 (s, 1H). MS: m/z 414 (M+H+).