Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6](=O)[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH:16]1[CH:21]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:13]([CH2:14][CH2:15]1)[CH2:12]2)C>C1COCC1>[C:26]([O:25][C:23](=[O:24])[NH:22][CH:21]1[CH:16]2[CH2:15][CH2:14][CH:13]1[CH2:12][C:11]1[C:18]([CH2:17]2)=[CH:19][CH:20]=[C:9]([O:8][CH2:7][CH2:6][OH:5])[CH:10]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)COc1ccc2c(c1)CC1CCC(C2)C1NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1C2CCC1Cc1cc(OCCO)ccc1C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.1 %

Procedure:
Lithium borohydride (56 mg) was added in a single portion to a stirred solution of the product from Step 2 (1.0 g) in dry THF. (20 mL). The resulting solution was stirred at room temperature for 18 hrs, quenched with NH4Cl (aq. satd 50 mL) and extracted into DCM. The organic extract was dried over MgSO4, filtered and the solvent removed under reduced pressure and the product purified by flash chromatography over silica (200–400 mesh, 10–60% EtOAc/isohexane) to give [5-(2-hydroxy-ethoxy)tricyclo [8.2.1.03,8]trideca-3,5,7-trien-13-yl]-carbamic acid tert-butyl ester as a white solid (340 mg). 1H NMR (CDCl3 400 MHz), δ 1.20 (2H, m), 1.47 (9H, s), 1.69 (2H, m), 2.04 (1H, m), 2.50 (4H, m), 2.96 (2H, m), 3.94 (2H, m), 4.05 (3H, m), 4.99 (1H, brm), 6.62 (1H, dd, J=8.0, 1.0 Hz), 6.67 (1H, d, J=1.0 Hz), 6.98 (1H, d, J=8.0 Hz).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=2)[CH:10]=[CH:9]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH:1]1([C:10]2[C:11]3[C:16](=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=3)[NH:8][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: O=C1CCCCC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Temperature: 10 °C
Reaction time: 12 h
Yield: 85.5 %

Procedure:
Cyclohexanone (42.46 mL, 0.40 mol) was added in a single portion to a stirred solution of methyl indole-6-carboxylate (47.8 g, 0.27 m) in dry dichloromethane (500 mL). The reaction mixture was then cooled to 10° C. and trifluoroacetic acid (63.13 mL, 0.8 m) was added dropwise followed by triethyl silane (174.5 mL, 1.09 m). Upon addition, the temperature was allowed to rise to rt, after which it was stirred for a further 12 h. Dichloromethane (200 mL) was then added and the reaction mixture was washed successively with 10% sodium bicarbonate solution and brine. The organic layer dried over sodium sulfate, filtered and concentrated under vacuum. The resultant residuce was purified by flash chromatography on silica (60-120) using hexane-ethyl acetate (9.5:0.5) mixture as eluant. Homogeneous fractions were combined and evaporated to give 60 g of the desired product (85%). Analytical data on this material was consistant with that observed with a sample prepared by the alternative route described above.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:25]1[CH:30]=[C:29]([CH2:31][NH2:32])[CH:28]=[N:27][CH:26]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>ClCCl.CO>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:32][CH2:31][C:29]3[CH:30]=[N:25][CH:26]=[N:27][CH:28]=3)=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: NCc1cncnc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NCc1cncnc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
In a 50 mL, 3N round-bottomed flask equipped with nitrogen inlet, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.2 g, 1.0 eq.) was charged along with dichloromethane (5 mL, 10V). The reaction mixture was cooled to −20° C. and then added pyrimidine-5-ylmethanamine (0.075 g, 1.2 eq), T3P (50% in EtOAc) (0.4 mL, 1.2 eq) followed by DIPEA (0.2 ml, 2 eq) dropwise into the reaction mixture. The reaction mixture was stirred at −20° C. for another 30 min. The progress of the reaction was followed by TLC analysis on silica gel with 5% Methanol in dichloromethane as mobile phase and visualization with UV. Reaction mixture was concentrated by rotary evaporation (25° C., 20 mm Hg) to afford crude compound. The crude reaction mixture was purified by column chromatography using 60/120 mesh silica and methanol: dichloromethane as mobile phase. The column was packed in dichloromethane and started eluting in MeOH in gradient manner starting with fraction collections (500 mL fractions). The compound started eluting from 4% methanol in dichloromethane. Fractions containing such TLC profile were collected together to obtain pure compound 0.2 g. Yield: 80%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=3)[CH:15]=[CH:16][C:17]=1[CH2:18][CH3:19])[N:5]=2.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[C:31]([C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][CH3:19])=[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:38](=[O:37])[CH2:39][OH:40])=[N:10][C:9]3=[CH:8][CH:7]=2)[CH:13]=1)=[O:33])([CH3:30])[CH3:29])#[N:32]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)CO)sc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.7 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-ethylphenyl}-3-(1-cyano-1-methylethyl)benzamide (150 mg, 0.327 mmol) in pyridine (4.0 mL) was added 2-chloro-2-oxoethyl acetate (56 μL, 0.523 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in methanol (10 mL), potassium carbonate (45 mg, 0.327 mmol) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, neutralized with 1% aqueous citric acid solution, and extracted with ethyl acetate (100 mL). The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→85/15), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate/diisopropyl ether/hexane to give the title compound (73.6 mg, 44%) as a colorless solid.
Reaction SMILES: C([NH:9][CH2:10][C:11]1[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=1)(=O)C1C=CC=CC=1.Cl.Cl.[N:22]1([C:27]2[CH:38]=[CH:37][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])=[CH:29][CH:28]=2)[CH:26]=[CH:25][N:24]=[CH:23]1.[OH-].[Na+].Cl>ClCCl.O>[NH2:9][CH2:10][C:11]1[S:15][C:14]([S:16]([NH:36][CH2:35][CH2:34][CH2:33][CH2:32][O:31][C:30]2[CH:37]=[CH:38][C:27]([N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)=[CH:28][CH:29]=2)(=[O:17])=[O:18])=[CH:13][CH:12]=1
Reactant: O=C(NCc1ccc(S(=O)(=O)Cl)s1)c1ccccc1
Reactant: NCCCCOc1ccc(-n2ccnc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: NCc1ccc(S(=O)(=O)NCCCCOc2ccc(-n3ccnc3)cc2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3.0 g of 5-benzoylaminomethyl-2-thiophenesulfonyl chloride, in 100 ml of dichloromethane, is added to a stirred mixture of 3.0 g of 4-[4-(1H-imidazol-1-yl)phenoxy]butaneamine dihydrochloride (Example 2) and 3.5 ml of 10N NaOH in 100 ml of water. The mixture is stirred at room temperature for 3 hours, a tacky precipitate being formed. The precipitate is mixed with 100 ml of concentrate HCl, and the mixture is stirred at reflux for 12 hours, solution taking place. The solution is taken to dryness in vacuo, and the dihydrochloride salt of the title compound was recrystallized from aqueous ethanol, m.p. 230°-232° C. (dec.); yield, 0.5 g.
Reaction SMILES: C([O:5][C:6](=[O:46])[C@@H:7]([NH:38]C(OC(C)(C)C)=O)[CH2:8][CH2:9][CH2:10][CH2:11][N:12]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])(C)(C)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[NH2:38][C@@H:7]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[C:6]([OH:46])=[O:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN(CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CCCCN(CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 23 h
Yield: 66.9 %

Procedure:
Under argon, 8 (271 mg, 0.422 mmol) was added to a mixture of trifluoroacetic acid (770 mg, 6.7 mmol), CH2Cl2 (3.0 mL), and triethylsilane (330 mg, 2.8 mmol); this was stirred at room temperature for 23 hours. The reaction mixture was concentrated; the resultant oil was dissolved in water (5.0 mL) and adjusted to pH 7 with saturated NaHCO3 solution. This solution was then concentrated; the residue was purified by chromatography on a C-18 column (30% acetone/water, followed by 55% acetone/water) to give 9 (137 mg, 67%) as a colorless oil: 1H NMR (19.7° C.) δ1.30-1.66 (m, 8 H), 1.78 (m, 2 H), 3.09 (m, 2 H), 3.20-3.33 (m, 4 H), 3.45 (m, 1 H), 5.05(s, 2H), 5.09 (s, 2 H), 7.26-7.37 (m, 10 H); HRMS m/z calcd for C26H36N3O6 486.2604, found 486.2614.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:12][O:13][NH:14][CH3:15].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCl.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([N:14]([O:13][CH3:12])[CH3:15])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccnc(Cl)n1
Reactant: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccnc(Cl)n1
Reaction time: 4 h
Yield: 65.7 %

Procedure:
To a solution of 2-chloropyrimidine-4-carboxylic acid (3.95 g, 24.9 mmol) and N-methoxymethanamine hydrogen chloride salt (2.43 g, 24.9 mmol) in dichloromethane (15 mL) were added triethylamine (6.95 mL, 50 mmol) and (benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (13 g, 24.91 mmol) and stirred for 4 hr. The solution was diluted with EtOAc, washed with brine, dried with MgSO4, filtered, and concentrated to dryness. Purification on silica gel by flash chromatography (0-100% EtOAc/hexanes) afforded 2-chloro-N-methoxy-N-methylpyrimidine-4-carboxamide (3.30 g, 16.37 mmol, 66% yield). MS ESI: [M+H]+ m/z 202.0. 1H NMR (500 MHz, CDCl3) δ 8.75 (d, J=4.6, 1H), 7.48 (d, J=4.6, 1H), 3.77 (s, 3H), 3.35 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[CH:6]=[O:7])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC#N.O>[CH2:19]([O:11][C:10]1[C:9]([CH3:12])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH2:1][CH3:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCc1cc(C=O)cc(C)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCc1cc(C=O)cc(C)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
To a solution of 3-ethyl-4-hydroxy-5-methyl-benzaldehyde (34.9 g, 0.213 mol) in MeCN (350 mL), K2CO3 (58.7 g, 0.425 mol) and benzylbromide (36.4 g, 0.213 mol) is added. The mixture is stirred at 60° C. for 2 h before it is cooled to rt, diluted with water and extracted twice with EA. The org. extracts are washed with water and concentrated to give crude 4-benzyloxy-3-ethyl-5-methyl-benzaldehyde as an orange oil (45 g). 1H NMR (CDCl3): δ1.29 (t, J=7.5 Hz, 3H), 2.40 (s, 3H), 2.77 (q, J=7.8 Hz, 2H), 4.90 (s, 2H), 7.31-7.52 (m, 5H), 7.62 (d, J=1.5 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 9.94 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17](OC)=[O:18])=[CH:14][C:13]=3[CH:21]=2)=[N:6][CH:7]=1.[NH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33]>>[F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]([NH:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])=[O:18])=[CH:14][C:13]=3[CH:21]=2)=[N:6][CH:7]=1
Reactant: CC(C)(N)CO
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2o1
Product: CC(C)(CO)NC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2o1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, 5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine and 2-amino-2-methylpropanol were reacted to yield 5-fluoro-N2-[2-(2-hydroxy-1,1-dimethylethylamino)carbonylbenzofuran-5-yl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.41 (s, 1H), 9.28 (s, 1H), 9.22 (s, 1H), 8.18 (t, 1H, J=2.4, Hz), 8.09 (d, 1H, J=3.6 Hz), 7.56 (dd, 1H, J=2.4 and 8.7 Hz), 7.47 (d, 1H, J=8.7 Hz), 7.32 (s, 1H), 7.26-7.21 (m, 1H), 7.13-7.07 (m, 2H), 6.53 (d, 1H, J=8.7 Hz), 5.05 (t, 1H, J=5.7 Hz), 3.46 (d, 2H, J=5.7 Hz), 1.32 (s, 6H); LCMS: ret. time: 17.93 min.; purity: 97%; MS (m/e): 452 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:24]=[CH:23][C:22](=[O:25])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(O)C.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:24]=[CH:23][C:22](=[O:25])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([OH:19])=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCOC(=O)COc1cc2c(=O)ccn3c4ccc(Br)cc4c(c1)c23
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: O=C(O)COc1cc2c(=O)ccn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
10-bromo-2-ethoxycarbonylmethyloxy-4H-pyrido[3,2,1-jk]carbazole-4-one (200 mg) obtained in Example 62 was suspended in a mixed solution of ethanol (10 ml) and methylene chloride (10 ml), and 1N aqueous solution of sodium hydroxide (1 ml) was added to the suspension. The mixture was stirred at room temperature for 10 minutes, and the solvent was evaporated under reduced pressure. To the residue was added water and 1N hydrochloric acid to pH 1, and the crystals precipitated were recovered by filtration to obtain the title compound (160 mg, 84%).
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:8]1)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:8]1
Reactant: O=C(OCc1ccccc1)N1CCOC(CNC(=O)C(F)(F)F)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: NCC1CN(C(=O)OCc2ccccc2)CCO1
Temperature: 22 °C
Reaction time: 36 h
Yield: 71.4 %

Procedure:
To a stirred solution of Intermediate 4 (4.4 g) in 1:1 methanol/water (300 ml) was added potassium carbonate (17.5 g). The mixture was stirred at 22° C. for 36 h before the volatiles were evaporated in vacuo. The residue was dissolved in water and the solution extracted with dichloromethane (×3). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered before evaporation of the solvent in vacuo. The residue was dissolved in methanol and purified by solid phase extraction (Isolute SCX sulphonic acid column), initially washing the cartridge with methanol before eluting with 10% 0.880 ammonia solution in methanol to give the title compound as a colourless oil (2.27 g).
Reaction SMILES: C([N:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=23)=[CH:6][CH:5]1[CH3:26])(=O)C.[S]>C1C2C(CCCC2)CCC1>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:11]2[C:10]([C:7]3[CH:8]=[CH:9][N:4]=[C:5]([CH3:26])[CH:6]=3)=[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][N:13]3[N:12]=2)=[CH:20][CH:21]=1
Reactant: CC(=O)N1C=CC(c2c(-c3ccc(F)cc3)nn3cccnc23)=CC1C
Agent: [S]
Solvent: C1CCC2CCCCC2C1
Product: Cc1cc(-c2c(-c3ccc(F)cc3)nn3cccnc23)ccn1
Temperature: 190 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
A mixture of 3-(1-acetyl-1,2-dihydro-2-methylpyridin-4-yl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine (315 mg) and sulfur (146 mg) in decaline (3 ml) was stirred at 190° C. for 2 hours. The reaction mixture was cooled and purified by column chromatography on silica gel to give 2-(4-fluorophenyl)-3-(2-methylpyridin-4-yl)pyrazolo[1,5-a]pyrimidine (135 mg) as crystals.
Reaction SMILES: [F-:1].[K+].I([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:8][CH:7]=1)(=O)=O.CO>C(#N)C.O.CS(C)=O>[F:1][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:8][CH:7]=1
Reactant: [F-]
Reactant: COc1ccc2nc(-c3ccc(I(=O)=O)cc3)sc2c1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC#N
Solvent: O
Product: COc1ccc2nc(-c3ccc(F)cc3)sc2c1
Temperature: 180 °C
Reaction time: 0.17 h

Procedure:
A solution of Kryptofix® 2.2.2 (23.4 mg, 0.062 mmol) in acetonitrile (2 mL) was added to a solution of KF (7.3 mg, 0.125 mmol) in water (0.5 mL). The solvents were evaporated at 120° C. and the residue was dried by azeotropic distillation with acetonitrile (3×1 mL). A solution of the iodyl precursor 2-(4-iodylphenyl)-6-methoxy-1,3-benzothiazole (7) (5.2 mg, 0.0125 mmol; dried over P2O5 under high vacuum for 2 hours before use) in hot DMSO (0.5 mL) was added to the dried KF-Kryptofix® complex. The reaction mixture was stirred at 120° C., 150° C. or 180° C. for 10 min. The reaction mixture was cooled and diluted with ice water (3 mL) and passed through a C-18 Sep-Pak® pre-activated with methanol (5 mL) followed by water (10 mL). The Sep-Pak was flushed with water (2×5 mL) and the crude product 9a retained on the Sep-Pak® was eluted off with CH2Cl2 (2×5 mL). The dichloromethane eluent was quantitatively analyzed by analytical HPLC (Waters Symmetry C18 column, 5μ particle size, 150×4.6 mm; eluent: MeCN/H2O 1:1; flow rate: 1 mL/min; UV 325 nm or 254 nm; RT=27 min) using an authentic sample of 2-(4-fluorophenyl)-6-methoxy-1,3-benzothiazole (9a) as a standard and the yield of the fluoro product 9a formed at 120° C., 150° C. and 180° C. was determined as 6.5%, 3.4% and 34.6%, respectively. The authentic sample of 9a was prepared in accordance with the nucleophilic displacement method for synthesis of non-rigid PBZ polymers described in U.S. Pat. No. 5,104,960.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([NH:10][CH3:11])=[O:9])=[O:4].[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:2][C:3]([NH:5][C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[C:8]([NH:10][CH3:11])=[O:9])=[O:4])=[CH:18][CH:19]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CNC(=O)c1ccccc1NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CNC(=O)c1ccccc1NC(=O)COc1ccc(C(C)=O)cc1
Yield: 84.3 %

Procedure:
To a solution of 2-(2-chloroacetamido)-N-methylbenzamide 22.65 g (0.1 mol) and p-hydroxyacetophenone 16.32 g (0.12 mol) in 200 mL of butanone was added 27.60 g (0.2 mol) potassium carbonate. The mixture was stirred and heated to reflux for 4-5 hours, and monitored by TLC until the reaction was over, the reaction mixture was concentrated under reduced pressure and extracted with 300 mL of ethyl acetate to separate the organic phase, the organic phase was washed with 50 ml of 5% sodium hydroxide aqueous solution and 50 ml of brine successively, dried via anhydrous magnesium sulfate and evaporated, and the residual was purified via silica gel column chromatography to obtain 27.50 g 2-(2-(4-acetylphenoxy)acetamido)-N-methylbenzamide as white solid with yield of 84.4%, m.p. 252-253° C.
Reaction SMILES: BrC1C=CC(O[CH2:11][CH2:12][O:13][Si:14]([C:17](C)(C)C)([CH3:16])[CH3:15])=C(C=1)C=O.C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.C[Si](Cl)(C)C.[CH2:40]([N:42](CC)CC)C.C(Cl)(=O)C>>[CH3:15][Si:14]([CH3:17])([CH3:16])[O:13][C:12](=[CH2:11])[N:42]=[CH2:40]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Br)cc1C=O
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CC(=O)Cl
Product: C=NC(=C)O[Si](C)(C)C

Procedure:
In a manner similar to the method described in example 1b, 5-bromo-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-benzaldehyde (17.25 g, 48 mmol) prepared in example 130a was reacted with 1,1,1,3,3,3-hexamethyldisilazane (8.28 g, 48 mmol), n-butyllithium (2.5 M, 19.2 mL, 48 mmol), trimethylsilyl chloride (6.07 mL, 48 mmol), triethylamine (8.7 mL, 62.5 mmol) and acetyl chloride (4.53 mL, 62 mmol) to give 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene as yellow oil and used for the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.Cl[C:53]1[C:58]([O:59][CH3:60])=[CH:57][N:56]=[C:55]([S:61][CH3:62])[N:54]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)(Cl)Cl>O1CCOCC1.O>[F:49][C:46]([F:47])([F:48])[C:44]1[CH:43]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:50])[F:51])[CH:45]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[C:53]1[C:58]([O:59][CH3:60])=[CH:57][N:56]=[C:55]([S:61][CH3:62])[N:54]=1)[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2B2OC(C)(C)C(C)(C)O2)nc1
Reactant: COc1cnc(SC)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2nc(SC)ncc2OC)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (300 mg) is dissolved in 1,4-dioxane (5 ml) and thereto are added 4-chloro-5-methoxy-2-methylsulfanyl-pyrimidine (117 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (33 mg) and cesium carbonate (199 mg), and the mixture is stirred under nitrogen atmosphere at 80° C. overnight. The reaction solution is cooled to room temperature, and thereto are added chloroform and water, and the insoluble materials are removed by filtration through Celite™. The filtrate is separated, and the organic layer is dried and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→7:3) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(5-methoxy-2-methylsulfanyl-pyrimidin-4-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (165 mg). MS (m/z): 764 [M+H]+