Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Cl)=[CH:10][C:9]=2[F:22])[C:6](=[O:23])[CH:5]=[CH:4][C:3]=1[C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].[CH:34]1([O:39][C:40](=[O:47])[C@H:41]([CH2:43][CH:44]([CH3:46])[CH3:45])[NH2:42])[CH2:38][CH2:37][CH2:36][CH2:35]1.[I-].[Na+].C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:42][C@H:41]([C:40]([O:39][CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)=[O:47])[CH2:43][CH:44]([CH3:46])[CH3:45])=[CH:10][C:9]=2[F:22])[C:6](=[O:23])[CH:5]=[CH:4][C:3]=1[C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Reactant: Nc1c(C(=O)c2ccc(F)cc2F)ccc(=O)n1-c1c(F)cc(OCCCCCCl)cc1F
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NCCCCCOc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)c(F)c1)C(=O)OC1CCCC1
Temperature: 90 °C
Yield: 52 %

Procedure:
From Intermediate 4G. To a solution of 6-Amino-1-{4-[(5-chloropentyl)oxy]-2,6-difluorophenyl}-5-(2,4-difluorobenzoyl)pyridin-2(1H)-one (138 mg, 0.29 mmol) in anhydrous DMF (3 ml) under an atmosphere of nitrogen was added cyclopentyl L-leucinate (Intermediate 8) (284 mg, 1.43 mmol, 5 eq), sodium iodide (86 mg, 0.57 mmol, 2 eq) and N,N-diisopropylethylamine (0.052 ml, 0.29 mmol, 1 eq). The mixture was heated at 90° C. for 16 hours, before being allowed to cool to room temperature and diluted with EtOAc (25 ml). The solution was washed with water (2×25 ml) and brine (25 ml). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography (3-4% MeOH in DCM) followed by preparative HPLC afforded the title compound as a cream coloured solid (96 mg, 52% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH2:17]([O:19][C:20]([C:22]1[C:26]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[C:25]([CH:35]=O)[NH:24][CH:23]=1)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[C:26]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[C:25]([CH:35]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])[NH:24][CH:23]=1)=[O:21])[CH3:18]
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: CCOC(=O)c1c[nH]c(C=O)c1-c1ccc(OC)cc1
Product: CCOC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)c1-c1ccc(OC)cc1

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 5-formyl-4-(4-methoxyphenyl)-1H-pyrrole-3-carboxylic acid ethyl ester (60 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: [C:1]1(=[O:40])[N:5]([CH2:6][CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=3)[N:10]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:9]=2)[C:4](=[O:35])[C:3]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:2]12.[Cl-].[Li+].[S:43]1[CH:47]=[CH:46][CH:45]=[C:44]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[C:4]1(=[O:35])[N:5]([CH2:6][CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:44]4[S:43][CH:47]=[CH:46][CH:45]=4)[CH:15]=3)[N:10]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:9]=2)[C:1](=[O:40])[C:2]2=[CH:39][CH:38]=[CH:37][CH:36]=[C:3]12
Reactant: OB(O)c1cccs1
Reactant: Cc1ccc(S(=O)(=O)n2cc(CCN3C(=O)c4ccccc4C3=O)c3cc(OS(=O)(=O)C(F)(F)F)ccc32)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(CCN3C(=O)c4ccccc4C3=O)c3cc(-c4cccs4)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.1 %

Procedure:
3-(2-Phthalimidoethyl)-1-(p-toluenesulfonyl)-5-(trifluoromethanesulfonyloxy)-1H-indole (Example 11) (71 mg, 0.12 mmol) was dissolved in 1,2-dimethoxymethane (10 mL). Tetrakis(triphenylphosphine) palladium (14 mg, 0.012 mmol) and lithium chloride (10 mg, 0.24 mmol) were added and the resulting solution was stirred under argon at room temperature for 20 minutes. Thiophene-2-boronic acid (20 mg, 0.15 mmol) and sodium carbonate (2M solution in water, 0.1 ml) were added and the resulting mixture was stirred under argon at reflux for 4 hours. After cooling to room temperature, the crude product mixture was poured into ethyl acetate (20 mL), washed with water (20 mL), dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel using hexane/ethyl acetate (4:1) as eluent to provide 3-(2-phthalimidoethyl)-1-(p-toluenesulfonyl)-5-(2-thienyl)-1H-indole (62 mg, 96%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ:-- 7.95 (d, J=8.9 Hz, 1H), 7.85-7.82 (A2 of A2B2 system, 2H), 7.80 (d, J=1.4 Hz, 1H), 7.73 (d, J=8.9 Hz, 2H), 7.72-7.69 (B2 of A2B2 system, 2H), 7.55 (dd, J=1.5 and 8.7 Hz, 1H), 7.46 (s, 1H), 7.29 (dd, J=1.2 and 3.5 Hz, 1H), 7.25 (dd, J=1.2 and 5.0 Hz, 1H), 7.19 (d, J=8.9 Hz, 2H), 7.07 (dd, J=3.5 and 5.0 Hz, 1H), 4.00 (t, J=7.4 Hz, 2H), 3.09 (t, J=7.4 Hz, 2H), 2.33 (s, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[CH3:16][O:17][CH2:18][CH2:19][CH2:20][N:21]1[CH:25]2[CH2:26][CH2:27][CH2:28][CH:24]2[NH:23][C:22]1=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:16][O:17][CH2:18][CH2:19][CH2:20][N:21]1[CH:25]2[CH2:26][CH2:27][CH2:28][CH:24]2[N:23]([C:2]2[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][N:3]=2)[C:22]1=[O:29]
Reactant: COCCCN1C(=O)NC2CCCC21
Reactant: Brc1ncc(C#Cc2ccccc2)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COCCCN1C(=O)N(c2ncc(C#Cc3ccccc3)cn2)C2CCCC21
Temperature: 90 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
In a 10 mL pyrex tube, 2-bromo-5-(phenylethynyl)pyrimidine (CAS: 1338493-52-9)(80 mg, 309 μmol, Eq: 1.00) and (rac)-(3aRS,6aSR)-1-(3-Methoxy-propyl)-hexahydro-cyclopentaimidazol-2-one (68.0 mg, 309 μmol, 1.0 equiv.) were dissolved in 2 ml of Toluene. Cesium carbonate (201 mg, 618 μmol, 2.0 equiv.), Xanthphos (7.15 mg, 12.4 μmol, 0.04 equiv.) and Pd2(dba)3 (5.65 mg, 6.18 μmol, 0.02 equiv.) were added and the red-brown reaction mixture was stirred at 90° C. for 3 hr. The reaction mixture was filtered, adsorbed on silica, and purified by flash chromatography (silica gel, 20 g with 1 g Silica-NH2, 30% to 100% EtOAc in heptane gradient at 301 nm). One obtained 65.6 mg of the title compound as a yellow oil; MS: m/e=377.6 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:21]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[CH3:33])[N:22]=1>CN(C=O)C>[CH3:31][N:30]1[C:29](=[O:32])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[CH3:33])[N:22]=[C:21]1[O:13][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([C:6](=[O:7])[C:5]2[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: Cc1cccc2nc(Cl)n(C)c(=O)c12
Reactant: O=C(c1ccc(F)cc1)c1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(OCc3ccc(C(=O)c4ccc(F)cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
To a solution of 4-(4-fluorobenzoyl)benzyl alcohol (1.0 g) in DMF (20 ml) was added 60% sodium hydride (210 mg) and the mixture was stirred at room temperature for 10 minutes. Then, 2-chloro-3,5-dimethyl-4(3H)-quinazolinone (907 mg) was added and the mixture was stirred at room temperature for 1 hour. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =3:1) to provide the title compound as colorless solid (560 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:21])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)cc(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(c2cc(F)cc(Cl)c2)CCNC1
Reaction time: 1.5 h
Yield: 64.4 %

Procedure:
To a solution of tert-butyl 3-(3-chloro-5-fluorophenyl)-3-hydroxypyrrolidin-1-carboxylate (2.43 g, 7.7 mmol) in dichloromethane (80 mL), was added trifluoroacetic acid (5 mL). The mixture was stirred for 1.5 h after which the mixture was basified with aqueous sodium carbonate (10%, 50 mL) and evaporated. Ethyl acetate (100 mL) was added, the mixture was washed with brine and the organic phase was dried (MgSO4) and evaporated. Purification on a Biotage (solute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1), and by HPLC on Waters OBD 018, 5 μm (MeOH/33 mM NH3, 20:80 to 0:100), gave the title compound (1.07 g). MS m/z (rel. intensity, 70 eV) 215 (M+, bp), 157 (47), 129 (65), 109 (61), 95 (43).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][N:6]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]2=[O:23])=[N:7]1.[OH-].[Na+]>C(OC(=O)C)(=O)C.O>[CH3:5][N:6]1[CH:10]=[C:9]([N+:1]([O-:4])=[O:2])[C:8]([N:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[C:12]2=[O:23])=[N:7]1
Reactant: Cn1ccc(N2CCN(C(=O)OC(C)(C)C)C2=O)n1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cn1cc([N+](=O)[O-])c(N2CCN(C(=O)OC(C)(C)C)C2=O)n1
Reaction time: 0.08 h

Procedure:
To acetic anhydride (30 mL) was added fuming nitric acid (3.77 mL) under ice-cooling, and the mixture was stirred for 5 min. The obtained solution was added dropwise to a solution of tert-butyl 3-(1-methyl-1H-pyrazol-3-yl)-2-oxoimidazolidine-1-carboxylate (12.1 g) in acetic anhydride (60 mL) under ice-cooling, and the mixture was stirred at 0° C. for 30 min. The reaction mixture was diluted with water, and the mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (11.3 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:12][C:11](=[O:13])[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[N:9][N:8]=1.S(Cl)(Cl)=O.O1CC[CH2:30][CH2:29]1.[O-]CC.[Na+]>O>[CH2:29]([O:13][C:11]1[N:12]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:8]=[N:9][C:10]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=1)[CH3:30]
Reactant: O=c1[nH]c(-c2ccccn2)nnc1-c1ccc(C(F)(F)F)cc1
Reactant: C1CCOC1
Agent: CC[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCOc1nc(-c2ccccn2)nnc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of 3-(2-pyridyl)-6-(4-trifluoromethylphenyl)-1,2,4-triazin-5-one (10.00 g, 31.4 mmol) and thionyl chloride (100 ml) was heated under reflux for two hours. The mixture was allowed to cool to room temperature, and the solvent was distilled off. To the residue were added tetrahydrofuran (100 ml) and sodium ethoxide (10.69 g, 157 mmol, 15.0 eq.), and the mixture was heated under reflux for two hours. The mixture was allowed to cool to room temperature, and water (300 ml) was added to the reaction mixture. The mixture was extracted with methylene chloride (300 ml), and washed with water (200 ml), and then washed with 5% brine (200 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The resulting solid was purified by flash silica gel column chromatography (ethyl acetate-hexane) to give the title compound (7.57 g, 70%) as pale yellow prisms.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1.Cl.Cl[CH2:14][C:15]1[C:16]([C:21]2[CH:25]=[CH:24][N:23]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[N:22]=2)=[N:17][CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:8]([C:7]1[CH:6]=[C:5]([O:10][CH3:11])[N:4]=[CH:3][C:2]=1[O:1][CH2:14][C:15]1[C:16]([C:21]2[CH:25]=[CH:24][N:23]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[N:22]=2)=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:9]
Reactant: COC(=O)CCn1ccc(-c2ncccc2CCl)n1
Reactant: COc1cc(C=O)c(O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCn1ccc(-c2ncccc2COc2cnc(OC)cc2C=O)n1
Temperature: 70 °C
Yield: 111 %

Procedure:
A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (30 mg, 0.20 mmol, 1 eq.), methyl 3-(3-(3-(chloromethyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate hydrochloride (63 mg, 0.20 mmol, 1 eq.), and K2CO3 (100 mg, 10.32 mmol, 4 eq.) in DMF (5.0 mL) was heated at 70° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give methyl 3-(3-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate (88 mg, quantitative yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.50 (s, 1H), 8.65 (dd, J=4.7, 0.9 Hz, 1H), 8.09 (s, 1H), 8.02 (dd, J=7.8, 0.8 Hz, 1H), 7.53 (d, J=2.3 Hz, 1H), 7.31 (dd, J=7.9, 4.8 Hz, 1H), 7.12 (s, 1H), 6.96 (d, J=2.3 Hz, 1H), 5.71 (s, 2H), 4.46 (t, J=6.6 Hz, 2H), 3.93 (s, 3H), 3.69 (s, 3H), 2.91 (t, J=6.6 Hz, 2H). LRMS (M+H+) m/z 397.1.
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=[O:2].[K+].[K+].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[N:21]=[CH:22][N:23]([CH:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[C:24]=1[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([S:31][CH3:32])[N:26]=1.[NH4+].[OH-]>O.CC(O)=O>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[N:21]=[CH:22][N:23]([CH:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[C:24]=1[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([S:31]([CH3:32])=[O:2])[N:26]=1
Reactant: CSc1nccc(-c2c(-c3ccccc3F)ncn2C2CCN(C)CC2)n1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CN1CCC(n2cnc(-c3ccccc3F)c2-c2ccnc(S(C)=O)n2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Potassium persulfate (3.2 g, 7.0 mmol) in water (75 mL) was added to a solution of 4-(fluorophenyl)-1-(methyl-4-piperidinyl)-5-(2-methylthio-4-pyrimidinyl)imidazole (2.7 g, 7.0 mmol) in glacial AcOH (150 mL). After stirring at ambient temperature for 72 h, the reaction mixture was neutralized by the portion-wise addition of concentrated aqueous NH4OH and extracted with CH2Cl2. The organic extract was washed with brine, dried (MgSO4) and concentrated. The residue was triturated with ethyl ether to afford the title compound as an off-white solid; yield 2.3 g (83%).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10].C(=O)([O-])[O-].[K+].[K+].[Cl:17]Cl>ClC1C=CC=CC=1Cl.O>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([Cl:17])=[O:10]
Reactant: ClCl
Reactant: Cc1nn(C)c(Cl)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Solvent: O
Product: Cc1nn(C)c(Cl)c1C(=O)Cl
Yield: 77 %

Procedure:
Initial charging of 11 g of a 10% solution of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde in 1,2-dichlorobenzene at 10° C., is followed by addition of a solution of 4.6 g of potassium carbonate in 20 ml of water. At 10° C., while illuminating with a mercury lamp, 8 g of chlorine gas are introduced within 1 hour. After the gas introduction has ended, the reaction solution is admixed with water, and the organic phase is removed and washed with water. After removal of the solvent, 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride is obtained in a yield of 77%.
Reaction SMILES: [CH3:1][CH:2]([C:4](=[O:13])[C:5]([CH3:12])([CH3:11])[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:3].[BH4-].[Na+]>>[CH3:3][CH:2]([CH:4]([OH:13])[C:5]([CH3:11])([CH3:12])[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:1]
Reactant: CC(C)=CCC(C)(C)C(=O)C(C)C
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)=CCC(C)(C)C(O)C(C)C

Procedure:
91 g of 2,4,4,7-tetramethyl-oct-6-en-3-one are stirred with 19 g of sodium borohydride in alcohol at 40° C. for 24 hours. The alcohol is distilled off, water is added and the product is extracted with tert-butyl methyl ether. The organic phase is washed neutral and distilled over a 40 cm packed column.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH2:26])=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH:26][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)c1cccc(F)c1
Product: Cc1nc(NC(=O)c2cccc(F)c2)sc1C(=O)NCc1ccccc1
Yield: 18 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 3-fluorobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 18% yield; m.p. 162-165° C.; 1H NMR (CDCl3, 300 MHz) δ 7.64-7.24 (m, 9H), 5.97 (t, J=5.4 Hz, 1H), 4.58 (d, J=5.4 Hz, 2H), 2.47 (s, 3H); MS (ES+) m/z 370.2 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25].[Cl-].[NH4+]>CN(C)C=O>[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1
Reactant: C#CCOc1cc(Cl)ncn1
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(Oc2ccccc2C)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 52.6 %

Procedure:
To 5 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-propynyloxy)pyrimidine, 0.25 g of potassium carbonate, and 0.14 g of 2-methylphenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.15 g of 4-(2-methylphenoxy)-6-(2-propynyloxy)pyrimidine (the present compound (27)), m.p.: 64.8° C.
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:10]=[C:11]([CH3:14])[C:12]=1N.[I-:25].[K+]>O.Cl>[I:25][C:12]1[C:11]([CH3:14])=[CH:10][C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:8][C:7]=1[O:6][CH3:5]
Reactant: [I-]
Reactant: COc1cc(-c2cccc(C(F)(F)F)c2)cc(C)c1N
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(-c2cccc(C(F)(F)F)c2)cc(C)c1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
A solution of 3.10 g (45.0 mmol) of sodium nitrite in 20 ml of H2O was added to a suspension of 11.50 g (40.90 mmol) of 3-methoxy-5-methyl-3′-trifluoromethyl-biphenyl-4-ylamine in 35.0 ml of HCl (25%) and 190 ml of H2O at 2° C.; after 30 min, the light-brown solution formed was added at 0° C. to a solution of 6.95 g (433.4 mmol) of potassium iodide in 40 ml of H2O and the reaction mixture was warmed up to RT. 4 hours later, it was poured then into crashed ice and extracted twice with EtOAc; the organic phases were washed with sodium bicarbonate solution and with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (heptane/EtOAc 1:0 to 4:1) to give 7.79 g (49%) of the title compound as yellow oil. MS: 392.0 (M+).
Reaction SMILES: [C:1]([NH2:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1>[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[CH2:1][NH2:10])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(=O)c1ccccc1N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Solvent: C1COCCO1
Solvent: c1ccccc1
Solvent: O
Product: NCc1ccccc1NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 63.4 %

Procedure:
In this reference example, the mixture of 13.6 g of anthranilamide, 18.9 g of 1-benzyl-4-piperidone, 1.0 g of p-toluene-sulfonic acid monohydrate and 200 ml of benzene is refluxed in a Dean Stark apparatus for 6 hours to distil off water. The resultant suspension of the Schiff-base is concentrated. The residue is mixed with 250 ml of dry dioxane to form a suspension. Separately, 100 ml of dry dioxane and 12.4 g of lithium aluminum hydride are mixed. The above Schiff-base suspension is added little by little to the mixture with stirring without cooling. The mixture is stirred for one hour and then refluxed with heating for 18 hours. The reaction solution is cooled to room temperature and poured little by little into 1.3 l of ice water. The resultant suspension is poured little by little into a funnel previously coated with a filter aid and subjected to suction filtration. The cake on the funnel is washed with 500 ml of chloroform and filtered. The organic layer is washed with water, dried and concentrated to obtain 22.9 g of a crude product. The crude product is recrystallized from hot ethanol to obtain 18.7 g of the desired product.
Reaction SMILES: [Cl-].[CH2:2](N(CC)CC)C.CO.[C:11]([C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][C:16]([OH:24])([CH2:17]3)[CH2:15]1)[CH2:21]2)([OH:13])=[O:12]>CN(C=O)C>[CH3:2][O:12][C:11]([C:14]12[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][C:16]([OH:24])([CH2:22]3)[CH2:15]1)[CH2:23]2)=[O:13]
Reactant: O=C(O)C12CC3CC(CC(O)(C3)C1)C2
Reactant: CCN(CC)CC
Agent: [Cl-]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)C12CC3CC(CC(O)(C3)C1)C2
Reaction time: 2 h
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1-carboxy-3-adamantanol obtained by the method of Example 2 was dissolved in 10 ml of DMF. To the mixture, 15 mmole of tionyl chloride was added dropwise over 30 minutes while heating the mixture to the reflux temperature so as to begin to reflux at about the time the addition is finished. After refluxing for 2 hours, the mixture was cooled. To the mixture, 20 mmole of triethylamine was added and 11 mmole of methanol was added dropwise over 30 minutes while keeping the temperature of the solution at 10° C. or below, and the mixture was stirred for another 2 hours. As a result, the conversion of 1-carboxy-3-adamantanol was 99%, and 1-methoxycarbonyl-3-adamantanol (yield 95%) was formed.