Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S([O-])(=O)=O)=CC=1.C([N+:19]12[CH2:26][C:23]([OH:27])([CH2:24][CH2:25]1)[CH2:22][CH2:21][CH2:20]2)C1C=CC=CC=1.C([O-])=O.[NH4+].[OH-].[Na+]>[Pd].[C].CCO>[N:19]12[CH2:26][C:23]([OH:27])([CH2:24][CH2:25]1)[CH2:22][CH2:21][CH2:20]2
Reactant: OC12CCC[N+](Cc3ccccc3)(CC1)C2
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C[O-]
Solvent: CCO
Product: OC12CCCN(CC1)C2
Yield: 68.9 %

Procedure:
To 1-benzyl-5-hydroxy-1-azoniabicyclo[3.2.1]octane 4-methylbenzenesulfonate (800 mg) that had been synthesized by the method as described in Published Japanese Patent Application No. 63-290878 was added a mixture of EtOH (8 mL), 10% Pd/Carbon with a 50% hydration (200 mg), and ammonium formate (500 mg), followed by heating under reflux. The reaction mixture was alkalified with addition of a 1 M aqueous NaOH solution, and extracted with a mixed solvent (CHCl3:MeOH=9:1). The organic layer was dried over MgSO4 and then concentrated under reduced pressure to obtain 1-azabicyclo[3.2.1]octan-5-ol (180 mg) as a colorless oily substance.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1.Cl>ClCCl.C(OCC)(=O)C>[C:16]1([NH:15][S:2]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)(=[O:4])=[O:3])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1Cc2cc(S(=O)(=O)Nc3ccccc3)ccc2N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 5-chlorosulfonyl-2-oxindole (1.62 g, 7 mmol), aniline (0.782 mL, 8.4 mmol) and pyridine (1 mL) in dichloromethane (20 ml) was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate (300 mL) and acidified with 1N hydrochloric acid (16 mL). The organic layer was washed with sodium bicarbonate and brine, dried and concentrated. The residue was washed with ethanol (3 mL) and then chromatographed on silica gel eluting with methanol/dichloromethane 1:9 to give of 5-phenylaminosulfonyl-2-oxindole.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10](Br)[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[C:19]([F:21])[CH:20]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([C:17]2[CH:16]=[C:15]([F:14])[CH:20]=[C:19]([F:21])[CH:18]=2)[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(Br)cc(C)n1
Reactant: OB(O)c1cc(F)cc(F)c1
Product: CCOC(=O)c1cc(-c2cc(F)cc(F)c2)cc(C)n1

Procedure:
The title compound, was prepared from 4-Bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester (example 1, step 4) in accordance with the general method of example 1, step 6 using 3,5-Difluorophenylboronic acid instead of 3-Fluorophenylboronic acid to yield the final compound as a white crystalline solid, MS (ISP): m/e=278.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH:10]([F:12])[F:11])[C:3]=1[C@H:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([C:24]3[CH:25]=[N:26][N:27]([CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[C:28]=3[CH3:29])[CH:22]=2)[NH:17][CH:16]=1)[CH3:14].[C:36](O)(=[O:38])[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.C(Cl)Cl>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH:10]([F:12])[F:11])[C:3]=1[C@H:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([C:24]3[CH:25]=[N:26][N:27]([CH:30]4[CH2:31][CH2:32][N:33]([C:36](=[O:38])[CH3:37])[CH2:34][CH2:35]4)[C:28]=3[CH3:29])[CH:22]=2)[NH:17][CH:16]=1)[CH3:14]
Reactant: Cc1c(-c2cnc3[nH]cc([C@H](C)c4c(OC(F)F)ccc(F)c4Cl)c3c2)cnn1C1CCNCC1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(n2ncc(-c3cnc4[nH]cc([C@H](C)c5c(OC(F)F)ccc(F)c5Cl)c4c3)c2C)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-{(1S)-1-[2-chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-5-[5-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine (40.0 mg, 0.0794 mmol), acetic acid (23.8 mg, 0.397 mmol), TBTU (51.0 mg, 0.159 mmol), triethylamine (40.2 mg, 0.397 mmol) and DCM (4 mL, 60 mmol) was stirred at rt for 10 min. The solution was extracted with EtOAc, washed with 1 M HCl, and then sat. NaHCO3. The organic layer was concentrated in vacuo, loaded onto silica gel and purified via column chromatography. The product was eluted with 2-3% (7N NH3 in MeOH)/DCM, and the fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.84 (d, J=7.3 Hz, 3H), 1.93-2.04 (m, 3H), 2.12 (dd, J=15.4, 2.5 Hz, 1H), 2.16 (s, 3H), 2.26 (s, 3H), 2.76-2.88 (m, 1H), 3.32-3.35 (m, 1H), 4.08 (dd, J=14.0, 1.9 Hz, 1H), 4.43-4.54 (m, 1H), 4.64-4.73 (m, 1H), 5.11 (q, J=7.0 Hz, 1H), 6.43 (br. s., 1H), 7.12 (dd, J=8.8, 4.5 Hz, 1H), 7.19 (t, J=8.7 Hz, 1H), 7.38 (d, J=1.8 Hz, 1H), 7.39 (d, J=1.3 Hz, 1H), 7.48 (s, 1H), 8.13 (d, J=2.0 Hz, 1H). MS (ES+): m/z=546.17/548.18 (100/50) [MH+]. HPLC: tR=1.43 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[I:13][C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:21]=2)[NH:16][CH:15]=1.C([O-])(O)=O.[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.CO>[C:1]1([S:7]([N:16]2[C:17]3=[N:18][CH:19]=[C:20]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)[CH:21]=[C:22]3[C:14]([I:13])=[CH:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Ic1c[nH]c2ncc(N3CCOCC3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1cc(I)c2cc(N3CCOCC3)cnc21
Reaction time: 2 h
Yield: 64.7 %

Procedure:
Tetrabutylammonium hydrogen sulfate (0.020 g, 0.059 mmol), benzenesulfonyl chloride (0.055 mL, 0.43 mmol) and 50% aqueous NaOH solution (0.20 mL) were added to a solution of 54 (0.095 g, 0.29 mmol) in CH2Cl2 (3 mL). After stirring for 2 hours, the mixture was poured into saturated aqueous NaHCO3 solution and extracted with CH2Cl2 three times. The combined organic solutions were washed with saturated aqueous NaHCO3 solution, dried (MgSO4), and concentrated to afford a tan syrup. MeOH was added to the syrup and the mixture was cooled in an ice bath. The precipitate was filtered off, washed with MeOH and dried to afford 55 (0.088 g) as a brown solid. The filtrate was concentrated and purified by means of preparative TLC with hexane:AcOEt as eluent to afford additional 55 (0.016 g, total yield: 0.104 g, 77%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 3.08-3.12 (m, 4H), 3.80-3.84 (m, 4H), 7.00 (d, J=0.26 Hz, 1H), 7.38-7.44 (m, 2H), 7.48-7.54 (m, 1H), 7.72 (s, 1H), 8.08-8.11 (m, 2H), 8.12 (d, J=0.26 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([CH3:29])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:44](=O)([O-])[O-:45].[Cs+].[Cs+]>CO.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16]([O:45][CH3:44])=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([CH3:29])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C)c(C)c1
Agent: [Cu]I
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CO
Product: CCc1nc(OC)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C)c(C)c1

Procedure:
A solution of 8-[2-(3,4-dimethyl-phenyl)-ethyl]-3-ethyl-1-iodo-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.500 g; 2.944 mmol) in anhydrous MeOH (30 ml) was treated successively with copper(I) iodide (56 mg; 0.294 mmol), 1,10-phenanthroline (116.7 mg; 0.589 mmol), and cesium carbonate (1.535 g; 4.711 mmol). The resulting brown suspension was sealed and put in the microwave oven (150 W; 150° C.; 13 bars; 1h30). The resulting brown suspension was concentrated to dryness under reduced pressure and the crude was purified by FC (EA/heptane: 2/3 to 3/2]. The expected product 8-[2-(3,4-dimethyl-phenyl)-ethyl]-3-ethyl-1-methoxy-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester was obtained as a yellow oil (260.6 mg; 21%). LC-MS: tR=0.91 min.; [M+H]+=414.35 g/mol.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[I-].[Na+].Cl[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:14]([CH2:41][CH2:42][CH3:43])[N:15]=[C:16]2[C:25]=1[C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:18]=[C:17]2[N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>CN(C=O)C>[C:1]([O:4][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:14]([CH2:41][CH2:42][CH3:43])[N:15]=[C:16]2[C:25]=1[C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:18]=[C:17]2[N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])(=[O:3])[CH3:2]
Reactant: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1CCCCCl
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1CCCCOC(C)=O
Temperature: 90 °C
Yield: 77.1 %

Procedure:
Potassium acetate (0.83 g, 8.432 mmol) and sodium iodide (16 g, 1.05 mmol) was added to a solution of di(tert-butyl) 1-(4-chlorobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (2.18 g, 4.22 mmol) in DMF (15 mL). The reaction mixture was heated at 90° C. under a nitrogen atmosphere for 4.5 hours. The reaction was allowed to cool to ambient temperature and the volatiles were removed under reduced pressure. The resulting oil was partitioned between ethyl acetate and water. The organic layer was isolated and washed with water (2×25 mL) and brine (3×20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield an oil that was dried under vacuum to provide 1.76 g of 4-{4-[bis(tert-butoxycarbonyl)amino]-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl}butyl acetate.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4][C@H:3]2[CH2:6][NH:7][CH2:8][C@@H:2]12.Br[C:17]1[CH:18]=[C:19]([CH3:24])[C:20]([Cl:23])=[N:21][CH:22]=1>>[Cl:23][C:20]1[N:21]=[CH:22][C:17]([N:7]2[CH2:6][C@H:3]3[C@H:2]([N:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]3)[CH2:8]2)=[CH:18][C:19]=1[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2CNC[C@H]21
Reactant: Cc1cc(Br)cnc1Cl
Product: Cc1cc(N2C[C@@H]3CCN(C(=O)OC(C)(C)C)[C@@H]3C2)cnc1Cl
Yield: 41 %

Procedure:
The product from Example 15E and 5-bromo-2-chloro-3-methylpyridine were processed as described in Example 1E to provide the title compound (41% yield). MS (DCI/NH3) m/z 338/340 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[NH2:25][N:26]1[CH:30]=[N:29][N:28]=[CH:27]1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:25][N:26]2[CH:30]=[N:29][N:28]=[CH:27]2)=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1
Reactant: Nn1cnnc1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Product: COc1ccc(C(=O)Nn2cnnc2)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-triflouromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and 4-amino-1,2,4-triazole in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[CH:13]=[C:12]([C:22]([OH:24])=O)[CH:11]=1)#[N:2].Cl.Cl.[CH3:27][C:28]1[N:33]=[CH:32][C:31]([C@H:34]([NH2:36])[CH3:35])=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([CH:16]([OH:21])[C:17]([F:19])([F:18])[F:20])[CH:13]=[C:12]([C:22]([NH:36][C@@H:34]([C:31]2[CH:32]=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=2)[CH3:35])=[O:24])[CH:11]=1)#[N:2]
Reactant: Cc1ccc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(O)C(F)(F)F)c2)c(C#N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ccc(C)nc3)cc(C(O)C(F)(F)F)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2′-cyano-4′-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)biphenyl-3-carboxylic acid (32 mg, 0.095 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (50 mg, 0.24 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (100 mg, 0.26 mmol), and N,N-diisopropylethylamine (300 μL, 1.72 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a light color solid.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:12]=[CH:11][NH:10][C:7]=3[N:8]=[CH:9][C:4]2=[N:3][N:2]=1.C1N2CN3CN(C2)CN1C3.[C:23](O)(=[O:25])C>O>[CH:1]1[N:5]2[C:6]3[C:12]([CH:23]=[O:25])=[CH:11][NH:10][C:7]=3[N:8]=[CH:9][C:4]2=[N:3][N:2]=1
Reactant: c1cc2c(ncc3nncn32)[nH]1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1c[nH]c2ncc3nncn3c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
Water (1.0 mL) was added to a mixture of 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.200 g, 1.26 mmol, prepared using D from Preparation #BBBBB.1 and NaOH) and hexamethylenetetramine (0.264 g, 1.89 mmol). Acetic acid (0.5 mL) was added. The reaction vessel was sealed and the mixture was warmed to about 100° C. After about 8 h, the solution was allowed to cool to ambient temperature. After sitting for about 13 h, the mixture was cooled to about 0° C. The resulting mixture was diluted with water (1 mL) and then filtered rinsing with water. The solid was dried to afford 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-8-carbaldehyde (0.041 g, 18%): LC/MS (Table 1, Method n) Rt=0.23 min; MS m/z 188 (M+H)+.
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+].[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[OH:26].[Cl-].[NH4+]>CN(C)C=O>[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[O:26][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: Oc1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(Oc2cccc(Cl)c2Cl)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 71.4 %

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 0.21 g of 2,3-dichlorophenol, 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 0.25 g of 4-(2,3-dichlorophenoxy)-6-(2-propynyloxy)pyrimidine (the present compound (26)), m.p.: 91.9° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[SH:11].[C:12]1([CH3:20])[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH3:20][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:11][C:3]3[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=3[N:1]=2)=[CH:14][CH:13]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1S
Reactant: Cc1ccc(C=O)cc1
Solvent: c1ccncc1
Product: Cc1ccc(-c2nc3cc([N+](=O)[O-])ccc3s2)cc1
Temperature: 100 °C

Procedure:
To a stirred solution of 153.2 g (0.9 mole) of 2-amino-4-nitrothiophenol in pyridine is added 108.1 g (0.9 mole) of 4-tolualdehyde, and the reaction is heated at 100° C. until the starting materials are consumed. After cooling to room temperature, the mixture is acidified with cold 2N HCl, and the intermediate benzthiazoline is collected by filtration. The benzthiazoline is dissolved in methanol, then ferric chloride is added, and the solution is warmed at 40° C. for about 2 hours until oxidation to the benzthiazole is complete. The product is recrystallized from ethanol.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18](=O)[NH:19][CH2:20][C:21]2[C:26]([Cl:27])=[N:25][CH:24]=[CH:23][N:22]=2)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C=O>C(#N)C>[CH2:1]([O:8][C:9](=[O:29])[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[N:22]3[CH:23]=[CH:24][N:25]=[C:26]([Cl:27])[C:21]3=[CH:20][N:19]=2)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: O=C(NC[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1)OCc1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To benzyl((trans)-4-((3-chloropyrazin-2-yl)methylcarbamoyl)cyclohexyl)methylcarbamate (8.79 g, 18.98 mmol) in acetonitrile (anhydrous) (90 ml) were added phosphorus oxychloride (5.31 ml, 56.9 mmol) and N,N-dimethylformamide (a drop) and the mixture was stirred at 60° C. overnight. Then the mixture was concentrated, the residue was dissolved in dichloromethane and quenched with an excess of 7M ammonia in methanol. This mixture was concentrated again and the residue was purified by column chromatography (silica gel, dichloromethane with gradient 0 to 5% of methanol) to yield benzyl((trans)-4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)methylcarbamate (6.58 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([F:21])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].OO>C(O)C.C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:14][C:15]=1[F:21])#[N:18]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: OO
Solvent: CCO
Solvent: c1ccccc1
Product: COc1ccc(-c2ccc(C#N)c(F)c2)cc1
Temperature: 2 °C

Procedure:
A solution of compound 1 (10.64 g, 0.07 mol) in ethanol (90 ml) was added dropwise to a stirred mixture of compound 3 (12.0 g, 0.06 mol) and tetrakis(triphenylphosphine)palladium(O) (2.10 g, 1.82 mmol) in benzene (125 ml) and 2M-sodium carbonate (100 ml) at room temperature under dry nitrogen. The stirred mixture was heated under reflux (90°-95° C.) for 2.5 h (i.e., until glc analysis revealed absence of starting material). The mixture was cooled and stirred for 1 h at room temperature with 30% hydrogen peroxide (2 ml). The mixture was cooled further to 2° C., the product was filtered off and washed with water. The product was dried (CaCl2) in vacuo to give a yellow powder.
Reaction SMILES: S(=O)(=O)=O.N1C=CC=CC=1.[OH:11][C@@H:12]([CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)/[CH:13]=[CH:14]/[C@@H:15]1[C@@H:22]2[C@@H:18]([O:19][C:20](=[O:23])[CH2:21]2)[CH2:17][C@H:16]1[O:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:28][CH:27]=1.C(N(CC)CC)C.O>CS(C)=O.ClCCl>[O:11]=[C:12]([CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)/[CH:13]=[CH:14]/[C@@H:15]1[C@@H:22]2[C@@H:18]([O:19][C:20](=[O:23])[CH2:21]2)[CH2:17][C@H:16]1[O:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:28][CH:27]=1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/[C@@H](O)CCc3ccccc3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Agent: O=S(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccc(-c2ccccc2)cc1)CCc1ccccc1
Reaction time: 1 h
Yield: 83.7 %

Procedure:
A solution of pyridine sulfur trioxide (0.60 g) in DMSO (7.0 mL) was added dropwise to a stirred solution of compound [5a] (0.60 g) and triethylamine (0.80 g) in dichloromethane (8 mL) at −5-0° C. The mixture was stirred at the same temperature for 1 hour (TLC monitoring) and poured into cold water (30 mL). The mixture was stirred for 10 min at 0-5° C. The organic layer was separated, the water layer was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine (3×20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. A solution of the residue in methanol (2 mL) was cold to −10° C. and kept at the same temperature for 3 hours. The precipitated crystals were filtered, washed on filter with cold methanol (2×2 mL) and dried under reduced pressure to a constant weight to give 0.50 g (83.7% yield) of crystalline compound [4a].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[F:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[CH:17][C:18]=1[F:19]>>[F:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[F:19])[O:20][C:9]1[C:8]([F:11])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: Oc1ccc(F)c(F)c1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Product: O=Cc1cc(F)c(Oc2ccc(F)c(F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4,5-trifluorobenzaldehyde and 3,4-difluorophenol.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6](O)=[N:7][CH:8]=1.[CH2:12]([N:14](CC)CC)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl.O.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:10])[F:1])=[CH:8][N:7]=1)#[N:14]
Reactant: CCN(CC)CC
Reactant: Oc1ccc(C(F)(F)F)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [C-]#N
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To an ice-cooled solution of 5-(trifluoromethyl)pyridin-2-ol (10.24 g, 62.8 mmol) in anhydrous dichloromethane (200 ml) was added triethylamine (9.63 ml, 69 mmol), followed by dropwise addition of trifluoromethanesulfonic anhydride (12.68 ml, 75.4 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was washed with water (500 ml) and the aqueous layer extracted with dichloromethane (2×100 ml). The combined organic layers were washed with water (2×300 ml), brine (150 ml), then dried over Na2SO4, filtered through a 1 inch plug of silica gel and evaporated. The residue was dissolved in anhydrous N,N-dimethylformamide (150 ml) and zinc cyanide (3.98 g, 33.9 mmol) was added followed by tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) (3.56 g, 3.09 mmol). The mixture was degassed and heated at 80° C. overnight. The cooled reaction mixture was diluted with water (600 ml) and extracted with ethyl acetate (3×150 ml). The combined organic layers were washed with water (2×250 ml), brine (150 ml), dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica eluting with a gradient rising from neat iso-hexanes to 10% Et2O in iso-hexanes to give the title compound (8 g, 75%) as a white solid.