Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:39][CH2:40][C:41]([N:43]([CH3:45])[CH3:44])=[O:42].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:39][CH2:40][C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)CCCl
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Yield: 59.1 %

Procedure:
N-tert-Butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (100 mg, 188 μmol), 3-chloro-N,N-dimethylpropanamide (25.6 mg, 188 μmol) and cesium carbonate (184 mg, 565 mmol) in dimethylformamide (2 mL) were heated in a microwave at 150° C. for 30 min. The mixture was cooled, partitioned between ethyl acetate and water, washed with water 3 times, dried and concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-100% ethyl acetate in hexanes) gave N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(dimethylamino)-3-oxopropyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (70 mg, 59%) as an off-white solid. MS (M+H)+=630; 1H NMR (CDCl3) δ: 9.19 (s, 1H), 8.41 (s, 1H), 8.25 (d, J=1.9 Hz, 1H), 8.08 (s, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.31-7.37 (m, 1H), 6.22-6.78 (m, 1H), 5.72 (s, 2H), 4.79-4.88 (m, 2H), 3.53-3.63 (m, 2H), 3.11 (t, J=6.7 Hz, 2H), 2.95 (d, J=9.2 Hz, 6H), 1.61 (s, 9H), 0.87-1.01 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:9](=[O:16])[NH:10][C:11](=[S:15])[NH:12][C:13]=2[CH3:14])[CH:2]=1.CI.[O-][CH2:20]C.[Na+]>C(O)C>[CH3:20][S:15][C:11]1[NH:10][C:9](=[O:16])[C:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[C:13]([CH3:14])[N:12]=1
Reactant: Cc1[nH]c(=S)[nH]c(=O)c1Cc1cccnc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: CSc1nc(C)c(Cc2cccnc2)c(=O)[nH]1

Procedure:
Treatment of 5-(3-pyridylmethyl)-6-methyl-2-thiouracil with methyl iodide and sodium ethoxide in ethanol at 0° followed by acidification gave 2-methylthio-5-(3-pyridylmethyl)-6-methyl-4-pyrimidone m.p. 208°-211°.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:10])=[C:4]([F:22])[CH:3]=1.[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25]>>[F:22][C:4]1[CH:3]=[C:2]([C:30]2[CH:31]=[CH:32][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:28][CH:29]=2)[CH:7]=[C:6]([F:8])[C:5]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10]
Reactant: O=C(c1c(F)cc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CS(=O)(=O)c1ccc(-c2cc(F)c(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 14 via Procedure F′ from (4-bromo-2,6-difluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-methanesulfonylbenzene boronic acid (CAS 149104-88-1). MS (FIA) 489 (MH+)
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:6]1[C:11]([OH:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[OH:14])=[O:5].[CH2:15](Br)[CH2:16][C:17]([CH3:19])=[CH2:18]>[OH-].[K+]>[CH3:1][O:2][CH2:3][C:4]([C:6]1[C:7]([OH:14])=[C:8]([CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[C:9]([OH:13])=[C:10]([CH2:3][CH:4]=[C:6]([CH3:11])[CH3:7])[C:11]=1[OH:12])=[O:5]
Reactant: C=C(C)CCBr
Reactant: COCC(=O)c1c(O)cc(O)cc1O
Agent: [K+]
Agent: [OH-]
Product: COCC(=O)c1c(O)c(CC=C(C)C)c(O)c(CC=C(C)C)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
2-methoxy-1-(2,4,6-trihydroxyphenyl)ethanone (8.3 g, 42 mmol) was dissolved in a 5% potassium hydroxide aqueous solution (84 ml). After the reaction mixture was cooled below 0° C., Isopentenyl bromide (12.48 g, 84 mmol) was slowly added dropwise to within 30 minutes. The reaction mixture was stirred at room temperature (RT) for 2 hours, then poured into an ice water and acidified to pH 2. The reaction mixture was extracted with ethyl acetate. The extract was collected and dried over anhydrous sodium sulfate, followed by removing solvent. The desired compound was obtained by purifying the residue by silica gel column chromatography (dichloromethane as eluent) (5.7 g, yield 41%). 1H NMR (400 MHz, DMSO-d6): δ=11.44 (s, 2H), 9.24 (s, 1H), 5.00 (t, 2H, J=6.8 Hz), 4.63 (s, 2H,), 3.31 (s, 3H), 3.22 (d, 4H, J=6.8 Hz), 1.67 (s, 6H), 1.58 (s, 6H).
Reaction SMILES: C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[CH2:28]([O:31][C:32]([N:34]1[C@H:38]([C:39]([N:41]([CH2:43][C:44]2[N:51]3[C:47]([S:48][CH:49]=[CH:50]3)=[CH:46][N:45]=2)[CH3:42])=[O:40])[CH2:37][C@H:36]([S:52][C:53]2[C@H:54]([CH3:77])[C@@H:55]3[C@@H:65]([C@H:66]([O:68][Si](C(C)(C)C)(C)C)[CH3:67])[C:64](=[O:76])[N:56]3[C:57]=2[C:58]([O:60][CH2:61][CH:62]=[CH2:63])=[O:59])[CH2:35]1)=[O:33])[CH:29]=[CH2:30].P([O-])([O-])([O-])=O>C1COCC1>[CH2:28]([O:31][C:32]([N:34]1[C@H:38]([C:39]([N:41]([CH2:43][C:44]2[N:51]3[C:47]([S:48][CH:49]=[CH:50]3)=[CH:46][N:45]=2)[CH3:42])=[O:40])[CH2:37][C@H:36]([S:52][C:53]2[C@H:54]([CH3:77])[C@@H:55]3[C@@H:65]([C@H:66]([OH:68])[CH3:67])[C:64](=[O:76])[N:56]3[C:57]=2[C:58]([O:60][CH2:61][CH:62]=[CH2:63])=[O:59])[CH2:35]1)=[O:33])[CH:29]=[CH2:30]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(=O)N(C)Cc3ncc4sccn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(=O)N(C)Cc3ncc4sccn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 81.1 %

Procedure:
Acetic acid (0.132 ml) and 0.77 ml of a 1 M tetra-n-butylammonium fluoride/THF solution are added to a solution of 114 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[N-(imidazo[5,1-b]thiazol-5-yl)methyl-N-methylaminocarbonyl]pyrrolidin-3-yl]thio-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl)-1-methyl-carbapen-2-em-3-carboxylate in 2.3 ml of anhydrous THF, and the mixture is stirred in an argon atmosphere at room temperature for 22.5 hr. 1/15 M phosphate buffer (pH 7.0) (3 ml) is added thereto, and the mixture is extracted twice with 15 ml of ethyl acetate. The combined organic layers are dried over anhydrous magnesium sulfate and filtered, and the solvent is removed under reduced pressure and by filtrate to give a yellowish orange oil. This oil is purified by column chromatography on silica gel (ethyl acetate:methanol=9:1) to give 78.3 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[N-(imidazo[5,1-b]thiazol-5-yl)methyl-N-methylaminocarbonyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1N.N([O-])=[O:12].[Na+]>OS(O)(=O)=O>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[OH:12]
Reactant: O=N[O-]
Reactant: COc1ccc(C)c(N)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COc1ccc(C)c(O)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-5-(methyloxy)aniline (Intermediate 11, 6.0 g) in H2SO4 (5 M, 20 mL) was added portionwise NaNO2 (3.4 g, 49.3 mmol) at 0-5° C. The mixture was stirred at 50° C. for 1 hour and extracted with ethyl acetate (4 times 30 mL). The combined ethyl acetate layers were dried over sodium sulphate and concentrated under vacuum to give a residue, which was purified by column chromatography on silica gel (with EtOAc:PE=1:20 as eluents) to afford the title compound as a solid.
Reaction SMILES: Br[C:2]12[CH2:11][CH:7]([CH2:8][CH2:9][CH2:10]1)[CH:6]1[CH2:12][CH:3]2[CH2:4][CH2:5]1.[CH2:13]([OH:15])[CH3:14]>[Ag]=O>[CH2:13]([O:15][C:2]12[CH2:11][CH:7]([CH2:8][CH2:9][CH2:10]1)[CH:6]1[CH2:12][CH:3]2[CH2:4][CH2:5]1)[CH3:14]
Reactant: BrC12CCCC(C1)C1CCC2C1
Reactant: CCO
Agent: O=[Ag]
Product: CCOC12CCCC(C1)C1CCC2C1
Yield: 82.6 %

Procedure:
A mixture of 5.0 g of 1-bromotricyclo[4.3.1.12,5 ]undecane, 3.0 g of silver oxide and 30 ml of anhydrous ethanol was refluxed for 2 hours. Thereafter, the mixture was treated in the same manner as described in Example 1 to obtain 3.5 g (yield, 82.6%) of 1-ethoxytricyclo[4.3.1.12,5 ]undecane having a boiling point of 97° to 98° C./4 mmHg.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:11](Cl)=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9].[CH3:37][O-:38].[Na+].CO>CO>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:11]([O:38][CH3:37])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(Cl)nc2ccccc2c1-c1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc2ccccc2c(-c2ccccc2)c1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
To a solution of the compound obtained in Example 269 (100 mg) in methanol (2 ml) was added 28% NaOMe-methanol (2 ml), and the mixture was stirred for 3 hours with heating under reflux. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with water, dried and evaporated to yield the title compound as colorless crystals (85 mg).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([OH:9])=[CH:7][C:6]([OH:10])=[CH:5][C:4]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CC(C)=O>[CH2:22]([O:9][C:8]1[C:3]([CH2:1][CH3:2])=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([O:10][CH2:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCc1c(O)cc(O)cc1CC(=O)OC
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCc1c(CC(=O)OC)cc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 131.7 %

Procedure:
Methyl 2-ethyl-3,5-dihydroxyphenylacetate (1.70 g, 8.09 mmol) was dissolved in acetone (20 mL), and potassium carbonate (6.43 g, 46.5 mmol) and benzyl bromide (4.00 mL, 33.6 mmol) were added thereto ad stirred at room temperature for 6 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through silica gel column chromatography (n-hexane/ethyl acetate=20/1 to 9/1) to obtain methyl 3,5-bis(benzyloxy)-2-ethylphenylacetate (2.08 g, 66%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[C:18]1[N:22]([CH3:23])[N:21]=[CH:20][C:19]=1[Br:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[C:18]1[N:22]([CH3:23])[N:21]=[CH:20][C:19]=1[Br:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ncc(Br)c1-c1cc([N+](=O)[O-])ccc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: O
Product: Cn1ncc(Br)c1-c1cc(N)ccc1OCc1ccccc1
Yield: 39 %

Procedure:
The reaction mixture of 5-(2-benzyloxy-5-nitro-phenyl)-4-bromo-1-methyl-1H-pyrazole was reduced in the presence of SnCl2.2H2O, in a similar manner as described in Example 1. 1, providing 4-benzyloxy-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenylamine (0.079 g, 0.22 mmol, 39% for three steps). LCMS m/z (%)=358 (M+H79Br, 98), 360 (M+H81Br, 100). 1H NMR (400 MHz, CDCl3) δ: 7.45 (s, 1H), 7.15-7.26 (m, 3H), 7.10 (d, J=6.6 Hz, 2H), 6.83 (d, J=8.7 Hz, 1H), 6.66 (dd, J=2.8, 8.6 Hz, 1H), 6.55 (d, J=2.8 Hz, 1H), 4.83 (AB quartet, J=12.0, 17.2 Hz, 2H), 3.62 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:13].[OH:23][CH2:24][CH2:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[OH:23][CH2:24][CH2:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=1)=[O:13]
Reactant: C#CCOc1ccc(N)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: O=Cc1ccccc1OCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C#CCOc1ccc(NCc2ccccc2OCCO)c(C(=O)c2ccc(C(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 100 mg (0.341 mmol) (2-amino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone in 1.5 ml CH2Cl2 is added 61 mg (0.36 mmol) 2-(2-hydroxyethoxy)benzaldehyde and 84 mg (0.38 mmol) sodium triacetoxyborohydride. The mixture is stirred at r.t. for two days, diluted with water and extracted with CH2Cl2. Purification of the crude product by chromatography (ethyl acetate/hexanes 1:1) affords a yellow solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[C:8]([NH2:10])=[O:9].Cl[CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=1>>[NH2:2][C:3]1[N:7]([CH2:12][C:13]2[CH:14]=[C:15]([C:23]([F:25])([F:26])[F:24])[CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=2)[CH:6]=[N:5][C:4]=1[C:8]([NH2:10])=[O:9]
Reactant: NC(=O)c1nc[nH]c1N
Reactant: FC(F)(F)c1cc(CCl)cc(C(F)(F)F)c1
Agent: Cl
Product: NC(=O)c1ncn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Wash sodium hydride (2.71 g of a 60% solution in mineral oil, 67.66 mmol) three times with hexanes, then dilute with 85 mL of DMF. To this mixture add the HCl salt of 5-amino-1H-imidazole-4-carboxylic acid amide (5.0 g, 30.75 mmol) neat in four portions. The mixture generates gas and remains cloudy and turns a slightly green color. After mixing for 40 min., add 1-chloromethyl-3,5-bis-trifluoromethyl-benzene (8.88 g, 33.83 mmol). (The mixture again generates gas and darkens). Stir at RT for 2 days, then pour through a plug of Celite and wash with DMF (50 mL) and xylenes (50 mL). Remove the DMF via azeotropic distillation with xylenes under reduced pressure (5×50 mL), and then concentrate the residue under a steady stream of nitrogen for 18 h to provide the title compound as a dark purple solid. MS (ES) 351.1, 353.1 (M+1); 1H NMR (300 MHz, CDCl3) δ 7.70 (s, 1H), 7.58 (s, 2H), 7.31 (s, 2H), 6.96 (s, 1H), 5.46 (s, 2H), 5.10 (s, 2H).
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.[CH2:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[I-].[Na+].[H-].[Na+]>O.CN(C=O)C>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:3]2[N:2]=[N:1][C:5]([C:6]3[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=3)=[N:4]2)=[CH:27][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: Nc1ncccc1-c1nn[nH]n1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncccc1-c1nnn(Cc2ccc(OCc3ccccc3)cc2)n1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 17.2 %

Procedure:
To a solution of 3-(2H-tetrazol-5-yl)-pyridin-2-ylamine (100 mg) described in Manufacturing Example 5-1, 4-benzyloxybenzyl chloride (172 mg), sodium iodide (111 mg), and DMF (3 mL) was added NaH (18 mg), which was stirred for 40 minutes at 60° C. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=4:1, then 2:1, then 1:1). Ethyl acetate was added to the resulting residue, and the solids were filtered off to obtain the titled compound (38 mg).
Reaction SMILES: [CH3:1][C:2]1[C:17]([CH3:18])=[C:16]([O:19][CH2:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:15]=[CH:14][C:3]=1[O:4][CH2:5][C:6](C1C=CC=CC=1)=O.BrCC([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=O.O>C1(C)C(C)=CC=CC=1>[CH3:18][C:17]1[C:16]2[O:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]=2[C:14]2[C:6]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:5][O:4][C:3]=2[C:2]=1[CH3:1]
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1c(OCC(=O)c2ccccc2)ccc(OCC(=O)c2ccccc2)c1C
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1c(C)c2occ(-c3ccccc3)c2c2c(-c3ccccc3)coc12

Procedure:
A mixture of 2-[2,3-Dimethyl-4-(2-oxo-2-phenyl-ethoxy)-phenoxy]-1-phenyl-ethanone (480 mg, 1.28 mmol) synthesized as described in Example 11, an excess of bromoacetophenone, and polyphosphoric acid (PPA, 100 mg) in xylene (10 mL) was stirred at 150° C. for 10 h. The mixture was then poured into water, extracted with EtOAc, the organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column eluting with 10-20% EtOAc in hexane to give 190 mg of 4,5-dimethyl-1,8-diphenyl-benzo[1,2-b;4,3-b′]difuran (250 mg). 1H NMR (CDCl3, 300 MHz) δ: 7.60 (s, 2H), 7.05 (m, 4H), 6.90 (m, 2H), 6.85 (m, 4H), 2.60 (s, 6H) ppm. 13C NMR (CDCl3, 75 MHz) δ: 152.57,141.48, 133.19, 128.42, 127.52, 126.87, 124.05, 117.40, 116.29, 11.80 ppm. MS (m/z): 339 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:19]([C:20]2[N:25]=[C:24]([C:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=3)[CH:23]=[CH:22][CH:21]=2)[CH2:18][C:17]([C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[N:16]1.[CH3:39][N:40]([CH3:45])[S:41](Cl)(=[O:43])=[O:42]>>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:19]([C:20]2[N:25]=[C:24]([C:26]3[CH2:27][CH2:28][N:29]([S:41](=[O:43])(=[O:42])[N:40]([CH3:45])[CH3:39])[CH2:30][CH:31]=3)[CH:23]=[CH:22][CH:21]=2)[CH2:18][C:17]([C:32]([F:38])([F:37])[C:33]([F:34])([F:36])[F:35])=[N:16]1
Reactant: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(C3=CCNCC3)n2)C1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)S(=O)(=O)N1CC=C(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)n2)CC1

Procedure:
The titled compound was prepared in accordance with the same procedures as in Step 2 of Example 158, except for using 1-(2-chloro-phenyl)-5-[2-(1,2,3,6-tetrahydropyridin-4-yl)-pyridin-6-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole trifluoroacetate prepared in Step 1 of Example 158; and using dimethylsulfamoyl chloride instead of methanesulfonyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH2:13]Br.[H-].[Na+]>CN(C)C=O>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH2:13][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: O=Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2c(Cl)cccc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 107.6 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (3.59 g, 24.39 mmol) and 2,6-dichlorobenzyl bromide (7.05 g, 29.39 mmol) in dimethylformamide (20 mL) at 0° C. was added 60% sodium hydride (1.176 g, 29.39 mmol). After stirring at ambient temperature for 16 h, the reaction was partitioned between ethyl acetate and water. The organic layer was washed with aqueous sodium chloride and dried (MgSO4). Purification by flash column chromatography (silica gel, hexane/ethyl acetate) yielded the title compound as an off-white solid (7.38 g, 89%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].C(N(CC)CC)C.[C:13]([NH:17][C:18]1[O:19][C:20]([C:27](Cl)=[O:28])=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1)([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[CH3:14][C:13]([NH:17][C:18]1[O:19][C:20]([C:27]([NH:1][CH2:2][CH:3]([OH:5])[CH3:4])=[O:28])=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1)([CH3:16])[CH3:15]
Reactant: CC(O)CN
Reactant: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)Cl)o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(O)CNC(=O)c1oc(NC(C)(C)C)nc1C(F)(F)F
Yield: 46.1 %

Procedure:
By the procedure of Example 38, a stirred mixture of 70 ml methylene chloride, 1.80 g (24 mmol) of 1-amino-2-propanol, 2.68 g (13.2 mmol) of triethylamine, and 6.50 g (24 mmol) of 2-(tert-butylamino)-4-trifluoromethyl-5-oxazolecarbonyl chloride was reacted for 16 hours at ambient temperature. The product was separated and then recrystallized to yield 3.42 g of a white solid product (m.p.=105°-107° C.) identified in Table I.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([C:11]3[CH:16]=[CH:15][NH:14][C:13](=S(=O)=O)[N:12]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:27]1([N:33]2C(C3C=CNC(=S(=O)=O)N=3)=C(C3C=CC(F)=CC=3)N=C2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:1]1([N:6]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:12]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)=c1nc(-c2c(-c3ccc(F)cc3)ncn2C2CCCC2)cc[nH]1
Reactant: O=S(=O)=c1nc(-c2c(-c3ccc(F)cc3)ncn2C2CCCCC2)cc[nH]1
Product: Fc1ccc(-c2ncn(C3CCCC3)c2-c2ccnc(Nc3ccccc3)n2)cc1

Procedure:
The reaction was conducted in a manner analogous to Example 2d except substituting polymer-bound 1-cyclopentyl-4-(4-fluorophenyl)-5-[(2-sulfonyl)pyrimidin-4-yl]imidazole for polymer-bound 1-cyclohexyl-4-(4-fluorophenyl)-5-[(2-sulfonyl)pyrimidin-4-yl]imidazole: ESMS m/z=400 (MH)+
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10]C=C2.[I:15]Cl.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[NH2:10][C:11]1[CH:12]=[CH:13][C:5]([CH2:4][C:3]([NH:2][CH3:1])=[O:14])=[CH:6][C:7]=1[I:15]
Reactant: CNC(=O)Cc1ccc2[nH]ccc2c1
Reactant: ClI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CNC(=O)Cc1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
4-Amino-N-methyl-benzeneacetamide (6) (6.56 g, 0.04 mol) was dissolved in CH3CN (200 mL) and ICl (7.14 g dissolved in 60 mL of CH3CN, 0.044 mol) was added dropwise with vigorous stirring. After stirring at RT for 3 h, saturated aqueous Na2CO3 (50 mL) was added and the reaction was concentrated in vacuo. The residue was dissolved in EtOAc and extracted with saturated aqueous Na2CO3. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The product (7) (7.38 g, 63.6%) was isolated from the concentrate by trituration with CH2Cl2 /EtOAc and washing with Et2O. This material was found to be pure by NMR analysis.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12>>[C:14]1(=[O:24])[N:18]([CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4])[C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12
Reactant: O=C(CCl)NCCc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Product: O=C(CN1C(=O)c2ccccc2C1=O)NCCc1ccccc1

Procedure:
KR2002076486 describes a process for preparation of praziquantel by reacting phenylethylamine with chloroacetyl chloride to obtain 2-chloro-N-phenethylacetamide. The compound 2-chloro-N-phenethylacetamide is then reacted with pthalimide to give 2-pthalimido-N-phenethylacetamide, which is then treated with hydrazine monohydrate to give 2-amino-N-phenylethylacetamide. On further treatment with bromoacetal, 2-amino-N-phenylethylacetamide gives 2-[2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide. This compound on further cyclization and acylation using cyclohexanoylchloride forms praziquantel.