Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:32]1[CH2:31][CH2:30][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:34][CH2:33]1)=[O:20])=[N:5]2
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(F)c(F)cc2nc1OC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cccc(N2CCN(C(=O)Nc3nc4cc(F)c(F)cc4nc3OC)CC2)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 76.7 %

Procedure:
Ethyl N-(6,7-di fluoro-2-methoxyquinoxalin-3-yl)carbamate (25 mg, 0.088 mmol) and 1-(3-methoxy phenyl)piperazine (35 mg, 0.18 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (28 mg, 0.18 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (1:1) mixture and concentration gave 29 mg of the titled compound (yield, 76%). 1H NMR (300 MHz, CDCl3) δ 3.28-3.30 (m, 4H), 3.76-3.77 (m, 4H), 3.81 (s, 3H), 4.12 (s, 3H), 6.48-6.49 (m, 2H), 6.56-6.58 (m, 1H), 7.20-7.23 (m, 1H), 7.29-7.30 (m, 1H), 7.50-7.53 (m, 1H), 7.60-7.62 (m, 1H).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:38])[C:21]([CH3:37])=[C:22]([C:24]3[CH:36]=[CH:35][C:27]([C:28]([NH:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:29])=[CH:26][N:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:38])[C:21]([CH3:37])=[C:22]([C:24]3[N+:25]([O-:9])=[CH:26][C:27]([C:28]([NH:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:29])=[CH:35][CH:36]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC(C)C)cn1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC(C)C)c[n+]1[O-]
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 15 mg) was added to a solution of 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2-methylpropyl)-nicotinamide (Intermediate 30, 20 mg) in chloroform (3 ml) at 60° C. and the reaction maintained at 60° C. for 7 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (2 g) and an SCX SPE (1.0 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2-methylpropyl)-3-pyridinecarboxamide 1 oxide as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=1[NH2:6])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[Cl:17][CH2:18][C:19](Cl)=[O:20]>>[Cl:17][CH2:18][C:19]([NH:6][C:5]1[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:4]=1[CH:1]([CH3:3])[CH3:2])=[O:20]
Reactant: Cc1ccc(C(C)C)c(N)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc(C(C)C)c(NC(=O)CCl)c1
Temperature: 2.5 °C
Yield: 62.6 %

Procedure:
2-Isopropyl-5-methylaniline (286 g, 1.91 mol) and sodium bicarbonate (270 g, 3.22 mol) were charged in to a round bottomed flask with stirring under nitrogen atmosphere and cooled to 0-5° C. 2-Chloroacetyl chloride (218 g, 1.93 mol) was added drop wise at 0-5° C. over a period of 1 hour. The reaction was stirred at 0-5° C. for 1 hour. After completion of the reaction, purified water (2.86 L) was added and stirred at 25-30° C. for 15 minutes. The layers were then separated. The organic layer was washed with water (2×2.86 L) and with brine (1.43 L). The aqueous layers were combined and extracted with ethyl acetate (1.43 L). The organic layers were dried with sodium sulphate, filtered, and concentrated at 50-55° C. under vacuum (500-600 mm Hg) to ⅖ths volume. Hexanes (2.86 L) were added and the mixture was stirred at 25-30° C. for 1 hour. The solid was filtered, washed with hexanes (1.43 L), and dried at 45-50° C. under vacuum (500-600 mm Hg) to give 2-chloro-N-(2-isopropyl-5-methylphenyl)acetamide as an off-white solid (270 g, 66%): mp 97-99° C., 1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H), 7.60 (s, 1H), 7.20 (d, J=7.95 Hz, 1H), 7.04 (d, J=7.89 Hz, 1H), 4.25 (s, 2H), 2.99 (q, J=6.78 Hz, 1H), 2.34 (s, 3H), 1.26 (d, J=6.84 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 164.07, 137.28, 136.33, 132.95, 127.35, 125.62, 124.46, 43.21, 27.86, 22.98, 21.00; ESIMS m/z 226 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[N:22]1([C:28](=[O:30])[CH3:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:25]4[CH2:26][CH2:27][N:22]([C:28](=[O:30])[CH3:29])[CH2:23][CH2:24]4)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(CCCOc2ccc3c(-c4ccc(Br)cc4)nsc3c2)CC1

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and 1-piperazin-1-yl-ethanone were converted to yield 1-(4-{3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl}-piperazin-1-yl)-ethanone as colorless oil, MS: 474 (MH+,1Br).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=2[C:10](I)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][CH:29]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.O>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=2[C:10]([C:28]2[CH:29]=[CH:30][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:32][CH:33]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1nccc2c1c(I)nn2Cc1ccccc1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nccc2c1c(-c1ccc(N3CCOCC3)cc1)nn2Cc1ccccc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a mixture of 1-benzyl-3-iodo-4-methoxy-1H-pyrazolo[4,3-c]pyridine (0.75 g), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (0.60 g) and sodium carbonate (0.44 g) in DME/water (6 mL/3 mL) was added dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) (73 mg) under nitrogen atmosphere. The reaction mixture was stirred overnight at 85° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (0.72 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][C:9]3[N:11]=[C:12]([N:18]4[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]4)[CH:13]=[C:14]([CH2:15][CH2:16][CH3:17])[C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:25][CH2:26][C@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[OH:28].C([BH3-])#N>CN(C=O)C.C(O)(=O)C>[NH2:1][C:2]1[C:3]2[S:10][C:9]3[N:11]=[C:12]([N:18]4[CH2:19][CH2:20][CH:21]([NH:25][CH2:26][C@H:27]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[OH:28])[CH2:22][CH2:23]4)[CH:13]=[C:14]([CH2:15][CH2:16][CH3:17])[C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NC[C@@H](O)c1ccccc1
Reactant: CCCc1cc(N2CCC(=O)CC2)nc2sc3c(N)ncnc3c12
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCc1cc(N2CCC(NC[C@@H](O)c3ccccc3)CC2)nc2sc3c(N)ncnc3c12
Reaction time: 16 h
Yield: 56.2 %

Procedure:
1-(4-Amino-9-propyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-7-yl)-piperidin-4-one (Example 4) (341 mg, 1.00 mmol) and (S)-2-amino-1-phenylethanol (142 mg, 1.00 mmol) was dissolved in 10 mL of dry DMF. MP-Cyanoborohydride (0534 mg, 1.20 mmol) was added followed by 10 drops of glacial acetic acid. This mixture was shaken for 16 h. The resin was removed by filtration and washed with MeOH and dichloromethane. The filtrate was evaporated. The residue was treated with 2 M sodium carbonate solution. The resulting solid was collected by filtration and recrystalized from MeOH/acetonitrile to give the title compound as a pale-colored solid (0.260 g, 56%).
Reaction SMILES: [NH2:1][C:2](=[N:21][OH:22])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][N:7]([CH2:15][CH2:16][OH:17])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[CH3:23][O:24][CH2:25][C:26]1[CH:31]=[C:30]([C:32](O)=O)[CH:29]=[CH:28][C:27]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH3:41]>>[OH:17][CH2:16][CH2:15][N:7]([CH2:6][C:5]1[CH:18]=[CH:19][CH:20]=[C:3]([C:2]2[N:1]=[C:32]([C:30]3[CH:29]=[CH:28][C:27]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[CH3:41])=[C:26]([CH2:25][O:24][CH3:23])[CH:31]=3)[O:22][N:21]=2)[CH:4]=1)[C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:13])[CH3:11]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1cccc(C(N)=NO)c1
Product: COCc1cc(-c2nc(-c3cccc(CN(CCO)C(=O)OC(C)(C)C)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described for example 141, step 1, but starting from Intermediate 69 (185.62 mg; 0.60 mmol) and Intermediate 28 (161.47 mg; 0.63 mmol), the crude mixture was purified by flash chromatography (cHex/(DCM/EtOAc 1:1) to afford the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 8.43 (d, J=1.4 Hz, 1H), 8.17 (dd, J=7.9, 1.9 Hz, 1H), 8.13-8.11 (m, 2H), 7.50 (t, J=8.0 Hz, 1H), 7.43-7.41 (m, 1H), 7.36-7.24 (m, 4H), 7.13 (d, J=7.1 Hz, 1H), 4.58 (s, 2H), 4.23 (s, 2H), 3.73 (br s, 2H), 3.46 (br s, 2H), 3.33 (s, 3H), 2.08 (s, 3H), 1.52 (s, 9H). LC/MS (Method B): 530.4 (M+H)+. HPLC (Method A) Rt 5.91 min (Purity: 96.0%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].S(OC)(O[CH3:14])(=O)=O.Cl>[OH-].[K+]>[Cl:1][C:2]1[C:7]([O:8][CH3:14])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9]
Reactant: Oc1cccc(O)c1Cl
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COc1cccc(O)c1Cl
Temperature: 100 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
To an aqueous solution (100 mL) of potassium hydroxide (11.0 g) was added 2-chlorobenzene-1,3-diol (22.8 g). Then, dimethyl sulfate (19.9 g) was slowly added to the reaction mixture while keeping the reaction mixture at 10° C. to 20° C., and the mixture was stirred at 100° C. for 2 days. The reaction mixture was acidified with 2N hydrochloric acid, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (18.0 g).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=O)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:3][CH2:2]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C.C(P(=O)(OCC)OCC)#N>CN(C=O)C>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:21])([CH3:22])[C:18]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:20])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:3][CH2:2]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)O)ccc2n1CC1CC1
Reactant: C1COCCN1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)N3CCOCC3)ccc2n1CC1CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 48 %

Procedure:
To a solution of 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropanoic acid (Example 1, Step H, 180 mg, 0.46 mmol), morpholine (Wako Pure Chemical Industries, Ltd., 48 mg, 0.55 mmol), N,N′-diisopropylethylamine (71 mg, 0.55 mmol) in N,N′-dimethylformamide (3 mL) was added diethyl cyanophosphonate (Aldrich, 90 mg, 0.55 mmol) at room temperature. The mixture was stirred at room temperature for 20 h and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:4 as eluent) to afford the title compound (102 mg, 48%) as a white solid.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][O:8][CH2:9][C:10]([CH2:27][O:28][CH2:29][CH2:30][N:31]2C(=O)C3=CC=CC=C3C2=O)([CH2:12][O:13][CH2:14][CH2:15][N:16]2C(=O)C3=CC=CC=C3C2=O)[CH3:11])C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:31][CH2:30][CH2:29][O:28][CH2:27][C:10]([CH2:9][O:8][CH2:7][CH2:6][NH2:5])([CH2:12][O:13][CH2:14][CH2:15][NH2:16])[CH3:11]
Reactant: CC(COCCN1C(=O)c2ccccc2C1=O)(COCCN1C(=O)c2ccccc2C1=O)COCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(COCCN)(COCCN)COCCN
Temperature: 50 °C
Yield: 82.9 %

Procedure:
A solution of 1,1,1-tris(phthalimidoethoxymethyl)ethane (4.0 g, 6.30 mmol) in 100 mL of absolute ethanol was heated to 50C. Then a 55% solution of hydrazine hydrate (3.7 mL, 63.00 mmol) was added dropwise and the resulting mixture was heated at 50° C. for 5 hrs. The reaction was cooled to 25° C. and the solids were filtered. The filtrate was evaporated to give an oil which was purified over reversed phase packing (C-18) using a methanol/water gradient as eluant to yield 1,1,1-tris(aminoethoxymethyl)ethane (1.3 g, 5.22 mmol, 83 % ).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([CH3:13])[CH:5]=1)[CH3:2].CO>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([CH3:13])[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc([N+](=O)[O-])c(C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOc1ccc(N)c(C)c1
Reaction time: 4 h
Yield: 92 %

Procedure:
Compound 404a (250 mg, 1.38 mmol) was dissolved in EtOAc (10 mL) and MeOH (10 mL) and transferred to a 250 mL hydrogenation flask. 10% Pd/C (25 mg, 10% w/w) was added and the sample was hydrogenated for 4 h at 35 psi H2. Upon completion, the mixture was filtered over a bed of Celite and then concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with NaHCO3 (50 mL×3). The organic layer was dried over Na2SO4 to yield a dark-red oil (192 mg, 92%): TLC Rf 0.30 (20% EtOAc/hexanes). 1NMR (600 MHz, CDCl3) δ 6.67 (s, 1H), 6.62 (m, 2H), 3.97-3.93 (q, 2H, J=6.96 Hz), 3.42 (s, 2H), 2.16 (s, 3H), 1.38-1.35 (t, 3H, J=7.02 Hz). NMR (150 MHz, CDCl3) δ 152.3, 138.1, 124.4, 117.45, 116.34, 113.1, 64.2, 17.9, 15.2. Elemental analysis calculated for C9H13NO: C, 71.49; H, 8.67; N, 9.26. Found: C, 71.42; H, 8.76; N, 9.04.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:21]=[C:20]([CH3:22])[N:19]=[CH:18][C:7]=3[CH2:8][NH:9][CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[CH2:25]=O>C(O)=O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:21]=[C:20]([CH3:22])[N:19]=[CH:18][C:7]=3[CH2:8][N:9]([CH3:25])[CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)NC2
Reactant: C=O
Solvent: O=CO
Product: Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)N(C)C2

Procedure:
A mixture of 4 g (11 mmole) of 9-chloro-7-(2-chlorophenyl)-6,7-dihydro-2-methyl-5H-pyrimido[5,4-d][2]benzazepine 2 ml of 88% formic acid and 2 ml of 37.5% formaldehyde solution was heated on the steambath for 3 hours. The reaction mixture was poured into an excess of dilute ice cold sodium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was crystallized from ether to give the crude product, m.p. 155°-156° C. Recrystallization from ether gave the pure product as colorless prisms, m.p. 156°-157° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8](Cl)=[C:7]([S:10]([CH3:13])(=[O:12])=[O:11])[S:6](=[O:15])(=[O:14])[N:5]=1)[CH3:2].C[Si]([NH:20][Si](C)(C)C)(C)C.CO>C(#N)C>[CH2:1]([O:3][C:4]1[C:8]([NH2:20])=[C:7]([S:10]([CH3:13])(=[O:12])=[O:11])[S:6](=[O:15])(=[O:14])[N:5]=1)[CH3:2]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CCOC1=NS(=O)(=O)C(S(C)(=O)=O)=C1Cl
Solvent: CO
Solvent: CC#N
Product: CCOC1=NS(=O)(=O)C(S(C)(=O)=O)=C1N
Temperature: 25 °C
Yield: 79.6 %

Procedure:
To a solution of 3-ethoxy-4-chloro-5-methylsulfonylisothiazole-1,1-dioxide (1.1 g, 4.0 mmol) in acetonitrile (15 ml) under a nitrogen atmosphere was added hexamethyldisilizane (0.85 ml, 4.0 mmol). After an immediate exothermic reaction, the solution was heated at gentle reflux for 1 hour. Upon cooling to room temperature, methanol (1.0 ml) was added and any solid removed by filtration. The organic solution was evaporated and the solid residue triturated with ethyl acetate/methanol to give crystalline title compound (0.81 g), mp 214°-217°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][N:10]2[C:14]([C:15]([O:17]CC)=O)=[CH:13][C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[N:11]2)=[CH:4][CH:3]=1.[CH2:27]([NH2:30])[CH2:28][NH2:29]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[NH:30][CH2:27][CH2:28][N:29]2[C:15](=[O:17])[C:14]2[N:10]([N:11]=[C:12]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH:13]=2)[CH2:9]3)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2ccccn2)nn1CC(=O)c1ccc(Cl)cc1
Reactant: NCCN
Solvent: C1COCCO1
Product: O=C1c2cc(-c3ccccn3)nn2CC2(c3ccc(Cl)cc3)NCCN12

Procedure:
Ethyl 1-[2-(4-chlorophenyl)-2-oxoethyl]-3-(pyridin-2-yl)-1H-pyrazole-5-carboxylate (630 mg, 1.77 mmol) and ethane-1,2-diamine (1.77 mL, 26.6 mmol) was combined and stirred at reflux in 1,4-dioxane. After 48 hours (monitored by LCMS) the reaction mixture was concentrated in vacuo and the residue partitioned between CH2Cl2 (20 mL) and brine (10 mL). The organic layer was separated and the aqueous layer extracted with further CH2Cl2 (2×10 mL). The combined organic layers were dried (MgSO4), filtered and evaporated in vacuo to give a yellow residue that was purified by flash column chromatography (Biotage SP4, 40 g cartridge, gradient 2 to 15% methanol in CH2Cl2). To give 10a-(4-chlorophenyl)-7-(pyridin-2-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrazolo[1,5-d]pyrazin-5-one as an off white solid (150 mg, yield: 23%). ESI-MI m/z [M+H]+ 366.1.
Reaction SMILES: C(O[C:4]1[C:5](=[O:15])[C:6](=[O:14])[C:7]=1[NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][CH3:11])C.[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20]>C(#N)C>[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][C:4]1[C:5](=[O:15])[C:6](=[O:14])[C:7]=1[NH:8][C:9]([CH3:12])([CH3:13])[CH2:10][CH3:11]
Reactant: CCOc1c(NC(C)(C)CC)c(=O)c1=O
Reactant: NCc1ccc(F)cc1F
Solvent: CC#N
Product: CCC(C)(C)Nc1c(NCc2ccc(F)cc2F)c(=O)c1=O

Procedure:
This compound was prepared according to the procedure for Example 59. From 3-ethoxy-4-(1,1 -dimethyl-propylamino)-cyclobut-3-ene- 1,2-dione and 2,4-difluorobenzylamine in acetonitrile. The title compound was obtained, after recrystallization from diethyl ether, as a white solid (80%): mp 242°-244° C.; 1H NMR (DMSO-d6) δ0.82 (t, 3H), 1.30 (s, 6H), 1.68 (q, 2H), 4.76 (d, 2H), 7.09 (m, 1H), 7.27 (m, 1H), 7.50 (m, 2H), 7.80 (m, 1H) ppm; IR (KBr) 3250, 3150, 2970, 1790, 1652, 1580, 1538, 1510 cm-1 ; MS (m/z) 309 ([M+H]+).
Reaction SMILES: C1C=CC=CC=1.[F:7][C:8]1[C:9](=[O:42])[NH:10][C:11](=[O:41])[N:12]([CH:40]=1)[C@@H:13]1[O:39][C@H:17]([CH2:18][O:19]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:15]([OH:16])[CH2:14]1.[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[OH-].[K+]>O1CCOCC1>[CH2:43]([O:16][C@@H:15]1[C@@H:17]([CH2:18][OH:19])[O:39][C@@H:13]([N:12]2[CH:40]=[C:8]([F:7])[C:9](=[O:42])[NH:10][C:11]2=[O:41])[CH2:14]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: c1ccccc1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)cc1F
Reaction time: 2 h
Yield: 20 %

Procedure:
To a mixture of 50 ml of benzene and 50 ml of dioxane were added 1.00 g of 2'-deoxy-5-fluoro-5'-O-trityluridine, 0.30 ml of benzyl bromide and 0.23 g of potassium hydroxide powder, and the mixture was refluxed for 25 hours. The insolubles were removed by filtration and the filtrate was concentrated and the concentrate was dissolved in 5 ml of 80% acetic acid. The solution was left to stand at 80° C. for 2 hours. The solvent was distilled off and the residue was placed on a silica gel column to conduct a gradient elution using chloroform and mixtures of methanol (up to 2%) and chloroform. The fractions corresponding to 3'-O-benzyl-2'-deoxy-5-fluorouridine were collected and concentrated. The concentrate was recrystallized from ethanol, giving 0.14 g of the title compound in a yield of 20%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.I[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CCCCCCCCCCI
Product: CCCCCCCCCCOc1ccc(CC(=O)OC)cc1

Procedure:
First, a dibenzyl ketone having the alkoxy (OC10H21) groups is prepared to produce the polyphenylene (a). Specifically, 4-hydroxybenzeneacetic acid methyl ester is reacted with 1-iododecane to obtain 4-decyloxybenzeneacetic acid methyl ester as shown in the following reaction formula (32).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:41])[NH:9][CH2:10][C:11]1[CH:40]=[CH:39][C:14]2[N:15]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:16]([CH2:18][N:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22](=[O:29])[N:21]([CH:30]4[CH2:32][CH2:31]4)[C:20]3=[O:33])=[N:17][C:13]=2[CH:12]=1)([CH3:6])([CH3:5])[CH3:4].I[CH3:43]>CN(C=O)C>[C:3]([O:7][C:8](=[O:41])[N:9]([CH2:10][C:11]1[CH:40]=[CH:39][C:14]2[N:15]([CH2:34][CH2:35][CH:36]([CH3:37])[CH3:38])[C:16]([CH2:18][N:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22](=[O:29])[N:21]([CH:30]4[CH2:32][CH2:31]4)[C:20]3=[O:33])=[N:17][C:13]=2[CH:12]=1)[CH3:43])([CH3:5])([CH3:4])[CH3:6]
Reactant: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c(=O)c3ccccc32)nc2cc(CNC(=O)OC(C)(C)C)ccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c(=O)c3ccccc32)nc2cc(CN(C)C(=O)OC(C)(C)C)ccc21
Reaction time: 8 h
Yield: 76 %

Procedure:
To a suspension of NaH (60% mineral oil, 11.2 mg, 0.28 mmol) in DMF (2 mL) at room temperature was added [2-(3-cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (50 mg, 0.094 mmol). After stirring for 5 min iodomethane (47 μL, 0.75 mmol) was added. The mixture was stirred overnight under a nitrogen atmosphere and partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic phases washed with 5% sodium meta-bisulfite and brine. After drying over MgSO4 the residue was purified by flash chromatography (eluent 2% MeOH in CH2Cl2) to give [2-(3-cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-methyl-carbamic acid tert-butyl ester (39 mg, 76%) as a white solid:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]1.[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22](F)[C:19]=1[C:20]#[N:21].CC(C)([O-])C.[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][CH:5]1[CH2:6][CH2:7][CH:8]([CH2:11][O:12][C:22]2[CH:23]=[CH:24][CH:25]=[C:18]([F:17])[C:19]=2[C:20]#[N:21])[CH2:9][CH2:10]1
Reactant: N#Cc1c(F)cccc1F
Reactant: OCC1CCC(Cc2ccccc2Cl)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCC1CCC(Cc2ccccc2Cl)CC1
Yield: 99.8 %

Procedure:
4-(2-Chlorobenzyl)cyclohexylmethanol (68 mg; 0.28 mmol) and 2,6-difluorobenzonitrile (40 mg; 0.28 mmol) were carried out using Method I with potassium t-butoxide (35 mg; 0.31 mmol) in 1.5 mL of dimethylformamide. Material was purified by flash chromatography to give 100 mgs of title compound as a colorless oil. (100% yield).