Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[C:30]([O:31][CH3:32])=[CH:29][C:6]2[C:7]([OH:28])=[CH:8][C:9]3[C:10]([CH3:27])([CH3:26])[C:11]4[CH:12]=[C:13]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[O:24][CH3:25])[CH:14]=[CH:15][C:16]=4[C:17]=3[C:5]=2[CH:4]=1.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C([Li])CCC.Cl>CCCCCC.O1CCCC1>[N:33]1([C:3]2[C:30]([O:31][CH3:32])=[CH:29][C:6]3[C:7]([OH:28])=[CH:8][C:9]4[C:10]([CH3:27])([CH3:26])[C:11]5[CH:12]=[C:13]([C:18]6[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=6[O:24][CH3:25])[CH:14]=[CH:15][C:16]=5[C:17]=4[C:5]=3[CH:4]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: COc1cc2c(O)cc3c(c2cc1OC)-c1ccc(-c2ccccc2OC)cc1C3(C)C
Reactant: C1CCNCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccc2c(c1)C(C)(C)c1cc(O)c3cc(OC)c(N4CCCCC4)cc3c1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 500 mL one-neck flask was added the product from Step 1(10 g), piperidine (5.2 mL and anhydrous tetrahydrofuran (150 mL). n-Butyl lithium in hexane solution (2.5M, 35 mL) was dropped to the mixture through addition funnel slowly. The reaction mixture was stirred at room temperature for 3 hours. The mixture was poured into cold aqueous hydrochloric acid (10%, 60 mL). The resulting mixture was extracted with ethyl acetate (200 mL) and the recovered top layer was filtered through a silica gel plug using ethyl acetate and hexane mixture as eluent. All silica gel plug and chromatography mentioned herein was carried out using ethyl acetate and hexanesmixture as eluent if not specified. Solid 2-(piperidin-1-yl)-3-methoxy-7,7-dimethyl-9-(2-methoxyphenyl)-7H-benzo[C]fluoren-5-ol (10 g) was obtained by re-crystallization from solution in ethyl acetate/hexanes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([NH2:12])=[CH:5][CH:4]=1.[C:13](Cl)(Cl)=[O:14].C(Cl)(Cl)=S.C1(C)C=CC=CC=1>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:8]([O:10][C:13](=[O:14])[NH:12][C:6]2=[CH:5][CH:4]=1)=[O:9]
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(N)c(C(=O)O)c1
Agent: S=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COc1ccc2[nH]c(=O)oc(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a mixture of 10.0 g (60.0 mmol) of 5-methoxyanthranilic acid in 80 mL of 1,4-dioxane was slowly added 100 mL (193 mmol) of a 1.93 molar solution of phosgene, or thiophosgene in an inert solvent, preferably a hydrocarbon solvent such as toluene, at room temperature. The mixture was stirred overnight at room temperature. This mixture was then concentrated in vacuo to a small volume. This concentrated reaction mixture was filtered through silica and the filter cake was washed with hexane to give 10.99 g (95.2%) of the 5-methoxyisatoic anhydride as an off white solid. MS (Cl mode) m/z 176 (M-18, 100%), 194 (M+H, 71%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:31])[N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]([C:32]([OH:34])=[O:33])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd].C(O)(=O)C>[C:32]([OH:34])(=[O:33])[CH3:13].[C:25]1([N:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:17]([N:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH:13]2[C:32]([OH:34])=[O:33])=[O:31])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: [H][H]
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)N(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)C1CNCCN1C(=O)N(c1ccccc1)c1ccccc1

Procedure:
A solution of 109 mg. (0.24 mmole) of (±)-4-(benzyloxycarbonyl)-1-(diphenylcarbamoyl)piperazine-2carboxylic acid (from Step A) in 3 ml of methanol containing 3 drops of acetic acid and 50 mg of 10% Pd/C was hydrogenated with rocking at 40 psi of hydrogen for 16 hours. The mixture was filtered through Celite and the solution was concentrated in vacuo to 66 mg (71%) of solid which was homogeneous by TLC (1:1:1:1 n-butyl alcohol-acetic acid-water-ethyl acetate, Rf =0.70). 1H NMR (CDCl3, 300 MHz, ppm): δ2.05 (s, 3H), 2.72 (m, 1H), 2.96 (m, 1H), 3.12 (m, 1H), 3.26 (m, 1H), 3.67 (m, 1H), 3.79 (m, 1H), 4.78 (br.s, 1H), 7.0-7.3 (m, 10H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])=[CH:4][C:3]=1[S:17](Cl)(=[O:19])=[O:18].[CH3:21][NH2:22].Cl>O>[CH3:21][NH:22][S:17]([C:3]1[CH:4]=[C:5]([NH:9][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])(=[O:19])=[O:18]
Reactant: CN
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)cc1NS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: O
Product: CNS(=O)(=O)c1cc(NS(=O)(=O)C(F)(F)F)c(C)cc1C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A mixture of 2,4-dimethyl-5-(trifluoromethanesulfonamido)benzenesulfonyl chloride (1.5 g), a 40% aqueous soltution of methylamine (1 g) and water (20 ml) was stirred at room temperature and allowed to stand overnight at the same temperature. The resultant mixture was made acidic with 5% aqueous hydrochloric acid to precipitate an oily substance, which was then extracted with chloroform. The organic layer was washed with a 5% aqueous solution of hydrochloric acid and water in order and dried over anhydrous magnesium sulfate, followed by concentration. The residue was allowed to stand to give crytals, which were recrystallized from toluene to give 1.1 g of N-methyl-2,4-dimethyl-5-(trifluoromethanesulfonamido)benzenesulfonamide (Compound No. 29). M.P., 134.5°-135.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:30]=[C:31](OS(C(F)(F)F)(=O)=O)[CH:32]=1)[C:26]([O:28][CH3:29])=[O:27])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:30]=[C:31]([N:11]2[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]2)[CH:32]=1)[C:26]([O:28][CH3:29])=[O:27])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Product: COC(=O)c1cc(OCc2ccccc2)cc(N2CCCC(NC(=O)OC(C)(C)C)C2)c1
Yield: 6 %

Procedure:
Using 3-(tert-butoxycarbonylamino)piperidine (301 mg, 1.50 mmol) and methyl 3-benzyloxy-5-(trifluoromethanesulfonyloxy)benzoate (595 mg, 1.52 mmol), the same procedure was followed as in Example 58 to give 39.7 mg (6.0%) of the desired compound as a brown oil.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[C:12]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:11][C:8]([CH2:9]Br)=[C:7]([F:17])[CH:6]=1.O>CN(C=O)C>[Cl:4][C:5]1[C:12]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:11][C:8]([CH2:9][C:1]#[N:2])=[C:7]([F:17])[CH:6]=1
Reactant: [C-]#N
Reactant: CC(C)Oc1cc(CBr)c(F)cc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cc(CC#N)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
26 g (0.53 mol) of sodium cyanide was dissolved in 700 ml of DMF, and 143 g (0.50 mol) of 4-chloro-2-fluoro-5-isopropoxybenzyl bromide was dropwise added thereto at room temperature. After stirring at room temperature for 8 hours, the reaction solution was poured into water and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure to obtain 107 g (yield: 92%) of the desired product.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:7]=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C=O.[C:20]([O-])(=[O:22])C.[Na+]>C(O)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:7]([CH2:20][OH:22])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)[O-]
Reactant: CCCCc1nccn1Cc1ccccc1Cl
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCc1ncc(CO)n1Cc1ccccc1Cl
Reaction time: 4 h
Yield: 41.1 %

Procedure:
A mixture of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazole (95.5 g, 0.384 mol), 37% formaldehyde (500 mL), sodium acetate (80 g) and acetic acid (60 mL) was heated to reflux for 40 hours under argon. The reaction was concentrated in vacuo, and the residue was stirred with 500 mL of 20% sodium hydroxide solution for 4 hours, diluted with water and extracted with methylene chloride. The extract was washed, dried, and concentrated. The crude product (117 g) was flash chromatographed over 600 g of silica gel with a gradient of ethyl acetate to 10% of methanol in ethyl acetate to give 8.3 g of starting material, 24.5 g of a mixture of starting material and product, and 44 g (41%) of 2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole; mp 86°-88° C. (from ethyl acetate). Further elution provided the bis (4,5-hydroxymethyl) derivative; mp 138°-140° C. (from ethyl acetate).
Reaction SMILES: [CH:1]1([CH:5]([OH:15])[C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:1]1([CH:5]([OH:15])[C:6]2[CH:7]=[CH:8][C:9]([C:10]([NH:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:12])=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)CCN
Reactant: O=C(O)c1ccc(C(O)C2CCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1ccc(C(O)C2CCC2)cc1
Reaction time: 1.5 h
Yield: 104.3 %

Procedure:
N,N-dimethylformamide (9.00 mL) was added to a vial containing 4-(cyclobutyl(hydroxy)methyl)benzoic acid (370 mg, 1.79 mmol), ethyl 3-aminopropanoate hydrochloride (551 mg, 3.59 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.36 g, 3.59 mmol). Diisopropylethylamine (1.56 mL, 8.97 mmol) was then added. The reaction was stirred for 1.5 h, and was then concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) afforded ethyl 3-(4-(cyclobutyl(hydroxy)methyl)benzamido)propanoate (570 mg, 100% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H), 4.63 (d, J=7.8 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 3.72 (q, J=6.0 Hz, 2H), 2.64 (t, J=5.9 Hz, 2H), 2.61-2.54 (m, 1H), 2.08-1.95 (m, 2H), 1.88-1.75 (m, 4H), 1.27 (t, J=7.1 Hz, 3H). MS (M+1): 306.3.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)(=O)=O.O>CN(C=O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:41][CH2:42][N:43]4[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)[CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(O)c3)nn3ccnc23)n1
Reactant: CS(=O)(=O)OCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(OCCN4CCCCC4)c3)nn3ccnc23)n1
Temperature: 50 °C
Yield: 40.2 %

Procedure:
To a mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (40 mg, 0.1 mmol) and K2CO3 (28 mg, 0.2 mmol) in DMF (5 mL) was added 2-(piperidin-1-yl)ethyl methanesulfonate (25 mg, 0.12 mmol). The mixture was heated at 50° C. for 16 h. After cooling, the mixture was poured into water and extracted with EtOAc (8 mL 3). The combined organic layers were washed with brine, then dried over MgSO4. After filtration and concentration, the residue was purified by chromatography (silica gel, EtOAc) to give N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(3-(2-(piperidin-1-yl)ethoxy)phenyl)imidazo[1,2-b]pyridazin-8-amine (20 mg, 40%). 1H NMR (300 MHz, CDCl3): δ 8.67 (s, 1H), 8.08 (s, 1H), 7.93 (s, 1H), 7.60-7.53 (m, 3H), 7.45-7.37 (m, 2H), 7.05-7.01 (m, 1H), 6.23 (d, 1H, J=7.5 Hz), 6.04 (d, 1H, J=8.4 Hz), 4.31-4.21 (m, 3H), 3.71-3.65 (m, 1H), 3.54-3.48 (m, 1H), 2.85 (t, 2H, J=6.0 Hz), 2.57 (brs, 4 h), 2.17-2.04 (m, 3H), 1.76-1.62 (m, 5H), 1.48 (brs, 2H), 1.26 (d, 3H, J=6.6 Hz). LC/MS: 498 [M+H]+, tR=1.15 min. HPLC: 99.14% at 214 nm, 99.51% at 254 nm, tR=3.97 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[C:9](Cl)[N:8]=[C:7]([Cl:14])[N:6]=1)=[O:4].[NH3:15]>C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[C:9]([NH2:15])[N:8]=[C:7]([Cl:14])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Cl)nc(Cl)c1OC
Reactant: N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1nc(Cl)nc(N)c1OC
Reaction time: 0.5 h
Yield: 29 %

Procedure:
2,6-Dichloro-5-methoxypyrimidine-4-carboxylic acid methyl ester (750 mg, 3.16 mmol; see J. Med. Chem. 49(5), 1693-1705; 2006 for preparation) was dissolved in chloroform and 2N ammonia in methanol (2 eq) was added dropwise while in a cooling bath. The reaction mixture was stirred for 30 min, after which an additional 2 eq of 2N ammonia in methanol was added. The reaction was stirred at ambient temperature for 16 h. Additional 2N ammonia in methanol (2 eq) was added. The reaction was stirred for 2 h during which time a solid precipitated. The solid was filtered off and water was added to the filtrate. The crude material was extracted from the filtrate with dichloromethane three times and the combined organic phases were washed with brine, dried and concentrated under vacuum. The product was purified by flash chromatography on silica gel (hexane/ethyl acetate gradient) to provide the title compound (202 mg, 29% yield): mp 162-167° C.; 1HNMR (CDCl3): δ 5.75 (br s, 2H), 3.97 (s, 3H), 3.92 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]#[N:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:23][C:24]1[CH:25]=[CH:26][C:27](F)=[N:28][CH:29]=1.O>O1CCCC1>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([C:8]2([C:11]#[N:12])[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[N:28][CH:29]=1
Reactant: N#CC1CCC2(CC1)OCCO2
Reactant: Fc1ccc(Br)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
After 1,4-dioxaspiro[4,5]decane-8-carbonitrile (2.5 g) was dissolved in tetrahydrofuran (8 ml), 1M tetrahydrofuran-solution of lithium bis(trimethylsilyl)amide (15 ml) was added at 0° C. and stirred for 30 minutes. 5-Bromo-2-fluoropyridine (2.64 g) was further added and stirred at room temperature for two hours. Water was added to the reaction solution, extracted with ethyl acetate and concentrated in vacuo. The residue was purified with silica gel chromatography (n-hexane/ethyl acetate) and the resulting solid was washed with n-hexane to give the titled compound (3.32 g).
Reaction SMILES: [CH3:1][C:2]1[O:10][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[F:19][C:20]([F:37])([F:36])[C:21](=[O:35])[CH2:22][C:23]([C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[O:33][CH3:34])([CH3:25])[CH3:24]>C1COCC1>[F:37][C:20]([F:19])([F:36])[C:21]([CH2:1][C:2]1[O:10][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=1)([OH:35])[CH2:22][C:23]([C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[O:33][CH3:34])([CH3:25])[CH3:24]
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Reactant: Cc1cc2cnccc2o1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc2cnccc2o1)C(F)(F)F
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A solution of 2-methylfuro[3,2-c]pyridine (prepared according to the procedure by T. Kitamura, K. Tsuda, and Y. Fujiwara, Tetrahedron Lett. 1998, 39, pp. 5375-5376) (26.0 mg, 0.195 mmol) in 2 mL of THF was treated with lithium diisopropylamide (LDA; 1.5 M in cyclohexane, 195 μL) dropwise at −78° C. The mixture was stirred for 30 minutes (the color changed from yellow to orange-red) and was slowly treated with a solution of 1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (81.5 mg, 0.293 mmol) in 1 mL of THF. The reaction was stirred at −78° C. for 4.5 hours, quenched with 5 mL of saturated ammonium chloride solution, and diluted with 20 mL of ethyl acetate. The phases were separated and the aqueous layer was extracted with three 10 mL portions of ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. Flash chromatography (ethyl acetate-hexanes, 5% to 50% gradient) gave 36.0 mg (45% yield) of the title product as a clear oil.
Reaction SMILES: [C:1]([NH:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:21])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28].O.Cl>CN(C1C=CN=CC=1)C.CN(C)C=O>[C:1]([NH:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]([C:27]([C:23]2[O:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[C:13]1=[O:21])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccco1
Reactant: O=C(NC(=O)N1C(=O)Cc2ccccc21)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC(=O)N1C(=O)C(C(=O)c2ccco2)c2ccccc21)c1ccccc1
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
To 30 ml of N,N-dimethylformamide was added, with stirring, 2.8 g (10 mmole) of N-benzoyl-2-oxindole-1-carboxamide, followed by 2.9 g (24 mmole) of 4-(N,N-dimethylamino)pyridine. The mixture was cooled in an ice-bath and then to it was added, dropwise, with stirring, during 10 minutes, a solution of 1.6 g (12 mmole) of 2-furoyl chloride in 10 ml of N,N-dimethylformamide. Stirring was continued for 30 minutes and then the reaction mixture was poured into a mixture prepared from 250 ml of water and 8.5 ml of 3N hydrochloric acid. The resulting mixture was cooled in an ice-bath and the solid was removed by filtration. The solid was recrystallized from ca. 75 ml of acetic acid to give 2.94 g of the title compound as yellow-brown crystals, mp 190° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][S:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:16])=[O:15])[C:8]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.Cl[C:33]1[N:38]=[CH:37][CH:36]=[CH:35][N:34]=1>C1COCC1>[N:34]1[CH:35]=[CH:36][CH:37]=[N:38][C:33]=1[O:3][CH2:4][CH2:5][O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][S:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:15])=[O:16])[C:8]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1
Reactant: Clc1ncccn1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)CCc3ccccc3)ncnc2OCCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(NS(=O)(=O)CCc3ccccc3)ncnc2OCCOc2ncccn2)cc1
Temperature: 0 °C
Reaction time: 17 h
Yield: 74.6 %

Procedure:
To sodium hydride (50 mg, 60% in mineral oil) was added THF (25 ml) followed by 2-phenyl-ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (150 mg, Referential Example 1). The mixture was stirred for 1 h at rt before 2-chloro-pyrimidine (86 mg) was added. Stirring was continued for 17 h at 80° C. The solvent was evaporated and diethylether (20 ml) was added to the residue. The precipitate was filtered off and washed with diethylether, dissolved in water (20 ml) and acidified with citric acid and extracted twice with EA (50 ml). The organic phase was washed with water, dried over Na2SO4 and evaporated. The residue is suspended in 2-propanol (15 ml) and stirred at 70° C. for 10 min and cooled to 0° C. before the solid material is collected, washed with 2-propanol (2 ml) and dried under high vacuum to furnish 2-phenyl-ethanesulfonic acid {6-[2-(pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide (133 mg) as a white powder. LC-MS: tR=4.97 min, [M+1]+=492.34, [M−1]−=490.28.
Reaction SMILES: [OH:1][C@@H:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@@H:3]1[OH:4].[NH:11]1[CH:18]=[CH:17][C:15]([NH2:16])=[N:14][C:12]1=[O:13].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[OH:1][C@@H:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@@H:3]1[OH:4].[C:19]([NH:16][C:15]1[CH:17]=[CH:18][NH:11][C:12](=[O:13])[N:14]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: OC[C@H]1O[C@@H](O)[C@@H](O)[C@@H]1O
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C(Nc1cc[nH]c(=O)n1)c1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A suspension of 1.22 g (5.02 mmol) of cytosine-β-D-arabinofuranoside in 50 mL of dry pyridine was cooled to 0° C. 10 mL of benzoyl chloride was added and the mixture was stirred at room temperature for 16 hours. The mixture was poured into 75 mL of 5% aq sodium bicarbonate solution and extracted with CH2CL2 (2×150 mL). The organic phases were washed with water (50 mL), dried over anhydrous MgSO4 and concentrated in vacuo. The mixture was dissolved in 50 mL of pyridine/methanol/water (5:3:2 v/v) and cooled in an ice bath. To this solution was added cold 50 mL of 2M sodium hydroxide in pyridine/methanol/water (5:3:2 v/v). The reaction mixture was stirred at 0° C. for 15 minutes and then the pH was adjusted to 7 with the addition of ammonium chloride. The mixture was concentrated in vacuo and 20 mL of methanol was added. The mixture was filtered and the solid washed with more methanol (3×20 mL). All washings and filtrate were collected, combined and concentrated in vacuo. Redissolved in 50 mL of methanol/CH2Cl2 (2:8 v/v) and the mixture was purified by flash chromatography using methanol/CH2Cl2 (1:9-2:8 v/v). A second flash chromatography as described above was needed to remove all impurities to give 1.5 g (86%) of N4-Benzoylcytosine-β-D-arabinofuranoside 16.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[C:8]1([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[CH:23][C:22]=2[NH2:31])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][C:5]([NH:31][C:22]1[CH:23]=[N:24][C:25]2[C:30]([C:21]=1[NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][S:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:6]
Reactant: Nc1cnc2ccccc2c1NCCCCCSc1ccccc1
Reactant: COCCC(=O)Cl
Solvent: c1ccncc1
Product: COCCC(=O)Nc1cnc2ccccc2c1NCCCCCSc1ccccc1
Temperature: 25 °C
Yield: 104.1 %

Procedure:
A solution of 3-methoxypropanoyl chloride (2.04 g, 16.6 mmol) in pyridine (20 mL) was slowly added to a chilled (0° C.) solution of N4-[5-(phenylthio)pentyl]quinoline-3,4-diamine (5.1 g, 15.2 mmol) in pyridine. The reaction was allowed to warm to ambient temperature. More acid chloride (1 g) was added and the reaction was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure to provide 6.7 g of 3-methoxy-N-(4-{[5-(phenylthio)pentyl]amino}quinolin-3-yl)propanamide as a sticky brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:32])[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=3[O:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][Cl:39].[OH-].[Na+].O>CC(C)=O>[Cl:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:32])[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=3[O:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(O)cc2)cc1
Reactant: ClCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(OCCCCCCl)cc2)cc1
Temperature: 25 °C
Yield: 113.7 %

Procedure:
4-(4-Hydroxyphenyl)-4-hydroxy-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-2,3-dihydro-4H-benzopyran (180 mg, 0.4 mmol), 1-bromo-5-chloropentane (0.39 ml, 2 mmol) and 2N aqueous sodium hydroxide solution (70 μl, 2 mmol) were dissolved in acetone (4 ml) and then refluxed for 6 hours. The reaction mixture was cooled to room temperature and, after adding water, extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to remove the organic solvent. The concentrate was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to obtain 247 mg (yield: 97%) of the title compound as a colorless oil.