Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][CH2:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11](F)=[CH:10][CH:9]=1)[CH3:2].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+].[ClH:29]>CO.O.CS(C)=O>[OH2:15].[ClH:29].[ClH:29].[CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][CH2:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CCN(CC)CCC(=O)Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Solvent: O
Product: CCN(CC)CCC(=O)Cc1ccc(-n2ccnc2)cc1
Temperature: 165 °C

Procedure:
A mixture of 50.0 g (0.211 mol) 4-(diethylamino)-1-(4-fluorophenyl)butanone, 29.0 g (0.42 mol) imidazole, 58.24 g (0.42 mol) anhydrous potassium carbonate and 50 mL dimethylsulfoxide is heated to 150° C. for 18 hr and to 165° C. for 3 hr. After this time, the mixture is treated with 500 mL H2O and is extracted with 2×400 mL methylene chloride. The organic layers are washed with 5×300 mL water. The organic layer is dried over sodium sulfate, filtered and the solvent evaporated to provide crude title compound as free base. This material is dissolved in 200 mL methanol, acidified to pH=1 with hydrochloric acid (gas) and the solvent removed in vacuo. The residue is recrystallized from methanol-isopropanol (2/3) to provide the title compound.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.N1C=CC=CC=1.[C:22]1([CH2:28][C:29]([NH:31][CH:32]2[C:48](=[O:49])[N:34]3[CH:35]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:36]([CH2:39][OH:40])[CH2:37][S:38][C@H:33]23)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.FC(F)(F)C(O)=O>CS(C)=O.C1C=CC=CC=1>[C:22]1([CH2:28][C:29]([NH:31][CH:32]2[C:48](=[O:49])[N:34]3[CH:35]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH:36]([CH:39]=[O:40])[CH2:37][S:38][C@H:33]23)=[O:30])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)C1C(CO)CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)C1C(C=O)CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Reaction time: 8 h
Yield: 99.1 %

Procedure:
N,N'-Dicyclohexylcarbodiimide (10.8 g.) and pyridine (1.4 g.) were added to a solution of t-butyl 7-(2-phenylacetamido)-3-hydroxymethylcepham-4-carboxylate (7.1 g.) in dimethylsulfoxide (30 ml.) and benzene (80 ml.). Trifluoroacetic acid (1.0 g.) was added dropwise to the stirred solution at room temperature and stirred overnight. The insoluble substance was filtered off and then ethyl acetate (100 ml.) and water (100 ml.) were added to the filtrate. After filtration, the organic layer was separated and adjusted to pH 3.0, washed with water and saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with petroleum ether to give t-butyl 7-(2-phenylacetamido)-3-formylcepham-4-carboxylate (7.0 g.)
Reaction SMILES: [Br:1][C:2]1[C:15]([I:16])=[CH:14][C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][C:8]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[C:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.[H-].C([Al+]C(C)C)(C)C.Cl.[Cl-].[Na+]>C1(C)C=CC=CC=1.C1COCC1>[Br:1][C:2]1[C:15]([I:16])=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][C:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[C:8]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:7]=3)[CH:3]=1
Reactant: CCCCCCCCCCCCc1cc2c(cc1CCCCCCCCCCCC)C(=O)c1cc(I)c(Br)cc1C2=O
Agent: CC(C)[Al+]C(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCc1cc2cc3cc(Br)c(I)cc3cc2cc1CCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
After 14 ml of THF was added to 678 mg of 2-bromo-3-iodo-6,7-didodecylanthraquinone obtained in the above and the compound was dissolved therein, 2.7 ml (2.7 mmol) of a toluene solution of diisopropylaluminum hydride (manufactured by Kanto Chemical Co., Ltd., 0.99M) was added, followed by 2 hours of stirring at room temperature. After ice cooling, 5 ml of 6N hydrochloric acid was added and then the mixture was heated to 65° C., followed by 4 hours of reaction. Toluene and an aqueous sodium chloride solution were added thereto and phase separation was conducted. Further, after washing with an aqueous sodium chloride solution, the organic phase was concentrated under reduced pressure and dried under vacuum. The obtained residue was again subjected to repeated reduction with diisopropylaluminum hydride and dehydration operation with 6N hydrochloric acid. The crude product was purified by recrystallization from toluene to obtain 469 mg of 2-bromo-3-iodo-6,7-didodecylanthracene as a light yellow solid (yield 72%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:3]1.[CH:22](=O)[CH:23]([CH3:25])[CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:22]([N:18]1[CH2:17][CH2:16][N:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:4]2[CH2:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:21])([CH3:1])[CH:3]=2)[CH2:20][CH2:19]1)[CH:23]([CH3:25])[CH3:24]
Reactant: CC1(C)C=C(c2ccccc2N2CCNCC2)CC1(C)C
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)CN1CCN(c2ccccc2C2=CC(C)(C)C(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18 %

Procedure:
To a solution of the 1-[2-(3,3,4,4-tetramethylcyclopent-1-enyl)phenyl]piperazine (20 mg, 0.0703 mmol) produced in Example (54d) in tetrahydrofuran (1 mL) were added isobutyraldehyde (6.6 mg, 0.0914 mmol), sodium triacetoxyborohydride (19.4 mg, 0.0914 mmol) and acetic acid (0.0076 mL, 0.134 mmol), followed by stirring for 4 hours at room temperature. After further adding isobutyraldehyde (6.6 mg, 0.0914 mmol), sodium triacetoxyborohydride (19.4 mg, 0.0914 mmol) and acetic acid (0.0076 mL, 0.134 mmol) to the mixture, stirring was continued for 3 hours at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed three times with ethyl acetate. The obtained organic layers were concentrated and the resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 4.3 mg of 1-isobutyl-4-[2-(3,3,4,4-tetramethylcyclopent-1-enyl)phenyl]piperazine as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[C:17](Cl)(=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>ClC(Cl)C>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:17](=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CCCCCCCCC(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
p-Nitroaniline, 13.0 g (0.094 mole), is dissolved in 200 ml dichloroethane, containing 25 ml pyridine. The solution is stirred at 50° C. while nonanoylchloride, 16.5 g (0.094 mole), is added slowly. The solution is stirred for 2 hours. Excess pyridine is removed by washing the product with 4N hydrochloric acid. The product is then passed through a florisil column and crystallized at -20° C. There is obtained N-(4-nitrophenyl) nonanamide, (M.P. 76.0°-76.5°). Analysis shows 9.91% nitrogen as against a calculated value of 10.06% for C15H21N2O3.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH:15]1([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[C:20]([F:26])[CH:19]=2)[CH2:17][CH2:16]1>>[CH:15]1([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:1][C:2]3[N:6]([C:7]4[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=4)[N:5]=[CH:4][CH:3]=3)=[C:20]([F:26])[CH:19]=2)[CH2:17][CH2:16]1
Reactant: OCc1ccc(C2CC2)cc1F
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(C3CC3)cc2F)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-cyclopropyl-2-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (800 MHz, CDCl3): δ 0.68-0.73 (2H, m), 0.99-1.04 (2H, m), 1.86-1.92 (1H, m), 5.24 (2H, s), 5.80 (1H, d, J=4.0 Hz), 6.78 (1H, dd, J=4.0 Hz, 23.2 Hz), 6.88 (1H, dd, J=3.2 Hz, 16.0 Hz), 7.30-7.34 (1H, m), 7.39 (1H, dd, J=1.6 Hz, 9.6 Hz), 7.57 (1H, d, J=3.2 Hz), 8.00 (1H, s), 8.69 (1H, d, J=9.6 Hz). [M+H] Calc'd for C19H15FN4O, 335; Found, 335.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:4][O:3]1.C(Cl)CCl.C1C=C2N=NN(O)C2=CC=1.O.[Cl:34][C:35]1[CH:36]=[C:37]([CH:42]=[CH:43][C:44]=1[O:45][CH:46]([CH3:48])[CH3:47])/[C:38](=[N:40]/O)/[NH2:39]>CN(C=O)C>[Cl:34][C:35]1[CH:36]=[C:37]([C:38]2[N:40]=[C:13]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][C@@H:5]4[CH2:4][O:3][C:2]([CH3:1])([CH3:18])[O:6]4)=[CH:17][CH:16]=3)[O:15][N:39]=2)[CH:42]=[CH:43][C:44]=1[O:45][CH:46]([CH3:48])[CH3:47]
Reactant: CC1(C)OC[C@@H](COc2ccc(C(=O)O)cc2)O1
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(OC[C@@H]4COC(C)(C)O4)cc3)n2)cc1Cl
Temperature: 140 °C
Yield: 69.9 %

Procedure:
To a slurry of (R)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzoic acid (0.303 g, 1.203 mmol) in DMF (1.367 ml) was added EDC (0.231 g, 1.203 mmol) followed by HOBT hydrate (0.163 g, 1.203 mmol). After about 1.5 h a solution of (Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (0.250 g, 1.09 mmol) in DMF (1.367 ml) was added. The reaction mixture was heated to about 140° C. for about 2 hrs. After cooling to room temperature the reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (eluting with EtOAc/Hep) to provide (R)-3-(3-chloro-4-isopropoxyphenyl)-5-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-1,2,4-oxadiazole (0.339 g, 70%) as a colorless solid. LCMS (Table 1, Method c) Rt=3.36 min, m/z 445 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:14][CH2:15][C:16]3([CH3:24])[CH2:23][CH2:22][C:19]4([CH2:21][CH2:20]4)[CH2:18][CH2:17]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9](O)=[O:10])[CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39]>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]1([C:4]2[C:5]([O:14][CH2:15][C:16]3([CH3:24])[CH2:23][CH2:22][C:19]4([CH2:21][CH2:20]4)[CH2:18][CH2:17]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:10])[CH2:3][CH2:2]1
Reactant: CS(N)(=O)=O
Reactant: CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CCC2(CC1)CC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC1(COc2cc(F)c(C(=O)NS(C)(=O)=O)cc2C2CC2)CCC2(CC1)CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.3 %

Procedure:
To a stirred solution of 5-cyclopropyl-2-fluoro-4-((6-methylspiro[2.5]octan-6-yl)methoxy)benzoic acid (0.085 g, 0.256 mmol) in dichloromethane (7 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.076 g, 0.384 mmol) and 4-dimethylaminopyridine (0.072 g, 0.589 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes; methanesulfonamide (0.039 g, 0.41 mmol) was added and the stirring continued at ambient temperature for 17 hours. The reaction mixture was concentrated, diluted with ethyl acetate (20 mL) and washed with 5% aqueous hydrochloric acid solution (10 mL). The organic layer was separated and washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (0% to 30% ethyl acetate in hexanes) afforded the title compound (0.058 g, 55%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.70 (d, J=16.5 Hz, 1H), 7.59 (d, J=9.0 Hz, 1H), 6.58 (d, J=14.6 Hz, 1H), 3.74 (s, 2H), 3.40 (s, 3H), 2.09-1.95 (m, 1H), 1.69-1.42 (m, 6H), 1.29-1.02 (m, 5H), 0.96-0.87 (m, 2H), 0.67-0.60 (m, 2H), 0.31-0.16 (m, 4H); MS (ES−) m/z 408.3 (M−1).
Reaction SMILES: BrC1C=CC([NH:8][C:9]2[N:14]=[C:13](Cl)[N:12]=[C:11]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=3[CH3:23])[N:10]=2)=CC=1.[CH3:24][O-:25].[Na+]>CO>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]([CH3:23])=[C:16]([C:11]2[N:12]=[C:13]([O:25][CH3:24])[N:14]=[C:9]([NH2:8])[N:10]=2)[CH:21]=1
Reactant: C[O-]
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Nc2ccc(Br)cc2)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc(-c2cc(Cl)ccc2C)n1
Reaction time: 72 h
Yield: 59 %

Procedure:
To a solution of the title compound of Example 20 (100 mg, 0.25 mmol) in methanol (5 ml) was added a solution of sodium methoxide in methanol (25-30%, 0.5 ml). After stirring for 72 hours, the mixture was concentrated under reduced pressure. The residue was stirred with water (20 ml). The solid was collected by filtration, washed with hexane (5 ml), and dried under reduced pressure to provide the title compound (60 mg, 59% yield). 1H NMR (DMSO-d6) 10.40 (s, 1H), 7.90 (s, 1H), 7.75 (m, 2H), 7.48-7.55 (m, 3H), 7.38 (m, 1H), 3.98 (s, 3H), 2.54 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:28][S:29]([OH:32])(=[O:31])=[O:30].FC1C=CC=CC=1C1OC(C([NH:47][C:48]([NH2:50])=[NH:49])=O)=CC=1>C1COCC1.[Cl-].[Na+].O>[CH3:28][S:29]([OH:32])(=[O:31])=[O:30].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([NH:49][C:48]([NH2:50])=[NH:47])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: N=C(N)NC(=O)c1ccc(-c2ccccc2F)o1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: N=C(N)NC(=O)c1ccc(-c2ccc(Cl)cc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
5-(4-chlorophenyl)furan-2-carboxylic acid (208 mg, 0.93 mmol) was dissolved in THF (5 ml), to which 1,1′-carbonyldiimidazole (CDI) (182 mg, 1.12 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. 2 M guanidine solution (2.73 ml, 5.45 mmol) prepared in Example 1 was added thereto, and the mixture was reacted at room temperature for 12 hours. After completion of the reaction, the solution was added with saturated brine (20 ml) and extracted with ethyl acetate (30 ml×3). The organic layer was washed with 10% brine, dried over anhydrous magnesium sulfate (MgSO4), and concentrated in vacuo. The residue was dissolved in acetone (4 ml), to which methanesulfonic acid (0.2 ml) was added and then cooled down to 0° C. to precipitate solid. The precipitated solid was collected by filtration to give 234 mg of a title compound (yield: 70%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25]([NH:12][C@H:10]([C:8]2[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]3[CH:19]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[N:24]=[CH:23][N:22]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 90 °C
Yield: 71.6 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine (281 mg, 1.1 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (170 mg, 1.1 mmol) and DIPEA (1 mL, 5.5 mmol) in IPA (2 mL) was heated for 16 h at 90° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-20% DCM in EtOAc) to afford 275 as a white solid (295 mg, 72%). LCMS (Method K): RT 3.37 min [M+H]+ 375.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.60 (1H, ddd, J=4.88, 1.91, 0.81 Hz), 8.06 (1H, td, J=7.75, 1.94 Hz), 7.86 (1H, s), 7.78-7.68 (3H, m), 7.50 (1H, ddd, J=7.52, 4.87, 0.98 Hz), 7.21-7.11 (4H, m), 5.87-5.78 (1H, m), 1.53 (3H, d, J=6.83 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:9][C:8](Br)=[C:7]([Br:11])[CH:6]=1)=[O:4].[CH3:12][Zn]Cl>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[O:9][C:8]([CH3:12])=[C:7]([Br:11])[CH:6]=1)=[O:4]
Reactant: C[Zn]Cl
Reactant: COC(=O)c1cc(Br)c(Br)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(C)o1
Reaction time: 12 h
Yield: 84.8 %

Procedure:
To a solution of 2,3-dibromo-furan-5-carboxylic acid methyl ester (200 mg, 0.70 mmol) in THF (4 mL) was added Pd(PPh3)2Cl2 (50 mg) and MeZnCl (2 M in THF, 420 μL, 0.84 mmol) at room temperature. The reaction was stirred at this temperature for 12 hr before the solvent was removed. Column chromatography afforded 4-Bromo-5-methyl-furan-2-carboxylic acid methyl ester (130 mg, 84%). Suzuki coupling of 4-Bromo-5-methyl-furan-2-carboxylic acid methyl ester with the corresponding boronic acid (See the synthesis of Example 1, Step B) provided Methyl 4-(4-(2,6-difluorobenzamido)phenyl)-5-methylfuran-2-carboxylate.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[S:15][CH:14]=[CH:13][C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1.[C:16](Cl)(=[O:18])[CH3:17].O>N1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[S:15][CH:14]=[CH:13][C:8]=2[N:9]=[C:10]([NH:12][C:16](=[O:18])[CH3:17])[N:11]=1
Reactant: CC(=O)Cl
Reactant: Nc1nc(-c2ccco2)c2sccc2n1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(-c2ccco2)c2sccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
An ice-cold solution of 4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine (130 mg, 0.6 mmol) in pyridine (1 mL) was treated with acetyl chloride (47 μL, 0.66 mmol), stirred at room temperature for 16 h, poured into water, extracted with EtOAc, dried (MgSO4) and concentrated in vacuo and purified by chromatography (SiO2:EtOAc:Heptane, 1:1) to give the title compound (125 mg, 80%) as a cream solid.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]2[N:3]=1.[CH3:25][NH2:26]>>[CH2:15]([N:14]1[C:10]2[N:9]=[CH:8][C:7]3[C:2]([NH:26][CH3:25])=[N:3][C:4]4[N:5]([N:17]=[CH:18][C:19]=4[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]=3[C:11]=2[CH:12]=[N:13]1)[CH3:16]
Reactant: CN
Reactant: CCOC(=O)c1cnn2c1nc(Cl)c1cnc3c(cnn3CC)c12
Product: CCOC(=O)c1cnn2c1nc(NC)c1cnc3c(cnn3CC)c12

Procedure:
3.5 g of 5-chloro-8-ethyl-8H-pyrazolo[1,5-a]pyrazolo-[4',3':5,6]pyrido[3,4-e]pyrimidine-3-carboxylic acid, ethyl ester (0.01 mol) and 3.5 g of methylamine are heated in 50 ml of alcohol in an autoclave for 10 hours at 100°. The solvent is removed in vacuo and the residue treated with water, filtered off and recrystallized from butyl alcohol, yield 2.9 g (86%); m.p. 321°-322°.
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[CH2:13]([O:15][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:14].ICCCC.CN1CCCN(C)C1=O>C1COCC1>[CH2:8]([CH:17]([CH2:18][CH2:19][CH2:20][CH3:21])[C:16]([O:15][CH2:13][CH3:14])=[O:22])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC(=O)OCC
Reactant: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CCCCI
Product: CCCCC(CCCC)C(=O)OCC
Temperature: -40 °C
Reaction time: 8 h

Procedure:
Diisopropylamine (45.5 g, 450 mmol) was dissolved in anhydrous THF 150 mL and cooled to −40° C. in an acetonitrile/dry ice bath under nitrogen protection. 2.5M n-butyllithium (n-BuLi)/hexane solution (126 mL, 315 mmol) was added with stirring. After the addition, the mixture was kept in the ice water bath for 30 minutes, cooled down to −78° C. in an acetone/dry ice bath, and ethylhexanoate (43.3 g, 300 mmol) was added dropwise. The reaction mixture was stirred at the same temperature for 1 hour and then, iodobutane (60.7 g, 330 mmol) in 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (11.5 g, 90 mmol) was added dropwise. The resulting solution was warmed to −40° C., stirred for 2 hours, and kept at room temperature overnight. The reaction mixture was quenched with a saturated NH4Cl aqueous solution, and concentrated via rotary evaporation. Into the flask, 200 mL of Et2O and 200 mL of water were added. After acidification of the mixture using a 2N HCl aqueous solution, the organic layer was separated, washed with 10% (v/v) HCl aqueous solution (150 mL×2), and concentrated via rotary evaporation. The resulting crude yellow oil was purified via vacuum distillation. The compound 16 was collected as colorless oil (45.0 g, 75%). 1H NMR (CDCl3): δ 0.86-0.90 (6H, m), 1.07-1.62 (12H, m), 1.25 (3H, t), 2.27-2.32 (1H, m), 4.12 (2H, q). MS (EI): calcd, 200.3. found M+H+, 201.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[O:6][C:5]1([CH:8]1[CH:15]([O:16][CH3:17])[CH:14]([O:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:13][CH2:12][C:9]21[O:11][CH2:10]2)[CH3:7].[H-].[Na+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C1(C)C=CC=CC=1.CN(C)C=O>[CH2:34]([O:33][C:31]([CH2:30][O:1][CH2:2][CH2:3][CH:4]1[O:6][C:5]1([CH:8]1[CH:15]([O:16][CH3:17])[CH:14]([O:18][C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:13][CH2:12][C:9]21[O:11][CH2:10]2)[CH3:7])=[O:32])[CH3:35]
Reactant: CCOC(=O)CBr
Reactant: COC1C(OC(=O)N2CCOCC2)CCC2(CO2)C1C1(C)OC1CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)COCCC1OC1(C)C1C(OC)C(OC(=O)N2CCOCC2)CCC12CO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To a solution of 4-[3-(2-hydroxyethyl)-2-methyloxiranyl]-5-methoxy-6-(morpholinocarbonyloxy)-1-oxaspiro[2,5]octane (76.2 mg) in a mixture of toluene (2 ml) and N,N-dimethylformamide (1 ml) was added sodium hydride (20.5 mg) in one portion under ice cooling. The mixture was stirred for half an hour at the same temperature and ethyl bromoacetate (68.5 mg) was added. After stirred for 3 hours at ambient temperature, the reaction mixture was quenched with aqueous saturated ammonium chloride solution (2 ml). The organic layer was washed with brine, dried, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (diethyl ether) to give 4-[3-(2-ethoxycarbonylmethoxyethyl)-2-methyloxiranyl]-5-methoxy-6-(morpholinocarbonyloxy)-1-oxaspiro[2,5]octane (66.9 mg).
Reaction SMILES: [O-:1][CH2:2]C.[Na+].[CH2:5]([O:7][C:8](=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=1)[CH3:6].C=O.C(O)(=O)C>C(O)C.CS(C)=O>[CH2:5]([O:7][C:8](=[O:19])[CH:9]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=1)[CH2:2][OH:1])[CH3:6]
Reactant: CCOC(=O)Cc1ccc(OCC)cc1
Reactant: CC[O-]
Agent: C=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(CO)c1ccc(OCC)cc1
Reaction time: 0.08 h

Procedure:
Sodium ethoxide solution in ethanol (0.5 M, 18 ml) was added to a solution of ethyl-p-ethoxyphenylacetate (30 g) in dry dimethyl sulphoxide (180 ml) under argon cover. The mixture was stirred for 5 minutes and dry paraformaldehyde (5.4 g) added. After 19 h stirring, acetic acid (1.5 ml) was added, the solution quenched in ice and extracted with ether. The ether layer was washed with sodium bicarbonate solution and water, dried over anhydrous sodium sulphate, and the solvent evaporated. The resulting oil crystallized from petroleum ether (40°-60°) to yield 27.8 g product m.p. 35°-36° C.