Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]([NH:11][C:12](=[O:29])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][C:14]=2[N+:26]([O-])=O)=[C:9]2[CH2:30][N:31]([S:35]([C:38]3[CH:43]=[C:42]([F:44])[CH:41]=[C:40]([F:45])[CH:39]=3)(=[O:37])=[O:36])[C:32]([CH3:34])([CH3:33])[C:8]2=[N:7]1)=[O:5])[CH3:2].C1CCCCC=1.[ClH:52]>O1CCCC1.O.C(O)C.[Pd]>[ClH:52].[ClH:52].[CH2:1]([O:3][C:4]([N:6]1[C:10]([NH:11][C:12](=[O:29])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][C:14]=2[NH2:26])=[C:9]2[CH2:30][N:31]([S:35]([C:38]3[CH:43]=[C:42]([F:44])[CH:41]=[C:40]([F:45])[CH:39]=3)(=[O:37])=[O:36])[C:32]([CH3:34])([CH3:33])[C:8]2=[N:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(N3CCN(C)CC3)cc1[N+](=O)[O-])CN(S(=O)(=O)c1cc(F)cc(F)c1)C2(C)C
Agent: [Pd]
Agent: Cl
Solvent: C1=CCCCC1
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(N3CCN(C)CC3)cc1N)CN(S(=O)(=O)c1cc(F)cc(F)c1)C2(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
A suspension of 5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-3-[4-(4-methyl-piperazin-1 yl)-2-nitro-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (1.50 g, 2.3 mmol), cyclohexene (15 eq., 20 mL), 2N HCl (13 eq., 15 mL), in tetrahydrofuran-water-ethanol (2:1.5:1.5, 50 mL) was treated with 10% Pd—C (0.55 g). The reaction mixture was stirred at 70° C. for 3 hours, and then filtered on decalite. The filtering pad was washed thoroughly with tetrahydrofuran and ethanol. The filtrate was then evaporated to dryness affording the title compound as beige powder (1.4 g, 93% yield) that was used in the next steps without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:13])[C:10](O)=[O:11].[NH3:14]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:13])[C:10]([NH2:14])=[O:11]
Reactant: COc1ccccc1C(C)C(=O)O
Reactant: N
Solvent: ClCCl
Product: COc1ccccc1C(C)C(N)=O
Reaction time: 0.5 h

Procedure:
N,N'-Carbonyldiimidazole (16.2 g) is added to a solution of 2-(2-methoxyphenyl)propionic acid (17.5 g) in dry dichloromethane (200 cc), cooled to +5° C. The mixture is stirred for 30 minutes at +5° C. and a stream of ammonia is then passed into the solution for 1 hour, maintaining the same temperature. After stirring for 2 hours at 20° C., the reaction mixture is washed with water (200 cc), dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from isopropyl ether and the crystals are drained and dried under reduced pressure (2.7 kPa). (RS)-2-(2-Methoxyphenyl)propionamide (12.1 g) is obtained in the form of a white solid melting at 138° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[C:36]([F:42])=[CH:37][CH:38]=[CH:39][C:40]=3[F:41])=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: Fc1cccc(F)c1Sc1ccc(Br)cc1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3c(F)cccc3F)cc2)c1C
Yield: 16.1 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.18 g, 0.48 mmol) in dimethoxyethane (4 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.055 g, 0.048 mmol), crude 1-(4-bromo-phenylsulfanyl)-2,6-difluorobenzene (0.14 g) and 2.0 M aqueous sodium carbonate (1 mL, 2 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-4-[4-(2,6-difluoro-phenylsulfanyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.035 g, 13%) as a solid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:14][CH:13]=1
Reactant: Nc1ccc(S)cc1
Reactant: Clc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1ccc(Sc2nc3ccccc3o2)cc1
Yield: 79.4 %

Procedure:
2-Chlorobenzoxazole (0.065 moles, 10.0 g), 4-aminothiophenol (0.065 moles, 8.1 g) and potassium carbonate (0.065 moles, 9.0 g) were stirred for 3 days at room temperature in 250 ml ethanol, filtered, and concentrated. Ethyl acetate was added and the solution washed with water, dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with 50% ethyl acetate in hexane to yield 2-(4-aminophenylthio)benzoxazole 12.5 g, 79%. Mass spec (FD) 243. Calculated for C11H10N2OS: C, 64.44; H, 4.16; N, 11.56. Found: C, 64.53; H, 4.22; N, 11.58.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.[I-].[Na+]>[Cl:19][C:20]1[CH:21]=[C:22]([CH2:23][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:25]=[CH:26][CH:27]=1
Reactant: Clc1cccc(CBr)c1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(Cl)c2)CCCC1=O
Yield: 67.4 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (527.0 mg, 2.17 mM), 3-chlorobenzyl bromide (802.2 mg, 3.90 mM), a catalytic amount of sodium iodide (ca. 1 mg), and potassium carbonate (500.0 mg, 3.62 mM) was stirred at room temperature for 150 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 537.1 mg (67%) of the 9-[(3-chlorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a yellow foam. 1H NMR (CDCl3) δ 7.5-7.2 (m, 5H), 7.1 (s, 1H), 6.85 (m, 1H), 5.35 (s, 2H), 4.05 (s, 3H), 2.9 (t, 2H, J=6 Hz), 2.65 (t, 2H, J=6 Hz), and 2.3 (m, 2H). IR (CHCl3, cm−1) 3050, 2950, 1725, 1654, 1464, 1444, 1432, 1288 and 1120. MS (ES) m/e 366, 368, 370.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=12.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])[N:23]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:24][C:22]1[N:23]=[C:18]([NH:10][C:7]2[CH:8]=[CH:9][N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=2)[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=1
Reactant: Nc1ccn2ccnc2c1
Reactant: Cn1cc(Br)nc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)nc(Nc2ccn3ccnc3c2)c1=O
Temperature: 100 °C
Yield: 43.7 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with imidazo[1,2-a]pyridin-7-amine (665 mg, 5.0 mmol), Cs2CO3 (3.26 g, 10 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (1.86 g, 7.0 mmol), Xantphos (289 mg, 0.50 mmol), Pd2(dba)3 (458 mg, 0.50 mmol), and 1,4-dioxane (30 mL). After bubbling nitrogen through the mixture for 30 minutes, it was heated at 100° C. under nitrogen atmosphere for 16 h. Analysis of the reaction mixture by LCMS showed little starting material remained. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with dichloromethane (60 mL) and water (50 mL). The aqueous layer was separated and extracted with dichloromethane (3×20 mL). The combined organic layers was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (60/1 to 30/1) to afford 185a (700 mg, 44%) as a light yellow solid. MS-ESI: [M+H]+ 320
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[O:5][CH2:6][C:7]1[CH:25]=[CH:24][C:10]([C:11]([NH:13][CH2:14][C:15]2[C:16]([OH:23])=[N:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])=[O:12])=[CH:9][CH:8]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:2]2[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=2)[O:5][CH2:6][C:7]2[CH:25]=[CH:24][C:10]([C:11]([NH:13][CH2:14][C:15]3[C:16]([OH:23])=[N:17][C:18]([CH3:22])=[CH:19][C:20]=3[CH3:21])=[O:12])=[CH:9][CH:8]=2)=[CH:38][CH:39]=1
Reactant: Cc1cc(C)c(CNC(=O)c2ccc(COc3cccc(Br)c3)cc2)c(O)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2ccc(COc3cccc(-c4ccc(N)nc4)c3)cc2)c(O)n1
Temperature: 90 °C
Reaction time: 15 h
Yield: 36.7 %

Procedure:
A mixture of 4-((3-bromophenoxy)methyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (80 mg, 0.18 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (40 mg, 0.43 mmol) and sodium carbonate (75 mg, 0.7 mmol), tetra(triphenylphosphine) palladium (23 mg, 0.02 mmol) in 1,4-dioxane (8 ml) and water (2 ml) was stirred for 15 hours at 90° C. under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give product 4-((3-(6-aminopyridin-3-yl)phenoxy)methyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (30 mg, 37%) as a white solid. LRMS (M+H+) m/z: calcd 454.20. found 454. HPLC purity (214 nm): 97%. 1H NMR (300 MHz, d6-DMSO): δ 11.45 (s, 1H), 8.34 (t, J=4.5 Hz, 1H), 8.22 (s, 1H), 7.85-7.83 (m, 2H), 7.73-7.69 (m, 1H), 7.51-7.48 (m, 2H), 7.32-7.12 (m, 3H), 6.91-6.88 (m, 1H), 6.52 (d, J=8.7 Hz, 1H), 6.16 (s, 2H), 5.85 (s, 1H), 5.20 (s, 2H), 4.29 (d, J=4.5 Hz, 2H), 2.16 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([CH3:23])=[C:8]([C:10]2[CH:11]=[N:12][N:13]3[CH:18]=[C:17]([O:19][CH:20]([F:22])[F:21])[CH:16]=[N:15][C:14]=23)[CH:9]=1)=[O:4].[OH-].[K+].CO.Cl>C1COCC1>[F:22][CH:20]([F:21])[O:19][C:17]1[CH:16]=[N:15][C:14]2[N:13]([N:12]=[CH:11][C:10]=2[C:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[S:6][C:7]=2[CH3:23])[CH:18]=1
Reactant: COC(=O)c1cc(-c2cnn3cc(OC(F)F)cnc23)c(C)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1sc(C(=O)O)cc1-c1cnn2cc(OC(F)F)cnc12
Temperature: 40 °C
Yield: 64.8 %

Procedure:
Methyl-4-[6-(difluoromethoxy)pyrazolo[1,5-a]pyrimidin-3-yl]-5-methylthiophene-2-carboxylate (0.916 g, 2.70 mmol) was dissolved in THF (4 mL). 1 M KOH in MeOH (12.0 mL, 12.0 mmol) was added and the reaction heated to 40° C. for 16 h. After the hydrolysis was complete, treated with 1N HCl and the resulting solids were filtered, washed with water and dried to afford the title compound (0.568 g, 1.75 mmol). LRMS (APCI) calc'd for (C13H9F2N3O3S) [M+H]+, 326.0; found 326.0.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][C:5]2[NH:6][C:7]([NH:9][CH:10]([CH3:12])[CH3:11])=[N:8][C:4]=2[C:3]=1[F:16].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[CH:45]1[O:57][C@H:56]([CH3:58])[C@@H:51]([O:52][C:53](=[O:55])[CH3:54])[C@H:46]1[O:47][C:48](=[O:50])[CH3:49])(=O)C>ClCCCl>[Cl:15][C:14]1[C:2]([Cl:1])=[C:3]([F:16])[C:4]2[N:8]([C@@H:45]3[O:57][C@H:56]([CH3:58])[C@@H:51]([O:52][C:53](=[O:55])[CH3:54])[C@H:46]3[O:47][C:48](=[O:50])[CH3:49])[C:7]([NH:9][CH:10]([CH3:12])[CH3:11])=[N:6][C:5]=2[CH:13]=1
Reactant: CC(C)Nc1nc2c(F)c(Cl)c(Cl)cc2[nH]1
Reactant: CC(=O)OC1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCCl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(NC(C)C)nc2cc(Cl)c(Cl)c(F)c21
Yield: 26 %

Procedure:
5,6-Dichloro-4-fluoro-N-(1-methylethyl)-1H-benzimidazol-2-amine (0.85 g, 3.24 mmol), N,O-bis(trimethylsilyl)acetamide (0.89 mL, 0.73 g, 3.60 mmol), trimethylsilyl trifluromethanesulfonate (0.45 mL, 0.53 g, 2.25 mmol), 1,2,3-tri-O-acetyl-5-deoxy-ribofuranose (1.15 g, 4.42 mmol) and 1,2-dichloroethane were used according to general procedure II. The title compounds were purified by silica gel chromatography using 95:5 dichloromethane-acetonitrile to first provide 5,6-dichloro-4-fluoro-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-N-(1-methylethyl)-1H-benzimidazol-2-amine as a white foam (0.66 g, 44%); 1H NMR (DMSO-d6) δ: 7.49 (s, 1H, Ar—H), 7.05 (d, J=7.4 Hz, 1H, NH), 6.09 (d, J=6.8 Hz, 1H, CH), 5.57 (t, J=7.2 Hz, 1H, CH), 5.24 (dd, J=7.4, 5.3 Hz, 1H, CH), 4.12 (m, 2H, overlapping CH), 2.14 (s, 3H, CH3), 2.01 (s, 3H, CH3), 1.49 (d, J=6.3 Hz, CH3), 1.24 (m, 6H, overlapping CH3). The second fraction provided 5,6-dichloro-7-fluoro-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-N-(1-methylethyl)-1H-benzimidazol-2-amine as a white foam (0.39 g, 26%); 1H NMR (DMSO-d6) δ: 7.37 (s, 1H, Ar—H), 7.12 (d, J=7.4 Hz, 1H, NH), 6.08 (d, J=5.4 Hz, 1H, CH), 5.32 (t, J=6.8 Hz, 1H, CH), 4.98 (t, J=7.3 Hz, 1H, CH), 4.10 (m, 2H, overlapping CH), 2.10 (s, 3H, CH3), 2.04 (s, 3H, CH3), 1.41 (d, J=6.2 Hz, CH3), 1.23 (m, 6H, overlapping CH3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[C:9]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25]N(C)C=O.CI>>[C:1]([O:5][C:6](=[O:24])[N:7]([CH3:25])[C:8]1[C:9]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc(NC(=O)OC(C)(C)C)c(Oc2ccccc2C)n1
Reactant: CN(C)C=O
Solvent: CI
Product: CSc1ncc(N(C)C(=O)OC(C)(C)C)c(Oc2ccccc2C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of 1.60 g (4.61 mmol) (2-methylsulfanyl-4-o-tolyloxy-pyrimidin-5-yl)-carbamic acid tert.-butyl ester in 20 ml N,N-dimethylformamide 0.25 g (6.4 mmol) sodiumhydride (60% dispersion in mineraloil) was added and the reaction mixture stirred for 1 h. After the addition of 0.48 ml (7.83 mmol) methyl iodide at 0°, the reaction mixture was stirred for 3 hrs. The reaction mixture was poured into 100 ml ice-water and three times extracted with 80 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 19:1) to give 1.60 g (98%) methyl-(2-methylsulfanyl-4-o-tolyloxy-pyrimidin-5-yl)-carbamic acid tert-butyl ester as a colorless oil, MS (EI): 361 (M+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]=[C:14]=S)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:16][C:17]1[CH:18]=[C:19]([CH:31]=[CH:32][C:33]=1[NH:34][CH2:35][CH2:36][CH2:37][N:38]([CH3:47])[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)[C:20]([N:22]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21].N.[ClH:49]>O1CCCC1.C(OCC)C>[ClH:49].[CH2:27]([N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([C:19]1[CH:31]=[CH:32][C:33]2[N:34]([CH2:35][CH2:36][CH2:37][N:38]([CH3:47])[CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)[C:14]([NH:13][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)=[N:16][C:17]=2[CH:18]=1)=[O:21])[CH:28]([CH3:29])[CH3:30]
Reactant: CC(C)CN(CC(C)C)C(=O)c1ccc(NCCCN(C)CCc2ccccn2)c(N)c1
Reactant: COc1cc(N=C=S)cc(OC)c1OC
Agent: Cl
Agent: N
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3cc(C(=O)N(CC(C)C)CC(C)C)ccc3n2CCCN(C)CCc2ccccn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3,4,5 trimethoxyphenylisothiocyanate (27 mg, 1.2 eq) and N-methylcyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired from Novabiochem; load 1.69 mmol/g, 236 mg, 4 eq) are added successively to a solution of 3-amino-N,N-diisobutyl-4-({3-[methyl(2-pyridin-2-ylethyl)amino]propyl}amino) benzamide (48 mg, 1 eq) in tetrahydrofuran (2 ml). The mixture is heated under reflux for 18 hours then cooled down to ambient temperature and aminomethyl polystyrene resin (acquired from Novabiochem, 2 eq) is added. After stirring for 4 hours at ambient temperature, the mixture is filtered on frit and the filtrate is concentrated under reduced pressure at 40° C. The residue obtained is dissolved in ethyl ether and a solution of 1N HCl in ethyl ether is added dropwise in order to produce the expected compound in the form of the hydrochloride salt (80 mg, 89% yield).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]#[C:6][C:7](=O)[C:8]([F:11])([F:10])[F:9])[CH3:2].Br.[CH2:17]([S:23][C:24](=[NH:26])[NH2:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>C1COCC1>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[N:26]=[C:24]([S:23][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[N:25]=1)[CH3:2]
Reactant: CCCCCCSC(=N)N
Reactant: CCOC(C#CC(=O)C(F)(F)F)OCC
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCSc1nc(C(OCC)OCC)cc(C(F)(F)F)n1
Temperature: 20 °C
Reaction time: 4 h
Yield: 76.7 %

Procedure:
5,5-Diethoxy-1,1,1-trifluoro-pent-3-yn-2-one (2 g, 8.9 mmol) and 2-hexyl-isothiourea hydrobromide (2.4 g, 9.8 mmol) were dissolved under nitrogen in THF (20 mL). Then triethylamine (2.7 mL, 19.6 mmol) was added slowly. The reaction was exothermic (40° C.). The suspension was stirred for 4 h at 20° C. The product was extracted with AcOEt, sat. NH4Cl solution, dried and concentrated. The residue was purified by silica gel chromatography in heptane/AcOEt 20:1. One obtained 2.5 g (76%) of a colorless oil. MS: m/z=367 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:44])[C:19](=[O:43])[N:20](COCC[Si](C)(C)C)[N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:44])[C:19](=[O:43])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(-c4ccccc4F)c(N4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1C(=O)NN=C2COc3cc(-c4ccccc4F)c(N4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Temperature: 80 °C
Yield: 54.2 %

Procedure:
4-[7-(2-Fluoro-phenyl)-4-methyl-3-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.2 g, 0.320 mmol) was dissolved in tetrabutylammonium fluoride (1M in THF, 20 mL, 20.00 mmol) and the reaction mixture was heated at 80° C. overnight. The reaction mixture was cooled to ambient temperature, quenched by the addition of water (20 mL) and extracted with EtOAc (3×15 mL). The combined organic phase was washed with brine (2×30 mL) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 7-50% EtOAc in petroleum ether) to give 4-[7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.086 g, 54%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 8.07 (brs, 1H), 7.40 (m, 1H), 7.36-7.29 (m, 1H), 7.22-7.09 (m, 2H), 6.96 (s, 1H), 6.62 (s, 1H), 4.75 (q, J=6.8 Hz, 1H), 4.60 (d, J=13.2 Hz, 2H), 3.26 (brs, 4H), 2.72 (brs, 4H), 1.57 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.Br[C:17]([CH3:22])([CH3:21])[C:18](Br)=[O:19].[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[CH3:21][CH:17]1[C:18](=[O:19])[C:5]2=[CH:4][C:3]3[C:2]([CH3:15])([CH3:1])[C:14]4[C:9]([C:8]=3[CH:7]=[C:6]2[CH2:22]1)=[CH:10][CH:11]=[CH:12][CH:13]=4
Reactant: CC(C)(Br)C(=O)Br
Reactant: CC1(C)c2ccccc2-c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC1Cc2cc3c(cc2C1=O)C(C)(C)c1ccccc1-3
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
A 2000 mL round flask was charged with 9,9-dimethyl-9H-fluorene (50 g, 257.4 mmol) and 2-bromo-2-methylpropanoyl bromide (61.0 g, 265.1 mmol), and then dissolved with 700 mL of carbon disulfide inputted thereto. Then, the reactor was cooled with ice water. Under nitrogen atmosphere, aluminum trichloride (85.8 g, 643.4 mmol) was slowly added thereto in ten lots over 2 hours. The mixture was stirred at room temperature for 8 hours, and then the reaction was terminated by addition of 500 mL of distilled water. The resultant mixture was diluted by adding 500 mL of methyl chloride and washed with 500 mL of distilled water three times. The organic layer was dried over magnesium sulfate, followed by removal of volatile materials and drying, and then recrystallized by using methyl chloride and methanol, to thereby obtain 64.0 g of 2,9,9-trimethyl-2,3-dihydrocyclopenta[b]fluoren-1(9H)-one (yield: 94.8%) as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][CH:5]=1)[CH3:2].S(OC)([O:14][CH3:15])(=O)=O.[NH4+].[NH4+].[O-]S(OOS([O-])(=O)=O)(=O)=O>CO>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:15][OH:14])[CH:5]=1)[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CCOc1cc[n+]([O-])cc1
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: CCOc1ccnc(CO)c1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
4-nitropyridine-N-oxide (12 g) was dissolved in ethanol, sodium ethoxide (8.8 g) was added to the mixture, and the mixture was stirred for 40 hours at 50° C. After allowing the mixture to be cooled to room temperature, the precipitates were filtered, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-ethoxypyridine-N-oxide (11.8 g). To 4-ethoxypyridine-N-oxide (11.8 g) was added dimethyl sulfate (8.56 ml), and the mixture was stirred for 1 hour at 110° C. After diluting with methanol (180 ml), the mixture was heated to reflux for 1 hour, an aqueous solution (18 ml) of ammonium peroxodisulfate (20.6 g) was added dropwise to the solution under heat reflux, and the mixture was heated to reflux for 1 hour. After allowing the mixture to be cooled to room temperature, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give (4-ethoxy-2-pyridinyl)methanol (2.8 g).