Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=[O:2].[Br:5][C:6]1[NH:7][C:8]2[CH2:9][CH2:10][CH2:11][C:12](=[N:15]O)[C:13]=2[CH:14]=1>C1COCC1.CCOC(C)=O>[Br:5][C:6]1[NH:7][C:8]2[CH2:9][CH2:10][CH2:11][NH:15][C:12](=[O:2])[C:13]=2[CH:14]=1
Reactant: ON=C1CCCc2[nH]c(Br)cc21
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1NCCCc2[nH]c(Br)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.3 %

Procedure:
Thionyl chloride (0.06 mL, 0.90 mmol) was added to a solution of 2-bromo-6,7-dihydro-1H-indol-4(5H)-one oxime (305a) (186 mg, 0.81 mmol) in THF (8.0 mL) at 25° C., and the resulting solution was stirred at 25° C. for 18 h. The reaction mixture was then diluted with EtOAc (40 mL), sequentially washed with saturated aq. NaHCO3 (2×30 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-10% MeOH/DCM) furnished 2-bromo-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one (102 mg, 0.44 mmol, 55% yield) as a light-brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.59 (1H, br. s.), 7.36 (1H, t, J=4.5 Hz), 6.27 (1H, d, J=2.7 Hz), 3.09-3.16 (2H, m), 2.82 (2H, t, J=6.6 Hz), 1.82-1.91 (2H, m). m/z (ESI, +ve) 228.9/231.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26](=[O:32])[CH2:27][NH:28]CCO)[CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:33][C:34]([C:36]2[NH:37][CH:38]=[C:39]([C:41]#[N:42])[N:40]=2)=[O:35])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.[BH-](OC(C)=O)(OC(C)=O)[O:44][C:45]([CH3:47])=O.[Na+].C=O>CO>[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:32])[C:27]([CH3:2])([NH2:28])[CH2:47][CH2:45][OH:44])[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:33][C:34]([C:36]2[NH:37][CH:38]=[C:39]([C:41]#[N:42])[N:40]=2)=[O:35])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)CNCCO)CC3)cc2C2=CCCCC2)n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(N)(CCO)C(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 113.8 %

Procedure:
A solution of 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-{1-[2-(2-hydroxy-ethylamino)-acetyl]-piperidin-4-yl}-phenyl)-amide trifluoroacetic acid salt (as prepared in Example 44, step (c), 50.0 mg, 0.085 mmol) in MeOH (3 mL) was treated with Na(OAc)3BH (39.5 mg, 0.19 mmol) and 37% aqueous formaldehyde (8.2 μL, 0.10 mmol). The mixture was stirred at room temperature for 5.5 h, and the solvents were removed in vacuo. Reverse phase HPLC (C-18 column) (10% to 50% acetonitrile in water with 0.1% TFA over 30 min) afforded the title compound (19.5 mg, 47%) as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.12 (d, 1H, J=8.4 Hz), 8.02 (s, 1H), 7.19 (dd, 1H, J=8.4, 2.0 Hz), 7.09 (d, 1H, J=2.0 Hz), 5.84-5.79 (m, 1H), 4.72-4.64 (m, 1H), 4.39-4.23 (m, 2H), 3.84-3.79 (m, 1H), 3.31-3.21 (m, 1H), 3.03-2.94 (m, 6H), 2.92-2.80 (m, 2H), 2.32-2.24 (m, 4H), 2.00-1.90 (m, 2H), 1.90-1.76 (m, 5H), 1.78-1.59 (m, 2H). LC-MS (ESI, m/z): Calcd. for C27H34N6O3 491.3 (M+H), found 491.2.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[CH:6]=[CH:7][C:8]=2[CH3:12])[CH2:3]1.C(N(CC)CC)C.[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C(Cl)Cl>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[C:4]2[C:9]=1[CH2:10][CH2:11][C@@H:2]([NH:1][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([Cl:27])=[CH:29][CH:30]=1)[CH2:3]2
Reactant: Cc1ccc(N2CCN(C)CC2)c2c1CC[C@@H](N)C2
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(N2CCN(C)CC2)c2c1CC[C@@H](NC(=O)c1ccc(Cl)cc1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a solution of (R)-2-amino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (52 mg, 0.20 mmol) and triethylamine (1 mL, 7.7 mmol) in methylene chloride (10 mL) was added a solution of 4-chlorobenzoyl chloride (50 mg, 0.29 mmol) in methylene chloride (10 mL) and the reaction was stirred at 0° C. for 30 min. The stirring was continued for another 2 h at ambient temperature and then the solvent was evaporated in vacuo. The remains were purified on a silica gel column using ethyl acetate containing triethylamine (7.5%) as the eluent to give 50 mg (63% yield) of the title compound as white crystals: mp 210-212° C.; EIMS (70 eV) m/z (relative intensity) 397 (28, M+).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@H:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][C@H:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:29]=[CH:30][C:31]([CH2:34][CH3:35])=[CH:32][CH:33]=3)[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: CCOC(=O)[C@@H](Cc1ccc2[nH]ccc2c1)OCC
Reactant: CCc1ccc(-c2nc(CCl)c(C)o2)cc1
Product: CCO[C@H](Cc1ccc2c(ccn2Cc2nc(-c3ccc(CC)cc3)oc2C)c1)C(=O)O
Yield: 60 %

Procedure:
Starting from (R)-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-2-(4-ethyl-phenyl)-5-methyl-oxazole, the title compound was obtained in 60% yield as a pale yellow solid. AS: (M−H)− 431.2.
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.[F:15][C:16]1([F:22])[CH2:19][CH:18]([CH2:20]O)[CH2:17]1>>[F:15][C:16]1([F:22])[CH2:19][CH:18]([CH2:20][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH2:17]1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCC1CC(F)(F)C1
Product: N#Cc1ccnc(-n2nccc2OCC2CC(F)(F)C2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3,3-difluorocyclobutyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.48-2.71 (5H, m), 5.14 (2H, d, J=4.4 Hz), 5.64 (1H, d, J=1.6 Hz), 7.34 (1H, dd, J=0.4 Hz, J=4.8 Hz), 7.51 (1H, d, J=2.0 Hz), 7.93 (1H, s), 8.61 (1H, d, J=4.8 Hz). [M+H] Calc'd for C14H12F2N4O, 291; Found, 291.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[CH2:12]([N:19]1[C:27]([OH:28])=[N:26][C:25]2[C:20]1=[N:21][C:22]([CH2:30]Cl)=[N:23][C:24]=2[NH2:29])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH2:12]([N:19]1[C:27]([OH:28])=[N:26][C:25]2[C:20]1=[N:21][C:22]([CH2:30][CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[N:23][C:24]=2[NH2:29])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(CCl)nc2c1nc(O)n2Cc1ccccc1
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To dimethyl malonate (493 mg, 3.73 mmol) in DMF (8 ml) was added in an ice bath sodium hydride (75 mg, 3.13 mmol). Then the mixture was stirred at room temperature for 30 minutes. Thereto was added 9-benzyl-2-chloromethyl-8-hydroxyadenine (0.10 g, 0.37 mmol), and the mixture was stirred at room temperature for 21 hours. After removing the solvent, the residue was poured into water, concentrated, and neutralized with hydrochloric acid. The resulting solid was filtered, washed with water and dried in vacuo under heating to give 9-benzyl-2-(2,2-dimethoxycarbonylethyl)-8-hydroxyadenine (92 mg, 0.24 mmol) as a white solid. Thus obtained 9-benzyl-2-(2,2-dimethoxycarbonylethyl)-8-hydroxyadenine (79 mg, 0.20 mmol) was added to a mixed solvent of concentrated hydrochloric acid (2 ml) and 1,4-dioxane (6 ml), and the mixture was refluxed for 6 hours. After the reaction mixture was neutralized in an ice bath with saturated sodium hydrogencarbonate solution, the resulting solid was filtered, washed with water and dried in vacuo under heating to give the captioned compound (55 mg, 0.18 mmol) as a white solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4](S(C2C=CC(C)=CC=2)(=O)=O)[N:3]=1.[C:24]([Si:28]([CH3:34])([CH3:33])[O:29][CH2:30][C:31]#[CH:32])([CH3:27])([CH3:26])[CH3:25].C1COCC1>[Cu]I.C(N(CC)CC)C>[Si:28]([O:29][CH2:30][C:31]#[C:32][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1)([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:33])[CH3:34]
Reactant: Cc1ccc(S(=O)(=O)n2nc(Br)c3cc([N+](=O)[O-])cnc32)cc1
Reactant: C#CCO[Si](C)(C)C(C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC#Cc1n[nH]c2ncc([N+](=O)[O-])cc12
Temperature: 25 °C
Yield: 17.1 %

Procedure:
Triethylamine (4 mL) was added to a solution of 3-bromo-5-nitro-1-tosyl-1H-pyrazolo[3,4-b]pyridine (0.825 g, 3.40 mmol), tert-butyldimethyl(prop-2-ynyloxy)silane (0.89 g, 5.09 mmol) in THF (20 mL) PdCl2(PPh3)2 (0.119 g, 0.170 mmol) was added to the mixture, and the mixture was stirred at room temperature for 5 minutes before CuI (0.065 g, 0.34 mmol) was added. The reaction mixture was heated to reflux under argon for 40 hours. The reaction mixture was cooled to room temperature and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (4:1) to give 3-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (0.193 g, 17%) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH:21]4[CH2:25][CH2:24][O:23][CH2:22]4)[N:19]=[CH:18][N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([CH:33]2[CH2:37][CH2:36][CH2:35][NH:34]2)[CH2:29][CH2:28]1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([CH:33]2[CH2:37][CH2:36][CH2:35][N:34]2[C:2]2[CH:15]=[CH:14][C:13]3[C:12]4[N:8]([CH:9]=[C:10]([C:16]5[N:20]([CH:21]6[CH2:25][CH2:24][O:23][CH2:22]6)[N:19]=[CH:18][N:17]=5)[N:11]=4)[CH2:7][CH2:6][O:5][C:4]=3[CH:3]=2)[CH2:29][CH2:28]1
Reactant: CN1CCC(C2CCCN2)CC1
Reactant: Brc1ccc2c(c1)OCCn1cc(-c3ncnn3C3CCOC3)nc1-2
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1CCC(C2CCCN2c2ccc3c(c2)OCCn2cc(-c4ncnn4C4CCOC4)nc2-3)CC1
Temperature: 110 °C
Reaction time: 1 h
Yield: 163.4 %

Procedure:
A mixture of 12-bromo-4-[1-(oxolan-3-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene (40 mg, 0.010 mmol), 1-methyl-4-(pyrrolidin-2-yl)piperidine (3.0 mg, 0.020 mmol), Pd(PtBu3)2 (1.0 mg, 0.0010 mmol), NaOtBu (2.9 mg, 0.030 mmol) in toluene (2.0 ml) in a seal tube was degassed with N2 for three times. The resulting mixture was stirred at 110° C. for 1 h. The solid was filtered off and the filtrate was concentrated to give the crude product, which was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/1% formic acid, 17 min) to afford 232 (8.0 mg, 16% yield). LCMS (ESI): RT=3.39 min, m/z: 490.2 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.31 (s, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 6.60 (d, J=9 Hz, 1H), 6.42 (d, J=2.5 Hz, 1H), 4.54-4.52 (m, 4H), 4.29 (q, J=16 Hz, 1H), 4.16 (q, J=23 Hz, 1H), 4.03-4.01 (m, 1H), 3.97-3.95 (m, 1H), 3.86 (s, 1H), 3.55-3.53 (m, 1H), 3.24 (d, J=8 Hz, 1H), 2.98 (t, J=21 Hz, 2H), 2.56-2.48 (m, 2H), 2.29 (d, J=12 Hz, 3H), 2.04-1.93 (m, 5H), 1.78 (s, 1H), 1.69 (d, J=11.5 Hz, 1H), 1.53-1.44 (m, 3H)
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([CH3:26])[C:22]=1[N+:23]([O-:25])=[O:24])[C:17]([OH:19])=O.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>O1CCCC1>[CH3:26][C:21]1[CH:20]=[C:16]([C:17]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:19])[CH:15]=[C:14]([CH3:13])[C:22]=1[N+:23]([O-:25])=[O:24]
Reactant: Cc1cc(C(=O)O)cc(C)c1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N2CCOCC2)cc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,1′-Carbonyldiimidazole (1.66 g) is added to a solution of 3,5-dimethyl-4-nitrobenzoic acid (1 g) in tetrahydrofuran (10 mL). The mixture is stirred for 3 hours at room temperature, morpholine (0.9 mL) is added and the mixture is stirred for further 30 minutes. After concentration the mixture is diluted with ethyl acetate and washed with hydrochloric acid (0.2 M), saturated aqueous NaHCO3 solution and brine. The organic phase is dried (Na2SO4) and concentrated to give the title compound. Yield: 1.3 g; LC (method 20): tR=5.10 min; Mass spectrum (ESI+): m/z=265 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:37]([CH:39]([CH2:42][CH2:43][CH2:44]C)[CH2:40]O)C>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH:43]([CH2:42][CH:39]([CH3:40])[CH3:37])[CH3:44])=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCCCC(CC)CO
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Product: CC(C)CC(C)Oc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 178, starting with 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 4-methyl-2-pentanol for 2-ethyl-1-hexanol (yield: 115 mg, 50%). mp 132–133° C. 1H NMR (300 MHz, DMSO-d6) δ 0.80 (d, J=7 Hz, 3H), 0.87 (d, J=7 Hz, 3H), 1.10 (d, J=7 Hz, 3H), 1.26 (m, 1H), 1.50 (m, 1H), 1.63 (m, 1H), 3.30 (s, 3H), 5.31 (m, 1H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 463 (M+H)+; (APCI−) m/z 497 (M+Cl)−. Anal. calc. for C23H24F2N2O4S: C, 59.72; H, 5.23; N, 6.05. Found: C, 59.44; H, 5.26; N, 5.99.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=4)=[CH:10]3)[C:6]=2[CH:22]=1.[CH:23]([N:26]1[CH2:31][CH2:30][CH:29]([SH:32])[CH2:28][CH2:27]1)([CH3:25])[CH3:24].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.CCN(C(C)C)C(C)C>O1CCOCC1.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]>[CH:23]([N:26]1[CH2:31][CH2:30][CH:29]([S:32][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[C:7](=[N:8][C:9]([C:15]5[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=5)=[CH:10]4)[C:6]=3[CH:22]=2)[CH2:28][CH2:27]1)([CH3:25])[CH3:24]
Reactant: CC(C)N1CCC(S)CC1
Reactant: Cc1cccnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
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
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)C)CC3)ccc1OCC2
Temperature: 120 °C
Yield: 53.7 %

Procedure:
A mixture of 9-bromo-2-(3-methylpyridin-2-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (107 mg, 0.30 mmol), 1-isopropylpiperidine-4-thiol (72 mg, 0.45 mmol), Pd2(dba)3 (14 mg, 0.015 mmol, 5 mol %), XantPhos (17 mg, 0.030 mmol, 10 mol %) and DIPEA (210 μl, 1.20 mmol) in dioxane (4 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. The reaction mixture was diluted with DCM (75 mL) and purified by column chromatography (Si-PCC, gradient 0-10% 2M NH3/MeOH in DCM followed by C18, gradient 5-45% MeOH in 0.5% TFA/H2O). The product containing fractions were combined and concentrated in vacuo and the resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The basic fractions were concentrated under reduced pressure affording 9-(1-Isopropylpiperidin-4-ylsulfanyl)-2-(3-methylpyridin-2-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene as a colorless gum (70 mg, 54%). LCMS: RT1.83 min [M+H]+ 435.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([I:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:28]O>S(=O)(=O)(O)O>[CH3:28][O:19][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:24]([F:26])([F:25])[F:27])[O:13][N:12]=2)=[CH:15][C:16]=1[I:23]
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1I
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1I

Procedure:
In a solution of 0.60 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-iodo benzoic acid synthesized similarly to Steps 1 to 4 of Synthetic Example 4 in 10 ml of methanol, 2 drops of concentrated sulfuric acid was added, and stirred under reflux with heat for 20 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was neutralized with 10 ml of saturated sodium hydrogen carbonate aqueous solution, then extracted with ethyl acetate (10 ml×2). The organic phase was washed with water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:4), and 0.56 g of the aimed product was obtained as colorless oily substance.
Reaction SMILES: [O:1]=[C:2]([NH:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20])[CH2:3][C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:5].[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1C=CC=CC=1>[O:5]=[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])[C:3](=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]([NH:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20])=[O:1]
Reactant: O=C(CC(=O)Nc1ccccc1C(=O)O)Nc1ccccc1C(=O)O
Reactant: O=Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1C(=O)O)C(=Cc1ccccc1)C(=O)Nc1ccccc1C(=O)O
Yield: 54.6 %

Procedure:
2,2'-[(1,3-Dioxo-1,3-propanediyl)diimino]bisbenzoic acid (1.0 g) and benzaldehyde (0.46 g, 1.5 mol equivalent) were heated under reflux in dry pyridine (8 1) for 16 hours. After removing pyridine, the mixture was treated with water, made alkaline with 10% aqueous ammonia under ice cooling, and the aqueous layer was washed with ether. The aqueous layer was made acidic (pH=2) with 1N HCl, and the precipitated crystals were collected by filtration. After washing with water, the resulting solid was purified by dissolving in tetrahydrofuran, adsorbing on the silica gel column and separating the desired compound using a developing solvent [ethyl acetate:benzene=1:1 (containing 1% acetic acid)]. After removing the initially eluted impurities, the solvent was removed from the effluent out liquid containing the desired compound. The residue was crystallized by adding water, collected on a filter, washed with water, and dried to give the title compound (0.686 g, yield, 51%), which was recrystallized from the mixed solvent of CH3OH--H2O system to obtain pale yellow crystals of monohydrate (Crystal a, 0.507 g) (Drying: 1 mm Hg, 100° C., 15 hours), m.p., 195°-196° C.
Reaction SMILES: C(OC([N:8]1[CH2:21][CH2:20][C:11]2[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[N:14]=[CH:15][C:10]=2[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:19][C:16]([F:17])([F:18])[C:13]1[N:14]=[CH:15][C:10]2[CH2:9][NH:8][CH2:21][CH2:20][C:11]=2[N:12]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(C(F)(F)F)ncc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ncc2c(n1)CCNC2

Procedure:
Reaction of the product from Step A above with trifluoroacetic acid in dichloromethane according to the procedure outlined for Intermediate 28, Step C afforded the title compound as a white powder. LC/MS 204.0 (M+1).
Reaction SMILES: [N:1]1([C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][CH2:21]Cl)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][CH2:21][NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:18][CH:17]=1
Reactant: Nc1ccccc1N1CCCCC1
Reactant: COc1ccc(CCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CCNc2ccccc2N2CCCCC2)cc1
Temperature: 100 °C

Procedure:
To 1 g of 2-piperidinoaniline in 10 mL of DMF are added 1.72 mL of 4-methoxyphenethyl chloride (2 equivalents) and 2.35 g of potassium carbonate (3 equivalents). The whole is heated to 100° C. for 60 hrs and then poured on ice and extracted with ethyl acetate. The organic phase washed with a saturated solution of sodium chloride is dried on magnesium sulfate, filtered and evaporated under reduced pressure. With several silica gel chromatographies of the residue (petroleum ether, petroleum ether/ethyl acetate: 98/2), 255 mg of the desired product were able to be isolated.
Reaction SMILES: [C:1]([S:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1(C)C=CC=CC=1>[C:1]([S:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[S:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)SC(=O)c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)SC(=S)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of S-t-butyl thiobenzoate (1.94 g, 0.01 mol) and Lawesson's reagent (2.43 g, 0.006 mol) in anhydrous toluene (10 mL) was refluxed for 25 hours. After cooling to room temperature, the reaction mixture was concentrated and the residue subjected to column chromatography (Kieselgel-60, 70-230 mesh, petroleum spirit/diethyl ether 19:1) The title compound was obtained as an oil, 1.37 g (65.5%). 1H-nmr (CDCl3) d (ppm): 1.69 (s, 9H, 3×CH3), 7.36 (m, 2H, meta-ArH), 7.50 (m, 1H, para-ArH) and 7.88 (d, 2H, ortho-ArH). 13C-nmr (CDCl3) d (ppm): 28.2, 52.2, 126.6, 128.1, 131.7 and 147.0. The signal due to C═S (d>220.0 ppm) was beyond the frequency range of the spectrum.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:12].[C-:13]#[C-:14].[Na+].[Na+]>CN(C=O)C>[Br:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:13]#[CH:14]
Reactant: BrCCCCCCCCCCBr
Reactant: [C-]#[C-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCCCCCCCCCCBr
Yield: 106 %

Procedure:
A 100 mL round-bottom dry flask was purged with Argon gas. Anhydrous DMF (20 mL) and 1,10-dibromdecane (7.5 g, 25 mmol) were mixed and stirred with a stir bar. Sodium acetylide (7.4 g, 18% wt in xylene) was added slowly. The mixture was stirred at 70° C. overnight. The reaction was quenched with DI water (40 ml). The solution was extracted with CH2Cl2 (3×50 mL), re-extracted with DI water (2×50 mL), dried with sodium sulfate overnight, and filtered. After the removal of the solvent by rotoevaporation, 12-bromo-dodec-1-yne (6.5 g) was obtained. The resultant product was added to triethyl phosphate (10.9 ml, 62.5 mmol) and stirred for 24 h at 150° C. After cooling to room temperature, the excess amount of triethyl phosphate was removed under vacuum. A light yellow liquid was obtained (1 g, 20%).