Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=3.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[C:16]1([C:2]2[CH:3]=[CH:4][C:5]3[NH:6][C:7]4[C:12]([C:13]=3[CH:14]=2)=[CH:11][C:10]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:13][CH:14]=2)=[CH:9][CH:8]=4)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
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: Cc1ccccc1
Product: c1ccc(-c2ccc3[nH]c4ccc(-c5ccccc5)cc4c3c2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
Under a nitrogen gas atmosphere, to a flask, 3,6-dibromocarbazole (5 g, 15.4 mmol), phenylboronic acid (4.1 g, 33.9 mmol), tetrakis(triphenylphosphine)palladium (0.7 g, 0.6 mmol), toluene (45 ml) and 2M sodium carbonate (45 ml) were mixed in sequence, and were stirred for eight hours at 80 degrees C. An organic phase was separated and then concentrated under reduced pressure by an evaporator. The obtained residue thereof was refined by silica-gel column chromatography, so that 3.6-diphenylcarbazole (3.6 g, a yield of 74%) was obtained.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)[C:12]3[C:31]([Cl:35])=[CH:32][CH:33]=[N:34][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36][N:37]1[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:20]=[CH:21][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH:40]6[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]6)[CH2:27][CH2:26]5)=[CH:23][CH:24]=4)=[CH:16][CH:17]=3)[C:12]3[C:31]([Cl:35])=[CH:32][CH:33]=[N:34][C:11]2=3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1c2ccc(-c3ccc(N4CCNCC4)cc3)cc2c2c(Cl)ccnc21
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCC(N2CCN(c3ccc(-c4ccc5c(c4)c4c(Cl)ccnc4n5S(=O)(=O)c4ccccc4)cc3)CC2)CC1
Temperature: 25 °C
Yield: 93 %

Procedure:
Under an inert atmosphere 9-benzenesulfonyl-4-chloro-6-(4-(piperazin-1-yl)phenyl)-9H-pyrido[2,3-b]indole (30 mg, 0.0596 mmol) was dissolved in anhydrous DCM (1.2 mL, c=0.05M). N-methyl-4-piperidone (22 μL, 3 eq) was added, followed by the addition of two drops of glacial acetic acid. The mixture was stirred for 1 h15 at r.t. and then cooled to 0° C. Sodium triacetoxyborohydride (38 mg, 3eq) was added in portions and the resultant mixture was allowed to warm to room temperature, and then stirred 22 h. The reaction mixture was then quenched with water and saturated aq. NaHCO3. The aqueous layer was extracted with EtOAc (3×7 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield the desired compound (33 mg, 93%) as a white solid that was used without further purification.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]2[CH2:18][CH:17]([CH2:19][CH2:20][CH:21]=O)[O:16][N:15]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH:29]([N:30]1[CH2:35][CH2:34][N:33]([CH2:21][CH2:20][CH2:19][CH:17]2[O:16][N:15]=[C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[CH2:18]2)[CH2:32][CH2:31]1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=CCCC1CC(c2cccc(Oc3ccccc3)c2)=NO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(Oc2cccc(C3=NOC(CCCN4CCN(C(c5ccccc5)c5ccccc5)CC4)C3)c2)cc1
Yield: 48.7 %

Procedure:
3-[3-(3-Phenoxyphenyl)-4,5-dihydroisoxazol-5-yl]propanal (27.1 mg, 0.087 mmol), 1-(diphenylmethyl)piperazine (20.0 mg, 0.078 mmol), molecular sieve (5 beads) and NaBH(OAc)3 (50.0 mg, 0.237 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 20.2 mg (53.3%) of the target compound was obtained.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[NH:12][C:11]2=[O:19])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.Cl[CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:29]1([CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:4]2[CH2:3][CH2:2][N:1]([CH2:7][CH2:8][CH2:9][N:10]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:11]3=[O:19])[CH2:6][CH2:5]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: ClC(c1ccccc1)c1ccccn1
Reactant: O=c1[nH]c2ccccc2n1CCCN1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccn2)CC1
Temperature: 50 °C
Yield: 23.4 %

Procedure:
A mixture of 5.2 parts of 1,3-dihydro-1-[3-(1-piperazinyl)propyl]-2H-benzimidazol-2-one, 5.28 parts of 2-(chlorophenylmethyl)pyridine hydrochloride, 5.3 parts of sodium carbonate and 90 parts of N,N-dimethylformamide is stirred and heated overnight at 50° C. The reaction mixture is cooled and poured onto ice-water. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 2 parts (23.4%) of 1,3-dihydro-1-[3-{4-[phenyl(2-pyridinyl)methyl]-1-piperazinyl}propyl]-2H-benzimidazol-2-one; mp. 141.7° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11](Cl)=[O:12])=[CH:2]1.[C:15]1([CH:21]([NH2:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC#N>[CH:21]([NH:28][C:11](=[O:12])[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:14])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: O=C(NC(c1ccccc1)c1ccccc1)C(=O)c1c[nH]c2ccccc12

Procedure:
N-Benzhydryl-2-(1H-indol-3-yl)-2-oxo-acetamide was synthesized following scheme I above starting from (1H-indol-3-yl)-oxo-acetyl chloride and C,C-diphenyl-methylamine. Yield (52%). HPLC ret. time 3.59 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 9.56 (d, J=9.1 Hz, 1H), 8.56 (d, J=3.2 Hz, 1H), 8.22 (m, 1H), 7.54 (m, 1H), 7.43-7.26 (m, 12H), 6.32 (d, J=9.1 Hz, 1H); ESI-MS 355.5 m/z (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[CH:10][S:11][CH:12]=2)=[C:4]([O:20][CH3:21])[CH:3]=1.[H-].[Na+].Cl[CH2:25][O:26][CH3:27]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:25][O:26][CH3:27])=[CH:15][CH:14]=3)=[CH:10][S:11][CH:12]=2)=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: COc1cc(Cl)ccc1-c1cscc1-c1ccc(O)cc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc(-c2cscc2-c2ccc(Cl)cc2OC)cc1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of 4-(4-(4-chloro-2-methoxyphenyl)thiophen-3-yl)phenol (700 mg, 2.1 mmol) in anhydrous THF (5 mL) was added NaH (90 mg, 2.3 mmol) at 0° C. After the mixture was stirred at the temperature for 0.5 h, chloro(methoxy) methane (184 mg, 2.3 mmol) was added. The mixture was stirred at 0° C. for 1 hour, and at room temperature for 2 hours. When TLC indicated the starting material was consumed, the mixture was quenched with water, and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give the crude product, which was purified by column to give 3-(4-chloro-2-methoxyphenyl)-4-(4-(methoxymethoxy)phenyl)thiophene (720 mg, 90%) which was taken forward to Step 3.
Reaction SMILES: [S-:1][C:2]#[N:3].[C:4]([O:7][C:8](=O)[CH3:9])(=[O:6])[CH3:5]>N1C=CC=CC=1.ClCCl>[C:4]([O:7][CH2:8][CH2:9][S:1][C:2]#[N:3])(=[O:6])[CH3:5]
Reactant: N#C[S-]
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCSC#N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-bromoethanol (7.0 g) and potassium thiocyanate (5.4 g) in methanol (40 ml) was refluxed for 7 hours. After precipitate was filtered off, the filtrate was evaporated under reduced pressure. The residue was suspended in chloroform/methanol (5/1). The precipitate was filtered off. The filtrate was evaporated under reduced pressure to give the thiocyanate (4.4 g). To a mixture of the thiocyanate in pyridine (4.8 ml)/dichloromethane (20 ml) was added acetic anhydride (5.3 ml) in dichloromethane (5 ml) at 5° C. The mixture was stirred at room temperature for 6 hours. The precipitate was filtered off. The filtrate was washed with water, dried over sodium sulfate and evaporated under reduced pressure to give 2-thiocyanatoethyl acetate (5.6 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(C(C)C)CC)(C)C.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[C:37](Cl)=[O:38].CO>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:42]([O:43][CH3:44])=[C:34]([O:33][CH3:32])[CH:35]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml), was added diisopropylethylamine (0.94 mL, 5.4 mmol) and 3,4-dimethyoxybenzoyl chloride (0.6 g, 2.8 mmol). The mixture was stirred at room temperature overnight followed by the addition of MeOH (1 mL). The reaction mixture was then washed with water (40 mL), 1N HCl (2×40 mL), and brine (40 mL), dried over MgSO4, and concentrated in vacuo. The resulting oil was purified by ISCO silica gel flash chromatography (eluent: 0% MeOH in CH2Cl2 to 5% MeOH in 10 min then stay at this ratio for 15 min) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl-methyl]-3,4-dimethoxy-benzamide as a white solid (0.8 g, 79%): mp, 198-200° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=2.2 min. (99%); 1H NMR (DMSO-d6): δ 2.06-2.10 (m, 1H), 2.51-2.59 (m, 2H), 2.64 (m, 1H), 3.81 (s, 6H), 4.94 (d, J=5.9 Hz, 2H), 5.14-5.20 (dd, J=5, 12 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 7.51-7.58 (m, 2H), 7.83-7.70 (m, 3H), 9.02 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.97, 30.92, 38.22, 48.86, 55.53, 55.60, 110.67, 110.92, 120.56, 121.80, 126.10, 127.05, 131.50, 133.06, 134.77, 139.66, 148.28, 151.44, 166.09, 166.96, 167.57, 169.83, 172.74. Anal Calcd for C23H21N3O7+0.2H2O: C, 60.71; H, 4.74; N, 9.23. Found: C, 60.39; H, 4.51; N, 8.99.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.[CH2:33](I)[CH3:34].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O>[CH2:33]([N:30]1[CH2:31][CH2:32][CH:27]([N:25]2[CH:26]=[C:22]([C:19]3[CH:20]=[CH:21][C:16]4[N:17]([C:13]([CH2:12][C:3]5[CH:4]=[C:5]6[C:10](=[CH:11][C:2]=5[F:1])[N:9]=[CH:8][CH:7]=[CH:6]6)=[CH:14][N:15]=4)[N:18]=3)[CH:23]=[N:24]2)[CH2:28][CH2:29]1)[CH3:34]
Reactant: CCI
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(C4CCNCC4)c3)nn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCN1CCC(n2cc(-c3ccc4ncc(Cc5cc6cccnc6cc5F)n4n3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7-fluoro-6-[6-(1-piperidin-4-yl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-quinoline (Example 180, 50 mg, 0.117 mmol) and ethyliodide (19 μL, 0.234 mmol) in dioxane (1 mL) was stirred at rt for 2 h. Cs2CO3 (19 mg, 0.059 mmol) was then added and the RM was stirred at rt for 5 h more. The mixture was diluted with EtOAc and washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with a 4 g RediSep® silica gel column, DCM/(DCM/MeOH 9:1+NH3)=100:0→0:100) to afford the title compound as a foam (tR 3.10 min (conditions 3), MH+=456.2, 1H-NMR in DMSO-d6: 8.84 (m, 1H); 8.50 (s, 1H); 8.34 (m, 1H); 8.08 (m, 2H); 8.04 (d, 1H); 7.76 (d, 1H); 7.60 (s, 1H); 7.53 (d, 1H); 7.47 (dd, 1H); 4.55 (s, 2H); 4.18 (m, 1H); 2.96 (m, 2H); 2.35 (q, 2H); 1.97 (m, 6H); 1.01 (t, 3H)).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17](Br)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:31]3[C:30]([F:29])=[CH:35][CH:34]=[CH:33][C:32]=3[F:36])[O:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(Br)c(-c3ccc(OC)cc3)c12
Reactant: OB(O)c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCNc1ncnc2oc(-c3c(F)cccc3F)c(-c3ccc(OC)cc3)c12
Temperature: 70 °C
Reaction time: 15 h

Procedure:
Dissolve 150 mg (0.34 mmol) 6-{[6-bromo-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester and 106 mg (0.70 mmol) (2,6-difluorophenyl)boronic acid in 3.5 ml toluene and 1.0 ml ethanol, and add 0.34 ml of 2 M aqueous sodium carbonate solution and 25 mg (0.03 mmol) 1,1′-bis(diphenylphosphano)ferrocene palladium(II) chloride. Next, stir for 15 h at 70° C. Purify the reaction mixture directly by preparative RP-HPLC (gradient: water/acetonitrile). 13 mg (8% of theor.) of the desired product is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[CH:3]1.[CH:16]([NH:19][NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH:16]([N:19]([C:13](=[O:15])/[CH:12]=[CH:11]/[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)[NH:20][C:21](=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([CH3:18])[CH3:17]
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: Cn1cc(/C=C/C(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)/C=C/c1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To solution containing (E)-3-(1-methyl-1H-indol-3-yl)acrylic acid (50 mg, 0.24 mmol, 1.0 equivalent), N′-isopropylbenzohydrazide (66.43 mg, 0.37 mmol, 1.5 equivalent) and HATU (141.72 mg, 0.37 mmol, 1.5 equivalent) dissolved in DMF (5.0 ml), N,N-diisopropylethylamine (DIPEA)(0.06 ml, 0.37 mmol, 1.5 equivalent) was slowly drop-wise added and stirred at room temperature for 24 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc:methanol=9:3:1) and dried so that white solid form of (E)-N′-isopropyl-N′-(3-(1-methyl-1H-indol-3-yl)acryloyl)benzohydrazide was obtained.(82.62 mg, 92%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[NH2:15])[CH2:3][CH2:2]1.[CH3:16][O:17][CH:18]([O:22][CH3:23])N(C)C>>[CH3:23][O:22][CH:18]([O:17][CH3:16])[N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[N:15]=[CH:9][N:10]([CH3:14])[CH3:11])[CH2:3][CH2:2]1
Reactant: Nc1nccn1CCCC1CCNCC1
Reactant: COC(OC)N(C)C
Product: COC(OC)N1CCC(CCCn2ccnc2N=CN(C)C)CC1
Temperature: 100 °C

Procedure:
A mixture of 1-[3(4-piperidinyl)propyl]-1H-imidazole-2-amine (0.5 g, 0.0024M) and dimethylformamide dimethylacetal (7 ml) was heated at 100° C. for 10 hrs. The reaction was then stripped to dryness to give 4-[3-(2[[[dimethylamino)methylene]amino]-1H-imidazol-1-yl]propyl]-1-piperidinecarboxaldehyde dimethylacetal. The solution of the piperidinecarboxaldehyde dimethylacetal in chloroform (4 ml) was added to the mixture of 6-aminopenicillanic acid (0.46 g, 0.0216M) and diisopropylethylamine (0.37 ml) in chloroform (10 ml) at 0° C. and then stirred at room temperature for 31/2 hrs. After this period, the solvent was removed and water (20 ml) was added. The aqueous solution, after being washed with ethylacetate, was acidified from about pH 3 to about 3.5 and purified on Sephadex L-20 columns to give [2S-(2alpha,5alpha,6beta)]-6-[[[4-[3 -[2-[[(dimethylamino)methylene]amino]-1H-imidazol-1-yl]propyl]-1-piperidinyl]-methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 1.7 molar hydrochloride 2.6 molar hydrate (0.64 g, 64% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:28])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:19][CH2:18]3)[CH3:16])[CH:8]=2)=[CH:4][CH:3]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([N:41]=[C:42]=[O:43])=[O:40])=[CH:34][CH:33]=1.C(OCC)C.CCCCCC>O1CCCC1>[CH3:27][N:25]([CH3:26])[CH2:24][CH2:23][N:20]1[CH2:21][CH2:22][CH:17]([N:15]([CH3:16])[C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:42]([NH:41][C:39](=[O:40])[CH2:38][C:35]4[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=4)=[O:43])=[CH:30][CH:29]=3)[CH:12]=[CH:11][N:10]=2)=[O:28])[CH2:18][CH2:19]1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3)ccn2)CC1
Temperature: 25 °C
Reaction time: 10.5 h
Yield: 13.5 %

Procedure:
To a solution of 3-[4-(4-aminophenoxy)-pyridin-2-yl]-1-[1-(2-dimethylaminoethyl)piperidin-4-yl]-1-methylurea (154 mg) in tetrahydrofuran (5.0 ml) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 3.73 ml) at room temperature, followed by stirring at room temperature for 10.5 hrs. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=10:1). Fractions containing a target compound were concentrated to give a residue, to which diethyl ether (1 ml) and hexane (1 ml) were added to give a precipitate. The precipitate was filtered off, and dried under aeration to provide the titled compound (29.8 mg, 13.5%) as white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9]Br.[Na+].[I-].[C:13]([S-:15])#[N:14].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][N:14]=[C:13]=[S:15]
Reactant: Fc1ccc(Br)c(CBr)c1
Reactant: N#C[S-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Br)c(CN=C=S)c1
Temperature: 80 °C

Procedure:
To a solution of 1-bromo-2-(bromomethyl)-4-fluorobenzene (12, 5.36 g, 20.0 mmol) in dry DMF (20 mL) was added NaI (1.20 g, 8.00 mmol) and KSCN (3.88 g, 40.0 mmol). The mixture was heated under N2 at 80° C. for 12 h. After cooling to RT, the mixture was diluted with water (100 mL), and extracted with EtOAc (50 mL×2). The combined extracts were washed with brine, dried over MgSO4 and concentrated to give crude product. This was purified by column chromatography on silica gel, and eluted with petroleum ether to provide 1-bromo-4-fluoro-2-(isothiocyanatomethyl)benzene (13).
Reaction SMILES: [C:1](/[CH:3]=[C:4](/[N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)\SC)#[N:2].O.[NH2:21][NH2:22]>CCO>[NH2:2][C:1]1[NH:22][N:21]=[C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH:3]=1
Reactant: CS/C(=C\C#N)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(N)[nH]n2)CC1
Temperature: 25 °C

Procedure:
A mixture of (Z)-tert-butyl 4-(2-cyano-1-(methylthio)vinyl)piperazine-1-carboxylate (5.94 g, 20.9 mmol) and hydrazine monohydrate (4.5 mL) in EtOH (50 mL) was heated to reflux for 14 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified by column chromatography, eluting with 0-10% MeOH/CH2Cl2 to give tert-butyl 4-(5-amino-1H-pyrazol-3-yl)piperazine-1-carboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15]Br)[CH:12]=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][S-:21].[Na+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][S:21][CH3:20])[CH:12]=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1OCc1ccccc1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-benzyloxy-4-bromomethyl-1-nitrobenzene (Example 83, step C) (1.0 g, 3.1 mmol) in 20 mL DMF is added sodium thiomethoxide (228 mg, 3.26 mmol). The solution is stirred at RT for 2 h then water is added and the mixture is extracted with EtOAc. The organic layer is washed with water and brine, and dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound as a yellow liquid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([F:21])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:22])[CH2:4]1.[O:23]=[C:24]1[CH2:29][S:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(=O)([O-])[O-].[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)[Cl:57]>CO>[ClH:57].[F:21][C:18]1[CH:19]=[C:20]2[C:15]([CH:14]=[CH:13][C:12](=[O:22])[N:11]2[CH2:10][CH2:9][N:5]2[CH2:6][C@@H:7]([OH:8])[C@@H:3]([CH2:2][NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[S:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:4]2)=[N:16][CH:17]=1
Reactant: ClCCl
Reactant: NC[C@H]1CN(CCn2c(=O)ccc3ncc(F)cc32)C[C@H]1O
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Cl
Product: O=C1CSc2ccc(CNC[C@H]3CN(CCn4c(=O)ccc5ncc(F)cc54)C[C@H]3O)nc2N1
Reaction time: 18 h
Yield: 46 %

Procedure:
1-{2-[(3S,4S)-3-(Aminomethyl)-4-hydroxy-1-pyrrolidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one (130 mg, 0.423 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde (for a synthesis, see WO2004058144, Example 7(d) (90 mg, 0.465 mmol) were combined in anhydrous DCM (5 ml) and anhydrous MeOH (1 ml) with a spatula of solid sodium carbonate. The reaction mixture was stirred under nitrogen for 18 h then sodium triacetoxyborohydride (282 mg, 1.27 mmol) was added and stirred for 1 h. The reaction mixture was concentrated and purified to obtain the free base of the title compound as a pale yellow oil (95 mg, 46%) after column chromatography (90:10:1: DCM:MeOH:NH4OH).