Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]=[CH:2]2.[CH3:8][SiH:9]([CH3:11])[Cl:10]>C1(C)C=CC=CC=1.[Pt]>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[Si:9]([CH3:11])([CH3:8])[Cl:10]
Reactant: C1=CC2CCC1C2
Reactant: C[SiH](C)Cl
Agent: [Pt]
Solvent: Cc1ccccc1
Product: C[Si](C)(Cl)C1CC2CCC1C2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Norbornene (141 g, 1.50 mol) is dissolved in toluene (100 ml) and heated to 80° C. After the addition of the platinum catalyst ([COD]PtCl2, 70 mg), dimethylchlorosilane (169 g, 1.8 mol) is slowly added dropwise within 60 min, and the temperature rises to 98° C. Heating is continued at 80° C. for a further 1 h. Excess silane, unconverted norbornene and the solvent are distilled off at atmospheric pressure. The residue is fractionally distilled using a membrane pump vacuum. 255 g (93%) of a colorless liquid having b.p. of 120° C./10 mbar are obtained. Purity 99.7% (assessed by GC (gas chromatography)).
Reaction SMILES: OOS([O-])=O.[K+].[CH3:7][S:8]([C:11]1[CH:12]=[C:13]([C:17]2[N:18]=[C:19]([CH:27]3[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]3)[CH:20]=[C:21]3[C:26]=2[N:25]=[CH:24][CH:23]=[CH:22]3)[CH:14]=[CH:15][CH:16]=1)(=O)=[O:9]>C1COCC1.O.C(OCC)(=O)C.O>[CH3:7][S:8]([C:11]1[CH:12]=[C:13]([C:17]2[N:18]=[C:19]([CH:27]3[CH2:28][CH2:29][CH:30]([C:33]([OH:35])=[O:34])[CH2:31][CH2:32]3)[CH:20]=[C:21]3[C:26]=2[N:25]=[CH:24][CH:23]=[CH:22]3)[CH:14]=[CH:15][CH:16]=1)=[O:9]
Reactant: CS(=O)(=O)c1cccc(-c2nc(C3CCC(C(=O)O)CC3)cc3cccnc23)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)c1cccc(-c2nc(C3CCC(C(=O)O)CC3)cc3cccnc23)c1
Reaction time: 0.25 h

Procedure:
A solution of 4-[8-(3-Methanesulfanyl-phenyl)-[1,7]naphthyridin-6-yl]-cyclohexanecarboxylic acid (30 mg, 0.079 mmol) in THF (1.4 ml) is cooled in a salt/ice bath and oxone (14.5 mg, 0.024 mmol) in water (0.5 ml) is added. After 15 minutes the reaction mixture is allowed to warm to room temperature and after a further 30 minutes more oxone (14.5 mg is added). The mixture is diluted with ethyl acetate/water and the aqueous layer extracted with ethyl acetate. The combined organic layers are washed with brine then dried over magnesium sulfate. Filtration followed by evaporation yields a foam consisting of title compound and 4-[8-(3-Methanesulfonyl-phenyl)-[1,7]naphthyridin-6-yl]-cyclohexanecarboxylic acid. MS (AP+) 395.87
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:30])[CH2:18][C:19]3[CH:24]=[CH:23][C:22](Br)=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1.C1(C)C=CC=CC=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.C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:30])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:36]4[CH:35]=[CH:34][N:33]=[C:32]([CH3:31])[CH:37]=4)=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Cc1cc(B(O)O)ccn1
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(Br)c(C(F)(F)F)c3)nc2)CC1
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
Solvent: CCO
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(C)c4)c(C(F)(F)F)c3)nc2)CC1
Temperature: 110 °C

Procedure:
To a reaction vessel charged with N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-bromo-3-(trifluoromethyl)phenyl)acetamide 192-1 (300 mg, 0.62 mmol), 2-methylpyridin-4-ylboronic acid 172-1 (127 mg, 0.93 mmol) and Pd(PPh3)4 (36 m g, 0.03 mmol) was added toluene (6 mL), ethanol (2 mL) and saturated sodium carbonate (2 mL). The reaction mixture was flushed with nitrogen and heated to 110° C. for 10 hours. After the reaction was cooled down to room temperature, it was partitioned between ethyl acetate and saturated NaHCO3 and the organic phase was washed with brine and dried over Na2SO4. The solvent was removed by rotary evaporation and the residue was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(2-methylpyridin-4-yl)-3-(trifluoromethyl)phenyl)acetamide 172. MS m/z 498.2 (M+1). 1H NMR 400 MHz (DMSO-d6) δ10.67 (s, 1H), 8.66 (d, 1H), 8.05 (m, 1H), 7.94 (m, 2H), 7.75 (d, 1H), 7.52 (s, 1H), 7.45 (m, 3H), 3.88 (s, 2H), 3.58 (b, 4H), 3.14 (b, 2H), 3.09 (b, 2H), 2.61 (s, 3H), 2.05 (s, 3H).
Reaction SMILES: [C:1]1([S:7]([NH:10][C@@H:11]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])[CH2:26][CH2:25]3)=[CH:19][CH:18]=2)[C:12]([O:14]C)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl.Cl.[NH2:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=1)[C:48]([NH2:50])=[NH:49].CCN=C=NCCCN(C)C>CO.O1CCCC1.N1C=CC=CC=1>[C:48]([C:47]1[CH:46]=[C:45]([NH:44][C:12](=[O:14])[C@@H:11]([NH:10][S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[O:31])[CH2:26][CH2:25]3)=[CH:21][CH:22]=2)[CH:53]=[CH:52][CH:51]=1)(=[NH:49])[NH2:50]
Reactant: N=C(N)c1cccc(N)c1
Reactant: COC(=O)[C@H](Cc1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2)cc1)NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Solvent: C1CCOC1
Product: N=C(N)c1cccc(NC(=O)[C@H](Cc2ccc(OC3CCN(C(=O)OCc4ccccc4)CC3)cc2)NS(=O)(=O)c2ccccc2)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
1.75 g (3.26 mmol) of methyl (2S)-2-(benzenesulfonylamino)-3-[4-[1-(benzyloxycarbonyl)-4-piperidyloxy]phenyl]propionate was dissolved in a mixed solvent of 10 ml of methanol and 10 ml of tetrahydrofuran. 6.52 ml (6.52 mmol) of 1 N aqueous sodium hydroxide solution was added to the solution, and they were stirred at 50° C. overnight. The reaction mixture was washed with ether and then made acidic with concentrated hydrochloric acid. After the isolation process with dichloromethane as the extractant in the same manner as that of step 1 in Example 1, an oily residue was obtained, which was dissolved in 60 ml of pyridine. 747 mg (3.61 mmol) of 3-aminobenzamidine dihydrochloride and 750 mg (3.92 mmol) of WSC were added to the solution, and they were stirred at room temperature overnight. The solvent was distilled off, and the residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11]/[C:10](=[CH:26]\N(C(C)C)C(C)C)/[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:11][C:10](=[CH2:26])[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N(/C=C1\C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O)C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C

Procedure:
(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) (7 g) is added to THF (210 ml) and the resulting mixture cooled to −78° C. Diisobutylaluminium hydride (109 ml, 103 mmol; 0.95 M in THF) is added over 1.5 h. To the mixture is then added Rochelle's Salt (430 ml; 1.2 M in water) and the mixture stirred vigorously. Ethyl acetate (400 ml) is added and the phases are separated. The organic phase is concentrated in vacuo. The resulting residue is dissolved in ethyl acetate (20 ml) and washed with brine (20 ml). Phases are separated. The organic phase is then concentrated in vacuo. Diethyl ether (50 ml) is added, filtered and the filtrate concentrated to give (R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4-a, R1=Boc).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[C:5](N)[CH:4]=1.N([O-])=O.[Na+].F[B-](F)(F)F.[Na+].[I-:25].[Na+]>Cl.O.C(#N)C>[I:25][C:5]1[CH:4]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2
Reactant: Nc1cc(C(F)(F)F)cc2[nH]ccc12
Reactant: [I-]
Agent: Cl
Agent: F[B-](F)(F)F
Agent: O=N[O-]
Solvent: CC#N
Solvent: O
Product: FC(F)(F)c1cc(I)c2cc[nH]c2c1
Reaction time: 0.25 h
Yield: 58.8 %

Procedure:
To a suspension of 6-trifluoromethyl-1H-indol-4-ylamine (10.7 g, 53.4 mmol) in HCl (aq., 15%, 240 mL) was added a solution of sodium nitrite (5.52 g, 80.1 mmol) in H2O (10 mL) slowly at 0° C. The reaction mixture was stirred at RT for 1 h before a solution of sodium tetrafluoroborate (23.5 g, 0.214 mol) in H2O (30 mL) was added. After stirring for 15 min, the resulting precipitate was collected by filtration and washed with a sodium tetrafluoroborate solution (aq., sat) before dissolving in acetonitrile (100 mL). This solution was added slowly to a suspension of sodium iodide (24.0 g, 0.160 mol) in acetonitrile (100 mL) and the mixture stirred at RT for 16 h. The reaction mixture was concentrated to 30% of the volume and partioned between EtOAc and H2O. The organic layer was isolated then washed in succession with sodium thiosulfate, H2O and brine, dried over Na2SO4 and evaporated to dryness. The resulting brown oil was purified by column chromatography to give the title compound (9.77 g, 59%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[C:28]([F:34])[C:27]=1[O:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1.[Cl:46][C:47]1[N:48]=[C:49]([CH:55]2[CH2:57][CH2:56]2)[NH:50][C:51]=1[C:52](O)=[O:53].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:46][C:47]1[N:48]=[C:49]([CH:55]2[CH2:56][CH2:57]2)[NH:50][C:51]=1[C:52]([NH:33][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([Cl:25])=[C:27]([O:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=[CH:38][CH:37]=2)[C:28]=1[F:34])=[O:53]
Reactant: NCc1ccc(Cl)c(Oc2cccc3ccccc23)c1F
Reactant: O=C(O)c1[nH]c(C2CC2)nc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)c(Oc2cccc3ccccc23)c1F)c1[nH]c(C2CC2)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.1 %

Procedure:
HATU (0.113 g, 0.298 mmol) was added to a solution of {[4-chloro-2-fluoro-3-(1-naphthalenyloxy)phenyl]methyl}amine (0.060 g, 0.199 mmol) and 4-chloro-2-cyclopropyl-1H-imidazole-5-carboxylic acid (0.037 g, 0.199 mmol) and diisopropylethylamine (0.052 mL, 0.298 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by reverse phase HPLC (acetonitrile:water with 0.1% TFA) to give the title compound (0.016 g, 14%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.284-8.37 (m, 1H), 8.00-8.13 (m, 1H), 7.95 (dd, 1H), 7.54-7.66 (m, 3H), 7.48 (dd, 1H), 7.25-7.37 (m, 2H), 6.49 (d, 1H), 4.33-4.62 (d, 2H), 1.75-2.03 (m, 1H), 0.85-0.93 (m, 2H), 0.77-0.84 (m, 2H). ES MS: m/z 470 (M+1).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]([C:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[C@H:4]1[CH3:23].[C:24]([N:31]([CH3:37])[C@H:32]([C:34](O)=[O:35])[CH3:33])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(OCC)(=O)C>[CH3:37][N:31]([C@@H:32]([CH3:33])[C:34]([NH:2][C@H:3]1[C@H:4]([CH3:23])[N:5]([C:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[NH:8][C:9]1=[O:10])=[O:35])[C:24](=[O:25])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29]
Reactant: C[C@H]1[C@H](N)C(=O)Nc2ccccc2N1C(=O)C1CCOCC1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
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: C[C@@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2N(C(=O)C2CCOCC2)[C@H]1C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a room temperature solution of (3S,4S)-3-amino-4-methyl-5-(tetrahydro-2H-pyran-4-carbonyl)-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one hydrochloride (173 mg, 509 μmol) in N,N-dimethylformamide (2 ml) was added Boc-N-methyl-L-alanine (114 mg, 560 μmol), N,N-diisopropylethylamine (440 μl, 2.55 mmol), and HBTU (212 mg, 560 μmol). The reaction was stirred at room temperature for 2 h. After this time, the reaction was diluted with ethyl acetate (20 mL), washed with a saturated aqueous sodium bicarbonate solution (20 mL) and the aqueous layer was then extracted with ethyl acetate (3×10 mL) and the combined organics were washed with a saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and the filterate concentrated in vacuo. The crude material was purified using an Initelliflash 280 system (4 g silica gel column Varian brand, 20-90% ethyl acetatehexanes) to afford tert-butyl methyl((S)-1-((2S,3S)-2-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (238 mg, 96%): LC-MS m/z 487 [M−H]−.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:13]1[S:14][C:15]([CH2:19]O)=[C:16]([CH3:18])[N:17]=1.S(Cl)([Cl:23])=O.C(=O)(O)[O-].[Na+].Cl.O>C(Cl)(Cl)Cl>[Cl:23][CH2:19][C:15]1[S:14][C:13]([C:3]2[CH:4]=[CH:5][C:6]([C:9]([F:12])([F:11])[F:10])=[C:7]([F:8])[C:2]=2[F:1])=[N:17][C:16]=1[CH3:18]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)c(F)c2F)sc1CO
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1nc(-c2ccc(C(F)(F)F)c(F)c2F)sc1CCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a solution of [2-(2,3-difluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-yl]-methanol (45 mg, 150 μmol) in chloroform (3 ml) was added thionyl chloride (20 μl, 290 μmol) at −10° C. under an argon atmosphere. The reaction mixture was stirred for 30 min, saturated aqueous sodium bicarbonate solution/ice water 1/1 was added and the layers were separated. The aqueous layer was extracted two times with dichloromethane. The combined organic layers were washed with ice water/brine 1/1 and dried over sodium sulfate. The solvent was evaporated in vacuo to give the title compound (44 mg, 134 μmol, 90%) as yellow oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH3:23])[C:15]=3[NH:14][C:13](=O)[C:12]=2[CH2:11][CH2:10]1.[OH-].[Na+].P(Cl)(Cl)([Cl:29])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH3:23])[C:15]=3[N:14]=[C:13]([Cl:29])[C:12]=2[CH2:11][CH2:10]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccccc1N1CCc2c1c1cccc(OC)c1[nH]c2=O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1N1CCc2c(Cl)nc3c(OC)cccc3c21

Procedure:
1-(2-Methoxyphenyl)-4-oxo-6-methoxy-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline (9.55 g) was dissolved in phosphoryl chloride (100 ml) and heated at reflux for 2.5 hours. After cooling, the solution was poured onto ice, made alkaline with aqueous sodium hydroxide solution, and extracted with dichloromethane. The organic extract was dried and evaporated, and the crude product purified by chromatography (silica gel, 50-100% diethyl ether in petroleum ether). The first compound to elute was 4-chloro-6-methoxy-2,3-dihydrofuro[3,2-c]quinoline, m.p. 99°-101°. Later fractions containing the desired product were recrystallised from ethyl acetate, then ethyl acetate/ethanol to give1-(2-methoxyphenyl)-4-chloro-6-methoxy-2,3-dihydropyrrolo[3,2-c]quinoline, m.p. 183°-184°.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O.CO>[O:11]1[CH2:12][CH2:13][CH2:14][CH:8]([C:7]2[C:2]([O:31][C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:16]4[S:15][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=5[N:17]=4)=[CH:30][CH:29]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: Fc1ncccc1C1CCCOCC1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CO
Product: c1cnc(Oc2ccc(Nc3nc4ccccc4s3)cc2)c(C2CCCOCC2)c1
Temperature: 120 °C
Reaction time: 17 h

Procedure:
2-Fluoro-3-(oxepan-4-yl)pyridine (0.055 g, 0.28 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (0.20 g, 0.85 mmol), and cesium carbonate (0.28 mL, 0.85 mmol) were mixed in NMP (0.75 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at 120° C. for 17 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic layers were washed with 1 M aqueous sodium hydroxide, washed with sat. sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to yield an orange solid. The solid was slurried in MeOH and filtered to give N-(4-(3-(oxepan-4-yl)pyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine. MS (ESI, pos. ion) m/z: 418.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][N:13]1[CH:17]=[C:16]([C:18]2[CH:19]=[C:20]3[C:28](=[O:29])[C:27]4[CH:30]=[C:31]([CH2:34][S:35]([NH:38][CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)(=[O:37])=[O:36])[CH:32]=[CH:33][C:26]=4[CH:25]=[CH:24][C:21]3=[N:22][CH:23]=2)[CH:15]=[N:14]1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:12][N:13]1[CH:17]=[C:16]([C:18]2[CH:19]=[C:20]3[C:28](=[O:29])[C:27]4[CH:30]=[C:31]([CH2:34][S:35]([NH:38][CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N+:41]=5[O-:6])(=[O:36])=[O:37])[CH:32]=[CH:33][C:26]=4[CH:25]=[CH:24][C:21]3=[N:22][CH:23]=2)[CH:15]=[N:14]1
Reactant: Cn1cc(-c2cnc3ccc4ccc(CS(=O)(=O)NCc5ccccn5)cc4c(=O)c3c2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1cc(-c2cnc3ccc4ccc(CS(=O)(=O)NCc5cccc[n+]5[O-])cc4c(=O)c3c2)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Chloroperoxybenzoic acid (26.1 mg, 0.106 mmol) was added to a solution of 1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide (50 mg, 0.106 mmol) in dichloromethane (1.06 mL) at 0 C. After 15 min., the reaction was allowed to warm to room temperature and stirring was continued for 6 hr. Then, aqueous sodium hydrogen carbonate (saturated, 50 mL) was added, and the mixture was extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with aqueous sodium hydrogen carbonate (saturated, 2×75 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA, to afford the title compound as a yellow solid. 1H NMR (600 MHz, DMSO-D6) δ 9.21 (d, 1H); 8.53 (d, 1H); 8.47 (s, 1H); 8.25 (d, 1H); 8.17 (s, 1H); 8.14 (s, 1H); 7.80 (m, 3H); 7.46 (d, 1H); 7.40 (d, 1H); 7.34 (m, 3H); 4.71 (s, 2H); 4.27 (d, 2H); 3.88 (s, 3H). LRMS (APCI) calculated for C25H21N5O4S [M+H]+, 488.1. found 488.1.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1>CS(C)=O.ClCCl>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([NH:15][CH:16]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]2)=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(NC2CCC(O)CC2)cc1C(F)(F)F
Temperature: 95 °C

Procedure:
5-Fluoro-2-nitrobenzotrifluoride (400 mg, 1.91 mmol) and trans-4-aminocyclohexanol (220 mg, 1.91 mmol) are dissolved in dimethylsulfoxide (10 mL) and the reaction is then heated at 95° C. for 3.5 hours. After cooling to room temperature, the mixture is diluted with dichloromethane (15 mL) and washed with water (3×10 mL). The organic phase is collected and dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product is recrystallised from petrol ether. The desired product is finally isolated as a yellow solid (84% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)(OC(C)(C)C)=O.[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH2:8][N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1
Reactant: O=Cc1cccs1
Reactant: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)N(CC1CCCN(Cc2cccs2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (31 mg, 0.090 mmol) in 0.5 mL of dry CH2Cl2 at 0° C. (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (0.5 mL) and 2-thiophene carboxaldehyde (12.5 μL, 1.5 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 28.45 mg, 1.5 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×10 mL). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford N-[1-(Thiophen-2-ylmethyl)-piperidin-3-ylmethyl]-N-phenyl-propionamide 8 as a colorless oil (25.2 mg, 82%). LRMS 343.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=O)(C)(C)C.[O:15]1[C:19](=[O:20])[N:18]=[CH:17][NH:16]1.[ClH:21]>C(OCC)(=O)C>[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[ClH:21].[O:15]1[C:19](=[O:20])[N:18]=[CH:17][NH:16]1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1
Agent: Cl
Agent: O=c1nc[nH]o1
Solvent: CCOC(C)=O
Product: Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl acetate (10 ml) containing 150 mg of 3-(tert-butyloxycarbonylamino)benzene-1,2,4-oxadiazol-5-one was cooled to 0° C. and treated with a continuous stream of hydrogen chloride gas for 10 minutes. The reaction mixture was stirred for 30 minutes more and the solvent and excess hydrogen chloride were removed under reduced pressure. The residue was azeotropically dried with toluene to give 120 mg of the title compound in sufficient purity to continue directly to the next step.