Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)C.C(=O)(O)[O-].[Na+].Cl.Br[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[S:19]1[C:23]([Sn](C)(C)C)=[CH:22][N:21]=[CH:20]1>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(OCC)(=O)C.C1C=CC=CC=1>[S:19]1[C:23]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=[CH:20]1
Reactant: Brc1ccncc1
Reactant: C[Sn](C)(C)c1cncs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: c1cc(-c2cncs2)ccn1
Temperature: 25 °C

Procedure:
Diethyl ether and a saturated aqueous solution of sodium bicarbonate were added to 4-bromopyridine hydrochloride (3.76 g). The organic layer thus separated was dried over anhydrous sodium sulfate and concentrated under reduced pressure, whereby a diethyl ether solution of 4-bromopyridine was obtained. To the resulting solution were added (5-thiazolyl)trimethyltin (4.00 g), benzene (150 ml) and tetrakis(triphenylphosphine)palladium (950 mg), followed by heating under reflux for 12 hours. After allowed to cool down to room temperature, the reaction mixture was added with a saturated aqueous solution (100 ml) of sodium bicarbonate and ethyl acetate (50 ml). The water layer thus separated was extracted with ethyl acetate (2×50 ml) and methylene chloride (2×50 ml). The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride:ethyl acetate=5:1→2:1), whereby 4-(5-thiazolyl)pyridine was obtained as a colorless, transparent oil. The resulting oil was dissolved in diethyl ether (80 ml), followed by the dropwise addition of n-butyl lithium (a 1.52N hexane solution, 11.5 ml) at −78° C. After stirring for 30 minutes, a carbon dioxide gas was blown into the reaction mixture. Ten minutes later, the temperature was increased gradually to room temperature. The reaction mixture was concentrated, whereby the residue of lithium 5-(pyridin-4-yl)thiazole-2-carboxylate was obtained as a colorless solid. To a solution of the resulting residue in N,N-dimethylformamide (50 ml) were added l-(tert-butoxycarbonyl)piperazine (3.30 g), 1-hydroxybenzotriazole monohydrate (2.40 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.40 g) at room temperature. The resulting mixture was stirred for 3 days. Ethyl acetate (200 ml) and water (2000 ml) were added to the reaction mixture. The water layer thus separated was extracted with ethyl acetate (2×200 ml). The organic layers were combined, washed with water (1000 ml) and a saturated aqueous solution (400 ml) of sodium bicarbonate, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was reprecipitated in a methylene chloride—hexane system, whereby the title compound (3.00 g) was obtained as pale brown powder.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].BrC1C=CC(C(F)(F)F)=NC=1.[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([C:29]3[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=3)=[O:28])[CH:25]=2)[N:20]=[C:19]([O:35][CH3:36])[C:18]=1[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=1.Cl>C1COCC1.C(Cl)Cl.O>[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([C:29]3[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=3)([OH:28])[CH2:1][CH3:2])[CH:25]=2)[N:20]=[C:19]([O:35][CH3:36])[C:18]=1[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([S:44]([CH3:47])(=[O:45])=[O:46])=[CH:42][CH:43]=1
Reactant: CC[Mg]Br
Reactant: COc1nc2ccc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: FC(F)(F)c1ccc(Br)cn1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CCC(O)(c1ccc2nc(OC)c(Cc3ccc(S(C)(=O)=O)cc3)c(Cl)c2c1)c1cncn1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Ethyl magnesium bromide solution (3 M in Et2O, 0.1 mL, 0.334 mmol) was added slowly to a solution of 5-bromo-2-(trifluoromethyl)pyridine (0.075 g, 0.334 mmol) in dry THF (3 mL). The resulting cloudy solution was stirred at room temperature for 20 minutes, cooled to 0° C. and then (4-chloro-2-methoxy-3-(4-(methylsulfonyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (0.056 g, 0.119 mmol, Intermediate 7: step e) in dry DCM (1 mL) was added. The resulting suspension was stirred at room temperature for 10 minutes then heated in a 60° C. oil bath, for 6 hours, then at 80° C. for an additional 12 hours. The mixture was cooled to room temperature, then H2O was added followed by 6 N aqueous HCl to bring the contents to a neutral pH. The solvents were removed under reduced pressure and the product extracted out with CH2Cl2 (2×). The combined organic extract was dried (Na2SO4), filtered, evaporated in vacuo and chromatographed (0-10% MeOH in DCM) to provide a yellow solid by-product. Further purification by RP-HPLC (water/acetonitrile/0.1% TFA) of this by-product provided the title compound as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.80 (s, 1H), 8.32 (d, J=2.0 Hz, 1H), 7.84 (d, J=7.6 Hz, 4H), 7.51 (d, J=8.6 Hz, 3H), 4.44 (s, 2H), 4.07 (s, 3H), 3.53 (s, 3H), 3.07 (s, 3H), 2.26-2.48 (m, 2H), 0.83 (t, J=7.0 Hz, 3H); MS (ESI) 500 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[OH:12])[O:8][C:7](=[O:14])[C:6]([C:15]([O:17]CC)=[O:16])=[CH:5]2.[OH-].[K+].Cl>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[OH:12])[O:8][C:7](=[O:14])[C:6]([C:15]([OH:17])=[O:16])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(F)c(O)c(F)c2oc1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2cc(F)c(O)c(F)c2oc1=O
Yield: 90.4 %

Procedure:
A solution of 14 (100 mg, 0.37 mmol) and KOH (70 mg, 85%, 1.1 mmol) in 7 mL of THF/MeOH/H2O (5:5:1) is heated at 60° C. for 2 hours. The reaction is poured into 50 mL 5% HCl and extracted with EtOAc (40 mL×2), washed with brine (30 mL), dried over anhydrous MgSO4, and concentrated in vacuo to yield 81 mg (94%) of Compound 15 as a green powder.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31](O)[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:37]2)=[CH:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31]([O:9][C:8](=[O:10])[CH:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:14][CH:13]=2)[CH2:11][CH3:12])[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[CH2:37]2)=[CH:24]1)([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCC(Oc1ccc(Cl)cc1)C(=O)O
Product: CCC(Oc1ccc(Cl)cc1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 104.6 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 730 mg of (2RS)-2-(4-chlorophenoxy)butyric acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.42 g of the title compound as a colorless foam.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([CH2:10][CH3:11])[CH:3]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][S:20]([CH3:19])(=[O:22])=[O:21])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: CCc1cc(Br)ccc1CN
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCc1cc(Br)ccc1CNS(C)(=O)=O
Reaction time: 1 h

Procedure:
To 4-bromo-2-ethyl-benzylamine (650 mg, 3 mmol) and triethylamine (500 μL, 3.6 mmol) in dichloromethane (5 mL) at room temperature was added methanesulfonyl chloride (283 μL, 3.6 mmol). The solution was stirred 1 h, diluted in water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, then saturated sodium chloride, dried (Na2SO4), filtered, and concentrated in vacuo to an off-white solid (880 mg, 100%). 1H NMR (300 MHz, CDCl3): δ ppm 1.25 (t, J=7.54 Hz, 3H) 2.69 (q, J=7.54 Hz, 2H) 2.90 (s, 3H) 4.27-4.31 (m, 2H) 4.40-4.50 (m, 1H) 7.21 (d, J=8.10 Hz, 1H) 7.32-7.40 (m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N:5]1([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH2:27][CH2:28][C:29]5[N:30]([C:32]([C:35]([F:38])([F:37])[F:36])=[N:33][N:34]=5)[N:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(N(CC)CC)C>C(Cl)Cl.O>[C:1]([N:8]1[CH2:9][CH2:10][N:5]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH2:27][CH2:28][C:29]5[N:30]([C:32]([C:35]([F:38])([F:36])[F:37])=[N:33][N:34]=5)[N:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:6][CH2:7]1)(=[O:3])[CH3:2]
Reactant: FC(F)(F)c1nnc2n1N=C(N1CCC(c3ccc(OCCN4CCNCC4)cc3)CC1)CC2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCN(CCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 49.7 %

Procedure:
A solution of acetyl chloride (0.027 mL, 0.38 mmol) in DCM (0.5 mL) was added dropwise to 6-[4-[4-[2-(piperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine (150 mg, 0.31 mmol) and triethylamine (0.088 mL, 0.63 mmol) in DCM (1 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 5 minutes then allowed to warm to room temperature and stirred for 15 minutes. The reaction mixture was diluted with water (2 mL), passed through a phase separating cartridge and then the organic layer was evaporated to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of is water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (80 mg, 49%) as a gum.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19].[OH-].[Na+].Cl>C(#N)C>[C:8]([C:6]1[CH:7]=[C:2]2[NH:1][C:18](=[O:19])[N:10]([C@H:11]3[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]3)[C:3]2=[N:4][CH:5]=1)#[N:9]
Reactant: N#Cc1cnc(N[C@H]2CC[C@H](O)CC2)c(N)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: N#Cc1cnc2c(c1)[nH]c(=O)n2[C@H]1CC[C@H](O)CC1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-amino-5-cyano-2-(trans-4-hydroxycyclohexylamino)pyridine (3.1 g) and 1,1′-carbonyldiimidazole (6.49 g) in acetonitrile (31 mL) was stirred at 50° C. under nitrogen atmosphere for 15 minutes. After adding 1N-NaOH(35 mL), the mixture was stirred at 60° C. for 1.5 hours. The reaction mixture was neutralized with concentrated hydrochloric acid to yield a precipitate. The resulting precipitate was collected by filtration and washed successively with water and aqueous ethanol to give 6-cyano-3-(trans-4-hydroxycyclohexyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (1.93 g) as a brown solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:32][C:33]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([C:45]([OH:47])=O)[CH2:41][CH2:40]1)=[O:38])([CH3:35])[CH3:34].[Br:48][C:49]1[N:54]=[CH:53][C:52]([NH2:55])=[CH:51][CH:50]=1>CN(C=O)C.O>[Br:48][C:49]1[N:54]=[CH:53][C:52]([NH:55][C:45]([CH:42]2[CH2:41][CH2:40][N:39]([C:37]([O:36][C:33]([CH3:32])([CH3:34])[CH3:35])=[O:38])[CH2:44][CH2:43]2)=[O:47])=[CH:51][CH:50]=1
Reactant: Nc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(Br)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
TBTU (2.86 g, 8.9 mmol) and diisopropylethylamine (1.55 mL, 8.9 mmol) were added to a mixture of 1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinecarboxylic acid (1.35 g, 5.9 mmol) in DMF (20 mL) at ambient temperature. The mixture was stirred at ambient temperature for 1 h, charged with 6-bromo-3-pyridinamine (1.13 g, 6.5 mmol), then stirred at 50° C. overnight. The mixture was cooled to ambient temperature, charged with water (200 mL), and extracted with EtOAc. The organics were dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 50% EtOAc/hexanes to give 1.75 g (77%) of 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)amino]carbonyl}-1-piperidinecarboxylate as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.32 (d, 1H, J=2.7 Hz), 8.07 (dd, 1H, Ja=8.6 Hz, Jb=2.8 Hz), 7.44-7.39 (m, 2H), 4.16 (bs, 2H), 2.90-2.65 (m, 2H), 2.45-2.35 (m, 1H), 1.95-1.80 (m, 2H), 1.79-1.65 (m, 2H), 1.44 (s, 9H); LRMS (ESI), m/z 384 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)(=[O:22])=[O:21])=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)(C)(C)C.[C:31](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.O>[NH2:7][CH2:8][CH:9]1[CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([N:19]([CH3:31])[S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)(=[O:22])=[O:21])[CH:16]=[CH:17][C:18]1=2
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NCC1CCCc2cc(NS(=O)(=O)c3cccc(F)c3)ccc21
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccc2c(c1)CCCC2CN)S(=O)(=O)c1cccc(F)c1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.22 grams (0.524 mmole) (+/−)-[6-(3-fluoro-benzenesulfonylamino)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamic acid tert-butyl ester in 10 mL DMF was added 0.08 grams (0.576 mmole) potassium carbonate and 0.033 mL (0.524 mmole) iodomethane. The reaction mixture was stirred at 23° C. for 0.5 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water saturated aqueous sodium chloride, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was dissolved in 3 mL warm TFA and immediately concentrated under reduced pressure. The residue was partitioned between saturated aqueous sodium carbonate ethyl acetate. The organic phase was dried (magnesium sulfate) and concentrated under reduced pressure. N-(5-Aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-fluoro-N-methyl-benzenesulfonamide was isolated as the crystalline oxalate salt, 0.06 grams (18%), m.p. 176-177° C., M+H=349.
Reaction SMILES: N[C:2](N)=[O:3].[N:5]1[C:12]([NH2:13])=[N:11][C:9]([NH2:10])=[N:8][C:6]=1[NH2:7]>O>[CH2:2]=[O:3].[N:5]1[C:12]([NH2:13])=[N:11][C:9]([NH2:10])=[N:8][C:6]=1[NH2:7]
Reactant: NC(N)=O
Agent: Nc1nc(N)nc(N)n1
Solvent: O
Product: C=O

Procedure:
Similarly, a suitable urea-formaldehyde resin syrup may be prepared by substituting an equivalent molar quantity of urea for the melamine. The thermosetting resinous condensate of the present invention is employed in the form of an aqueous dispersion, clear or turbid, aqueous solution, or solid suspension in water of a partially-condensed, highly cross-linkable resin. The solution, dispersion or suspension are capable of being diluted up to at least twice their volume with water before any appreciable separation of the resin occurs from the water, i.e. precipitates. Thus, the condensate as employed in the present invention may be an aqueous solution similar to that produced in the synthesis of the melamine-formaldehyde condensate previously described. Alternatively, the synthesis reaction may be continued beyond the time required to produce a clear solution so that the resulting product is either a clear or turbid dispersion of the condensate in water.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[S:3][C:4]3[CH2:5][C:6]4[C:12]([C:13]5[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=5)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:7]=4[C:8]=3[CH:9]=2)=[CH:32][CH:31]=1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Reactant: CC1(C)OB(c2ccc(F)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(F)cc4)cc2-3)cc1
Temperature: 100 °C
Yield: 66 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.87 g, 1.8 mmol), 2-(4-Fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.4 g, 2.7 mmol), Na2CO3 (2 M, 4.3 ml), and Pd(PPh3)2Cl2 (170 mg, 0.14 mmol) in toluene/ethanol (1:1, 10 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 2-(4-Fluoro-phenyl)-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as brown solid in 66% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:20]3[NH:19][C:18]4[N:21]=[CH:22][CH:23]=[CH:24][C:17]=4[CH2:16][NH:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:9])=[C:4]([Cl:25])[CH:3]=1.[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[Cl:25][C:4]1[CH:3]=[C:2]([C:28]2[CH:29]=[CH:30][S:26][CH:27]=2)[CH:7]=[CH:6][C:5]=1[C:8]([C:10]1[C:20]2[NH:19][C:18]3[N:21]=[CH:22][CH:23]=[CH:24][C:17]=3[CH2:16][NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: OB(O)c1ccsc1
Reactant: O=C(c1ccc(Br)cc1Cl)c1cccc2c1Nc1ncccc1CN2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(c1ccc(-c2ccsc2)cc1Cl)c1cccc2c1Nc1ncccc1CN2
Yield: 46.7 %

Procedure:
To a solution of the (4-bromo-2-chloro-phenyl)-(5,11-dihydro-pyrido[2,3-b][1,5] benzodiazepin-10-yl)-methanone of Example 7, Step A (0.5 g, 1.23 mmol), thiophene-3-boronic acid (0.158 g, 1.23 mmol) and sodium carbonate (0.568 g, 5.36 mmol) in toluene (20 mL), ethanol (10 mL) and water (10 mL) under nitrogen was added the tetrakis (triphenylphosphine) palladium(0) catalyst (0.06 g, 0.052 mmol). The reaction was heated at reflux for 20 hours, cooled, and filtered through Celite, which was then rinsed with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and evaporated to dryness. The residue (blue-green oil) was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with 25% ethyl acetate in hexane yielded a foam (0.24 g) which was triturated with diethyl ether-hexane to provide the title compound as a white solid, m.p. 125-130° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)CC)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C(I)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:32])[NH:7][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]2[CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(C(=O)OC(C)(C)C)c1ccc(Cc2ccc(OC)c(-c3cccc(Cl)c3)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Solvent: CN(C)C=O
Product: COc1ccc(Cc2ccc(NC(=O)OC(C)(C)C)cc2)cc1-c1cccc(Cl)c1
Reaction time: 0.17 h

Procedure:
Synthesis of [4-(3′-Chloro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-ethyl-carbamic acid tert-butyl ester (I-302) I-301 (140 mg, 0.33 mmol) was dissolved in 2 mL of DMF and stirred for 10 minutes under N2; then NaH was added. Once effervescence had ceased. ethyl iodide was added and the reaction mixture was stirred at room temperature for 2 hours and quenched with 20 mL of water. The mixture was extracted with ethyl acetate (3×5 mL), and the combined organic extracts were washed with brine and dried over Na2SO4. After filtration and removal of solvent, 120 mg (81%) of I-302 was collected.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][N:19]=1.Br.C(N(CC)CC)C>C(O)C>[I:24][C:21]1[CH:22]=[CH:23][C:18]2[N:19]([CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=2)[CH:20]=1
Reactant: Nc1ccc(I)cn1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(I)ccc2n1
Temperature: 25 °C
Yield: 28 %

Procedure:
A mixture of 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (420 mg, 1.5 mmol) and 2-amino-5-iodopyridine (330 mg, 1.5 mmol) in ethanol (6.7 mL) containing hydrobromic acid (48%, 84 μL, 0.75 mmol) and triethylamine (105 μL, 0.75 mmol) was heated under reflux under argon overnight. After cooling to room temperature, the mixture was evaporated and poured onto hydrochloric acid (0.5 N) and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulphate and evaporated to leave a yellow oil. Purification by chromatography (SiO2, dichloromethane:methanol=100:0 to 95:5) afforded the title compound (170 mg, 28%) which was obtained as a light yellow solid. MS: m/e=402.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N:13]1([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2cnc3ccccc32)nc1
Reaction time: 9 h
Yield: 65.2 %

Procedure:
To a mixture of ethyl 6-chloronicotinate (2.43 g), 1H-benzimidazole (1.7 g) and potassium carbonate (5.43 g) was added N,N-dimethylformamide (20 mL), and the mixture was stirred at 50° C.-60° C. for 9 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (2.28 g).