Azzindani/Open_Reaction_Data huggingface dataset:
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.[CH3:29][O:30][C:31]1[CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38].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>[CH3:29][O:30][C:31]1[CH:32]=[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]([CH3:26])([CH3:28])[CH3:27])[C:7]=4[C:8]=3[CH:9]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC
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(OC)c(OC)c4)cc2-3)cc1
Temperature: 100 °C
Yield: 65 %

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 (0.76 g, 1.5 mmol), 2-(3,4-Dimethoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.4 g, 2.3 mmol), Na2CO3 (2 M, 2.45 mL), and Pd(PPh3)2Cl2 (9.7 mg, 0.084 mmol) in toluene/ethanol (1:1, 8.0 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-(3,4-Dimethoxy-phenyl)-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as orange solid in 65% yield.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[CH:17]([CH3:19])[CH3:18])(=O)=O.[CH3:22][NH:23][C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25].[F-].[Cs+]>O1CCOCC1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[Pd]>[CH:17]([C:8]1[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]([CH3:13])=[CH:12][C:7]=1[C:29]1[CH:30]=[CH:31][C:26]([C:24]([NH:23][CH3:22])=[O:25])=[CH:27][CH:28]=1)([CH3:19])[CH3:18]
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)c(C(C)C)cc1[N+](=O)[O-]
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(-c2cc(C)c([N+](=O)[O-])cc2C(C)C)cc1
Temperature: 120 °C

Procedure:
To a mixture of crude 2-isopropyl-5-methyl-4-nitrophenyl trifluoromethanesulfonate (Step 2, 200 mg, 0.61 mmol), 4-(methylcarbamoyl)phenylboronic acid (142 mg, 0.79 mmol) and cesium fluoride (185 mg, 1.22 mmol) in dioxane (15 mL), is added palladium bis(tri-tert-butylphospine) (15 mg, 10% mmol) in a microwave tube. The tube is sealed. The mixture is purged with N2 for 3 min, and then heated at 120° C. for 10 min under microwave irradiation. The mixture is cooled, filtered and concentrated. The residue is purified with silica gel chromatography (60% ethyl acetate in hexanes) to afford white solid as 2′-isopropyl-N,5′-dimethyl-4′-nitrobiphenyl-4-carboxamide. ESMS m/z 313.2 (M+H+).
Reaction SMILES: [OH-].[Na+].CC(O)C.[OH:7][C:8]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][N:36]([CH:39]([CH3:41])[CH3:40])[CH2:35][CH2:34]2)=[CH:29][C:9]=1[C:10]([NH:12][C:13]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][C:14]=1[C:15]([O:17]C)=[O:16])=[O:11].Cl>O>[OH:7][C:8]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:34][CH2:35][N:36]([CH:39]([CH3:41])[CH3:40])[CH2:37][CH2:38]2)=[CH:29][C:9]=1[C:10]([NH:12][C:13]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][C:14]=1[C:15]([OH:17])=[O:16])=[O:11]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCN(C(C)C)CC2)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)N1CCC(c2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)O)c2)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A 2.0 mol/L aqueous solution of sodium hydroxide (0.27 mL) was added to a 2-propanol (1.5 mL) suspension of the obtained methyl 2-(2-hydroxy-5-(1-isopropylpiperidin-4-yl)benzamido)-4-phenylbenzoate (0.086 g), followed by stirring at 50° C. for 1 hour. A 2.0 mol/L aqueous solution of sodium hydroxide (0.091 mL) was added to the reaction mixture, followed by stirring at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature, and water was added thereto. After adjusting the pH to 6.0 with 1.0 mol/L hydrochloric acid, the solid substance was collected by filtration to obtain 0.062 g of 2-(2-hydroxy-5-(1-isopropylpiperidin-4-yl)benzamido)-4-phenylbenzoic acid as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[SH:10].[Br:11][CH2:12][C:13](Br)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Br:11][CH2:12][C:13]1[S:10][C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: O=C(Br)CBr
Reactant: COc1ccc(N)c(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc2nc(CBr)sc2c1

Procedure:
7.75 g (50 mmol) of 2-amino-5-methoxy-thiophenol are dissolved in 150 ml methylene chloride and 14.1 g (70 mmol) of bromoacetylbromide are added whilst cooling with ice. Then the mixture is heated for 1 hour to reflux temperature. After cooling solid potassium carbonate is added until foaming ceases, the mixture is filtered and the filtrate is evaporated down. The evaporation residue is purified by column chromatography on neutral aluminium oxide (eluant: petroleum ether/ethyl acetate=3:1). Yield: 6.8 g (52.7 of theory), Melting point: 90-91° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[C:9]([C:11]2[NH:15][N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].O[CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C>>[NH2:19][CH2:18][CH2:17][N:14]1[CH:13]=[CH:12][C:11]([C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([Cl:2])[CH:10]=2)=[N:15]1
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: N#Cc1ccc(-c2ccn[nH]2)cc1Cl
Agent: Cl
Product: N#Cc1ccc(-c2ccn(CCN)n2)cc1Cl

Procedure:
The title compound was prepared using the method of Example 34(c) starting from 2.3 g of 2-chloro-4-(1H-pyrazol-5-yl)benzonitrile hydrochloride, 1.7 ml dipea and 1.7 g tert-butyl 2-hydroxyethylcarbamate yielding 2.08 g of the product. 1H-NMR (400 MHz; d6-DMSO): δ 1.56 (s, 2H), 2.97 (t, 2H), 4.13-4.17 (t, 2H), 6.97 (s, 1H), 7.87 (d, 1H), 7.93-8.02 (m, 2H), 8.10 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](Cl)=[O:13])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:20]([CH3:33])=[CH:19]2.[Cl-].[Cl-].C([Al+2])C>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][CH2:26][N:27]1[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1)[C:20]([CH3:33])=[C:19]2[C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: Cc1ccc(C(=O)Cl)c2ccccc12
Reactant: Cc1cc2cc(Cl)ccc2n1CCN1CCOCC1
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2c(C)n(CCN3CCOCC3)c3ccc(Cl)cc23)c2ccccc12
Temperature: 25 °C

Procedure:
To a solution of 4-methyl-1-naphthoyl chloride (106 mg, 0.52 mmol) and 4-(2-(5-chloro-2-methyl-1H-indol-1-yl)ethyl)morpholine (154 mg, 0.55 mmol) in 8 mL CH2Cl2 at −70° C. was added dropwise ethyl aluminum dichloride (0.63 mL, 1.14 mmol, 1.8 M in toluene). The reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and cold H2O, and the aqueous layer extracted twice with ethyl acetate. The combined organic extract was washed successively with H2O, 10% K2CO3, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 10% MeOH in CH2Cl2 to give CBX002 (141 mg, 0.32 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.32 (s, 3H), 2.47 (t, J=4.3 Hz, 4H), 2.66 (t, J=6.9 Hz, 2H), 2.79 (s, 3H), 3.68 (t, J=4.4 Hz, 4H), 4.19 (t, J=6.9 Hz, 2H), 7.14-7.21 (m, 1H), 7.23 (d, J=8.6 Hz, 1H), 7.36 (d, J=7.2 Hz, 1H), 7.43-7.52 (m, 2H), 7.58 (t, J=7.6 Hz, 1H), 7.61 (d, J=1.8 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H). 13C NMR (500 MHz, CDCl3, δ): 12.69, 19.92, 41.47, 54.08, 57.34, 66.87, 110.25, 115.09, 121.16, 122.69, 124.45, 125.75, 125.99, 126.06, 126.23, 126.66, 127.98, 128.34, 130.46, 132.95, 134.43, 137.27, 138.21, 146.37, 193.24. MS m/z 447.5 [M+H]+.
Reaction SMILES: C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1.[N+:17]([C:20]1[C:33]2[C:32](=[O:34])[C:31]3[C:26](=[C:27]([N+]([O-])=O)[CH:28]=[CH:29][CH:30]=3)[C:25](=[O:38])[C:24]=2[CH:23]=[CH:22][CH:21]=1)([O-:19])=[O:18].[N+:39]([O-])([OH:41])=[O:40]>>[N+:39]([C:30]1[C:31]2[C:32](=[O:34])[C:33]3[C:24](=[CH:23][CH:22]=[CH:21][C:20]=3[N+:17]([O-:19])=[O:18])[C:25](=[O:38])[C:26]=2[CH:27]=[CH:28][CH:29]=1)([O-:41])=[O:40]
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2cccc([N+](=O)[O-])c21
Reactant: O=[N+]([O-])O
Agent: O=C1c2ccccc2C(=O)c2ccccc21
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2c1cccc2[N+](=O)[O-]

Procedure:
The procedure is as described in Example 5, except that the mixed dinitration of anthraquinone is carried out not only with the extract left after stirring of the 1,5-dinitroanthraquinone, but also with the HNO3 -moist filter cake containing 1,5- and 1,8-dinitroanthraquinone obtained in accordance with variant (a) or (b) of Example 5.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[N+:19]([O-])=O)[C:13]([OH:15])=[O:14])=[N:6][C:5]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)(=[O:3])[NH2:2].[CH:29](O)=O>[Pd]>[C:1]([C:4]1[S:8][C:7]([N:9]2[C:10]3[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[CH:16]=[CH:17][C:18]=3[N:19]=[CH:29]2)=[N:6][C:5]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)(=[O:3])[NH2:2]
Reactant: O=CO
Reactant: NC(=O)c1sc(Nc2cc(C(=O)O)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Agent: [Pd]
Product: NC(=O)c1sc(-n2cnc3ccc(C(=O)O)cc32)nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.280 g (0.67 mmole) of 3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazol-2-ylamino]-4-nitro-benzoic acid (VI.10), 0.20 g of 10% palladium on carbon catalyst and 3 mL of 96% formic acid was stirred under an atmosphere of hydrogen at room temperature for 16 hours. The mixture was filtered through Diatomaceous earth and the Diatomaceous earth pad was washed with formic acid. The filtrate was concentrated under reduced pressure and the residue was dissolved in 1 mL of tetrahydrofuran and then added dropwise to 50 mL of water. The solid was collected by filtration, washing with water, to give 0.163 g of 3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazol-2-yl]-3H-benzoimidazole-5-carboxylic acid (I.10a).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([N:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1)[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]([N:18]1[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]1)[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(COCc2ccccc2)c2ccc(F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(C(COCc2ccccc2)N2CCNCC2)cc1
Yield: 92.9 %

Procedure:
In the same way as that described in Example 8, Step 4 using 1-[2-benzyloxy-1-(4-fluorophenyl)ethyl]-4-(tert-butyloxycarbonyl)piperazine (1.58 g, 3.8 mmol), trifluoroacetic acid (5 mL) and CH2Cl2 (50 mL). The piperazine (1.11 g, 92%) was isolated as a colourless oil. 1H NMR (250 MHz, CDCl3) δ2.36-2.57 (4H, m), 2.84-2.89 (4H, m), 3.49-3.54 (1H, m), 3.65 (1H, dd, J=9.9 and 5.4 Hz), 3.79 (1H, dd, J=9.9 and 5.8 Hz), 4.47 (2H, s), 6.99 (1H, dd, JHA-HB =8.7 Hz and JHA-F =8.7 Hz), 7.20-7.35 (7H, m). MS (ES+) (315, M+1).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:10]([C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:10]([C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])([CH3:12])[CH3:11]
Reactant: O=Cc1ccccc1F
Reactant: CC(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cccc(Oc2ccccc2C=O)c1
Yield: 56.5 %

Procedure:
2-Fluorobenzaldehyde (1.0 mg, 8.1 mmol) was dissolved in DMF (20 mL), 3-isopropylphenol (1.1 g, 8.9 mmol) and potassium carbonate (1.1 g, 8.1 mmol) were added thereto, and then microwave was irradiated at 180° C. for 5 minutes. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 70:30) to give the title compound (1.1 g, yield 57%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.[CH:23]([C:25]([CH3:27])=[O:26])=[CH2:24].C(Cl)(Cl)Cl>C(OCC)(=O)C>[CH3:9][C:6]1([CH3:8])[CH2:7][C:2]([CH3:22])([CH3:1])[CH2:3][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:17][CH2:18][N:19]([CH2:24][CH2:23][C:25](=[O:26])[CH3:27])[CH2:20][CH2:21]2)[CH2:5]1
Reactant: C=CC(C)=O
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)CCN1CCN(c2ccccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
A mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (160 mg, 0.532 mmol) produced in Example (8b), methyl vinyl ketone (0.058 mL, 0.692 mmol) and chloroform (0.7 mL) was stirred for 21 hours and 30 minutes at an external temperature of room temperature. The reaction mixture was diluted with ethyl acetate and then washed with aqueous solution of sodium hydrogencarbonate. The separated organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/heptane) to give 155 mg of the title compound as a light brown oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:3]=1[OH:17].[H][H]>[OH-].[K+].[Pd]>[N:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:2]=[C:3]([OH:17])[CH:4]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Oc1cc(N2CCCC2)c2ccccc2c1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Product: Oc1cc(N2CCCC2)c2ccccc2c1

Procedure:
1-Chloro-4-pyrrolidino-2-naphthol (2.47 g;0.010 mol), prepared as described in Example 6(a), was dissolved in 10% aqueous potassium hydroxide (50 ml) and was treated in the presence of palladium on charcoal (1.00 g;5%) at room temperature under 3 atmospheres of hydrogen until a stoichiometric amount of hydrogen was absorbed (approximately 24h). The palladium catalyst was removed by filtration and the filtrate neutralised with glacial acetic acid. The solution was extracted with dichloromethane (2×50 ml), the extracts combined, dried and evaporated to afford crude 4-pyrrolidino-2-naphthol as an unstable dark oil (0.58 g;27%). The crude product could not be purified further using conventional methods. ##STR28##
Reaction SMILES: [Na].[CH3:2][O:3][CH2:4][CH2:5][OH:6].Br[C:8]1[CH:12]=[CH:11][S:10][CH:9]=1.CCOCC>[Cl-].[Na+].O.[Cu]Br>[CH3:2][O:3][CH2:4][CH2:5][O:6][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1
Reactant: Brc1ccsc1
Reactant: COCCO
Agent: [Cu]Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COCCOc1ccsc1
Temperature: 118 °C
Yield: 76 %

Procedure:
Sodium metal (1.05 g, 45.8 mmol) cut into small pieces was added to 2-methoxyethanol (12 mL) at room temperature under nitrogen. The reaction was heated at 75° C. until all the sodium metal dissolved (about 45 min). 3-Bromothiophene (2.49 g, 15.3 mmol) and copper(1) bromide (0.22 g, 1.53 mmol) were added to the reaction mixture and the heat was increased to 118° C. for 1.5 h. The reaction was allowed to cool to room temperature and the mixture was poured into a mixture of brine and ether (1:1, 100 mL). Vigorous stirring caused an emulsion which was removed by filtration through celite washing the filter cake with ether (40 mL). The organic layer was separated and the aqueous layer extracted with ether (3×30 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel chromatography to afford 1.83 g of 3-(2-methoxyethoxy)thiophene (76% yield) as a clear liquid. 1H NMR (300 MHz, CDCl3) δ ppm 7.17 (dd, J=5.3, 3.2 Hz, 1H), 6.80 (dd, J=5.1, 1.5 Hz, 1H), 6.26 (dd, J=3, 1.5 Hz, 1H), 4.14-4.08 (m, 2H), 3.77-3.70 (m, 2H), 3.44 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:8]([CH2:14][C:15]3[CH:34]=[CH:33][C:18]4/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=5[O:22][CH2:23][C:17]=4[CH:16]=3)=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[CH3:62][NH:63][CH3:64].C1COCC1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:11]1([C:9]2[N:10]=[C:3]3[C:2]([N:63]([CH3:64])[CH3:62])=[CH:7][CH:6]=[CH:5][N:4]3[C:8]=2[CH2:14][C:15]2[CH:34]=[CH:33][C:18]3/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=4[O:22][CH2:23][C:17]=3[CH:16]=2)[CH2:13][CH2:12]1
Reactant: C/C(C#N)=C1/c2ccc(Cc3c(C4CC4)nc4c(Br)cccn34)cc2COc2cc(F)ccc21
Reactant: CNC
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C/C(C#N)=C1/c2ccc(Cc3c(C4CC4)nc4c(N(C)C)cccn34)cc2COc2cc(F)ccc21
Temperature: 120 °C
Yield: 30.3 %

Procedure:
(E)-2-{8-[(8-bromo-2-cyclopropylimidazo[1,2-a]pyridin-3-yl)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (0.36 g, 0.69 mmol) obtained in Reference Example 14C, step 4 was dissolved in toluene (14 mL), Pd2(dba)3 (0.13 g, 0.14 mmol), 2-(di-tert-butylphosphino)biphenyl (0.04 g, 0.14 mmol), sodium tert-butoxide (0.13 g, 1.4 mmol) and 2 mol/L dimethylamine THF solution (4.5 mL, 9.0 mmol) were added, and the mixture was stirred with heating at 120° C. for 2.5 hr in an Emrys Optimizer microwave synthesizer. The mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (heptane/ethyl acetate=100/0 v/v-70/30 v/v) to give the title compound (0.10 g, 29%).
Reaction SMILES: [C:1]([NH:9][CH2:10][C@@H:11]([C@@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20](O)=[O:21])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:30])[NH:28][NH2:29].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[C:1]([NH:9][CH2:10][C@@H:11]([C@@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH:29][NH:28][C:27]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[O:21])[C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](CNC(=O)c1ccccc1)C(=O)OC(C)(C)C
Reactant: NNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NNC(=O)OCc1ccccc1)[C@H](CNC(=O)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
A solution of 1.9 g of 2(R)-[2-benzamido-1(R)-(tert-butoxycarbonyl)ethyl]-4-methylvaleric acid in 3 ml of dry dimethylformamide was cooled to 0° C. under a nitrogen atmosphere and treated with 2.61 g of benzyl carbazate and 1.20 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was allowed to warm to room temperature and then stirred overnight. The mixture was diluted with ethyl acetate and washed in sequence with water, 2M aqueous hydrogen chloride, water, 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. Drying over anhydrous magnesium sulphate and evaporation gave 2.68 g of 2(R)-[2-benzamido-1(R)-(tert-butoxycarbonyl)ethyl]-2′-benzyloxycarbonyl-4-methylvalerohydrazide in the form of a white foam.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.[NH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])=[O:13])=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Reactant: CC(C)(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
To a mixture of 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2 g, 5.37 mmol), 2-amino-2-methylpropan-1-ol (575 mg, 6.45 mmol) and HATU (2.25 g, 5.91 mmol) was added DIPEA (2.08 g, 2.81 mL, 16.1 mmol) and DMF (18 mL). The mixture was stirred at room temperature for 16 h then was diluted with EtOAc and 10% citric acid. The phases were separated and the organic phase was then washed successively with 10% citric acid, NaHCO3 and brine. The organic phase was dried (MgSO4), filtered and purified by chromatography (silica, 20-60% ethyl acetate in hexanes) to give 2-bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (1.95 g, 4.4 mmol, 82%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 8.47 (s, 1H), 8.34 (s, 1H), 8.13 (s, 1H), 5.69 (s, 2H), 3.78 (s, 2H), 3.57 (t, J=8.4 Hz, 3H), 1.52 (s, 60.96 (t, J=8.4 Hz, 3H), 0.00 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[H-].[Na+].[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>CN(C=O)C.O.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([F:18])[CH:20]=1)[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: Fc1cccc(CBr)c1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 556.7 %

Procedure:
A solution of 5.0 g (18.65 mmol) of ethyl 5-bromo-1H-indole-2-carboxylate in 25 ml of dry DMF is added dropwise, at 0° C., to a suspension of 0.96 g (24.24 mmol) of sodium hydride (60%) in 15 ml of dry DMF, maintained under an inert atmosphere. The reaction mixture is stirred at ambient temperature for 1 hour. 4.23 g (2.75 mmol) of 3-fluorobenzyl bromide are subsequently added dropwise, at 0° C. The reaction mixture is then stirred for 18 h at ambient temperature and then diluted with 200 ml of a mixture of water and ethyl acetate (1/1). The resulting mixture is separated by settling out and the aqueous phase is extracted with 2×30 ml of ethyl acetate. The combined organic phases are washed three times with water, dried over sodium sulphate, filtered and concentrated under reduced pressure. The resulting oil is purified by silica gel column chromatography, elution being carried out with a mixture of heptane and ethyl acetate. 5.76 g of the expected product are isolated.