Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][OH:41])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][OH:41])[CH2:38][CH2:39]3)(=[O:32])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)N1CCC(CO)CC1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCC(CO)CC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and (1-((2-bromophenyl)sulfonyl)piperidin-4-yl)methanol. MS (ESI): mass calcd. for C22H23FN4O3S, 442.15; m/z found, 443.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.36-8.29 (m, 2H), 8.11-8.07 (m, 1H), 7.98 (m, 1H), 7.74-7.67 (m, 1H), 7.64-7.59 (m, 1H), 7.44-7.41 (m, 1H), 7.36-7.29 (m, 2H), 3.40-3.32 (m, 4H), 2.46-2.36 (m, 2H), 1.59 (d, J=10.5, 2H), 1.48-1.36 (m, 1H), 1.01-0.89 (m, 2H).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:33])[CH2:23][NH:24][C:25]([CH2:27][C@H:28]4[CH2:30][C:29]4([CH3:32])[CH3:31])=[O:26])[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>C(O)C.[H][H].[C].[Pd]>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:17][CH2:18][N:19]([C:22](=[O:33])[CH2:23][NH:24][C:25]([CH2:27][C@H:28]4[CH2:30][C:29]4([CH3:31])[CH3:32])=[O:26])[CH2:20][CH2:21]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)C[C@@H]1CC(=O)NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1(C)C[C@@H]1CC(=O)NCC(=O)N1CCC(=C2c3ccccc3CCc3ccccc32)CC1

Procedure:
72.8 mg of palladium carbon (10% w/v) was added to 72.8 mg (0.171 mmol) of (1R)-N-{2-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-2-oxoethyl}-2,2-dimethylcyclopropanecarboxyamide in 10 ml of ethanol, and they were stirred at 4.0 MPa in hydrogen gas atmosphere overnight. After the filtration, the solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])(=[O:5])[CH3:4].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>C(OCC)(=O)C.CN(C)C=O>[CH2:23]([N:6]([C:7]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])[C:3](=[O:5])[CH3:4])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)Nc1cc(Oc2ccccc2)ccc1C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N(Cc1ccccc1)c1cc(Oc2ccccc2)ccc1C(=O)O
Reaction time: 0.5 h

Procedure:
60% Sodium hydride 30 mg was added to N,N-dimethylformamide 2.0 mL solution of 2-(acetamido)-4-phenoxybenzoic acid 0.10 g at room temperature, and it was stirred at same temperature for 30 minutes. Benzyl bromide 0.092 mL was added to the reaction mixture at room temperature, and it was stirred at same temperature for 2 hours and 30 minutes. 60% Sodium hydride 15 mg was added to the reaction mixture at room temperature, and it was stirred at same temperature for 30 minutes. Benzyl bromide 0.022 mL was added to the reaction mixture at room temperature, and it was stirred at same temperature for 1 hour and 30 minutes. 1.0 mol/L Hydrochloric acid and ethyl acetate were added to the reaction mixture. The organic layer was separated and collected,dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate:acetic acid=40:10:1] to give 2-(N-benzylacetamido)-4-phenoxybenzoic acid 0.10 g of colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.Cl.CN.[CH2:14]([N:16](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:16][CH3:14])=[O:9])=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
To a stirred solution of 6-chloropyridine-3-carbonyl chloride (1.5 g, 8.52 mmol) in DCM (10 ml) at 0° C. was added methylamine hydrochloride (1.73 g, 25.5 mmol) followed by drop wise additional of triethylamine (3.55 ml, 25.5 mmol) over 10 mins. The reaction mixture was stirred at RT for 2 h then quenched by addition of brine (15 ml) and saturated Na2CO3 (5 ml). The organic layer was collected and the aqueous layer extracted with DCM (2×20 ml). The combined organic phase was washed with brine (10 ml), dried (Na2SO4), filtered and evaporated to dryness. Recrystallisation from hot DCM (˜10 ml) provided the title compound (0.995 g, 5.8 mmol, 68%) as white crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[N:12]1([CH2:17][CH2:18][CH2:19][NH2:20])[CH:16]=[CH:15][N:14]=[CH:13]1>>[N:12]1([CH2:17][CH2:18][CH2:19][NH:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: NCCCn1ccnc1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Product: Cc1cc([N+](=O)[O-])ccc1NCCCn1ccnc1
Temperature: 96 °C
Yield: 44.2 %

Procedure:
Starting with 31.2 g (0.2 mol) of 1-fluoro-2-methyl-4-nitrobenzene and 37.5 g (0.3 mol) of 3-imidazol-1-ylpropylamine, and after purification by recrystallization from refluxing 96° C. ethanol, 23.0 g of orange-yellow crystals melting at 163° C. (Kofler) were obtained, the elemental analysis of which, calculated for C13H16N4O2.¼H2O, was:
Reaction SMILES: [CH3:1][Si:2]([CH3:50])([CH3:49])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][CH:32]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:31][CH2:30]2)[CH:9]=1.[Br:51]N1C(=O)CCC1=O>C(#N)C>[CH3:46][Si:45]([CH3:48])([CH3:47])[CH2:44][CH2:43][O:42][CH2:41][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:49])[CH3:50])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][CH:32]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:31][CH2:30]2)[C:9]=1[Br:51]
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOC(=O)CC1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate (Int-5n, 512 mg, 715 μmol) in acetonitrile (15 mL) was added N-bromosuccinimide (153 mg, 858 μmol). The resulting solution was allowed to stir at room temperature for 18 hours. After 18 hours, the solvent was reduced in vacuo and the title compound was purified via silica gel chromatography.
Reaction SMILES: [CH2:1]([SH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[H-].[Na+].S(O[CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][OH:59])(C1C=CC(C)=CC=1)(=O)=O>COCCOC>[CH2:58]([OH:59])[CH2:57][O:56][CH2:55][CH2:54][O:53][CH2:52][CH2:51][O:50][CH2:49][CH2:48][O:47][CH2:46][CH2:45][O:44][CH2:43][CH2:42][O:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][S:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCCOCCOCCOCCOCCO)cc1
Reactant: CCCCCCCCCCCCCCCCCCS
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCCCSCCOCCOCCOCCOCCOCCOCCOCCOCCO
Temperature: 85 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a heated (40° C.) solution of 20.1 g (0.97 mole) of n-octadecanethiol in 200 ml of dried 1.2-dimethoxyethane was slowly added under argon 0.07 mole (3.4 g., 50%) of sodium hydride (rinsed with hexane to remove the mineral oil) slurried in 1,2-dimethoxyethane. The reaction mixture was then heated at reflux (85° C.) with stirring for 2 hrs. A solution of 40 g. (0.07 mole) of the nonaethylene glycol monotosylate in 200 ml. 1,2-dimethoxyethane was added dropwise and the reaction mixture allowed to reflux with stirring for 16 hours. The mixture was cooled, insoluble salts were filtered, and the solvent was evaporated to yield a near quantitative yield (0.07 mole) of the thioether.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.OS(O)(=O)=O.[N+:24]([O-])([OH:26])=[O:25]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[O:9])=[CH:6][C:7]=1[N+:24]([O-:26])=[O:25]
Reactant: O=[N+]([O-])O
Reactant: O=C(c1ccc(Br)cc1)c1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: CC(Cl)Cl
Product: O=C(c1cccc([N+](=O)[O-])c1)c1ccc(Br)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
The crude (4-bromo-phenyl)-(3-nitro-phenyl)-methanone (11.1 g, 36.27 mmol) was dissolved in dichloroethane (35 mL) and added dropwise via addition funnel to a mixture of concentrated H2SO4(aq) (16 mL, 290 mmol) and fuming HNO3(aq) (13 mL, 290 mmol). The mixture was stirred at 60° C. overnight. Subsequently the mixture was poured over ice water and allowed to stir resulting in precipitation of the product. The product was filtered and dried affording 72% yield of the (4-Bromo-3-nitro-phenyl)-(3-nitro-phenyl)-methanone (9.17 g, 26.1 mmol).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([CH3:14])[CH:7]=1)(O)[CH3:4].Cl[CH2:18]Cl>[Ti](Cl)(Cl)(Cl)Cl>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:3]([CH3:18])([CH3:4])[C:2]([F:16])([F:15])[F:1])=[CH:7][C:8]=1[CH3:14]
Reactant: ClCCl
Reactant: COc1ccc(C(C)(O)C(F)(F)F)cc1C
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COc1ccc(C(C)(C)C(F)(F)F)cc1C
Temperature: -70 °C
Reaction time: 2 h

Procedure:
To an ice-cold solution of 1,1,1-trifluoro-2-(4-methoxy-3-methylphenyl)-propane-2-ol (440 mg) in dichloromethane (20 ml) were added titanium tetrachloride (357 mg). Under the same temperature, it was stirred for 2 hours. Ice-cold water and dichloromethane were added to the organic layer and the organic layer was separated. The obtained organic layer was washed with saturated sodium bicarbonate solution and dried over anhydrous potassium carbonate. After removing the drying agent, the organic layer was concentrated under reduced pressure. After the residue was dissolved in dichloro methane (15 ml), it was cooled at −70° C. and titanium tetrachloride (302 mg) and dimethylzinc (1M, n-hexane solution, 3.18 ml) was added. The mixture was brought back to room temperature and stirred for 3 hours. Ice-cold water and dichloromethane were added to the solution and the organic layer was separated. The obtained organic layer was washed with saturated sodium bicaronate solution and then dried over anhydroous magnesium sulfate. After removing the drying agent, the organic layer was concentrated under reduced pressure.
Reaction SMILES: N1C=[CH:5][C:4]([CH2:7][S:8][C:9]2[NH:14][C:13](=[O:15])[N:12]3[N:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:18]=[C:11]3[N:10]=2)=CC=1.C(S[C:33]1[NH:38]C(=O)N2N=C(C3C=CC=CC=3)C=C2[N:34]=1)C1C=CC=CC=1>>[NH:34]1[CH:5]=[C:4]([CH2:7][S:8][C:9]2[NH:14][C:13](=[O:15])[N:12]3[N:16]=[C:17]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:18]=[C:11]3[N:10]=2)[N:38]=[CH:33]1
Reactant: O=c1[nH]c(SCc2ccccc2)nc2cc(-c3ccccc3)nn12
Reactant: O=c1[nH]c(SCc2ccncc2)nc2cc(-c3ccccc3)nn12
Product: O=c1[nH]c(SCc2c[nH]cn2)nc2cc(-c3ccccc3)nn12

Procedure:
2-(4-pyridylmethyl)thio-7-phenylpyrazolo [1,5-a]-1,3,5-triazine-4-one; 2-benzylthio-7-phenylpyrazolo [1,5-a]-1,3,5-triazine-4-one; 3-benzyl-2-methylthio-7-phenyl pyrazolo [1,5-a]-1,3,5-triazine-4-one 2-(2-enzimidazolyl methylthio)-7-phenylpyrazolo [1,5-a]-1,3,5-triazine-4-one; and 2-(4-imidazolylmethylthio)-7-phenylpyrazolo [1,5-a]-1,3,5-triazine-4-one are prepared in analogous fashion by making appropriate modifications of the above-described procedures.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([N:15]([CH2:26][CH3:27])[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH3:14]>>[CH2:24]([N:21]([CH2:22][CH3:23])[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][N:15]([CH2:26][CH3:27])[CH2:13][CH3:14])[C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:25]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCN(CC)CCNCCN(CC)CC
Product: CCCCCCC/C=C/C(=O)N(CCN(CC)CC)CCN(CC)CC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and N-(2-(diethylamino)ethyl)-N′,N′ diethylethane-1,2-diamine as starting materials to give the aimed compound.
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[C:10]([O:17][CH3:18])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[H][H]>[Pd].CO>[C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([O:17][CH3:18])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])c(Oc2ccccc2C(C)(C)C)n1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(N)c(Oc2ccccc2C(C)(C)C)n1
Reaction time: 0.5 h

Procedure:
To a solution of 2a (580 mg, 1.9 mmol) in a 1:1 mixture of ethyl acetate and methanol (6 mL) was added palladium on charcoal (10% wt, 300 mg, 0.28 mmol). The mixture was stirred under 40 psi atmosphere of hydrogen. After 30 min, the solution was filtered over Celite® and the resulting solution was concentrated to afford the title compound 2b as a dark solution (500 mg, 96% yield). 2b was used in the next step without any further purification. [M+H]+=273.21. 1H NMR (500 MHz, CD3OD) δ ppm 1.43 (m, 9H), 3.58 (m, 3H), 6.33 (d, J=8.25 Hz, 1H), 6.93 (d, J=8.25 Hz, 1H), 7.09 (m, 2H), 7.17 (t, J=7.70 Hz, 1H), 7.41 (d, J=8.25 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[C@H:15]3[C@H:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=2)=[CH:4][CH:3]=1.[CH:27](O)=[O:28]>>[CH:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[C@H:15]3[C@H:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=2)=[CH:4][CH:3]=1)=[O:28]
Reactant: O=CO
Reactant: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(N)cc1
Product: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(NC=O)cc1

Procedure:
2,1 g of cis-6-(4-aminophenyl)-8,9-dimethoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6] naphthyridine are heated to 100° for 21/2 hours in 50 ml of 90% formic acid. The reaction solution is evaporated to dryness in a vacuum, the resulting residue is made alkaline with a dilute potash solution and this aqueous phase is extracted with methylene chloride. After drying and concentrating the organic phase by evaporation, the title compound is obtained as a yellow oil and crystallizes after the addition of ethanol in the form of yellowish prisms having a melting point of 140°-145°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13]CC)=O)[N:10]=2)[CH:7]=1.[CH:16]([Mg]Cl)([CH3:18])[CH3:17].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([CH:16]([CH3:18])[CH3:17])=[O:13])[N:10]=2)[CH:7]=1
Reactant: CC(C)[Mg]Cl
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(=O)c1cn2cc(Br)ccc2n1
Temperature: -78 °C

Procedure:
269 mg of 6-bromo-2-ethoxycarbonyl-imidazo[1,2-a]pyridine obtained in Example 117 was dissolved in 10 ml of tetrahydrofuran, cooled down to −78° C., and 0.5 ml of 2M isopropylmagnesium chloride was dropped thereto. After heating to −40° C., water was added and the products were extracted with ethyl acetate. Organic layer was dried with anhydrous magnesium sulfate, and the solvents were distilled outunder reduced pressure. The obtained residues were purified by silicagel column chromatography (hexane:ethyl acetate=50:50) to obtain 58.5 mg of the above compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][N:11]1[CH:15]=[CH:14][C:13]([Br:16])=[C:12]1[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18].[CH2:26]([O:33][C:34]([NH:36][CH2:37][C:38](O)=[O:39])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(OCC)(=O)C>[Br:16][C:13]1[CH:14]=[CH:15][N:11]([NH:10][C:38](=[O:39])[CH2:37][NH:36][C:34](=[O:35])[O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:12]=1[C:17](=[O:18])[NH:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nn1ccc(Br)c1C(=O)Nc1ccccc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNC(=O)OCc1ccccc1)Nn1ccc(Br)c1C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92.1 %

Procedure:
DIEA (10.5 ml, 60 mmol) was added at 0° C. over a mixture of 1-amino-3-bromo-N-phenyl-1H-pyrrole-2-carboxamide (5.1 g, 18 mmol) and 2-(benzyloxycabonylamino)acetic acid (5.33 g, 25 mmol) in anhydrous ethyl acetate (100 ml). After 15 min T3P® solution (50% AcOEt, 15 ml) was slowly added and stirred 20 min at 0° C. and then at room temperature overnight. Further DIEA (5 ml, 30 mmol), 2-(benzyloxycabonylamino)acetic acid (2.66 g, 25 mmol) and T3P® solution (50% AcOEt, 7 ml) were added and the reaction mixture was stirred at room temperature overnight. More ethyl acetate was added and the reaction crude was washed with water and brine, dried over magnesium sulphate and the solvent was removed under vacuum. The residue was purified by flash chromatography using Isolera® Purification System (0-40%, hexane-AcOEt) to give 7.81 g (41% yield) of the final product with a purity of 45% that was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[N:11](C(OC(C)(C)C)=O)[CH:12]=[C:13]([C:14]#[C:15][CH2:16][OH:17])[C:6]=12>C1COCC1.CO.[Pd]>[NH2:29][C:27]1[CH:26]=[CH:25][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[NH:11][CH:12]=[C:13]([CH2:14][CH2:15][CH2:16][OH:17])[C:6]=23)=[C:2]([F:1])[CH:28]=1
Reactant: CC(C)(C)OC(=O)n1cc(C#CCO)c2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc3[nH]cc(CCCO)c23)c(F)c1
Reaction time: 5 h
Yield: 13.3 %

Procedure:
A mixture of tert-butyl 4-(2-fluoro-4-nitrophenoxy)-3-(3-hydroxyprop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (50 mg, 0.15 mmol) and 10% Pd/C (containing 50% H2O, 120 mg) in THF (10 mL) and MeOH (2 mL) was hydrogenated at 1 atm for 5 h. The mixture was diluted with MeOH and filtered through a pad of Celite®. The crude mixture was purified by preparative HPLC to afford the desired product (6 mg, 13% yield) as a white solid. LC/MS (ESI+) m/z 302 (M+H)+.
Reaction SMILES: ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([Cl:21])[C:15]=1[C@H:22]([O:24][C:25]1[C:26]2[O:34][CH:33]=[C:32]([C:35]3[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=3)[C:27]=2[CH:28]=[N:29][C:30]=1[NH2:31])[CH3:23].CCN(C(C)C)C(C)C.[N:50]1([C:56](OC(C)(C)C)=[O:57])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>C(Cl)Cl>[NH2:31][C:30]1[N:29]=[CH:28][C:27]2[C:32]([C:35]3[CH2:36][CH2:37][N:38]([C:56]([N:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)=[O:57])[CH2:39][CH:40]=3)=[CH:33][O:34][C:26]=2[C:25]=1[O:24][C@@H:22]([C:15]1[C:16]([Cl:21])=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[Cl:13])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(=O)N4CCNCC4)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of triphosgene (4 mg, 0.01 mmol) in DCM (0.8 mL) was cooled to 0° C. A solution of 7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), DIPEA (0.04 mL, 0.2 mmol) and DCM was added, and the mixture was allowed to warm to rt. A solution of tert-butyl 1-piperazinecarboxylate (8.82 mg, 0.0474 mmol) in DCM was then added, and the mixture was stirred at rt for 30 min. The material was transferred to a separatory funnel and washed with sat. aq. NaHCO3. The organic layer was concentrated in vacuo, redissolved in dioxane and transferred to a sealed tube. 4 M HCl in 1,4-dioxane (0.2 mL) was added, and the solution was heated to 50° C. for 3 h. The material was concentrated in vacuo and redissolved in DMF (0.5 mL). The solution was purified by HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a brown solid. 1H NMR (CD3OD, 400 MHz): δ=1.89 (d, J=6.8 Hz, 3H), 2.56 (br, s, 2H), 3.21-3.29 (m, 4H), 3.44-3.52 (m, 4H), 3.56 (t, J=5.8 Hz, 2H), 4.08 (d, J=2.5 Hz, 2H), 6.26 (br, s, 1H), 6.50 (q, J=6.7 Hz, 1H), 7.22 (t, J=8.7 Hz, 1H), 7.40 (dd, J=9.0, 4.9 Hz, 1H), 7.66 (s, 1H), 8.19 (s, 1H). MS (ES+): m/z 534.14 [MH+]. HPLC: tR=2.16 min (ZQ2, polar—5 min).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11](Cl)=[N:12][C:13]([CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Si:1]([O:8][CH2:9][C:10]1[C:11]([C:30]2[CH:29]=[CH:28][C:27]([F:26])=[CH:32][C:31]=2[F:33])=[N:12][C:13]([CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Cc2c(F)cccc2F)nc1Cl
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: COCCOC
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Cc2c(F)cccc2F)nc1-c1ccc(F)cc1F
Temperature: 90 °C

Procedure:
To a crude 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-chloro-6-(2,6-difluorobenzyl)pyridine (from Step C above) in DME was added 2,4-difluorophenylboronic acid (6.5 g), tetrakis(triphenylphosphine)palladium (2 g) and 2N Na2CO3 (40 mL), and heated to 90° C. for a couple of hours until reaction completed. The mixture was cooled to room temperature and filtered through celite. The mixture was diluted with ethyl acetate, washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by silica gel (100% methylene chloride) to give title compound (4.81 g).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1CCN>C(#N)C>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:11][CH2:12][NH:8][C:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NCCc1ccccn1
Solvent: CC#N
Product: S=C(NCCc1ccccn1)n1ccnc1
Yield: 92.1 %

Procedure:
A solution of 1,1'-thiocarbonyldiimidazole (9.9 g, 50 mmol) and 2-(2-pyridyl)ethylamine (6.43 g, 50 mmol) in acetonitrile (120 mL) was stirred at room temperature for 24 h. The solution was concentrated under reduced pressure and the resulting brown oil was triturated with ethyl ether. The remaining oil was placed under vacuum to provide 10.7 g of crude titled product as a black solid: