Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([O:16][CH3:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([O:16][CH3:17])[CH:3]=2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: COc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1ccc(F)c(F)c1
Product: COc1cc(-c2ccc(F)c(F)c2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (66 mg, 80%), MS (ISP) m/z=329.4 [(M+H)+], mp 216° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-methoxy-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 18) (73.8 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]=[O:12])=[CH:5]2.CO.C1(C)C=CC(S([CH2:24][N+:25]#[C-:26])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CCCCCC>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[O:12][CH:26]=[N:25][CH:24]=1)=[CH:5]2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cc2cc(F)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCCCCC
Product: Fc1ccc2[nH]c(-c3cnco3)cc2c1
Yield: 26 %

Procedure:
To a 100 mL round-bottom flask was added 5-fluoro-1H-indole-2-carbaldehyde 47 (0.627 g, 3.84 mmol), methanol (40 mL), p-toluene sulfonylmethyl isocyanide (0.826 g, 4.23 mmol), followed by potassium carbonate (0.68 g, 4.92 mmol). The reaction mixture was stirred at reflux for about 1.5 hour and followed by TLC. The solvent was then evaporated and saturated aq. NaHCO3 was added. The resultant suspension was extracted with CH2Cl2 (2×20 mL). Combined organic layers were washed with brine, dried (anhydrous Na2SO4), and concentrated to leave a yellow solid. Crude product was further purified by silica-column chromatographed (Biotage) using Acetone:Hexane as an eluent to yield 5-(5-fluoro-1H-indol-2-yl)oxazole 48 (0.202 g, 72% yield). MS (ES) m/z 203 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:4].O[Li].O>O>[C:18]([O:17][C:15]([NH:14][CH2:13][C:5]1([C:3]([OH:4])=[O:2])[C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)C1(CNC(=O)OC(C)(C)C)CC12CCCCC2
Agent: [Li]O
Solvent: O
Product: CC(C)(C)OC(=O)NCC1(C(=O)O)CC12CCCCC2
Reaction time: 48 h
Yield: 62.4 %

Procedure:
To a solution of crude 1-(tert-butoxycarbonylamino-methyl)-spiro[2.5]octane-1-carboxylic acid methyl ester (35.0 g, ˜96.2 mmol) was added LiOH—H2O (12.3 g, 294 mmol) followed by the addition of water (75 mL). The mixture was heated to reflux. After 48 hours, an additional portion of LiOH—H2O (6.15 g, 146 mmol) was added and refluxed for an additional 24 hours. The solvent was removed under reduced vacuum. The residue was partitioned between water and ether. The aqueous layer was acidified to pH 2-3 with aqueous HCl with ice bath cooling with a layer of CH2Cl2 present. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 times). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give 17.0 g (63%, 2 steps) of 1-(tert-butoxycarbonylamino-methyl)-spiro[2.5]octane-1-carboxylic acid an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][Si:19]([CH2:22][Mg]Cl)([CH3:21])[CH3:20].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(O)(=O)C>C1COCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C[Mg]Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc([N+](=O)[O-])c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C[Si](C)(C)C)c([N+](=O)[O-])c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
A solution of (3-nitro-phenyl)-carbamic acid tert-butyl ester (1.20 g, 5.04 mmol) in THF (50 mL) was added ((trimethylsilyl)methyl)magnesium chloride (1.48 g, 10.1 mmol) at −70° C. under nitrogen gas. The solution was then stirred at −70° C. for one h. A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.74 g, 12.1 mmol) in THF (30 mL) was added, the reaction was warmed to 0° C. and the reaction was allowed to stir at 0° C. for another hour. The reaction mixture is poured into an aqueous solution of acetic acid (50 mL, 5%v/v) and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown oil. Flash chromatography (80/20 hexanes/ethyl acetate) afforded (3-nitro-4-trimethylsilanylmethyl-phenyl)-carbamic acid tert-butyl ester (1.20 g, 73%) as a light oil.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][CH2:9][CH:10]([OH:16])[CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:17]([SH:19])[CH3:18].C[O-].[Na+]>CO>[CH2:17]([S:19][C:2]1[C:3]([O:8][CH2:9][CH:10]([OH:16])[CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])=[N:4][CH:5]=[CH:6][N:7]=1)[CH3:18]
Reactant: CCS
Reactant: CC(C)NCC(O)COc1nccnc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCSc1nccnc1OCC(O)CNC(C)C

Procedure:
Analogously to the description in Example 8, 7.5 g (0.03 mol) of 3-chloro-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyrazine, 2.8 g (0.045 mol) of ethylmercaptan and 2.4 g (0.045 mol) of sodium methylate in 150 ml of methanol, when refluxed for 30 hours, give the crude base 3-ethylthio-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyrazine, and this is converted, with 1.74 g of fumaric acid, into the fumarate of melting point 158°-160° C. when crystallised from methanol-ether.
Reaction SMILES: CC([Si](C)(C)O[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([C:23]([OH:30])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[CH:9]=1)(C)C.CN(C=O)C.S(Cl)([Cl:40])=O>C(Cl)Cl>[Cl:40][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([C:23]([OH:30])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[CH:9]=1
Reactant: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C(O)(C(C)C)C(C)C)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ccc(CCl)cc2C(O)(C(C)C)C(C)C)c1
Reaction time: 1.5 h
Yield: 109.6 %

Procedure:
To a stirred solution of 69.19B (0.050 g, 0.1 mmol) in DCM (2.00 mL) at 23° C. was added DMF (0.0008 mL) followed by thionyl chloride (0.01 mL, 0.2 mmol). The reaction was then stirred for 1.5 hours and then concentrated in vacuo. The product was purified on silica gel (0-10% EtOAc in hexanes) to yield 69.19C as a colorless oil (0.04 g, 100% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([Cl:12])[N:3]=1.O.[NH2:14][NH2:15]>C(O)C>[Cl:12][C:4]1[N:3]=[C:2]([NH:14][NH2:15])[CH:7]=[CH:6][C:5]=1[C:8]([F:11])([F:10])[F:9]
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ccc(C(F)(F)F)c(Cl)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
To the solution of 2,6-Dichloro-5-trifluoromethyl-pyridine (18, 2 g, 9.26 mmol) in ethanol (30 mL) was added hydrazine hydrate (2.9 g, 46 mmol). The reaction mixture was stirred for 4 h at room temperature, then concentrated to remove the solvent, and added ethyl acetate, washed with water. The organic layer was dried over anhydrous Na2SO4. Column chromatography (Silica, petroleum ether/ethyl acetate=4/1˜3/1) afforded compound 19 as white solid (yield: 56%) and another isomer 20 (yield: 18%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][CH2:14][CH:15]([N:18]=[C:19]=S)[CH2:16][CH3:17]>C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[S:9](=[O:11])(=[O:10])[N:12]=[C:19]([NH:18][CH:15]([CH2:16][CH3:17])[CH2:14][CH3:13])[NH:1][C:2]=2[CH:7]=1
Reactant: CCC(CC)N=C=S
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Solvent: CCOC(C)=O
Product: CCC(CC)NC1=NS(=O)(=O)c2ccc(Cl)cc2N1

Procedure:
The title compound was prepared from 2-amino-4-chlorobenzenesulfonamide and 3-pentyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 224-226° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 0.88 (t, 6H, 2×CH3), 1.33-1.66 (m, 4H, 2×CH2), 3.65 (m, 1H, CH), 7.1 (br.s, 1H, NH), 7.21-7.32 (m, 2H, ArH), 7.68 (d, 1H, ArH), 10.30 (br.s, 1H, NH); MS: m/e 301-303 (M+); (C12H16N3Cl1O2S1) calc. C, 47.76; H, 5.34; N, 13.92; found C, 47.74; H, 5.49; N, 13.93.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH3:16])=[O:14])[CH:8]=2)=[CH:4][CH:3]=1.C([O:21][C:22](=O)[C:23]([Cl:26])([Cl:25])[Cl:24])C>C1(C)C=CC=CC=1>[CH3:16][NH:15][C:13](=[O:14])[C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:22](=[O:21])[C:23]([Cl:26])([Cl:25])[Cl:24])=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: CCOC(=O)C(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)C(Cl)(Cl)Cl)cc2)ccn1
Temperature: 100 °C
Yield: 87.6 %

Procedure:
4-(4-aminophenoxy)-N-methylpicolinamide (35 g, 0.144 mol) was mixed with ethyl-2,2,2-trichloroacetate (50 ml, 0.27 mol) in toluene (350 ml) at ambient temperature. The mixture was then heated to 100° C. under distillation mode for 2-3 hours. The organic solvent was degassed under reduced pressure to obtain oil. This oil was triturated with hexane (500 ml) to obtain (49 g) of the desired solid.
Reaction SMILES: C[O-].[Na+].[C:4]([OH:8])(=[O:7])[CH2:5][SH:6].Cl[CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].O>CO>[C:4]([OH:8])(=[O:7])[CH2:5][S:6][CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C(O)CS
Reactant: CCCCCCCCCC#CCC#CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCCCC#CCC#CCSCC(=O)O
Reaction time: 0.5 h
Yield: 26 %

Procedure:
3.2 ml of a 300% solution of sodium methoxide in methanol were added dropwise to a solution of 611 μl of thioglycolic acid in 7 ml of methanol, under an inert atmosphere. The mixture was maintained under stirring for 30 min and then a solution of 2 g of 1-chloro-2,5-pentadecadiyne in 20 ml of methanol was added under an inert atmosphere. The mixture was maintained under stirring for 20 hours at room temperature and then the reaction medium was poured over 100 ml of acid water (98 ml of water+2 ml concentrated H2SO4) and then extracted 3 times with ethyl ether. The combined organic phases were washed 3 times with water and then with a saturated aqueous solution of NaCl before being dried (Na2SO4), filtered and concentrated under vacuum in a rotary evaporator. The oily residue obtained crystallized on cooling. 3-Thia-5,8-octadecadiynoic acid was recrystallized from diisopropyl ether and thus isolated in the form of a white solid with a yield of 26%.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[NH:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:8]([C:10](ON1C(=O)CCC1=O)=[O:11])[CH3:9].CN1CCOCC1>CN(C=O)C>[NH:7]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[C@H:8]([C:10]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:11])[CH3:9]
Reactant: C[C@H](N)C(=O)O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O

Procedure:
L-Alanine (3.57 g, 40 mmol) was dissolved in 18.8 ml of Triton B (40 mmol), evaporated to dryness, and the oily residue re-evaporated twice with DMF (30 ml each). The salt obtained was stirred with 11.45 g of Boc-Ala-OSu (40 mmol) in 40 ml DMF, with 4 ml of NMM added, for 20 hours. The solvent was removed and the residue taken up in 10% HOAc (100 ml). The product was extracted into EtOAc (4 times 100 ml), washed twice with a small volume of H2O, dried over Na2SO4, evaporated to a small volume, and treated with petroleum ether until cloudiness developed. A crystalline product formed on storage in the refrigerator overnight: Yield, 8.2 g (76.3%); mp 115°-118°.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([OH:17])([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.[CH3:18]O>[OH-].[Pd+2].[OH-]>[OH:17][C:11]1([C:14]([O:16][CH3:18])=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CO
Reactant: O=C(O)C1(O)CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Product: COC(=O)C1(O)CCNCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 1-benzyl-4-hydroxypiperidine-4-carboxylic acid (1.2 g, 5.1 mmol) in MeOH (15 mL) was added palladium hydroxide and the resulting mixture was stirred at rt for 6 h under H2 atmosphere. After completion (by TLC), the mixture was passed through celite and the filtrate evaporated under reduced pressure. The crude (1 g) residue was carried forward to the next step without further purification. MS: 160.18 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4](=[O:13])[C:3]=1[N+:14]([O-:16])=[O:15].[NH3:17]>C1COCC1>[NH2:17][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4](=[O:13])[C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: Cn1c(=O)c([N+](=O)[O-])c(Cl)c2cccnc21
Reactant: N
Solvent: C1CCOC1
Product: Cn1c(=O)c([N+](=O)[O-])c(N)c2cccnc21
Temperature: 20 °C
Yield: 95.4 %

Procedure:
A solution of 4-chloro-1-methyl-3-nitro-1H-[1,8]naphthyridin-2-one (1.54 g, 6.43 mmol) (J. Med. Chem. 1992, 35, 2863-2870) in 40 mL of THF was treated with 7.2 mL of 28% aqueous ammonia (6.4 g, 51 mmol). After stirring at 20° C. 17 h, the solvent was evaporated under reduced pressure and water was added to the residue. The resulting precipitate was filtered and washed with water to give to give 4-amino-1-methyl-3-nitro-1H-[1,8]naphthyridin-2-one (1.35 g, 96% yield). 1H-NMR (DMSO): δ 8.74 (m, 2H), 8.35 (s, 2H), 7.38 (dd, 1H, J=8.0, 4.8 Hz), 3.58 (s, 3H).
Reaction SMILES: C(OC([N:8]([C:24]1[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]#[N:23])=[CH:12][CH:11]=1)=O)(C)(C)C.Cl>CO>[C:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:24]2[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])=[CH:11][CH:12]=1)#[N:23]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1NCc1ccc(-c2ccccc2C#N)cc1
Yield: 76.1 %

Procedure:
To the acetonitrile solution where BMB is mixing with 2-(4-methylphenyl)benzonitrile [MPB] which was not brominated and 2-(4,4-dibromomethylphenyl)benzonitrile which is a compound similar to BMB, was added a mixture of methyl 2-tert-butoxycarbonylamino-3-nitrobenzoate [BAN] 30.1 g, potassium carbonate 40.8 g and acetonitrile 160 ml and the solution was stirred at about 82° C. for about 5 hours to proceed the reaction. The solution was cooled to room temperature and precipitated crystals were filtered off. The filtrate was concentrated to give methyl 2-[N-t-butoxycarbonyl-N-[(2′-cyano-biphenyl-4-yl)methyl]amino]-3-nitrobenzoate [BBN]. The concentrate was dissolved in methanol 190 g. To the methanol solution was dropped concentrated hydrochloric acid 106 g and the solution was heated to refluxing temperature for 2 hours and thereafter stirred under reflux for 2 hours to proceed the reaction. The reaction solution was cooled and the precipitated crystals were filtered and dried to give methyl 2-[N-(2′-cyanobiphenyl-4-yl)methylamino]-3-nitrobenzoate [MBN] 35.1 g (yield based on 2-(4-methylphenyl)benzonitrile [MPB]: 76.1%).
Reaction SMILES: [Br:1][C:2]1[C:7]2[S:8][C:9]([NH2:11])=[N:10][C:6]=2[CH:5]=[C:4]([Br:12])[N:3]=1.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14]>O1CCOCC1.O>[Br:1][C:2]1[C:7]2[S:8][C:9]([NH:11][C:16]([NH:15][CH2:13][CH3:14])=[O:17])=[N:10][C:6]=2[CH:5]=[C:4]([Br:12])[N:3]=1
Reactant: Nc1nc2cc(Br)nc(Br)c2s1
Reactant: CCN=C=O
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(Br)nc(Br)c2s1
Temperature: 80 °C
Yield: 82.8 %

Procedure:
To a solution of 4,6-dibromothiazolo[5,4-c]pyridin-2-amine (1.47 g, 56.74% as per LCMS, 2.70 mmol) in 1,4-dioxane (75 mL) was added ethylisocyanate (1.30 mL, 16.25 mmol) and the resulting reaction mixture was heated to 80° C. for 16 h. The solvent was distilled off under reduced pressure and the residue was then co-distilled with hexane (twice). The solid thus obtained was stirred in hot water at 80° C. for 30 min then filtered. The solid material was purified over silica gel (100-200 M, 30-40% EtOAc-hexane) to obtain the desired product as an off-white solid (0.85 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.O=[C:23]([CH3:29])[C:24](OCC)=[O:25]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:9]2[CH:10]=[C:11]3[C:12](=[CH:13][CH:14]=2)[NH:15][C:24](=[O:25])[C:23]([CH3:29])=[N:16]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(c2cccc(Cl)c2)n2ccnc2)cc1N
Reactant: CCOC(=O)C(C)=O
Solvent: CO
Product: Cc1nc2cc(C(c3cccc(Cl)c3)n3ccnc3)ccc2[nH]c1=O
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
A mixture of 9.1 parts of 4-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-1,2-benzenediamine, 3.7 parts of ethyl 2-oxopropanoate and 160 parts of methanol was stirred for 30 minutes at reflux temperature. The reaction mixture was evaporated to dry. The residue was crystallized from a mixture of 36 parts of 2-propanone and 4 parts of methanol. After stirring for 30 minutes at room temperature, the precipitated product was filtered off (the filtrate was set aside) and recrystallized from a mixture of methanol and dichloromethane. The product was filtered off and dried, yielding 3 parts (28.1%) of 6-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-3-methyl-2(1H)-quinoxalinone; mp. 270.9° C. (comp. 73). The filtrate (see above) was evaporated and the residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was taken up in a mixture of 2-butanone and 2-propanone and the whole was allowed to stand for a few days. the precipitated product was filtered off and dried, yielding 1.4 parts (11.5%) of 7-[(3-chlorophenyl) (1H-imidazol-1-yl)methyl]-3-methyl-2(1H)-quinoxalinone hemihydrate; mp. 201.9° C. (comp. 81).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([N:10]([CH2:14][CH3:15])[C:11](Cl)=[O:12])[CH3:9].O>N1C=CC=CC=1>[CH2:8]([N:10]([CH2:14][CH3:15])[C:11](=[O:12])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:9]
Reactant: Nc1ccccc1
Reactant: CCN(CC)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCN(CC)C(=O)Nc1ccccc1
Reaction time: 6 h
Yield: 63 %

Procedure:
A solution of 10 g of aniline in 50 ml of pyridine is cooled to 0° C. and a solution of 14.56 g of diethylcarbamoyl chloride in 10 ml of pyridine is added slowly. The mixture is stirred for 6 hours, the temperature being allowed to rise to RT, and is then poured into water. It is extracted with AcOEt, washed with water and with a 5% solution of potassium hydrogensulfate, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica using DCM and then a DCM/AcOEt mixture (90/10; v/v) as the eluent to give 13 g of the expected product, which is used as such in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:36]([C:38]1[C:39]([N:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([CH:44]=1)[NH2:43])[CH3:37].Cl.O1CCOCC1.N>CO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[C:38]([CH2:36][CH3:37])[C:39]([N:47]4[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]4)=[CH:40][C:41]=3[O:45][CH3:46])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: CCc1cc(N)c(OC)cc1N1CCN(CCS(C)(=O)=O)CC1
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cl
Agent: N
Solvent: CO
Solvent: C1COCCO1
Product: CCc1cc(Nc2nccc(-c3c(-c4ccc(OC)c(C(=O)Nc5c(F)cccc5F)c4)nc4ccccn34)n2)c(OC)cc1N1CCN(CCS(C)(=O)=O)CC1
Temperature: 180 °C
Yield: 38 %

Procedure:
In a microwave vial with septum cap, 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (0.246 g, 0.5 mmol) and 5-ethyl-2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (0.171 g, 0.5 mmol) were taken up in 1,1,1-trifluoroethanol (3 mL) and 4M HCl in dioxane (0.25 mL, 1.0 mmol) was added. The vial was sealed and heated in the microwave at 180° C. for 40 min. Reaction was complete by MS, it was cooled rt, neutralized with 7N NH3 in MeOH, and concentrated in vacuo onto silica gel and flash chromatographed. The desired fractions were combined and concentrated and the resulting solid was triturated with diethyl ether, filtered and air dried to give the title compound (0.150 g, 0.19 mmol, 38%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.78 (s, 1H), 9.34 (dd, J=3.1, 2.2 Hz, 1H), 8.49 (s, 1H), 8.24 (d, J=5.1 Hz, 1H), 8.11 (d, J=1.3 Hz, 1H), 7.78 (dd, J=8.9, 1.4 Hz, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.54 (s, 1H), 7.33-7.50 (m, 2H), 7.28 (d, J=8.8 Hz, 1H), 7.18 (t, J=8.1 Hz, 2H), 6.94 (t, J=6.6 Hz, 1H), 6.83 (s, 1H), 6.57 (d, J=4.9 Hz, 1H), 3.98 (s, 3H), 3.80 (s, 3H), 3.28-3.40 (m, 2H), 3.06 (s, 3 H), 2.82-2.92 (m, 4H), 2.77 (t, J=6.5 Hz, 2H), 2.50-2.69 (m, 6H), 1.08 (q, J=7.0 Hz, 3H). MS (M+H, ES+) 797.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([CH2:19][OH:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: OCc1ccc(B(O)O)cc1
Product: Cc1c2n(c3c(-c4ccc(CO)cc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (78 mg, 92%), MS (ISP) m/z=341.5 [(M+H)+], mp 211° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-hydroxymethyl-phenylboronic acid (49.4 mg, 0.325 mmol).