Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:18])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1>>[F:19][C:5]1[C:6]([N:8]([CH3:18])[C:9]2[CH:10]=[C:11]([NH:15][C:30](=[O:29])[CH:31]=[CH2:32])[CH:12]=[CH:13][CH:14]=2)=[N:7][C:2]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([O:29][CH2:28][CH2:27][O:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH3:20])=[CH:36][CH:35]=2)=[N:3][CH:4]=1
Reactant: COCCOCOCCOc1ccc(N)cc1
Reactant: CN(c1cccc([N+](=O)[O-])c1)c1nc(Cl)ncc1F
Product: C=CC(=O)Nc1cccc(N(C)c2nc(Nc3ccc(OCCOCOCCOC)cc3)ncc2F)c1

Procedure:
Synthesis of I-24 was performed as described for I-3 (Example 1) using 2-chloro-5-fluoro-N-methyl-N-(3-nitrophenyl)pyrimidin-4-amine in place of 2-chloro-5-fluoro-N-(3-nitrophenyl)pyrimidin-4-amine and 4-(2-((2-methoxyethoxy)methoxy)ethoxy)aniline in place of 4-[(2-methoxyethoxy)methoxy]aniline. M+1=423.9. 1H NMR (DMSO-d6, 400 MHz) 3.44 (s, 3H), 3.664-3.688 (t, 2H, J=4.8), 3.900-3.924 (t, 2H, J=4.8), 5.754-5.779 (d, 1H, J=10), 6.232-6.274 (d, 1H, J=16.8), 6.385-6.453 (m, 2H), 6.810-6.832 (d, 1H, J=8.8), 7.009-7.028 (d, 1H, J=7.6), 7.328-7.368 (t, 1H, J=8), 7.512-7.572 (m, 3H), 7.652 (s, 1H), 7.965-9.978 (d, 1H, J=5.2), 8.196 (s, 1H), 9.120 (s, 1H), 10.245 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:12])[C:10]=2[CH:11]=1)[CH3:19]
Reactant: O=C1CCCc2ccc(O)cc21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(c1)C(=O)CCC2
Temperature: 60 °C
Reaction time: 6 h
Yield: 83.3 %

Procedure:
To a solution of 3,4-dihydro-7-hydroxy-1(2H)-naphthalenone (15.3 g, 94.3 mmol) in N,N-dimethylformamide (150 mL) were serially added ethyl bromoacetate (16.5 g, 99.0 mmol) and potassium carbonate (13.7 g, 99.0 mmol) and the mixture was stirred at 60° C. for 6 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was crystallized from hexane-ethyl acetate to provide 19.5 g of the title compound. Yield 83%.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[C:6](=[O:18])[NH:7][C:8]2[C:13]([C:14]=1[CH3:15])=[C:12]([OH:16])[CH:11]=[CH:10][C:9]=2[F:17].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:35][O:36][C:37](=[O:41])[C@H:38](Cl)[CH3:39]>O>[CH3:35][O:36][C:37](=[O:41])[C@@H:38]([O:16][C:12]1[CH:11]=[CH:10][C:9]([F:17])=[C:8]2[C:13]=1[C:14]([CH3:15])=[C:5]([CH2:4][C:3]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:2]=1[Cl:1])[C:6](=[O:18])[NH:7]2)[CH3:39]
Reactant: Cc1c(Cc2ccc(Cl)cc2Cl)c(=O)[nH]c2c(F)ccc(O)c12
Reactant: COC(=O)[C@@H](C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](C)Oc1ccc(F)c2[nH]c(=O)c(Cc3ccc(Cl)cc3Cl)c(C)c12
Temperature: 40 °C
Reaction time: 24 h

Procedure:
A mixture of 3-(2,4-dichlorobenzyl)-8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2-one (0.40 g), N,N-dimethylformamide (5.0 mL), potassium carbonate (0.17 g) and (R)-2-chloropropionic acid methyl ester (0.15 g) was stirred at 40° C. for 24 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of toluene, dichloromethane and ethyl acetate (1:1:0 to 0:1:0 to 0:10:1 by volume) to afford title compound as a cream solid, 0.21 g.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=1.[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[S:25]([NH:28][C:29]1[C:34](Cl)=[N:33][C:32]([Cl:36])=[CH:31][N:30]=1)(=[O:27])=[O:26]>>[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[S:25]([NH:28][C:29]1[C:34]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)=[N:33][C:32]([Cl:36])=[CH:31][N:30]=1)(=[O:27])=[O:26]
Reactant: OCc1ccc(COC2CCCCO2)cc1
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Product: O=S(=O)(Nc1ncc(Cl)nc1OCc1ccc(CO)cc1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Examples 106a and 106b using [4-(tetrahydro-2-pyranyloxymethyl)phenyl]methanol (2.0 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (1.0 g). Yield 0.7 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH2:13])[S:11][CH:12]=1.[CH2:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)[CH2:15][CH3:16]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH:13][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH2:14][CH2:15][CH3:16])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[S:11][CH:12]=1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2ccccc2Cl)cs1
Product: CCCc1ccc(S(=O)(=O)Nc2nc(-c3ccccc3Cl)cs2)cc1

Procedure:
The title compound was prepared from 4-(2-chlorophenyl)-1,3-thiazol-2-amine and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (30.9 mg) with purity >90%. MS (pos) m/z 393.1.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[K].Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-])=O>>[CH:8]1[C:2]2[C:1](=[O:9])[NH:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:4][C:3]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: O=Cc1ccccc1O
Agent: [K]
Product: O=C1Nc2ccccc2Oc2ccccc21

Procedure:
The starting material 10,11-dihydro-dibenz[b,f][1,4]oxazepin-11-one was prepared according to the procedures reported in Coyne et al (J. Med. Chem., 1967, 10:541). Briefly, this entailed coupling potassium salicylaldehyde with 2-chloronitrobenzene, followed by oxidation to the carboxylic acid, reduction of nitro, and finally ring closure, to yield the desired starting material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[C:6]2O.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2ncc([N+](=O)[O-])c(O)c2c1
Product: COc1ccc2ncc([N+](=O)[O-])c(Cl)c2c1

Procedure:
The title compound is prepared in analogy to Example 19c starting from 3.5 g (15.89 mmol) 6-methoxy-3-nitro-quinolin-4-ol (Example 44f) and 24 ml POCl3. mp: 281-283° C.; MS: 239 (M++1); HPLC: t-=12.29 min (Grad 1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:12][CH2:13][CH3:14].C([Li])CCC.CN(C)[CH:22]=[O:23]>O1CCCC1.[Cl-].[NH4+]>[CH2:13]([O:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:22]=[O:23])[CH:3]=2)[N:8]=[CH:7][CH:6]=1)[CH3:14]
Reactant: CCOc1ccnc2ccc(Br)cc12
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOc1ccnc2ccc(C=O)cc12
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
To a solution of 6-bromo-4-ethoxy-quinoline (0.53 g, 2.1 mmol) in THF (tetrahydrofuran) (21 mL) was added dropwise a 2.5M solution of n-butyllithium in hexanes (0.92 mL, 2.3 mmol, 1.1 equiv.) at −70° C. During the addition, the temperature of the reaction mixture was raised slightly to −65° C. and it gave a very dark brown solution. The resulting colored solution was stirred for 30 min at this temperature. Then, a solution of dimethylformamide (0.324 mL, 4.2 mmol) in THF (2 mL) was added dropwise. After addition, the mixture was allowed to warm to room temperature and stirred for 15 h. Then, the mixture was diluted with saturated ammonium chloride solution and the two layers were separated. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude brown solid which was purified by using a Biotage silica gel column chromatography to afford 0.370 g (88% yield) of 4-ethoxyquinoline-6-carbaldehyde as a white solid: EI-HRMS m/e calcd for C12H11NO2 (M+) 201.0790, found 201.0787
Reaction SMILES: Cl.[NH2:2][CH:3]([C:12]1[CH:13]=[CH:14][C:15](=[O:21])[N:16]([CH:18]([CH3:20])[CH3:19])[N:17]=1)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O=C1CCC(=O)N1[O:29][C:30](=O)[CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH:18]([N:16]1[C:15](=[O:21])[CH:14]=[CH:13][C:12]([CH:3]([NH:2][C:30](=[O:29])[CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])[C:4](=[O:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[N:17]1)([CH3:19])[CH3:20]
Reactant: CC(C)n1nc(C(N)C(=O)c2ccccc2)ccc1=O
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)n1nc(C(NC(=O)CNC(=O)OC(C)(C)C)C(=O)c2ccccc2)ccc1=O
Temperature: 22.5 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
Under ice-cooling, to a suspension of 6-(1-amino-2-oxo-2-phenylethyl)-2-isopropyl-3(2H)-pyridazinone hydrochloride (1.00 g) and tert-butyl {2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-2-oxoethyl}carbamate (973 mg) in CH2Cl2 (10 ml) was added ethyl(diisopropyl)amine (0.651 ml) and stirred at the same temperature for 2 hours and at 20-25° C. for 18 hours. The mixture was washed with water, dried over MgSO4 and concentrated under reduced pressure to give syrup. The syrup was purified by column chromatography on silica gel (EtOAc only) to give tert-butyl (2-{[1-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-oxo-2-phenylethyl]amino}-2-oxoethyl)carbamate as an amorphous solid (1.13 g).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([F:21])([F:20])([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][CH:7]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.[Na+]>CN(C)C=O>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH2:2][C:3]2[N:4]=[C:5]([CH:8]=[CH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16]([F:21])([F:20])([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[O:6][CH:7]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=S([O-])c1ccc(Br)cc1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cc1coc(C=Cc2ccc(S(F)(F)(F)(F)F)cc2)n1)c1ccc(Br)cc1

Procedure:
A solution of 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole (0.30 g, 1.28 mmol) and sodium 4-bromobenzenesulfinate (0.717 g, 2.57 mmol) in N,N-dimethyl formamide (20 ml) was stirred for 3 h at 60° C. After cooling the mixture was poured onto water, extracted with ethyl acetate (3×50 ml), the combined organic layers were washed with water, dried over sodium sulfate, concentrated in vacuo and crystallized from ether/isohexane yielding 4-(4-bromo-benzenesulfonylmethyl)-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole as white crystalline product. Yield 0.345 g (51%).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=[O:4].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C>C1COCC1>[Cl:13][C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=[CH:10][C:9]=1[Cl:12]
Reactant: Nc1ccccc1
Reactant: O=C(CBr)Nc1ccc(Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CNc1ccccc1)Nc1ccc(Cl)c(Cl)c1
Yield: 1000.4 %

Procedure:
To 2-bromo-N-(3,4-dichloro-phenyl)-acetamide (2 g) in THF (80 mL) was added aniline (41 mg) and N-ethyldiisopropylamine and the reaction mixture was stirred over night at reflux. The precipitated salt was then filtered off and the filtrate was then concentrated in vacuo. The residue was then purified by column chromatography to give the title compound as a light brown solid (1.3 g, mp=110-112° C.).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]1.C(N(CC)CC)C>ClCCl>[C:9]([N:12]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]1)([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: OC1CCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(O)C1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
A solution of 35.6 ml of benzylchloroformate in 200 ml of dichloromethane was added dropwise to a mixture of 10 g of (racemic)-3-pyrrolidinol, 48.3 ml of triethylamine and 725 ml of dichloromethane which was cooled to 0° C. The mixture was stirred for 48 hours at room temperature. The dichloromethane solution was extracted with 5% hydrochloric acid and 5% aqueous sodium bicarbonate. The acid and bicarbonate washes were combined, salted with sodium chloride and extracted with 2×750 ml of ethyl acetate. The combined organic extracts were dried and concentrated, giving 22.7 g of (racemic)-N-carbobenzyloxy-3-pyrrolidinol. A mixture of 2.5 g of (racemic)-N-carbobenzyloxy-3-pyrrolidinol, 2.0 ml of methyl iodide and 5.1 g of silver oxide in 50 ml of dimethylformamide was stirred at room temperature for 2 days. The mixture was diluted with ether and then filtered. The filtrate was concentrated to a small volume. The ether solution was washed with water, dried and concentrated to dryness in vacuo. The residue was purified by chromatography (silica gel) to give 2.4 g of (racemic)-N-carbobenzyloxy-3-methoxypyrrolidine as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH2:9]([C:17]1[CH:21]=[CH:20][S:19][C:18]=1[S:22](Cl)(=[O:24])=[O:23])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:22]([C:18]1[S:19][CH:20]=[CH:21][C:17]=1[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:23])=[O:24]
Reactant: O=S(=O)(Cl)c1sccc1CCc1ccccc1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2sccc2CCc2ccccc2)c1Br
Yield: 48 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenethylthiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 3-phenethyl-2-thiophenesulfonyl chloride in 48% yield. This was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) to give a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][CH:20]([CH3:25])[C:19]=3[CH:26]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:27]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][CH:20]([CH3:25])[C:19]=3[CH:26]=2)=[O:27])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc21
Reactant: OO
Product: CC1OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dichloro-phenylmercapto)-butoxy]-4-methyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[N+:11]([O-:12])=[C:10]([CH3:13])[CH:9]=[C:8]([N:14]([CH3:16])[CH3:15])[N:7]=1>C(N(CC)CC)C>[C:1]([NH:5][C:6]1[N+:11]([O-:12])=[C:10]([CH3:13])[CH:9]=[C:8]([N:14]([CH3:15])[CH3:16])[N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1cc(N(C)C)nc(N)[n+]1[O-]
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(N(C)C)cc(C)[n+]1[O-]

Procedure:
Following the procedure described in Example 11, acetyl chloride is reacted in the presence of triethylamine with 2-amino-4-methyl-6-dimethylaminopyrimidine 3-oxide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].CC(O)=O.[C:34]1([C:40]2[S:41][CH:42]=[C:43](C=O)[N:44]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:12][CH2:13][N:14]([CH2:17][C:43]3[N:44]=[C:40]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[S:41][CH:42]=3)[CH2:15][CH2:16]1)[CH2:10][C:9]2=[O:28]
Reactant: O=Cc1csc(-c2ccccc2)n1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3csc(-c4ccccc4)n3)CC1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
A suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester hydrochloride (600 mg, 1.78 mmol, Intermediate 1) in DCM (30 ml) was treated with TEA (0.25 ml, 1.77 mmol). The pH was adjusted to 5 with AcOH and then 2-phenylthiazole-4-carbaldehyde (404 mg, 2.13 mmol) and NaBH(OAc)3 (554 mg, 2.62 mmol) were added. The mixture was stirred for 2 h at RT and then partitioned between DCM and aqueous NaHCO3 solution. The organic layer was dried over Na2SO4 and evaporated. The crude residue was purified by column chromatography (eluent: DCM/MeOH 99:1) to give (E)-3-{1′-(2-phenyl-thiazol-4-yl-methyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (602 mg).
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:11][C:12]([F:22])([F:21])[S:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[F:11][C:12]([S:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[CH:10]=[N:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:16][CH:15]=1)([F:22])[F:21]
Reactant: Nc1ccc(SC(F)(F)F)cc1
Reactant: O=C(O)c1ccncc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccncc1Nc1ccc(SC(F)(F)F)cc1
Temperature: -78 °C
Yield: 10 %

Procedure:
3-Fluoro-isonicotinic acid (50 mg, 0.354 mmol) and 4-(trifluoromethylthio)aniline (68.5 mg, 0.354 mmol) was added to 2 ml dry THF and the mixture was cooled to −78° C. LiHMDS (1M in THF, 1.24 ml) was added and the mixture was allowed to warm to room temperature over night. Hydrochloric acid (1M in methanol, 5 ml) was added and the volatiles were removed in vacuo. The crude material was purified by preparative HPLC to give 11.4 mg (45 μmol; 10% yield) of pure desired product. LC-MS (method V): rt=3.09 min; m/z [M+H]+ 315.
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[N:7]([C:8]2[N:13]=[CH:12][C:11]([C:14]([NH2:16])=[O:15])=[CH:10][CH:9]=2)[NH:6][CH:5]=[C:4]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.[C:23](N)([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[ClH:1].[C:23]([NH:16][C:14]([C:11]1[CH:12]=[N:13][C:8]([N:7]2[C:3](=[O:2])[C:4]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:5][NH:6]2)=[CH:9][CH:10]=1)=[O:15])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N
Reactant: NC(=O)c1ccc(-n2[nH]cc(-c3cccnc3)c2=O)nc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ccc(-n2[nH]cc(-c3cccnc3)c2=O)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
337 mg (1.0 mmol) of 6-(5-oxo-4-pyridin-3-yl-2,5-dihydro-1H-pyrazol-1-yl)pyridin-3-carbonyl chloride from Example 17 (Step a) are initially charged, a solution of 293 mg (4.0 mmol) of tert-butylamine in 15 ml of THF is added and the mixture is stirred at RT for 1 h. The mixture is then concentrated on a rotary evaporator, and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with 0.1% TFA added to the water). The product-containing fractions are combined and concentrated. The residue is dissolved in 1 N hydrochloric acid, and the solution is then lyophilized.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[Na+].C(O)C.[F:20][C:21]([F:25])([F:24])[C:22]#[N:23]>O>[C:1]([C:6](=[C:22]([NH2:23])[C:21]([F:25])([F:24])[F:20])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: N#CC(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCC(=O)C(C(=O)OCC)=C(N)C(F)(F)F
Temperature: 0 °C
Yield: 56.8 %

Procedure:
To a mechanically stirred mixture of 100 g (0.632 mol) of ethyl butyrylacetate, 52 g of sodium acetate, 100 ml of ethanol and 100 ml of water at 70° C. was passed 63 g of trifluoroacetonitrile in 1 day. The reaction mixture was poured into ice water. The oil precipitate was extracted into ether. The ether solution was dried and concentrated. The residue was kugelrohr distilled at 133 Pa (pot temperature 70°-110° C.). The distillate was further distilled through a Vigreaux column at 106 Pa to give 90.9 g (36.3%) of product, bp 90°-97° C., nD25 1.4585.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:20])[CH2:18][CH2:17][CH2:16][CH:15]([CH3:19])[CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30]>>[CH3:20][C:13]1([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:25]4[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=4)[N:3]=3)[NH:8][CH:9]=2)=[O:12])[CH2:18][CH2:17][CH2:16][CH:15]([CH3:19])[CH2:14]1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: CC1CCCC(C)(C(=O)c2c[nH]c3ncc(Br)nc23)C1
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCCC(C)C4)c3n2)cc(OC)c1OC

Procedure:
(1,3-Dimethyl-cyclohexyl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1,3-dimethyl-cyclohexyl)-methanone and 3,4,5-trimethoxybenzeneboronic acid following general procedures as described in these Examples. MP 229-231° C., M+H=424.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][O:7][CH:6]1[N:19]=[C:20]=[S:21])(=[O:3])[CH3:2].[NH2:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>C1(C)C(C)=CC=CC=1>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][O:7][C@@H:6]1[NH:19][C:20]([NH:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1)=[S:21])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)C(N=C=S)OC[C@H]1OC(C)=O
Reactant: Nc1nc2ccccc2s1
Solvent: Cc1ccccc1C
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](NC(=S)Nc2nc3ccccc3s2)OC[C@H]1OC(C)=O

Procedure:
To 15 ml of anhydrous xylene were added 320 mg (1 mmol) of 2,3,4-tri-O-acetyl-D-arabinopyranosyl isothiocyanate and 150 mg (1 mmol) of 2-aminobenzothiazole (MW 150) and the mixture was treated in the same manner as that used in Example 4, yielding a syrup. The syrup was purified by column chromatography on silica-gel using benzene-acetone as eluent to give the tilted compound from the fraction of benzene-acetone (9:1). Yield: 110 mg (24%).