Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[N:16]4)=[CH:11][CH:10]=3)=[O:7])=[CH:4][N:3]=2)=[CH:24][CH:23]=1
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc(Cl)nc1
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(-c2ccc(Cl)cc2)nc1

Procedure:
Using the procedure outlined in Example 100, the title compound was prepared from 6-chloro-N-quinolin-7-yl-nicotinamide (D70) (40 mg, 0.14 mmol) and 4-chlorophenylboronic acid (27 mg, 0.17 mmol) as a pale yellow solid. 1H NMR (250 MHz, CDCl3) δ (ppm): 9.25 (dd, 1H), 8.82 (dd, 1H), 8.43 (dd, 1H), 8.33 (dd, 1H), 8.22 (br.d, 1H), 8.11 (d, 1H), 8.00 (d, 2H), 7.89 (d, 1H), 7.87 (d, 1H), 7.51 (d, 2H), 7.40 (dd, 1H).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5].[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1>>[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([C:4]([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH2:14][CH2:15][N:16]4[CH2:20][CH2:19][CH2:18][C@H:17]4[CH3:21])=[CH:11][C:10]=3[CH:22]=2)=[O:5])=[CH:27][CH:26]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Product: Cc1ccc(C(=O)c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)cc1

Procedure:
The product from Example 71E and 4-methylphenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.48 (d, 3H), 1.75 (m, 1H), 2.1 (m, 2H), 2.38 (m, 1H), 2.45 (s, 3H), 3.30 (m, 4H), 3.57 (m, 1H), 3.80 (m, 2H), 6.85 (s, 1H), 7.38 (dd, 2H), 7.60 (dd, 1H), 7.70 (dd, 2H), 7.75 (dd, 1H), 8.0 (d, 1H); MS (ESI) m/z 348 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([F:13])([C:6]([F:12])([F:11])[C:7](Cl)([F:9])[F:8])[CH:3](F)[F:4].CC(C#C)=C>>[CH3:1][C:2]([F:13])([C:6]([F:11])([F:12])[CH:7]([F:8])[F:9])[CH2:3][F:4]
Reactant: CC(F)(C(F)F)C(F)(F)C(F)(F)Cl
Agent: C#CC(=C)C
Product: CC(F)(CF)C(F)(F)C(F)F

Procedure:
As another example, 2-methyl-4-chloro-1,1,2,3,3,4,4-heptafluorobutane may be prepared by fluorinating commercially available 2-methyl-1-buten-3-yne to form 2-methyl-1,2,3,3,4,4-hexafluorobutane which may then be dehydrohalogenated to form 2-methyl-1,3,4,4-tetrafluoro-1,3-butadiene. The 2-methyl-1,3,4,4-tetrafluoro-1,3-butadiene may then be chlorofluorinated to form 2-methyl-4-chloro-1,1,2,3,3,4,4-heptafluorobutane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[O:20][C:21](Br)=[CH:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH:25]([C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[O:20][C:21]([O:34][C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]([CH3:27])[CH3:26])[CH:29]=3)=[CH:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1ccc(Br)o1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC(C)c1cccc(O)c1
Product: CC(C)c1cccc(Oc2ccc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)o2)c1
Yield: 16.3 %

Procedure:
5-Bromo-furan-2-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (37 mg, 0.09 mmol) was reacted with 3-isopropylphenol (23 mg, 0.18 mmol) to give the title compound (7 mg, 14%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6](O)[CH:5]=1.O=P(Cl)(Cl)[Cl:13]>C(Cl)Cl>[Cl:13][C:6]1[CH:5]=[C:4]([CH2:3][O:2][CH3:1])[N:9]=[CH:8][N:7]=1
Reactant: COCc1cc(O)ncn1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COCc1cc(Cl)ncn1
Reaction time: 18 h

Procedure:
6-(Methoxymethyl)pyrimidin-4-ol (948 mg, 6.8 mmole) was taken up in CH2Cl2 (10 mL) and POCl3 (6 mL) at room temperature. After 18 hours, the mixture was concentrated to dryness. The residue was taken up in ice water and the pH adjusted to 7. The mixture was extracted with CHCl3 (4×). The combined organic layers were dried (MgSO4), filtered, and concentrated to give the title compound which was sufficiently pure for use in the next step without purification. 1H-NMR (500 MHz, CDCl3) δ 8.95 (s, 1H), 7.58 (s, 1H), 4.48 (s, 2H), 3.50 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:11](OC(=O)C)(=O)[CH3:12]>>[CH3:11][C:12]1[O:9][C:8](=[O:10])[C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccnc1C(=O)O
Product: Cc1nc2cccnc2c(=O)o1

Procedure:
Imidazo[4,5-c][1,5]naphthyridine-2,4-diamines of the invention can be prepared according to Reaction Scheme V, wherein D, R, R1, R4a, Ph, m, and p are as defined above. 3-Aminopyridine-2-carboxylic acids of Formula XXXIII are known and can be prepared by known methods. The compound where n and m are both 0 is commercially available. In step (1) of Reaction Scheme V, a 3-aminopyridine-2-carboxylic acid of Formula III is heated with acetic anhydride to provide a 2-methyl-4H-pyrido[3,2-d][1,3]oxazin-4-one of Formula XXXIV.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:24][C@@H:25]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:26]C3CCCCO3)=[CH:17][CH:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:3])[CH3:2].C(OC(=O)C)C.Cl.[OH-].[Na+]>C(OCC)(=O)C>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]([CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:24][C@H:25]([OH:26])[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:17][CH:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc(CCN(Cc3ccccc3)C[C@H](OC3CCCCO3)c3ccccc3)cc2)cc1NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(CCN(Cc3ccccc3)C[C@H](O)c3ccccc3)cc2)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 3-(acetylamino)-4′-[2-[benzyl[(2R)-2-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino]ethyl]-4-biphenylcarboxylate in ethyl acetate (6 ml) was added hydrogen chloride ethyl acetate solution (4N, 2 ml) and stirred for 30 minutes at room temperature. The mixture was poured into sodium hydroxide aqueous solution (1N) and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to give methyl 3-(acetylamino)-4′-[2-[benzyl[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-4-biphenylcarboxylate (177 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C@H:11]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23]([O:25][CH3:26])=[O:24])[CH2:12]2)(=[O:10])=[O:9])=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[F:31][C:32]([F:36])([F:35])[CH2:33][OH:34].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[F:31][C:32]([F:36])([F:35])[CH2:33][O:34][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C@H:11]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C@H:13]([C:23]([O:25][CH3:26])=[O:24])[CH2:12]2)(=[O:9])=[O:10])=[C:4]([C:27]([F:28])([F:30])[F:29])[CH:3]=1
Reactant: OCC(F)(F)F
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(OCC(F)(F)F)cc2C(F)(F)F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 65.9 %

Procedure:
Under an atmosphere of argon, (2S,4R)-1-tert-butyl 2-methyl 4-(4-fluoro-2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-1,2-dicarboxylate ([prepared in analogy to General Procedure C, steps C1-C3, using 2-trifluoromethyl-4-fluorothiophenol in step C2] 0.79 g, 1.73 mmol, Eq: 1.00) was combined with N,N-dimethylacetamide (10 ml) to give a light yellow solution. 2,2,2-Trifluoroethanol (416 mg, 301 μl, 4.16 mmol, Eq: 2.4) and cesium carbonate (1.02 g, 3.12 mmol, Eq: 1.8) were added. The reaction mixture was stirred over night at RT. The crude reaction mixture was concentrated in vacuo. The residue was poured into HCl (0.5 M, 20 ml) and extracted with ethyl acetate. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 40% ethyl acetate in heptane) to yield the title compound as a white foam (610 mg, 65.7%, MS (m/e)=536.1 [M+H+]).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1B(O)O.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([C:12]2[O:11][CH:15]=[CH:14][CH:13]=2)[N:5]=[CH:4][N:3]=1
Reactant: CCc1c(Cl)ncnc1Cl
Reactant: OB(O)c1ccco1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCc1c(Cl)ncnc1-c1ccco1
Temperature: 80 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
A mixture of 4,6-dichloro-5-ethylpyrimidine (10 g), 2-furylboronic acid (6.33 g) tetrakis(triphenylphosphine)palladium (1.94 g), dimethoxyethane (100 ml), and sodium carbonate solution (2 mol/l) (60 ml) was stirred at 70° C. for 2 hours and at 80° C. for 2 hours. After standing to cool the reaction mixture to room temperature, to the reaction mixture, water was added, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 6.06 g of 4-chloro-5-ethyl-6-(furan-2-yl)-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](N)=[CH:6][C:5]=1[Cl:11].N([O-])=[O:14].[Na+]>OS(O)(=O)=O.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:14])=[CH:6][C:5]=1[Cl:11]
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(N)cc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(O)cc1Cl

Procedure:
Compound of example 162 (7.9 g, 42.5 mmol) suspended in 10% aqueous H2SO4 (80 mL) was reacted with NaNO2 (3.5 g, 52.1 mmol in 35 mL water) as described in example 174. It was treated with a solution of CuSO4.5H2O (128 g, 513 mmol) and Cu2O (5.5 g, 38.4 mmol) in water (800 mL) as described in the same procedure to obtain the title compound.
Reaction SMILES: CS[C:3]([N:7]1[CH2:11][C:10]([CH3:13])([CH3:12])[CH:9]=[N:8]1)=[N:4][CH2:5][CH3:6].[Cl:14][C:15]1[CH:16]=[C:17]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>C(#N)C>[Cl:14][C:15]1[CH:16]=[C:17]([S:23]([N:26]=[C:3]([N:7]2[CH2:11][C:10]([CH3:12])([CH3:13])[CH:9]=[N:8]2)[NH:4][CH2:5][CH3:6])(=[O:24])=[O:25])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: CCN=C(SC)N1CC(C)(C)C=N1
Reactant: COc1ccc(S(N)(=O)=O)cc1Cl
Solvent: CC#N
Product: CCNC(=NS(=O)(=O)c1ccc(OC)c(Cl)c1)N1CC(C)(C)C=N1
Yield: 0.4 %

Procedure:
0.75 g (1 mol equiv.) N-Ethyl-4,4-dimethyl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester and 0.94 g (1.05 mol equiv.) 3-chloro-4-methoxy-benzenesulfonamide were added to 10 mL acetonitrile. The reaction mixture was refluxed overnight and volatiles were removed in vacuo. The residue was taken up in ethyl acetate and extracted with 2N NaOH. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Purification by flash chromatography on silica gel (Et2O) afforded 1.43 g (97%) 3-chloro-N-[(4,4-dimethyl-4,5-dihydro-pyrazol-1-yl)-ethylamino-methylene]-4-methoxy-benzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 1.17 (t, J=7.3 Hz, 3H), 1.22 (s, 6H), 3.43-3.52 (m, 2H), 3.77 (br.s., 2H), 3.95 (s, 3H), 6.75 (s, 1H), 6.96 (d, J=8.6 Hz, 1H), 6.70-6.90 (br.s., 1H) 7.82 (dd, J=8.6, 2.3 Hz, 1H), 7.95 (d, J=2.3 Hz, 1H).
Reaction SMILES: C([O:4][C:5]1[CH:45]=[CH:44][C:8]([CH2:9][CH:10]([N:29]([CH3:43])[S:30]([C:33]2[C:34]3[CH:35]=[CH:36][N:37]=[CH:38][C:39]=3[CH:40]=[CH:41][CH:42]=2)(=[O:32])=[O:31])[CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)(O)[O-].[Na+]>CO>[CH2:22]([O:21][C:19]([N:15]1[CH2:16][CH2:17][CH2:18][N:12]([CH2:11][CH:10]([N:29]([CH3:43])[S:30]([C:33]2[C:34]3[CH:35]=[CH:36][N:37]=[CH:38][C:39]=3[CH:40]=[CH:41][CH:42]=2)(=[O:32])=[O:31])[CH2:9][C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:45][CH:44]=2)[CH2:13][CH2:14]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)Oc1ccc(CC(CN2CCCN(C(=O)OCc3ccccc3)CC2)N(C)S(=O)(=O)c2cccc3cnccc23)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CN(C(Cc1ccc(O)cc1)CN1CCCN(C(=O)OCc2ccccc2)CC1)S(=O)(=O)c1cccc2cnccc12
Reaction time: 0.17 h
Yield: 90.8 %

Procedure:
400 mg of the amorphous compound obtained in Example 112 was dissolved in 10 ml of methanol, to the solution was added 2 ml of 10% sodium hydroxide and the mixture was stirred for 10 minutes. The reaction mixture was acidified with citric acid aqueous solution and then alkalized with saturated sodium bicarbonate aqueous solution, and extracted twice with 50 ml of chloroform. The extract was dried over magnesium sulfate and evaporated to remove the solvent under a reduced pressure. The resulting residue was applied to a silica gel column and eluted with chloroform/methanol (100:2) to obtain 339 mg of the title compound in a colorless amorphous form.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>C(O)C>[C:12]1([C:7]2[C:6]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:11][C:10]=3[OH:9])=[N:20][NH:21][CH:8]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NN
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Solvent: O
Solvent: CCO
Product: Oc1ccc(-c2n[nH]cc2-c2ccccc2)c(O)c1
Temperature: 60 °C
Yield: 80.3 %

Procedure:
7-Hydroxy-3-phenyl-chromen-4-one (0.2 g, 0.84 mmol) was dissolved in ethanol (5 ml) and heated to ˜60° C. Hydrazine hydrate (5 ml) was added, and the solution refluxed until no starting material was visible by TLC (45 mins). After this time the majority of the ethanol was remove under vacuum and the residue quenched with cold water. The residue was extracted into ethyl acetate, washed (water), and the solvent removed under vacuum to give 4-(4-Phenyl-1H-pyrazol-3-yl)-benzene-1,3-diol as a white solid (0.17 g, 80.3%); Rf 0.65 ethyl acetate/hexane (70/30)].
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:30])[N:25]=[C:26]([CH3:29])[C:27]=4[Cl:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1.CC(C)=O>C1COCC1>[CH3:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][CH:2]=[C:3]3[C:11]4[C:10](=[CH:9][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH3:30])[N:25]=[C:26]([CH3:29])[C:27]=6[Cl:28])=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:7][CH:6]=4)[NH:5][C:4]3=[O:31])=[CH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: Cc1nn(C)c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)c1Cl
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: Cc1nn(C)c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)c1Cl
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A small screw cap test tube was charged with 4-Chloro-2,5-dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 70 mg, 0.160 mmol) and THF (1.5 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (30.6 mg, 0.160 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was dissolved in EtOAc. The resulting solution was diluted with Hexanes to initiate the precipitation of the product. The solid precipitate that formed was filtered then washed with ˜3 mL of acetone yielding 58% (56.7 mg, 0.093 mmol) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C)C=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[CH2:47]([NH:49][C:50]([NH:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[N:60]=[C:61]([N:69]3[CH2:74][CH2:73][O:72][CH2:71][CH2:70]3)[C:62]3[CH2:68][CH2:67][NH:66][CH2:65][C:63]=3[N:64]=2)=[CH:55][CH:54]=1)=[O:51])[CH3:48]>>[CH2:47]([NH:49][C:50]([NH:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[N:60]=[C:61]([N:69]3[CH2:70][CH2:71][O:72][CH2:73][CH2:74]3)[C:62]3[CH2:68][CH2:67][N:66]([C:8]([C:5]4[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=4)=[O:10])[CH2:65][C:63]=3[N:64]=2)=[CH:57][CH:58]=1)=[O:51])[CH3:48]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: Cc1cnc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)c2cnc(C)cn2)C3)cc1
Reaction time: 8 h

Procedure:
5-Methylpyrazine-2-carboxylic acid (0.0490 g, 0.000355 mol) in dry N,N-Dimethylformamide (1.80 mL, 0.0232 mol) was added 1-Hydroxybenzotriazole (0.0547 g, 0.000405 mol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.0797 g, 0.000416 mol) then followed by N,N-Diisopropylethylamine (0.114 mL, 0.000654 mol) and then 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.1007 g, 0.0002633 mol). The reaction mixture was stirred overnight. The reaction mixture was vacuum filtered, washed with DMF and then washed with water. 1H NMR (400 MHz, DMSO) δ 8.81 (d, J=3.3, 1H), 8.64 (d, J=12.5, 2H), 8.26-8.10 (m, 2H), 7.47 (dd, J=18.5, 8.7, 2H), 6.15 (dd, J=13.1, 5.8, 1H), 4.74 (d, J=15.5, 2H), 3.87 (s, 1H), 3.71 (dd, J=14.7, 4.6, 5H), 3.48 (d, J=3.9, 4H), 3.18-3.03 (m, 2H), 2.75 (d, J=13.1, 2H), 2.59 (s, 3H), 1.06 (dd, J=12.5, 7.1, 3H). LC/MS-m/z+503.2 (M+H)+,
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](I)[CH:7]=[C:6]([Br:11])[CH:5]=1.[O:13]1[CH2:17][CH2:16][NH:15][C:14]1=[O:18].C(=O)([O-])[O-].[K+].[K+].CNCCNC>C(#N)C.[Cu]I>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([N:15]2[CH2:16][CH2:17][O:13][C:14]2=[O:18])[CH:7]=[C:6]([Br:11])[CH:5]=1
Reactant: O=C1NCCO1
Reactant: COC(=O)c1cc(Br)cc(I)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: COC(=O)c1cc(Br)cc(N2CCOC2=O)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
A suspension of 3-bromo-5-iodo-benzoic acid methyl ester (682 mg, 2 mmol), oxazolidin-2-one (191 mg, 2.2 mmol), CuI (76 mg, 0.4 mmol), potassium carbonate (545 mg, 4 mmol) and N,N′-dimethyl-ethane-1,2-diamine (86 uL, 0.8 mmol) in acetonitrile (15 mL) was stirred for 16 hours at 90° C. The precipitate was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo to afford 3-bromo-5-(2-oxo-oxazolidin-3-yl)-benzoic acid methyl ester (480 mg, 80%) which was used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:24])([F:23])[F:22])=[C:6]([C:8]2[S:9](=[O:20])(=[O:19])[CH2:10][C:11]3[N:12]=[CH:13][CH:14]=[N:15][C:16]=3[C:17]=2[OH:18])[CH:7]=1.C(N(CC)C(C)C)(C)C.[CH2:34]([O:36][CH2:37]Cl)[CH3:35]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:23])([F:24])[F:22])=[C:6]([C:8]2[S:9](=[O:19])(=[O:20])[CH2:10][C:11]3[N:12]=[CH:13][CH:14]=[N:15][C:16]=3[C:17]=2[O:18][CH2:37][O:36][CH2:34][CH3:35])[CH:7]=1
Reactant: O=S1(=O)Cc2nccnc2C(O)=C1c1cc(Cl)ccc1C(F)(F)F
Reactant: CCOCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCOC1=C(c2cc(Cl)ccc2C(F)(F)F)S(=O)(=O)Cc2nccnc21
Temperature: 25 °C

Procedure:
To a mixture of 7-(5-chloro-2-trifluoromethyl-phenyl)-6,6-dioxo-5,6-dihydro-6-thia-1,4-diaza-naphthalen-8-ol (Compound C7 of Table C) (0.54 g) and N,N-diisopropylethylamine (0.25 ml) in N,N-dimethylformamide (5 ml) under nitrogen atmosphere was added chloromethyl ethyl ether (0.20 ml) and the reaction mixture was stirred at ambient temperature. After 2 hr further diisopropylethylamine (0.10 ml) and chloromethyl ethyl ether (0.10 ml) were added. After a further 3 hours stirring the reaction was concentrated and the residue purified by chromatography on silica gel (eluent: 0-100% v/v ethyl acetate in hexane) to give 7-(5-chloro-2-trifluoromethyl-phenyl)-8-ethoxymethoxy-5H-6-thia-1,4-diaza-naphthalene 6,6-dioxide (0.276 g) 1H-NMR (400 MHz, CDCl3): 1.04 (3H, t), 3.25-3.41 (2H, m), 4.76-4.87 (2H, q), 5.13 (1H, d), 5.33 (1H, d), 7.58-7.61 (2H, m), 7.76 (1H, d), 8.62 (1H, d), 8.73 (1H, d).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:12]=[C:11](C(O)=O)[C:10]2[C:5](=[C:6]([C:16]([F:19])([F:18])[F:17])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.CC[O:24][CH2:25][CH3:26]>>[F:20][C:2]([F:1])([F:21])[C:3]1[CH:12]=[C:11]([C:25]([C:26]2[CH:10]=[CH:11][CH:12]=[CH:3][N:4]=2)=[O:24])[C:10]2[C:5](=[C:6]([C:16]([F:17])([F:18])[F:19])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCOCC
Reactant: O=C(O)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Product: O=C(c1ccccn1)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12

Procedure:
A process for the preparation of erythro-α-piperid-2-yl-2,8-bis-(trifluoromethyl)-quinolin-4-yl-methanol which comprises the steps of reacting 2,8-bis-(trifluoromethyl)-quinoline-4-carboxylic acid or a salt thereof with a pyrid-2-yl-magnesium halide in a cyclic saturated ether or in an aliphatic dialkyl ether or an alkoxyalkyl ether in a molar ratio of from 1:2 to 1:8 at from 0° to 80° C. to give pyrid-2-yl 2,8-bis-(trifluoromethyl)-quinolin-4-yl ketone and the latter is hydrogenated in a conventional manner to give erythro-α-piperid-2-yl-2,8-bis-(trifluoromethyl)-quinolin-4-yl-methanol.
Reaction SMILES: [OH:1][CH:2]([CH3:37])[CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[N:11](COCC[Si](C)(C)C)[C:10]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=3)=[N:9][C:8]=2[N:7]([CH3:35])[C:6]1=[O:36].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[OH:1][CH:2]([CH3:37])[CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:33])([F:34])[F:32])[CH:25]=3)=[N:9][C:8]=2[N:7]([CH3:35])[C:6]1=[O:36]
Reactant: CC(O)CCn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2COCC[Si](C)(C)C)n(C)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)CCn1c(=O)c2[nH]c(Oc3cccc(OC(F)(F)F)c3)nc2n(C)c1=O
Yield: 83.8 %

Procedure:
To a solution of 1-(3-hydroxybutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (1.1 g, 2.02 mmol) in THF (5 mL) was added TBAF (5 mL, 1 mmol/L in THF) and the mixture was heated at reflux for 16 h. The mixture was cooled and diluted with ethyl acetate. The organic phase was washed with brine and saturated aqueous ammonium chloride; then it was dried and concentrated to give a crude product which was purified by silica gel chromatography eluting with DCM/methanol (45:1) to give (701 mg, 83.8% yield) as white solid. LCMS retention time 1.372 min; LCMS MH+ 415.