Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.Cl.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][O:22][CH2:23][C:24]([NH2:26])=[NH:25])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][O:22][CH2:23][C:24]2[NH:26][C:8](=[O:10])[C:7]3[CH:6]=[CH:5][C:4]([F:11])=[N:3][C:2]=3[N:25]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccc(F)nc1F
Reactant: N=C(N)COCCc1cccc(Cl)c1
Agent: Cl
Product: O=c1[nH]c(COCCc2cccc(Cl)c2)nc2nc(F)ccc12

Procedure:
The title compound was prepared in analogy to example 85 from 2,6-difluoropyridine-3-carboxylic acid and 2-[2-(3-chloro-phenyl)-ethoxy]-acetamidine hydrochloride (example 79.2). Light brown solid. MS: m/e=334.1 [M+H+].
Reaction SMILES: [CH3:1][Mg]Cl.[O:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[CH2:7][CH2:6][CH2:5]1.O.[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:8]1([OH:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:4][CH2:5][CH2:6][CH2:7]1
Reactant: C[Mg]Cl
Reactant: O=C1CCCOc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(O)CCCOc2ccccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 119.5 %

Procedure:
A solution [sic], maintained under an inert atmosphere, of 33.5 ml (0.1 mol) of 3M methylmagnesium chloride in solution in tetrahydrofuran is heated to 50° C. 11.3 g (0.069 mol) of 3,4-dihydro-2H-benzoxepin-5-one, dissolved in 150 ml of tetrahydrofuran, are added fairly quickly. This solution is brought to reflux for 4 hours and is then left stirring overnight at room temperature. The reaction mixture is subsequently gently hydrolysed with water under cold conditions. An ammonium chloride solution (120 g per litre) is then poured into the reaction mixture. The latter is extracted with ethyl acetate and then the organic phase is dried over anhydrous sodium sulphate and concentrated under reduced pressure. 14.7 g of a yellow oil are obtained, which oil is purified by crystallization from isoctane. 11.9 g of the title compound are thus obtained, the melting point of which is 92° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Br:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>>[Br:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)=[O:32])=[CH:29][CH:28]=1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc(Br)cc4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 4-bromobenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]([N+:14]([O-:16])=[O:15])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[C:25]1([S:31]([O-:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Na+]>O1CCCC1>[CH3:1][C:2]1[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]([N+:14]([O-:16])=[O:15])=[C:4]([S:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:33])=[O:32])[CH:3]=1
Reactant: COC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1=O
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Cn1c(C)cc(S(=O)(=O)c2ccccc2)c([N+](=O)[O-])c1=O
Reaction time: 3 h

Procedure:
5.24 g (14 mmol) of methyl 6-methyl-3-nitro-2-oxo-4-[[(trifluoromethyl)sulphonyl]oxy]-1,2-dihydropyridine-1-acetate in solution in 50 ml of tetrahydrofuran are added dropwise to 2.38 g (14.5 mmol) of sodium benzenesulphinate in suspension in 100 ml of tetrahydrofuran and the mixture is left for 3 hours at room temperature. The solvent is evaporated off, the residue is taken up in 200 ml of dichloromethane and washed with 50 ml of a 1 N aqueous hydrochloric acid solution. The organic phase is recovered, it is dried over magnesium sulphate and evaporated off.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]2=[O:26])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:27]I>O>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:27])[C:17]2=[O:26])[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: O=C1Nc2ccccc2CN1C1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN1C(=O)N(C2CCN(Cc3ccccc3)CC2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 g sodium hydride (60% oil dispersion) was added to 7 g 3-(1-benzyl-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one at 0° C. under nitrogen. The reaction was stirred at RT for 1 h and 1.5 mL methyliodide was added. The reaction was stirred 1 h at RT and poured into 600 mL water. The water layer was extracted with ethyl acetate. The organic layer was dried and evaporated to give 7.3 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH2:14])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:18]([CH3:17])=[CH:19][CH:20]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: N[C@@H]1CCCN(C(=O)c2ccc(Cl)cc2)C1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C(=O)N[C@@H]2CCCN(C(=O)c3ccc(Cl)cc3)C2)cc1
Temperature: 15 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
To the aqueous solution of (R)-1-(p-chlorobenzoyl)-3-amino piperidine obtained in Example 14 (amount: 3 g), p-Methylbenzoyl chloride (0.16 g) was added. The pH of the mixture was kept from 8.0 to 9.0 using sodium hydroxide. The mixture was stirred at 15° C. for 3 hours, and the precipitated crystal was filtered off. The crystal was dried under reduced pressure to obtain the title compound as white crystal (0.28 g, yield: 66%).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:20])=[CH:9][C:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[C:11]=2[C:18]=1[CH3:19])=[O:5]>C1COCC1.CCCCCC>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:20])=[CH:9][C:10]2[O:14][C:13]([CH3:15])([CH3:16])[CH:12]([OH:17])[C:11]=2[C:18]=1[CH3:19])=[O:5]
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)C(=O)C(C)(C)O2
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)C(O)C(C)(C)O2
Yield: 82 %

Procedure:
Using 3,3-dimethyl-N-(2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamide obtained in Reference Example 342, the title compound was synthesized in the same manner as in Example 234. Yield: 82%. Melting point: 217-218° C. (THF-hexane).
Reaction SMILES: Cl[C:2]1(Cl)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[N:4]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:3]1=[O:19]>C(O)(=O)C.C(OCC)(=O)C.[Zn]>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:3](=[O:19])[CH2:2]2
Reactant: COC(=O)CN1C(=O)C(Cl)(Cl)c2cc([N+](=O)[O-])ccc21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)CN1C(=O)Cc2cc(N)ccc21
Reaction time: 2 h
Yield: 55.4 %

Procedure:
To a suspension of methyl 2-(3,3-dichloro-5-nitro-2-oxoindolin-1-yl)acetate (0.314 g, 0.984 mmol) in acetic acid (10 ml), zinc powder (0.901 g, 13.78 mmol) was added potion wise at room temperature, and the mixture was stirred for 2 hours. Then the mixture was diluted with ethyl acetate, the solid was filtered off and washed with ethyl acetate and water. The filtrate was basified with solid K2CO3 (pH=8), and the phases were separated. The aqueous phase was extracted with DCM, and the combined organic layers were dried over sodium sulfate. The solvent was removed, and the crude was purified by filtration on silica gel cartridge (DCM:EtOAc from 80:20 to 50:50) affording methyl 2-(5-amino-2-oxoindolin-1-yl)acetate (0.120 g, 0.545 mmol, 55% yield). MS/ESI+ 220.9 [MH]+.
Reaction SMILES: C([O-])(=O)C.[Na+].[O:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=O)[CH2:8][CH2:7]1.Cl.[NH2:18][OH:19]>CCO.CCOC(C)=O>[O:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)/[C:9](=[N:18]/[OH:19])/[CH2:8][CH2:7]1
Reactant: O=C1CCOc2ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O/N=C1\CCOc2ccccc21
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Sodium acetate (503.852 mg, 6.14 mmol) was added to a stirred solution of 4-chromanone ([CAS491-37-2], 700 mg, 4.73 mmol) and hydroxylamine hydrochloride ([CAS5470-11-1], 426.808 mg, 6.14 mmol) in EtOH (31 mL). The mixture was stirred at 80° C. for 16 h. The mixture was cooled to RT, diluted with EtOAc, and washed with water. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo to yield I-36 (727.7 mg, 93%) as a white solid, which was used in the next step without further purification.
Reaction SMILES: O[C:2]1C=C(C=CC=1C)C(O)=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:17]([OH:19])=[O:18]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:17]([O:19][CH3:2])=[O:18]
Reactant: COc1cc(C(=O)O)ccc1C
Reactant: Cc1ccc(C(=O)O)cc1O
Product: COC(=O)c1ccc(C)c(OC)c1

Procedure:
The process according to claim 1, wherein 3-hydroxy-4-methylbenzoic acid in the form of a mixture with 3-methoxy-4-methylbenzoic acid is reacted to give methyl 3-methoxy-4-methylbenzoate.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[CH2:15]=[O:16].Cl>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:15][OH:16]
Reactant: C=O
Reactant: c1ccc2sccc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCc1cc2ccccc2s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Benzothiophene (5.0 g, 37.3 mmol) in anhydrous THF (100 ml) stirring at −20° C. was treated with n-butyllithium (34 ml, 1.6 M, 55.8 mmol) and stirred for 1 hour. The mixture was cooled to −78° C. and treated with paraformaldehyde (7.8 g, 261 mmol) in four portions. The mixture was allowed to slowly warm to room temperature with stirring overnight. The mixture was treated with 2N HCl (100 ml) and extracted with diethyl ether (2×100 ml). The organic phases were combined, dried over NaSO4, filtered, and the filtrate concentrated under reduced pressure. The residue was crystallized from DCM/hexanes to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 4.94 (s, 2H) 7.23 (s, 1H) 7.33 (m, 3H) 7.74 (m, 1H); (ESI) m/z 165 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=[C:5](Cl)[N:4]=1.[CH3:20][NH2:21]>C1COCC1.[OH-].[Na+]>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=[C:5]([NH:21][CH3:20])[N:4]=1
Reactant: CN
Reactant: CNc1nc(Cl)cc(NS(=O)(=O)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CNc1cc(NS(=O)(=O)c2ccccc2)nc(NC)n1
Temperature: 130 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
0.25 g (0.00084 mol) of N-(2-methylamino-6-chloro-pyrimidin-4-yl)-benzenesulfonamide was dissolved in 20 ml of 2M methylamine in THF and stirred in an autoclave at 130° C. for 3 hours. The mixture was freed from solvent, the residue was dissolved in 25 ml of 2N NaOH, filtered and the pH value of the filtrate was adjusted to 6 with 1N HCl. The precipitate was filtered off under suction, dried and chromatographed on silica gel with dichloromethane/methanol 95:5. There was obtained 0.09 g (36%) of N-(2,6-bis-methylamino-pyrimidin-4-yl)-benzenesulfonamide as yellowish crystals; m.p.: >260° C. (dec).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:8][C:7]([O:17][CH3:18])=[CH:6][C:3]=1[CH:4]=O.CC1(C)O[C:25](=[O:26])[CH2:24][C:22](=[O:23])[O:21]1>O>[N:11]1([CH2:10][C:9]2[CH:8]=[C:7]([O:17][CH3:18])[CH:6]=[C:3]3[C:2]=2[O:1][C:25](=[O:26])[C:24]([C:22]([OH:23])=[O:21])=[CH:4]3)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: COc1cc(C=O)c(O)c(CN2CCOCC2)c1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: O
Product: COc1cc(CN2CCOCC2)c2oc(=O)c(C(=O)O)cc2c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
2-hydroxy-5-methoxy-3-(4-morpholinylmethyl)benzaldehyde (0.349 g, 1.39 mmol) and Meldrum's acid (0.200 g, 1.39 mmol) were combined in H2O (2 mL). The solution was stirred at 75° C. for 2 h. After cooling to room temperature, the precipitate was filtered and dried at suction to give 0.381 g of 8-(4-morpholinylmethyl)-3-carboxy-6-methoxy-coumarin in an 85% yield: LCMS (ESI) m/z 320 (MH+).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(NC(C)C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[CH3:9][N:8]([CH3:10])[C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:3][CH:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: CN(C)C(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CN(C)C(=O)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 57 °C

Procedure:
To a mixture under Ar of 4-Iodo-N,N-dimethyl-benzamide (237 mg), trimethylsilylacetylene (169 mg), [PdCl2(PPh3)2] (30 mg) and copper(i) iodide (15 mg) is added a degassed mixture of THF (4.5 ml) and diisopropylamine (4.5 ml). After stirring over night at 57° C. and aqueous work up, the organic layer is dried over Na2SO4 and the solvent is evaporated. Flash chromatography (silica gel, CH2Cl2/MeOH/25% NH4OH 97:3:0.3) yields N,N-Dimethyl-4-trimethylsilanylethynyl-benzamide as a brown oil, 1H-NMR (300 MHz): 0.25 (s, 3H); 2.96 (s, 3H); 3.10 (s, 3H); 7.35 (d, J=8.5, 2H); 7.49 (d, J=8.5, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:18]2[C:9](=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(OCC)(O[CH2:23][CH3:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([NH:4][C:5]1[C:18]2[NH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:23][CH3:24])[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOS(=O)(=O)OCC
Reactant: CC(=O)Nc1cccc2nc3ccccc3nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCN1c2ccccc2Nc2c(NC(C)=O)cccc21

Procedure:
Scheme 8 provides a synthetic route to a 1-acetamido-N-ethyl phenazine derivative (35). A 3-amino-catechol hydrochloride (30) is reacted with silver oxide and anhydrous sodium sulfate in ethyl acetate to give 3-amino-1,2-quinone (31), which is further reacted in situ with ortho phenylenediamine (32) to give 1-amino phenazine (33). The amino phenazine (33) is acetylated with acetic anhydride in acetic acid to give 1-acetamido phenazine (34). The resulting 1-acetamido phenazine is reacted with diethyl sulfate in the presence of potassium carbonate to give N-ethyl-1-acetamido-phenazine (35).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[CH2:12]([C:14]1[CH:15]=[C:16]([CH3:26])[C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:18][CH:19]=1)[CH3:13]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:17]3[C:16]([CH3:26])=[CH:15][C:14]([CH2:12][CH3:13])=[CH:19][N:18]=3)[CH2:21][CH2:22]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Yield: 85 %

Procedure:
Using 4-bromo-2-methylbenzoic acid (1.42 g) and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (1.23 g) described in Preparation Example 81 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (2.05 g) was obtained.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[CH3:25][CH:26]1[O:31][CH:30]([CH3:32])[CH2:29][NH:28][CH2:27]1>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:28]3[CH2:27][CH:26]([CH3:25])[O:31][CH:30]([CH3:32])[CH2:29]3)=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CC1CNCC(C)O1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: CCCCO
Product: Cc1nc(N2CC(C)OC(C)C2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 55 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 95 mg of 2,6-dimethylmorpholine in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2,6-dimethylmorpholino)-2-methylnicotinamide. MS (Q1) 436.2 (M)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.C([O-])(=O)C.[Na+].[I:26]Cl>C(O)(=O)C>[I:26][C:18]1[N:4]2[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:15])[F:17])=[CH:10][CH:9]=3)[CH:7]=[C:2]([CH3:1])[C:3]2=[N:20][CH:19]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2ccnc12
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(I)cnc12
Temperature: 23 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
To a solution of 8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.20 step 2) (5.0 g, 18 mmol) in 50 mL of acetic acid was added sodium acetate (1.68 g, 20 mmol) and a solution of iodine monochloride (2M, 10.3 mL, 20.6 mmol)—slightly exothermic. The reaction mixture was stirred at 23° C. for 16 h, then partitioned between 300 mL of water and 300 mL of EtOAc. The organic layer was washed with sat. NaHCO3, water, aq. sodium sulfite, water, then dried over Na2SO4, filtered and concentrated to give the title compound as an off-white solid (6.47 g, 89%). MS (ISP) 403.3 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](=O)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:15][NH2:16].[BH4-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH:16][CH3:15])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(C)=O)cc1OC
Reactant: CN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNC(C)Cc1ccc(OC)c(OC)c1
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A solution of 15.1 g (78 mmol) of (3,4-dimethoxyphenyl)acetone (1) in 102 mL of methanol was cooled to 4° C. and was treated with 35 mL of 40% aqueous methylamine. To the reaction mixture, 3.5 g (92.5 mmol) of sodium borohydride was then added, and the temperature of the reaction was maintained at 4° C. The reaction mixture was allowed to stir for an additional 30 minutes, then concentrated under reduced pressure. To the residue, 60 mL of water was added, and the resulting reaction mixture was acidified to pH 1 using 6N HCl. The aqueous layer was extracted with 5×50 mL of dichloromethane, and the pH was adjusted to pH 13 using 6N NaOH. The aqueous layer was extracted with 4×75 mL of dichloromethane. The organic layers were combined, dried and concentrated to give 15 g (72 mmol, 92%) of 1A as a colorless oil (M+H, 210).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14](O)=[O:15])=[C:11]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:10]3=[N:9]2)=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31](=[O:44])[C:32]([O:35][C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[C:38]([F:43])[CH:37]=1)([CH3:34])[CH3:33])[CH3:29]>S(Cl)(Cl)=O.CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:28]([O:30][C:31](=[O:44])[C:32]([O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:14](=[O:15])[CH:13]([C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=[C:10]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C:11]=23)[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:38]([F:43])[CH:37]=1)([CH3:34])[CH3:33])[CH3:29]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(N)c(F)c1
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCCC2)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C)(C)Oc1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCCC3)C2CCCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 24.3 %

Procedure:
A solution of [2-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazol-3-yl]-cyclohexyl-acetic acid (40 mg, 103 umol) in thionyl chloride (2 ml) was heated under reflux conditions for 45 min. The solvent was removed under reduced pressure and the resulting crude [2-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazol-3-yl]-cyclohexyl-acetyl chloride was dissolved in CH2Cl2 (1 ml) and added to a solution of 2-(4-amino-3-fluoro-phenoxy)-2-methyl-propionic acid ethyl ester (37 mg, 155 umol) and DMAP (38 mg, 310 umol) in CH2Cl2 (1 ml). The reaction mixture was stirred at ambient temperature for 14 h. Ice water/brine 1/1 was added and the mixture was extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a brown oil which was purified by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water to obtain the title compound (15 mg, 25 umol; 24%) as brown solid. MS: m/e=610.3 [M+H+].
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:13]1[C:12]2[C:17](=[CH:18][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:21])([F:20])[F:1])=[CH:10][CH:11]=2)[N:16]=[CH:15][CH:14]=1
Reactant: Oc1ccnc2cc(-c3ccccc3C(F)(F)F)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccccc1-c1ccc2c(Cl)ccnc2c1

Procedure:
Heat a mixture of 7-(2-trifluoromethyl-phenyl)-quinolin-4-ol (50 mg, 0.17 mmol) in POCl3 (10 mL) at 90° C. for 16 hours. Evaporate the POCl3, and add ice (100 g) followed by careful addition of saturated NaHCO3. Extract with EtOAc, dry (Na2SO4), and evaporate to provide 4-chloro-7-(2-trifluoromethyl-phenyl)-quinoline as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[OH:8].[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][C:26]1[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C(CC(=O)Nc1ccc(O)c(F)c1)Nc1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CC(=O)Nc1ccc(Oc2ccncc2)c(F)c1)Nc1ccc(F)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 20.9 %

Procedure:
N1-(3-Fluoro-4-hydroxyphenyl)-N3-(4-fluorophenyl)malonamide (31 mg, 0.10 mmol), copper(II) acetate (27 mg, 0.15 mmol), pyridin-4-ylboronic acid (25 mg, 0.20 mmol), and pyridine (16 μL, 0.20 mmol) were placed in a pressure tube in that order. The tube was charged with methylene chloride (0.5 mL) and sealed. The reaction was stirred at 120° C. for 5 h. The reaction mixture was filtered through silica gel using 5% methanol/ethyl acetate. After concentration, the crude product was purified by prep HPLC. The appropriate fraction was concentrated to remove methanol and the resulting aqueous solution was made basic with saturated NaHCO3 solution (5 mL). The aqueous solution was extracted with EtOAc (3×10 mL) and the combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The product was treated with 4N HCl in dioxane and concentrated. Lyophilization with water gave the title compound (8 mg, 21%) as a yellow solid. 1H NMR (CD3OD) δ 8.31 (d, 2H, J=6.1 Hz), 7.72 (dd, 1H, J=12.7, 2.4 Hz), 7.49-7.46 (m, 2H), 7.27-7.25 (m, 1H), 7.15 (t, 1H, J=8.8 Hz), 6.97 (t, 2H, J=8.7 Hz), 6.85 (dd, 2H, J=5.1, 1.2 Hz), 3.46 (s, 2H); MS(ESI+) m/z 384.21 (M+H)+.