Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@H:13]([NH:29][CH3:30])[CH2:14][O:15][C:16](=[O:28])[NH:17][C:18]1[N:19]=[CH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31][C:32]1[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:33]=1[CH2:34][NH:35][C:36](=[O:47])OC1C=CC([N+]([O-])=O)=CC=1.CCN(C(C)C)C(C)C>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C@H:13]([N:29]([CH3:30])[C:36]([NH:35][CH2:34][C:33]1[CH:48]=[CH:49][CH:50]=[C:51]([F:52])[C:32]=1[Cl:31])=[O:47])[CH2:14][O:15][C:16](=[O:28])[NH:17][C:18]1[N:19]=[CH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN[C@@H](CNC(=O)OCc1ccccc1)COC(=O)Nc1cc2ccccc2cn1
Reactant: O=C(NCc1cccc(F)c1Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CNC(=O)OCc1ccccc1)COC(=O)Nc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
To a solution of the crude isoquinolin-3-yl-carbamic acid (S)-3-benzyloxycarbonylamino-2-methylamino-propyl ester (9.0 mmol) in THF (35 mL) were added 4-nitrophenyl 2-chloro-3-fluorobenzylcarbamate (2.85 g, 8.79 mmol) and DIEA (2.3 mL, 13.2 mmol) at RT. The reaction mixture was stirred at RT for 30 min. The solvent was removed and the residue was dissolved in EtOAc (400 mL). The organic mixture was washed with NaOH (1 N, 50 mL×3), HCl (0.5 N, 50 mL), saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of EtOAC and hexanes to give Isoquinolin-3-yl-carbamic acid (S)-3-benzyloxycarbonylamino-2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-propyl ester (3.8 g, 71% for two steps) as white foam. LRMS (M+H+) m/z 594.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[NH:6][C:5](=[O:7])[C:4]([CH3:9])([CH3:8])[NH:3]1.[H-].[Na+].[CH2:13]1[O:15][CH:14]1[CH2:16][OH:17]>CN(C)C=O>[OH:15][CH:14]([CH2:16][OH:17])[CH2:13][N:6]1[C:5](=[O:7])[C:4]([CH3:9])([CH3:8])[NH:3][C:2]1([CH3:10])[CH3:1]
Reactant: OCC1CO1
Reactant: CC1(C)NC(=O)C(C)(C)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)NC(C)(C)N(CC(O)CO)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5.5 %

Procedure:
2,2,5,5-Tetramethylimidazolidin-4-one (3.54 g, 24.9 mmol), prepared as described in U.S. Pat. No. 5,126,057 (Worely et al., Jun. 30, 1992), was dissolved in N,N-dimethylformamide (150 ml). To the stirring room temperature solution was added sodium hydride (60%, 913 mg, 22.8 mmol), in 4 portions over 10 minutes. After an additional one hour of stirring at room temperature, the glycidol (1.4 ml, 21.1 mmol) was added to the reaction mixture. After the reaction mixture was stirred for 18 hours at room temperature, the mixture was concentrated in vacuo, and crude material is purified by silica gel column chromatography (0 to 20% methanol in dichloromethane) to give 250 mg (5%) the title compound.
Reaction SMILES: C[Mg]Br.[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[CH:5]=1.[Cl-].[NH4+].[C:14](OCC)(=O)C>O1CCCC1>[OH:11][CH:10]([C:6]1[CH:5]=[N:4][CH:9]=[CH:8][CH:7]=1)[CH3:14]
Reactant: CCOC(C)=O
Reactant: O=Cc1cccnc1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1cccnc1
Yield: 76 %

Procedure:
To methylmagnesium bromide (a 0.96 mol/L solution in tetrahydrofuran, 16.6 mL, 15.9 mmol), a solution of 3-pyridinecarboxaldehyde (500 μL, 5.30 mmol) in tetrahydrofuran (5.0 mL) was slowly added under a nitrogen atmosphere at 0° C., and the mixture was stirred at the same temperature for 1. Then, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol 9/1) to give 3-(1-hydroxyethyl)pyridine (Compound CA) (498 mg, yield: 76%).
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[Si:15]([CH2:22][CH2:23][CH:24]([OH:30])[C:25]([CH3:29])([CH3:28])[C:26]#[N:27])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C)C1C=CN=CC=1.CCOCC>[Si:15]([CH2:22][CH2:23][CH:24]([O:30][C:8](=[O:10])[CH3:9])[C:25]([CH3:29])([CH3:28])[C:26]#[N:27])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C#N)C(O)CC[Si](C)(C)C(C)(C)C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)OC(CC[Si](C)(C)C(C)(C)C)C(C)(C)C#N
Temperature: 0 °C

Procedure:
14.43 g (142.64 mmol) of triethylamine and 200 mg of 4-dimethylaminopyridine (DMAP), dissolved in 128 ml of MTB-ether, and, at 0° C., 14.56 g (142.64 mmol) of acetic acid anhydride are added to 28.24 g (109.7 mmol) of 5-tert-butyldimethylsilyl-2,2-dimethyl-3(R,S)-hydroxy-pentane-nitrile, the title compound of Example 6a, and it is stirred for 5 hours at room temperature. It is poured onto 2 l of ice water and extracted twice with 300 ml each of MTB-ether. The combined MTB-phases are washed once with 300 ml of 5% hydrochloric acid and then with water. It is evaporated to the dry state in a vacuum. The residue is purified by flash chromatography on silica gel (hexane/MTB-ether).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]#[N:30])=[CH:24][CH:23]=1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29]#[N:30])=[CH:24][CH:23]=2)=[CH:9][CH:8]=1
Reactant: N#CCc1ccc(O)cc1
Reactant: CON=C(COc1ccc(CO)cc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CO/N=C(\COc1ccc(COc2ccc(CC#N)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged dry Toluene. To the stirred solvent was added 2-(4-Hydroxymethyl-phenoxy)-1-phenyl-ethanone O-methyl-oxime (0.20 g, 0.74 mmol) and (4-hydroxyphenyl)acetonitrile (0.098 g, 0.74 mmol) at 0° C. for 5 min. Then added tributylphosphine (0.0.24 g, 1.2 mmol) stirred at 0° C. for 15 min, was added 1,1′aza(dicarbonyl)dipiperidine (0.303 g, 1.2 mmol), this resulting mass stirred at RT for 16 h, The solvent removed, the residue was extracted with ethyl acetate. The organic layer washed with water and brine solution and dried by anhydrous sodium sulphate and evaporated, purified by 100-200 silica column using pet-ether and ethylacetate. The product obtained as a colourless oily liquid (0.18 g, 60.00%)
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([C@H:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH3:13])[C:7](=[O:21])[C@@H:6]3[CH2:22][O:23][CH2:24][CH2:25][N:5]3[C:4]=2[N:3]=1.[NH:26]1[C:34]2[C:29](=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27]1>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C@@H:12]([N:8]2[C:7](=[O:21])[CH:6]3[CH2:22][O:23][CH2:24][CH2:25][N:5]3[C:4]3[N:3]=[C:2]([C:30]4[CH:31]=[CH:32][CH:33]=[C:34]5[C:29]=4[CH:28]=[CH:27][NH:26]5)[N:11]=[CH:10][C:9]2=3)[CH3:13])=[CH:19][CH:18]=1
Reactant: C[C@@H](c1ccc(Cl)cc1)N1C(=O)[C@@H]2COCCN2c2nc(Cl)ncc21
Reactant: OB(O)c1cccc2[nH]ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: C[C@@H](c1ccc(Cl)cc1)N1C(=O)C2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc21
Yield: 44.3 %

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 85 using (S)-2-chloro-5-((S)-1-(4-chlorophenyl)ethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (43 mg, 0.113 mmol), 1H-indol-4-ylboronic acid (36.5 mg, 0.227 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (4.66 mg, 5.67 μmol). The crude product was purified by preparatory HPLC using a gradient of 35-50% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). Lyophilization of the collected fractions gave a diastereomeric mixture of title compound (TFA salt) as a yellow powder (23 mg, 44.1%). 1H NMR (400 MHz, DMSO-d6) δ 1.74-1.81 (m, 2H), 1.82-1.89 (m, 1H), 11.20-11.34 (m, 1H), 3.07-3.18 (m, 1H), 3.58-3.77 (m, 3H), 4.03-4.12 (m, 2H), 4.23-4.31 (m, 2H), 4.41-4.60 (m, 3H), 6.32-6.08 (m, 1H), 7.12-7.19 (m, 1H), 7.22-7.30 (m, 1H), 7.35-7.55 (m, 6H), 7.81-7.73 (m, 1H), 7.91-8.01 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C25H22ClN5O2, 460.15. found 460.4.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10](F)=[C:11](F)[C:12]=3F)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:21]([NH:23][CH2:24][CH2:25][CH:26]1[O:31][CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:22]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N:28]4[CH2:29][CH2:30][O:31][CH:26]([CH2:25][CH2:24][NH:23][CH2:21][CH3:22])[CH2:27]4)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCNCCC1CNCCO1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Product: CCNCCC1CN(c2ccc3c(=O)c(C(=O)O)cn(C4CC4)c3c2)CCO1

Procedure:
By the use of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(2-ethylaminoethyl)morpholine, the reaction is similarly carried out as Example 11 to give 1-cyclopropyl-7-[2-(2-ethylaminoethyl)morpholino] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([NH:15][C:16]1[CH:21]=[C:20]([CH2:22][S:23][C:24]2[C:29]([C:30]([NH:32][C:33]3[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[CH:34]=3)=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=2)[CH:19]=[CH:18][N:17]=1)(=[O:14])[CH3:13]>C(Cl)Cl.C(OCC)(=O)C>[C:12]([NH:15][C:16]1[CH:21]=[C:20]([CH2:22][S:23]([C:24]2[C:29]([C:30]([NH:32][C:33]3[CH:34]=[C:35]([CH3:40])[CH:36]=[C:37]([CH3:39])[CH:38]=3)=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=2)=[O:9])[CH:19]=[CH:18][N:17]=1)(=[O:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)Nc1cc(CSc2ncccc2C(=O)Nc2cc(C)cc(C)c2)ccn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(CS(=O)c2ncccc2C(=O)Nc2cc(C)cc(C)c2)ccn1
Reaction time: 1 h
Yield: 48 %

Procedure:
m-Chloroperbenzoic acid(75%, 60 mg, 0.26 mmol) was added to a solution of 2-(2-acetylaminopyridin-4-ylmethylthio)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide (Compound No. 4-1, 60 mg, 0.15 mmol) in methylene chloride (3 mL) under ice-cooling, and the mixture was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (30 mL), the whole was washed with saturated aqueous sodium hydrogen carbonate solution (10 mL) twice and brine (10 mL), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the precipitated solid was filtered off with ethyl acetate to give 30 mg of the target compound as a colorless solid. (Yield 48%)
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].CCN(CC)CC.Br[CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C=O)C>[CH:22]1([CH2:21][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrCC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1OCC1CCCCC1
Temperature: 50 °C
Reaction time: 15 h
Yield: 52.8 %

Procedure:
To a stirred solution of N-hydroxyphthalimide (10.0 g, 61.30 mmol) in DMF (40 mL) at RT was added NEt3 (9.40 mL, 67.43 mmol) and, in a dropwise fashion, (bromomethyl)cyclohexane (9.41 mL, 67.43 mmol). The reaction was then stirred for 15 hours at 50° C., after which it was allowed to cool to RT and then concentrated under vacuum. The residue was dissolved in Et2O (100 mL) and washed with water, brine, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by column chromatography (eluting with CH2Cl2/PE, 1:1 to 3:1) to afford N-(cyclohexylmethoxy)phthalimide (8.40 g, 53%), as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12.[O:25]=[C:26]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:27][C:28](O)=[O:29].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:28](=[O:29])[CH2:27][C:26]([NH:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:25])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: O=C(O)CC(=O)Nc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccccc4)cc3F)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.3 %

Procedure:
To a solution of the amine 9 (80 mg, 0.235 mmol), 3-oxo-3-(phenylamino)propanoic acid (1) (42 mg, 0.235 mmol) and BOP (114.6 mg, 0.259 mmol) in DMF (2.4 mL), DIPEA (0.164 mL, 0.941 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between EtOAc and water. Organic phase was collected, washed with H2O and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (EtOAc/MeOH 95:5) followed by crystallization (MeOH) to afford the title compound 5b (11 mg, 9% yield). 1H NMR (DMSO-d6) δ (ppm): 10.55 (s, 1H), 10.19 (s, 1H), 8.5 (d, J=5.4 Hz, 1H), 7.86 (m, 2H), 7.59 (m, 2H), 7.49 (t, J=8.8 Hz, 1H), 7.41 (m, 2H), 7.30 (m, 2H), 7.05 (m, 2H), 6.69 (d, J=5.4 Hz, 1H), 3.99 (s, 3H), 3.52 (s, 2H). MS (m/z): 502.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.Cl[CH2:8][CH2:9][CH2:10][C:11]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:12]>>[CH3:1][C:2]1[N:3]=[C:4]([C:11]2([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[CH2:10][CH2:9][CH2:8][O:12]2)[S:5][CH:6]=1
Reactant: Cc1cscn1
Reactant: O=C(CCCCl)c1cccs1
Product: Cc1csc(C2(c3cccs3)CCCO2)n1

Procedure:
The title compound was prepared from 4-methylthiazole and 4-chloro-1-(2-thienyl)-1-butanone, using the general method of Example 36.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=1)=[C:5]2[Cl:21].[F:22]C1C=CC(CC(C(O)=O)C(O)=O)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:22])=[CH:16][CH:15]=1)=[C:5]2[Cl:21]
Reactant: O=C(O)C(Cc1ccc(F)cc1)C(=O)O
Reactant: Clc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Product: Fc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1

Procedure:
The title compound was prepared by substituting 2-(4-chlorobenzyl)malonic acid (Intermediate 3: step b) with 2-(4-fluorobenzyl)malonic acid (Intermediate 4: step b) then following the procedure described for the preparation of 6-bromo-2,4-dichloro-3-(4-chlorobenzyl)quinoline (Intermediate 3: step c).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Mg].C(O[CH2:21][C:22]([F:38])=[CH:23][C:24]([CH3:37])([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=1)[CH3:25])(=O)C>O1CCCC1>[F:38][C:22](=[CH:23][C:24]([CH3:37])([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:28][CH:27]=1)[CH3:25])[CH2:21][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=1
Reactant: CC(=O)OCC(F)=CC(C)(C)c1ccc(OC(F)(F)F)cc1
Reactant: Fc1ccc(Br)cc1Oc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C=C(F)Cc1ccc(F)c(Oc2ccccc2)c1)c1ccc(OC(F)(F)F)cc1
Yield: 31.7 %

Procedure:
The method of Example 16 was repeated using a Grignard reagent, prepared from 4-fluoro-3-phenoxyphenyl bromide (0.4 g), tetrahydrofuran (4 ml) and magnesium (26 mg), and 2-fluoro4-methyl-4-(4-trifluoromethoxyphenyl)pent-2-enyl acetate (Example 15) (90 mg). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) to give the title compound (40 mg, 33%).
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:26](OC3C=CC([N+]([O-])=O)=CC=3)=[O:27])[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:38]1[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:44]=[S:41]1(=[O:45])[CH2:42][CH2:43][N:38]([C:26]([N:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=3)[CH2:15][CH:10]([NH:9][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:8])[CH2:11]2)=[O:27])[CH2:39][CH2:40]1
Reactant: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Reactant: O=S1(=O)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCS(=O)(=O)CC2)C1)c1ccccc1

Procedure:
200 mg (0.39 mmol) of 4-nitrophenyl 3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethyl)phenyl]piperidine-1-carboxylate were initially charged in 4.3 ml of DMF, and 158 mg (1.17 mmol) of thiomorpholine 1,1-dioxide and 54 mg (0.39 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150° C. for 15 min. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[C:10]=2[O:16][CH2:17][CH3:18])[CH2:4][CH2:3]1.[Cl-].[CH:20]1([CH2:26][CH2:27][CH2:28][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([CH2:26][CH2:27][CH:28]=[C:2]2[CH2:7][CH2:6][CH:5]([NH:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[C:10]=3[O:16][CH2:17][CH3:18])[CH2:4][CH2:3]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: c1ccc([P+](CCCC2CCCCC2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOc1c(NC2CCC(=O)CC2)ccnc1C
Agent: [Cl-]
Product: CCOc1c(NC2CCC(=CCCC3CCCCC3)CC2)ccnc1C
Yield: 42 %

Procedure:
Preparation was carried out analogously to Example 27 from 4-(4-oxocyclohexylamino)-3-ethoxy-2-methylpyridine and 3-cyclohexylpropyltriphenylphosphonium chloride. Yield: 42%
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.O.[NH2:10][NH2:11]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:10][NH2:11])[CH:3]=1
Reactant: NN
Reactant: Fc1cc(Br)ccn1
Solvent: O
Solvent: CCO
Product: NNc1cc(Br)ccn1
Temperature: 45 °C
Reaction time: 16 h
Yield: 91.4 %

Procedure:
To a solution of 4-bromo-2-fluoropyridine (23.75 g, 135 mmol) in ethanol (120 mL) was added hydrazine monohydrate (65.5 mL, 1350 mmol). The mixture was stirred at 45° C. for 16 h then concentrated. The resulting solid was triturated with water, collected by filtration, rinsed with water, and dried under vacuum, to give the title compound (23.2 g) as a white solid. LCMS m/z=188.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 4.19 (s, 2H), 6.69 (dd, J=5.3, 1.8 Hz, 1H), 6.92 (d, J=1.7 Hz, 1H), 7.69 (s, 1H), 7.84 (d, J=5.3 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:9]=2[C:10]=1[NH:11][C:12](OCC)=[O:13])=O)C.O.[NH2:23][NH2:24]>C(O)C>[NH2:23][N:24]1[C:4](=[O:3])[C:6]2[O:7][C:8]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:9]=3[C:10]=2[NH:11][C:12]1=[O:13]
Reactant: NN
Reactant: CCOC(=O)Nc1c(C(=O)OCC)oc2ccc(Cl)cc12
Solvent: CCO
Solvent: O
Product: Nn1c(=O)[nH]c2c(oc3ccc(Cl)cc32)c1=O

Procedure:
To a solution of 5-chloro-3-ethoxycarbonylamino-benzofuran-2-carboxylic acid ethyl ester (3.6 g, 11.6 mmol) in ethanol (50 mL) was added hydrazine hydrate (6.2 mL, 127 mmol). After heating at reflux for 4 h, the title compound was collected by filtration (2.9 g) and was used in the next step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:10]([CH2:23][C:24](=O)[CH3:25])=[C:11]([NH:15]C(=O)OC(C)(C)C)[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])O.[Na+]>ClCCl>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:10]=1[CH:23]=[C:24]([CH3:25])[NH:15]2
Reactant: CC(=O)Cc1c(F)cccc1NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(F)cccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.3 %

Procedure:
1.43 ml of trifluoroacetic acid are added to a solution of 0.35 g of tert-butyl [3-fluoro-2-(2-oxopropyl)phenyl]carbamate in 13 ml of anhydrous dichloromethane at ambient temperature. The reaction mixture is then stirred at ambient temperature for 24 h, and is then diluted with 27 ml of dichloromethane and treated with 25 ml of a 5% sodium hydrogen carbonate solution. After stirring at ambient temperature for 1 hour and then settling out, the organic phase is separated and the aqueous phase is extracted with 25 ml of dichloromethane. The organic phases are combined, washed with saturated brine, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. 0.19 g of 4-fluoro-2-methylindole is thus obtained in the form of a dark red-colored oil, the characteristics of which are the following:
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[NH:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:15][CH:14]=3)[N:10]=[C:9]([NH:29][CH:30]3[CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:32]1[CH2:31][CH:30]([NH:29][C:9]2[N:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([NH:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[O:28])=[CH:17][CH:18]=3)[N:10]=2)[CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2nc(-c3ccc(NC(=O)Nc4cccnc4)cc3)nc(N3CCOCC3)n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2nc(NC3CNC3)nc(N3CCOCC3)n2)cc1)Nc1cccnc1
Reaction time: 24 h

Procedure:
To a stirred solution of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(pyridin-3-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate 30 mg (0.055 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at room temperature and stirred for 24 hours. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. Yield: 21 (83%); (M+H) 448.5.
Reaction SMILES: [C:1]1([CH:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([CH:25]=[C:26]([C:28]([CH3:35])([CH3:34])[C:29]([O:31]CC)=[O:30])[N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:36]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([CH:25]=[C:26]([C:28]([CH3:35])([CH3:34])[C:29]([OH:31])=[O:30])[N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C(=O)O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.1 %

Procedure:
468 mg of ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate was dissolved in 3 ml of ethanol; 2 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 15 hours. After the mixture was concentrated under reduced pressure, the residue was diluted with water and washed with ethyl acetate; the water layer was adjusted to pH 7 by the addition of 1 N hydrochloric acid, followed by extraction with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saturated saline and dried with magnesium sulfate. After the dry product was concentrated under reduced pressure, ethyl acetate was added to the residue; the crystal precipitated was collected by filtration, washed with ethyl acetate and dried to yield 267 mg of the title compound.