Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[O:11].[CH4:13].CS(O)(=O)=O>C(Cl)Cl>[C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([C:13]1[CH:7]=[CH:6][C:5]([N:10]=[O:11])=[C:4]([C:3]([O:2][CH3:1])=[O:12])[CH:9]=1)[OH:11])([O:2][CH3:1])=[O:12]
Reactant: C
Reactant: COC(=O)c1ccccc1N=O
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: COC(=O)c1cc(N(O)c2ccccc2C(=O)OC)ccc1N=O
Reaction time: 1 h
Yield: 43.6 %

Procedure:
8.2 g (50 mmol) of 2-nitroso-benzoic acid methyl ester were dissolved in 50 ml of methylene chloride and 7.2 g (75 mmol) of methane solufonic acid added thereto at 0° C. Upon addition of the methane sulfonic acid, the green solution turned dark red. During the entire duration of the reaction the temperature of the reaction mixture did not exceed 10° C. After 1 hour (as described in detail in previous Examples), the solution was sprayed onto water under a vacuum and the methylene chloride removed at the same time. By means of filtration it was possible to obtain 3.6 g (44% of theoretical) of N-(2-carbomethoxyphenyl)-N-(3-carbomethoxy-4-nitrosophenyl)-hydroxylamine in the form of a beige powder (decomposition from 85° C. on), the identity of which was ascertained by means of elementary analysis, titration and spectra (NMR, UV, IR).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[CH2:31][CH3:32]>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:30][CH2:31][CH3:32])[C:5]=1[O:21][CH3:22]
Reactant: CCCBr
Reactant: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1c(-c2cccc3c2CCC3=O)ccc(OC(F)F)c1OC
Temperature: 80 °C
Yield: 33.1 %

Procedure:
To a stirring solution of 4-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (104 mg, 0.75 mmol) and propyl bromide (92 mg, 0.75 mmol) and the resultant reaction mixture was heated to 80° C. for 3 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) to afford title compound as a solid (30 mg, 33.3%).
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=1.Br[CH2:13][CH2:14][O:15][CH3:16].O>CN(C=O)C>[CH3:16][O:15][CH2:14][CH2:13][N:11]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[S:2][CH3:1]
Reactant: CSc1nc2cccnc2[nH]1
Reactant: COCCBr
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1c(SC)nc2cccnc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
A mixture of 2-(methylthio)-3H-imidazo[4,5-b]pyridine (400 mg) and 1-bromo-2-methoxyethane (370 mg) in DMF (7 mL) was stirred at 80° C. for 3 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (200 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH:10]([C:12](O)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:15](=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.[CH2:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[CH3:28].CCN=C=NCCCN(C)C.O.[Cl-].[Na+].O>N1C=CC=CC=1>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([N:29]([CH2:27][CH3:28])[C:12]([C@@H:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]([C:15](=[O:26])[C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=3)[C@@H:2]([CH3:1])[CH2:11]2)=[O:13])=[CH:31][CH:32]=1
Reactant: CCNc1ccc(Cl)cc1
Reactant: CC1CC(C(=O)O)c2ccccc2N1C(=O)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CCN(C(=O)[C@H]1C[C@H](C)N(C(=O)c2ccc(C(F)(F)F)cc2)c2ccccc21)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 39 %

Procedure:
A round bottom flask with magnetic stirrer was charged with 2-methyl-1-(4-trifluoromethyl-benzoyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (886 mg, 2.44 mmol) in anhydrous pyridine (25.0 mL). To the reaction was added N-ethyl-p-chloroaniline (0.410 mL, 2.95 mmol), followed by EDCI (833 mg, 4.34 mmol). The reaction was stirred at room temperature under an argon atmosphere for 18-20 hours. The reaction was poured into a 1:1 mixture of water/brine (50 mL) and extracted with ethyl acetate (3×35 mL). The combined extractions were washed with brine (1×50 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to afford a brown residue. The residue was purified via silica gel chromatography (hexanes/ethyl acetate) to yield (±)-trans-2-methyl-1-(4-trifluoromethyl-benzoyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide (39%). 1H-NMR (CDCl3) δ: 1.02 (d, 3H), 1.12 (t, 3H), 1.64-1.74 (m, 1H), 2.49-2.58 (m, 1H), 3.59-3.72 (m, 1H), 3.77-3.90 (m, 2H), 5.03-5.14 (m, 1H), 6.35-6.41 (m, 1H), 6.74-6.84 (m, 2H), 6.89-6.95 (m, 1H), 7.17-7.25 (m, 2H), 7.44-7.52 (m, 2H), 7.63-7.69 (m, 2H). MS m/z: 501 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][CH2:11][C:12]2([CH3:15])[CH2:14][O:13]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:14][C:12]([CH3:15])([OH:13])[CH2:11][CH2:10][N:3]2[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]2[Cl:1])=[CH:28][CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CC1(CCn2cc([N+](=O)[O-])nc2Cl)CO1
Product: CC(O)(CCn1cc([N+](=O)[O-])nc1Cl)COc1ccc(OCc2ccccc2)cc1
Yield: 79 %

Procedure:
Reaction of epoxide 140 (see Example 2JJ) with 4-(benzyloxy)phenol as in Example 2AA at 82° C. for 10 h, followed by chromatography of the product on silica gel, eluting with CH2Cl2 (foreruns) and then with 2% EtOAc/CH2Cl2, gave 1-[4-(benzyloxy)phenoxy]-4-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-methyl-2-butanol (142) (79%) as an oil; 1H NMR (CDCl3) δ 7.79 (s, 1H), 7.44-7.29 (m, 5H), 6.92 (dt, J=9.2, 3.0 Hz, 2H), 6.83 (dt, J=9.2, 3.0 Hz, 2H), 4.28 (ddd, J=14.0, 9.7, 6.1 Hz, 1H), 4.23 (ddd, J=14.0, 9.7, 6.3 Hz, 1H), 3.81 (d, J=9.1 Hz, 1H), 3.77 (d, J=9.0 Hz, 1H), 2.29 (s, 1H), 2.22 (ddd, J=13.8, 9.6, 6.2 Hz, 1H), 2.02 (ddd, J=13.6, 9.7, 6.5 Hz, 1H), 1.38 (s, 3H); HRESIMS calcd for C21H23ClN3O5 m/z [M+H]+ 434.1293, 432.1321. found 434.1298, 432.1319.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.Cl.[H][H]>C(O)C.[Pd]>[ClH:1].[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C(NNc1ccc([N+](=O)[O-])cc1)c1ccc(Cl)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc(NNC(=O)c2ccc(Cl)cc2)cc1

Procedure:
1-(4-Chlorobenzoyl)-2-(4-nitrophenyl)hydrazine (2.92g, 0.01 mole) and 5% palladium on barium sulfate (catalytic amount) were suspended in a mixture of ethanol (350 ml) and concentrated hydrochloric acid (5 ml) in a Parr shaker bottle. The reaction mixture was hydrogenated at room temperature until the theoretical amount of hydrogen had been taken up. The reaction mixture was filtered and the solvent was evaporated from the filtrate leaving a tan solid. Yield 2.9 g (99%), m.p. 209° C (dec.).
Reaction SMILES: [CH3:1]OC(OC)N(C)C.FC(F)(F)C(O)=O.[CH3:16][N:17]([CH2:19][C:20]1[C:28]([OH:29])=[C:27]([F:30])[CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][N:24]2[S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH3:18]>CN(C=O)C>[F:30][C:27]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][N:24]2[S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[C:20]([CH2:19][N:17]([CH3:16])[CH3:18])[C:28]=1[O:29][CH3:1]
Reactant: CN(C)Cc1c(O)c(F)cc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1c(F)cc2c(ccn2S(=O)(=O)c2ccccc2)c1CN(C)C

Procedure:
N,N-dimethylformamide dimethyl acetal (0.964 ml, 7.233 mmol) was added to a solution of 4-[(dimethylamino)methyl]-6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol (252 mg, 0.723 mmol; Example 146) in DMF (8 ml) and the mixture was divided into two tubes and heated in microwave oven at 180 0 C for 180 s. Solvent was evaporated and residue purified on Gilson HPLC using 30-70% MeCN in 50 nM ammonium bicarbonate buffer as eluent (Xterra). Yield: 101.7 mg (39%); white solid. MS (ESI+) for C18H19FN2O3S m/z 363 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=3)[CH2:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=2)=[CH:4][CH:3]=1.CCO>C1COCC1.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]([C:13]3[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=3)[NH2:19])[CH2:11][CH2:10][CH:9]2[C:22]2[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=2)[NH2:28])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(C2CCC(c3cccc([N+](=O)[O-])c3)N2c2ccc(F)cc2)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cccc(C2CCC(c3cccc(N)c3)N2c2ccc(F)cc2)c1
Reaction time: 20 h

Procedure:
A suspension of Pd/C (0.0527 g, 0.050 mmol) in THF (2 mL) was added to a solution of Example 55D (0.45 g, 1.105 mmol) in THF (7 mL)/EtOH (7 mL) under N2. The flask was flushed with H2 and stirred under 1 atm H2 for 20 hours. The reaction was filtered through a celite plug, rinsed with ˜100 mL (1:1 EtOH:THF) and solvent was removed under vacuum. The material was used without purification. MS (DCI) m/z 348 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=O)[CH2:10][C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.C(=O)([O-])O.[Na+].Cl.[NH2:45][OH:46]>C(O)C.O>[OH:46]/[N:45]=[C:9](/[C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)\[CH2:10][C@H:11]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1[C@H](C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 120 °C
Yield: 102.7 %

Procedure:
To a microwave vial was added (R)-tert-butyl 4-(4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)phenyl)piperidine-1-carboxylate (35 mg, 68.0 μmol), sodium hydrogencarbonate (17.1 mg, 204 μmol) and hydroxylamine hydrochloride (14.2 mg, 204 μmol) in ethanol (1 mL) and water (0.02 mL). The vial was capped and heated at 120° C. for 15 min. The reaction mixture was poured onto aq. sat. sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to afford the title compound (37 mg), which contained ca. 15% of the (Z)-stereoisomer. White foam; MS (ESI+): m/z=: 530.3 [M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12]C(=O)O)[S:11][C:7]=2[C:6]([CH:16]=[CH2:17])=[CH:5][CH:4]=1.O>C(O)CO>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([CH:16]=[CH2:17])=[CH:5][CH:4]=1
Reactant: C=Cc1ccc(OC)c2nc(NC(=O)O)sc12
Solvent: O
Solvent: OCCO
Product: C=Cc1ccc(OC)c2nc(N)sc12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
(4-Methoxy-7-vinyl-benzothiazol-2-yl)-carbamic acid methyll ester was dissolved in ethylenglycol/2N KOH (2:1) and stirred at 100° C. for 3 hrs. Then water was added and the mixture was extracted with CH2Cl2, the organic phase was washed with brine and dried over MgSO4. After evaporation the residue was crystallized from CH2Cl2. White crystals (64%); F.p.: 155-159° C.
Reaction SMILES: [N:1]1([C:5](=[O:7])[CH3:6])[CH:4]=[CH:3][CH2:2]1.[CH:8](=[N:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.FC1C=CC=CC=1N>C(#N)C.FC(F)(F)S([O-])(=O)=O.[Y+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[N:15]=[C:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]([CH2:2][NH:1][C:5](=[O:7])[CH3:6])=[CH:4]2
Reactant: Fc1ccccc1/N=C/c1ccccc1
Reactant: CC(=O)N1C=CC1
Agent: Nc1ccccc1F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Y+3]
Solvent: CC#N
Product: CC(=O)NCc1cc2cccc(F)c2nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolved 1-(azet-1(2H)-yl)ethanone (22 mg, 227 μmol, 1 eq), (E)-N-benzylidene-2-fluorobenzenamine (45 mg, 227 μmol, 1 eq), 2-fluorobenzenamine (22 μl, 227 μmol, 1 eq), and yttrium trifluoromethanesulfonate (6 mg, 11 μmol, 0.05 eq) in 9 mL of acetonitrile. The reaction was stirred at rt overnight. The reaction was heated to 90° C. for 5 h. The reaction was cooled to rt and the solvent was removed under vacuum. The residue was dissolved in 20 mL of DCM and washed with 1×5 mL of NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated. Purification by column chromatography (7:3 hexanes:ethyl acetate) afforded N-((8-fluoro-2-phenylquinolin-3-yl)methyl)acetamide. 1H NMR (400 MHz, CDCl3) δ ppm 8.20 (s, 1H), 7.60 (d, J=7.83, 1H), 7.50 (m, 2H), 7.45 (m, 4H), 7.37 (ddd, J=10.6, 7.8, 1.6 Hz, 1H), 5.92 (br t, J=5.9 Hz, 1H), 4.55 (d, J=6.3 Hz, 2H), 1.96 (s, 3H). Mass Spectrum (ESI) m/e=295.0(M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:37])[C:5]([CH3:36])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:32]C(=O)C)=[C:17]([CH:31]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:37])[C:5]([CH3:36])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:32])=[C:17]([CH:31]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:28])([F:30])[F:29])=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccccc3C(F)(F)F)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccccc3C(F)(F)F)c2)=C(C)C1=O
Yield: 97.9 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-2-trifluoromethylaniline (0.100 g, 0.193 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.090 g, 0.189 mmol, 98%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[NH:4][N:3]=1.[H-].[Na+].[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([CH2:25]OS(C(F)(F)F)(=O)=O)[CH2:21][CH2:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(#N)C.O>[C:11]([O:15][C:16](=[O:17])[NH:18][C@H:19]1[CH2:20][CH2:21][C@H:22]([CH2:25][N:3]2[C:2]([CH3:1])=[C:6]([CH3:7])[C:5]([CH3:8])=[N:4]2)[CH2:23][CH2:24]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](COS(=O)(=O)C(F)(F)F)CC1
Reactant: Cc1n[nH]c(C)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1nn(C[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c(C)c1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3,4,5-trimethyl-1H-pyrazole (84 mg, 0.761 mmol) in dry acetonitrile (4 mL) at room temp is added sodium hydride (33 mg of a 60% dispersion on mineral oil, 0.83 mmol). The mixture is stirred at room temp for 10 minutes and then treated with a solution of trans-trifluoro-methanesulfonic acid 4-tert-butoxycarbonylamino-cyclohexylmethyl ester (step 1) (250 mg, 0.692 mmol) in dry acetonitrile (3 mL). The reaction mixture is stirred at room temp for 17 hours. The mixture is diluted with water (20 mL) and extracted with EtOAc (3×10 mL). The EtOAc extracts are combined, washed with brine (20 mL), dried (MgSO4), filtered and evaporated to give the title compound as a colourless oil. This is used in the next step without further purification; MS m/z 322.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH2:5][OH:6].CN(C)CCN(C)C.C([Li])CCC.[I:24]I.S(=O)(=O)(O)O>CCCCC.C1COCC1>[I:24][C:7]1[CH:8]=[C:9]([CH3:10])[C:2]([CH3:1])=[CH:3][C:4]=1[CH2:5][OH:6]
Reactant: II
Reactant: Cc1ccc(CO)cc1C
Agent: CN(C)CCN(C)C
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1cc(I)c(CO)cc1C
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 22.5 %

Procedure:
A solution, cooled to 0° C., of 6.81 g of 3,4-dimethylbenzyl alcohol and 11.62 ml of N,N,N′,N′-tetramethyl-ethylenediamine in 150 ml of pentane was treated with 62.5 ml of n-butyllithium solution (1.6M in hexane). The reaction mixture was boiled at reflux for 11 hrs. Then, 12.69 g of iodine in 50 ml of THF were added dropwise at −30° C. The mixture was stirred for 15 min. at −30° C. and then left to warm to room temperature. The reaction mixture was added to 100 ml of 10% sulphuric acid. The crude product was isolated by extraction and purified by chromatography on silica gel. There were obtained 2.95 g of (2-iodo-4,5-dimethyl-phenyl)-methanol as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC=O)C.C1COCC1>[CH3:9][NH:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOC=O
Product: CNc1cccc(O)c1
Reaction time: 18 h
Yield: 4810.1 %

Procedure:
3-Aminophenol (5.37 g, 49.2 mmol) in ethylformate (30 mL) was treated with p-toluenesulfonic acid (50 mg) and heated at reflux. After 18 hours, the volatiles were evaporated under reduced pressure. The residue was taken up in ethyl acetate and washed with 1N HCl, saturated NaHCO3, brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was dissolved in THF (25 mL) and treated with 1M borane tetrahydofuran complex (27.2 mL, 27.2 mmol) in THF. After 18 hours at ambient temperature, the mixture was carefully quenched by addition of 1N HCl. After stirring for 30 minutes, the solution was basified and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (30% ethyl acetate/hexanes) to provide the title compound as a viscous yellow oil (1.72 g, 28% yield). 1H NMR (300 MHz, CDCl3) δ 7.03 (t, 1H), 6.13-6.24 (m, 2H), 6.11 (t, 1H), 4.54 (bs, 1H), 3.72 (bs, 1H), 2.82 (s, 3H); MS (DCI/NH3) 124 (M+H)+, 141 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[O:25]1[C:29]2[CH:30]=[C:31]([NH2:34])[CH:32]=[CH:33][C:28]=2[CH2:27][CH2:26]1>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14]([NH:34][C:31]3[CH:32]=[CH:33][C:28]4[CH2:27][CH2:26][O:25][C:29]=4[CH:30]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: Nc1ccc2c(c1)OCC2
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Solvent: CC(=O)O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccc4c(c3)OCC4)nc21

Procedure:
1 g of compound of formula (II), 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one, and 352 mg of the compound of formula (III), (2,3-dihydro-6-benzofuranyl)amine, are heated at 80° C. in 10 ml of acetic acid for 1 h 30. After returning to ambient temperature, the medium is filtered in order to remove an impurity, diluted with water and ethyl acetate and brought to pH 9 with NaHCO3. The organic phase is then washed with a saturated NaCl solution, dried over Na2SO4 and concentrated under vacuum. The residue is chromatographed on silica (gradient: heptane 100 to heptane/ethyl acetate 40:60) to give 201 mg of the expected product in the form of a yellow solid.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:18])[CH:5]([NH:10][C:11](=[O:17])[CH:12]([NH3+:16])[CH2:13][C:14]#[CH:15])[CH2:6][CH:7]([CH3:9])[CH3:8].CCN(C(C)C)C(C)C.[CH2:28]([O:35][C:36](Cl)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:28]([O:35][C:36]([NH:16][CH:12]([CH2:13][C:14]#[CH:15])[C:11]([NH:10][CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([O:3][CH3:2])=[O:18])=[O:17])=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C#CCC([NH3+])C(=O)NC(CC(C)C)C(=O)OC
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C#CCC(NC(=O)OCc1ccccc1)C(=O)NC(CC(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
To a solution of compound 2 (8.5 g; 31 mmol) in dry THF (100 mL) was added DIEA (16.02 g; 124 mmol) and the reaction mixture was stirred for 30 min at room temperature. Benzylchloroformate (6.87 g; 40.3 mmol) was added and stirring was continued at room temperature for 16 h. The solvent was removed on the rotary evaporator and the residue was taken up in ethyl acetate (150 mL) and washed sequentially with water (50 mL), 5% HCl (2×50 mL), and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give 3 as a white solid (10.46 g: 90% yield). 1H NMR (CDCl3) δ 7.3 (m, 5H), 6.7 (s, 1H), 5.6 (s, 1H), 5.1 (s, 2H), 4.6 (m, 1H), 4.4 (m, 1H), 3.7 (s, 3H), 2.6 (m, 2H), 2.8 (s, 1H), 2.6 (m, 1H), 1.6 (m, 2H), 1.5 (m, 1H), 0.9 (d, 6H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2)=O)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=2)[CH2:31][CH2:30]1.C[Al](C)C>C(Cl)Cl.CO>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:4]([C:6]3[CH:7]=[CH:8][C:9]([C:16]4[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=4[F:22])=[C:10]4[C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]4)=[O:3])=[N:40][CH:41]=2)[CH2:31][CH2:30]1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2cccnc12
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1
Agent: C[Al](C)C
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3ncccc23)c1F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 5-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid ethyl ester (Step 174.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 2 h at 80° C. Title compound: ESI-MS: 534.1 [M+H]+; tR=3.56 min (System 1); TLC: Rf=0.14 (DCM/MeOH/NH3aq, 94:5:1).