Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:22]1[C:27]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)(=[O:30])=[O:29])=[CH:26][N:25]=[C:24]([CH3:39])[N:23]=1>C1COCC1>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([S:28]([C:27]2[C:26]([NH:4][C:3]3[C:5]([CH3:10])=[CH:6][C:7]([CH3:9])=[CH:8][C:2]=3[CH3:1])=[N:25][C:24]([CH3:39])=[N:23][CH:22]=2)(=[O:29])=[O:30])=[CH:36][CH:35]=1
Reactant: COc1ccc(S(=O)(=O)c2cnc(C)nc2Cl)cc1
Reactant: Cc1cc(C)c(N)c(C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)c2cnc(C)nc2Nc2c(C)cc(C)cc2C)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 45.1 %

Procedure:
To a solution of 2,4,6-trimethylaniline (0.089 mL, 0.64 mmol) in THF (2 mL), NaHMDS (1.0 M in THF, 0.64 mL, 0.64 mmol) was added dropwise at 0° C. The mixture was stirred under N2 at 0° C. for 10 min, and then 4-chloro-5-(4-methoxy-benzenesulfonyl)-2-methyl-pyrimidine (158 mg, 0.53 mmol) in THF (3 mL) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h, and then quenched with saturated ammonium chloride. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (1:2 ethyl acetate/hexanes) to provide the target compound (95 mg, 45%) as a light yellow solid: mp 153–155° C.; 1H NMR (300 MHz, CDCl3) δ 8.74 (s 1H), 8.22 (br s, 1H), 7.88 (d, J=7.0 Hz, 2H), 6.98 (d, J=7.0 Hz, 1H), 6.91 (s, 2H), 3.86 (s, 3H), 2.38 (s, 3H), 2.30 (s, 3H), 2.01 (s, 6H); ESI MS m/z 398 [(M+H)+, calcd for C21H24N3O3S, 398.2].
Reaction SMILES: [CH:1]1([CH2:5][C:6]2([CH3:38])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([NH:27]C(=O)OC(C)(C)C)=[CH:26][C:20]=4[S:19](=[O:36])(=[O:35])[N:18]=3)[C:7]2=[O:37])[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[NH2:27][C:25]1[CH:24]=[CH:23][C:21]2[NH:22][C:17]([C:8]3[C:7](=[O:37])[C:6]([CH2:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)([CH3:38])[C:15]4[C:10]([C:9]=3[OH:16])=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:18][S:19](=[O:36])(=[O:35])[C:20]=2[CH:26]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3C(C)(CC3CCC3)C1=O)N2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(CC2CCC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21

Procedure:
A solution of Example 55H (0.105 g, 0.195 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid (2 mL) at room temperature for 1 hour. After concentrating in. vacuo, the resulting oil was partitioned between ethyl acetate and NaHCO3(aq,), the organic layer was removed and the bicarb layer extracted 3× with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in. vacuo. to yield a solid that was used without further purification. 1H NMR (300 MHz, DMSO-d6): δ ppm 1.22 (m, 3H) 1.47 (m, 3H) 1.57 (s, 3H) 1.71 (m, 2H) 2.18 (m, 1H) 2.32 (m, 1H) 7.01 (m, 2H) 7.45 (d, J=8.46 Hz, 1H) 7.54 (t, J=7.17 Hz, 1H) 7.76 (m, 2H) 8.15 (d, J=7.72 Hz, 1H) 13.54 (m, 1H). MS (ESI+) m/z=438 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[C:35]1[CH:36]=[N:37][CH:38]=[N:39][CH:40]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[N:37]1[CH:36]=[C:35]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:13]3[O:14][C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=4)=[N:11][N:12]=3)=[CH:16][CH:17]=2)[CH:40]=[N:39][CH:38]=1
Reactant: Brc1cncnc1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)o2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Nc2nnc(-c3ccc(Oc4cncnc4)cc3)o2)c1
Temperature: 80 °C
Yield: 43.6 %

Procedure:
4-(5-{[3-(trifluoromethyl)-phenyl]amino}-1,3,4-oxadiazol-2-yl)phenol (160.6 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (149.6 mg, 0.75 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 5-bromopyrimidine (119.2 mg, 0.75 mmol) was added, followed by anhydrous K2CO3 (69.1 mg, 0.5 mmol). Then the vial was capped and microwaved at 200° C. for 20 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed in vacuo to give the title product as a beige solid (87.0 mg). Yield 43.5%.
Reaction SMILES: [Cl:1][C:2]1[C:21](I)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:29]=1.CCCCCC>C(Cl)Cl>[Cl:1][C:2]1[C:21]([C:28]2[CH:27]=[N:26][CH:25]=[C:24]([F:23])[CH:29]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(I)c1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 223.1 using 6-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide and 3-fluoropyridine-5-boronic acid pinacol ester. The crude product was dissolved in DCM (20 mL) and treated with n-hexane. The resulting solid was filtered off, washed with n-hexane and dried to afford the title product as a beige solid. UPLC-MS (Condition 3) tR=1.13 min, m/z=412 [M+H]+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C)C=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
15.26 g of 50% sodium hydride in oil is added, at 0° C., to a solution under inert gas of 50 g of parabromophenol in 320 ml of dimethylformamide, followed by agitation for 30 minutes at 0° C., then 37.7 ml of benzyl bromide is added. Agitation is carried out for 2 hours 30 minutes while allowing the temperature to return to 20° C., then the reaction mixture is poured into ice-cooled water, the precipitate is filtered and dried. 73.35 g of expected product is obtained. Rf: 0.85 (thin layer chromatography, support: silica, eluant: cyclohexane/ethyl acetate 7/3).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[CH3:12][N:13]([CH3:26])[C:14]([C:16]1[S:24][C:23]2[C:18](=[N:19][CH:20]=[CH:21][C:22]=2Cl)[CH:17]=1)=[O:15]>>[CH3:12][N:13]([CH3:26])[C:14]([C:16]1[S:24][C:23]2[C:18](=[N:19][CH:20]=[CH:21][C:22]=2[NH:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2]([CH3:1])=[CH:10]3)[CH:17]=1)=[O:15]
Reactant: CN(C)C(=O)c1cc2nccc(Cl)c2s1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N(C)C)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid dimethylamide by a procedure analogous to Example 1C. MS: 351 (MH+); HPLC Rf: 3.87 min.; HPLC purity: 94%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[CH2:10][C@H:9]2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:16][C:17]1[O:21][N:20]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>O>[C:22]([C:19]1[CH:18]=[C:17]([NH:16][C:13]([C@@H:9]2[CH2:10][C:11](=[O:12])[N:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:15])[O:21][N:20]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1cc(N)on1
Reactant: O=C(O)[C@@H]1CC(=O)N1c1ccc(Cl)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CC(=O)N2c2ccc(Cl)cc2)on1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cold slurry of (S)-1-(4-Chloro-phenyl)-4-oxo-azetidine-2-carboxylic acid (0.2 g; 1.037 mmol) and 5-amino-3-tert-butylisoxazole (0.145 g; 1.037 mmol) in pyridine (1.258 mL; 15.555 mmol) is added phosphorous oxychloride (0.116 mL; 1.244 mmol). The mixture is stirred at 0° C. for 30 minutes and then diluted with water and extracted with ethyl acetate several times. The organics are combined and washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by preparative HPLC affords title compound, m/z 348 [M+H+]
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]([CH2:13][CH2:14][CH3:15])([CH2:11][OH:12])[CH2:9][OH:10].[OH2:16]>N1C=CC=CC=1.C(OCC)C>[CH3:1][S:2]([OH:4])(=[O:6])=[O:3].[CH3:1][S:2]([OH:4])(=[O:16])=[O:3].[CH3:1][S:2]([OH:4])(=[O:6])=[O:3].[OH:6][CH2:7][C:8]([CH2:13][CH2:14][CH3:15])([CH2:11][OH:12])[CH2:9][OH:10]
Reactant: O
Reactant: CS(=O)(=O)Cl
Agent: CCCC(CO)(CO)CO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CS(=O)(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulphonyl chloride (74.0 g) was added dropwise over 30 minutes to a solution of 2-hydroxymethyl-2-n-propylpropan-1,3-diol 2× 2× 2-hydroxymethyl-2-n-propyl g) (m.pt. (28.0 g) in dry pyridine (200 ml) under nitrogen at 0° C. The mixture was allowed to warm to room temperature. After stirring for 18 hours the mixture was poured into water (200 ml) and extracted with chloroform (2 × 200 ml). The chloroform extracts were washed with water (2 × 100 ml), dried over anhydrous magnesium sulphate and evaporated in vacuo to give a brown solid. This was stirred in dry diethyl ether (200 ml) to give 2-hydroxymethyl-2-n-propyl propan-1,3-diol trimethanesulphonate as a white solid. (70.0 g)(m.pt.103.6°).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1.CO.[OH-].[Na+]>O1CCCC1>[CH3:23][S:20]([C:17]1[CH:16]=[CH:15][C:14]([S:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[CH:5][CH:6]=2)(=[O:13])=[O:12])=[CH:19][CH:18]=1)(=[O:21])=[O:22]
Reactant: COC(=O)c1ccc(NS(=O)(=O)c2ccc(S(C)(=O)=O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1ccc(S(=O)(=O)Nc2ccc(C(=O)O)cc2)cc1
Yield: 90 %

Procedure:
To a stirring solution of 4-(4-methanesulfonyl-benzenesulfonylamino)-benzoic acid methyl ester (0.456 g, 1.26 mmol) in a mixture of tetrahydrofuran (10 mL)/methanol (10 mL) is added 2N sodium hydroxide (2 ml, 4.0 mmol) and the reaction is heated to reflux for 1 hour. The reaction is then concentrated to dryness and the residue is dissolved in 95% dichloromethane/5% isopropanol and washed with 0.1N HCl. The organic layer is separated and dried over anhydrous sodium sulfate, filtered, and concentrated to provide 0.403 g (90%) of the pure title compound. MS (ES−) m/e 354.0 (M−1)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=3[F:23])[N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([N:36]=[C:37]=[O:38])=[O:35])=[CH:29][CH:28]=1.C1(C)C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[N:10]=[CH:11][N:12]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:37]([NH:36][C:34](=[O:35])[CH2:33][C:30]4[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=4)=[O:38])=[CH:18][C:17]=3[F:23])[CH:14]=2)=[CH:24][CH:25]=1
Reactant: COc1ccc(CNc2cc(Oc3ccc(N)cc3F)ncn2)cc1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of N-(4-methoxybenzyl)-6-(4-amino-2-fluorophenoxy)pyrimidin-4-amine (88 mg, 0.26 mmol) in THF (2 mL) was treated with 0.36 M 2-(4-fluorophenyl)acetyl isocyanate in toluene (0.72 mL, 0.26 mmol) and the reaction mixture was stirred at RT for 1 h. The mixture was concentrated in vacuo and the solid obtained was triturated with isopropyl ether to give the title compound (125 mg, 93%) as an off-white solid. 1H NMR (DMSO-d6) δ 11.00 (s, 1H), 10.50 (s, 1H), 8.09 (s, 1H), 7.85 (br s, 0.5 H), 7.66 (d, 1H, J=12.6 Hz), 7.36-7.15 (m, 9.5 H), 6.88 (d, 1H, J=8.1 Hz), 5.91 (s, 1H), 4.42 (br s, 2H), 3.72 (s, 2H), 3.71 (s, 3H); MS(ESI+) m/z 520.14 (M+H)+.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][CH2:7][O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]2[O:18][CH:17]2[CH2:19][CH2:20][C:21]#[N:22])[CH:13]=[CH:14][CH:15]=1.C[Si](C)(C)N[Si](C)(C)C.[Li].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1COCC1>[OH:18][CH:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][O:8][CH2:7][O:6][CH3:5])[CH:11]=1)[CH:17]1[CH2:19][CH:20]1[C:21]#[N:22]
Reactant: COCOCc1cccc(C2OC2CCC#N)c1
Agent: C[Al](C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COCOCc1cccc(C(O)C2CC2C#N)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Under a nitrogen atmosphere, a solution (1.8 M, 5.29 mL) of trimethylaluminum in toluene was added to a solution of 3-(3-(3-((methoxymethoxy)methyl)phenyl)oxiran-2-yl)propanenitrile (1.07 g) in THF (50 mL) at −78° C., and the mixture was stirred at −78° C. for 20 min. To the reaction mixture was added dropwise a solution (1.0 M, 6.49 mL) of lithium hexamethyldisilazane in THF at −78° C., and the mixture was stirred at −78° C. for 30 min. The reaction mixture was stirred at room temperature for 10 min, saturated aqueous ammonium chloride solution was added at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (457 mg, less polar) as a pale-yellow oil and a stereoisomer (345.5 mg, more polar) of the title compound as a pale-yellow oil.
Reaction SMILES: [CH2:1]([N:27]1[C:31]([CH3:33])([CH3:32])[C:30](=[O:34])[N:29]([C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[C:37]([C:44]([F:47])([F:46])[F:45])[CH:36]=2)[C:28]1=[O:48])[CH2:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([C:22]([F:25])([F:24])[F:23])[CH:14]=2)[C:6]1=[O:26].ClC/C=C\CCl>>[CH2:1]([N:27]1[C:31]([CH3:33])([CH3:32])[C:30](=[O:34])[N:29]([C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[C:37]([C:44]([F:47])([F:46])[F:45])[CH:36]=2)[C:28]1=[O:48])/[CH:2]=[CH:3]\[CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([C:22]([F:25])([F:23])[F:24])[CH:14]=2)[C:6]1=[O:26]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCN1C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)C1(C)C
Agent: ClC/C=C\CCl
Product: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1C/C=C\CN1C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)C1(C)C
Yield: 40 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 1, cis-1,4-dichloro-2-butene replacing 1.4 dibromobutane. The expected compound is obtained in the form of a pale yellow solid with a yield of 40%. Melting point: 191-193° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH2:6][C@@H:5]1[CH3:42])(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH3:41][CH:39]([O:38][C:36](=[O:37])[NH:35][C@H:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:16][CH:15]=3)[CH:9]=2)[N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([CH3:42])[CH2:6]1)[CH3:40]
Reactant: CC(=O)N1c2ccc(-c3ccc(CNC4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1c2ccc(-c3ccc(CNC4CCNCC4)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
A solution of 1,1-dimethylethyl 4-[({4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}methyl)amino]-1-piperidinecarboxylate (for a preparation see Intermediate 109) (605 mg, 1.045 mmol) in dichloromethane (DCM) (5 mL) was treated with TFA (1 mL, 12.98 mmol) and the resulting mixture was stirred at room temperature for 1.5 h then concentrated in vacuo. The residue was loaded on a 20 G SCX column and eluted with MeOH then with 2N NH3 in MeOH). The ammonia fractions were combined and concentrated in vacuo to give 1-methylethyl((2S,4R)-1-acetyl-2-methyl-6-{4-[(4-piperidinylamino)methyl]phenyl}-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (443 mg, 0.879 mmol, 84%) as a white glassy solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]3[CH:11]=[CH:10][N:9]=[C:8]4[NH:12][C:13](=[O:15])[NH:14][C:7]=34)[CH:3]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1ccc(Cl)cc1
Yield: 15 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 4-chlorobenzoyl chloride to afford the title compound (11 mg, 15%). 1H-NMR (δ, ppm, DMSO-d6): 6.49 (d, 1H, HPy,5, J=6.0 Hz), 6.91 (d, 1H, Harom, J=8.0 Hz), 7.42 (t, 1H, Harom, J=8.0 Hz), 7.59-7.63 (m, 3H, Harom), 7.65 (d, 1H, Harom, J=8.0 Hz), 7.80 (d, 1H, HPy,6, J=6.0 Hz), 7.96 (d, 2H, Harom, J=9.0 Hz), 10.40 (s, 1H, NHamide), 11.19 (s, 1H, NHPy3), 11.38 (s, 1H, NHPy2). HRMS (EI): m/z [M+H] calcd for C19H14N4O3Cl: 381.0754; found: 381.0753.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:14]([O:16][C:17]([C:19]1[C:20](=[O:42])[C:21]2[CH:26]=[N:25][C:24](S(C)(=O)=O)=[N:23][C:22]=2[N:31]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[CH2:38][CH2:37][CH2:36]3)[CH:32]=1)=[O:18])[CH3:15]>>[CH2:14]([O:16][C:17]([C:19]1[C:20](=[O:42])[C:21]2[CH:26]=[N:25][C:24]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[CH:12][CH:11]=3)=[N:23][C:22]=2[N:31]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[CH2:38][CH2:37][CH2:36]3)[CH:32]=1)=[O:18])[CH3:15]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(N4CCOCC4)cc3)ncc2c1=O
Yield: 64.6 %

Procedure:
Using the procedure outlined in Example 1 (g) the title compound was prepared from 4-morpholin-4-yl-phenylamine (6.5 mg, 0.036 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 15 mg, 0.036 mmol). 11.9 mg of 8-indan-5-yl-2-(4-morpholin-4-yl-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a yellow solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.38 (br, 1H), 8.53 (s, 1H), 7.69 (br, 1H), 7.43 (d, 1H), 7.23 (m, 4H), 6.64 (br, 2H), 4.36 (q, 2H), 3.87 (m, 4H), 3.04 (m, 8H), 2.22 (m, 2H), 1.39 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H29N5O4: 512.24 (M+H), Found: 512.4.
Reaction SMILES: Cl.C([O:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[NH:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=[C:15]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:14]=2)=O)(=O)C.[OH-].[Na+]>CO.O>[CH2:27]([O:26][C:15]1[CH:16]=[CH:17][C:18]2[C:19]3[N:20]([CH2:21][C:22]([CH3:24])([OH:25])[CH3:23])[C:7]([CH2:6][OH:5])=[N:9][C:10]=3[CH:11]=[N:12][C:13]=2[CH:14]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(=O)OCC(=O)Nc1cnc2cc(OCc3ccccc3)ccc2c1NCC(C)(C)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(O)Cn1c(CO)nc2cnc3cc(OCc4ccccc4)ccc3c21
Temperature: 55 °C
Yield: 97.8 %

Procedure:
A mixture of 2-({7-benzyloxy-4-[(2-hydroxy-2-methylpropyl)amino]quinolin-3-yl}amino)-2-oxoethyl acetate hydrochloride (54.0 g, 0.114 mol) in methanol (270 mL) was heated to 55° C., at which point a solution was obtained. A solution of sodium hydroxide (9.2 g, 0.23 mol) in water (90 mL) was then added over a period of five minutes while heating the reaction mixture at reflux. Following the addition, the addition funnel was rinsed with water (10 mL), and the reaction mixture was heated at reflux for one hour. The reaction mixture was then cooled to ˜0° C., and the solid product was isolated by filtration, washed with methanol, deionized water, and a small volume of acetone, and dried under vacuum at 50° C. to provide 42.1 g of 1-[7-benzyloxy-2-(hydroxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as an off-white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)[C@@]2(C3C(=CC4OCCOC=4C=3)OC2)C1=O.Cl[CH2:46][C:47]1[CH:56]=[CH:55][C:50]2[N:51]([CH3:54])[N:52]=[N:53][C:49]=2[CH:48]=1.BrCCCCC>>[CH3:54][N:51]1[C:50]2[CH:55]=[CH:56][C:47]([CH2:46][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]4([C:21]5[C:12](=[CH:13][C:14]6[O:19][CH2:18][CH2:17][O:16][C:15]=6[CH:20]=5)[O:11][CH2:10]4)[C:2]3=[O:22])=[CH:48][C:49]=2[N:53]=[N:52]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: Cn1nnc2cc(CCl)ccc21
Agent: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Solvent: CCCCCBr
Product: Cn1nnc2cc(CN3C(=O)C4(COc5cc6c(cc54)OCCO6)c4ccccc43)ccc21

Procedure:
Following the procedure as described in EXAMPLE 7.3 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 5-(chloromethyl)-1-methyl-1H-benzo[d][1,2,3]triazole to replace 1-bromopentane, 1′-[(1-methyl-1H-benzotriazol-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (15%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.52 (dd, J=8.6, 1.2 Hz, 1H), 7.20-7.28 (m, 1H), 7.18 (d, J=6.9 Hz, 1H), 7.08 (d, J=7.7 Hz, 1H), 7.02 (t, J=7.4 Hz, 1H), 6.54 (s, 1H), 6.08 (s, 1H), 5.10 (ABq, 2H), 4.77 (ABq, 2H), 4.28 (s, 3H), 4.22-4.07 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.8, 154.7, 145.2, 144.2, 142.0, 137.8, 132.9, 132.4, 131.7, 128.8, 126.7, 123.7, 123.1, 121.2, 117.6, 111.3, 110.9, 109.5, 98.9, 79.4, 64.2, 63.6, 57.3, 43.1, 34.2; MS (ES+) m/z 440.9 (M+1).