Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH2:12][C:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[CH:4][C:3]=1[Cl:32].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5]([CH2:12][C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:14][C:15]([OH:17])=[O:16])=[CH:4][C:3]=1[Cl:32]
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)(Cc1cc(Cl)c(N)c(C(F)(F)F)c1)C(=O)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(CC(=O)O)(Cc1cc(Cl)c(N)c(C(F)(F)F)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 30.0 g (62.25 mmol) tert. butyl 4-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-3,3-bis-ethoxycarbonyl-butyrate (Intermediate product 65) in 200 mL CH2Cl2 was added 20 mL TFA while cooling with ice and the mixture was stirred for 16 hours at RT. The reaction mixture was evaporated i. vac. and the residue recrystallised from petroleum ether. The precipitate was filtered off, washed with petroleum ether and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.C(N(C(C)C)C(C)C)C.Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C=O)C>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]([C:11]([C:10]2[C:5]([O:4][C:3]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=3[Cl:1])=[N:6][CH:7]=[CH:8][CH:9]=2)=[O:12])[CH2:14][CH2:15]1)[CH3:43]
Reactant: CCOC(=O)CBr
Reactant: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN1CCN(C(=O)c2cccnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 100 °C
Yield: 58.5 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (60 mg, 0.15 mmol, 1.0 equiv; Example 122) in anhydrous DMF (0.5 mL) was added N-ethyldiisopropylamine (96 mg, 129 μL, 0.75 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and ethyl bromoacetate (55.1 mg, 37 μL, 0.33 mmol, 2.2 equiv; [CAS RN 105-36-2]) and the reaction mixture heated by microwave irradiation to 100° C. for 2 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μM, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 42.7 mg (62%) of the title compound as a light yellow powder. MS (ISP): 486.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:8]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:18][O:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:7][C:6]([CH:19]([F:21])[F:20])=[CH:5][C:3]=1[NH2:4].[CH:22]1([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C:26]2[C:31]3=[N:32][CH:33]=[C:34]([C:35]#[N:36])[N:30]3[N:29]=[C:28](S(C)(=O)=O)[N:27]=2)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:1][C:2]1[C:8]([N:9]2[CH2:10][CH2:11][N:12]([CH:15]3[CH2:18][O:17][CH2:16]3)[CH2:13][CH2:14]2)=[CH:7][C:6]([CH:19]([F:21])[F:20])=[CH:5][C:3]=1[NH:4][C:28]1[N:27]=[C:26]([N:25]([CH:22]2[CH2:24][CH2:23]2)[CH2:41][C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C:31]2=[N:32][CH:33]=[C:34]([C:35]#[N:36])[N:30]2[N:29]=1
Reactant: COc1ccc(CN(c2nc(S(C)(=O)=O)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: Nc1cc(C(F)F)cc(N2CCN(C3COC3)CC2)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(c2nc(Nc3cc(C(F)F)cc(N4CCN(C5COC5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 40 °C
Reaction time: 72 h
Yield: 76.8 %

Procedure:
A mixture of 2-chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)aniline (50 mg, 0.157 mmol), 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (94 mg, 0.236 mmol) and cesium carbonate (103 mg, 0.315 mmol) in DMF (1574 μl) was stirred at 40° C. for 72 h. The reaction mixture was cooled to rt, diluted with H2O and extracted with EtOAc (3×). The combined organics were washed with 10% LiCl solution and concentrated. Column chromatography (12 g SiO2, 0 to 100% EtOAc-hexane gradient elution) afforded 2-((2-chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (76.7 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][C:13](=[O:17])[NH:14]2)=[CH:10][CH:9]=1.[CH3:18][N:19]1[C:23]([NH:24][C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[SH:32])=[CH:22][C:21]([CH3:34])=[N:20]1>[Cu]I>[CH3:18][N:19]1[C:23]([NH:24][C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32][C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][C:13](=[O:17])[NH:14]3)=[CH:10][CH:9]=2)=[CH:22][C:21]([CH3:34])=[N:20]1
Reactant: O=C1Cc2ccc(I)cc2N1
Reactant: Cc1cc(NC(=O)c2ccccc2S)n(C)n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(NC(=O)c2ccccc2Sc2ccc3c(c2)NC(=O)C3)n(C)n1
Temperature: 80 °C
Reaction time: 24 h
Yield: 52.3 %

Procedure:
CuI (40 mg, 0.05 mmol), potassium carbonate (1.66 g, 12 mmol), 6-iodooxindole (as prepared in Preparation 1; 0.5 g, 1.93 mmol) and N-(2,5-Dimethyl-2H-pyrazol-3-yl)-2-mercapto-benzamide (as prepared in step 3 above; 0.477 g, 1.93 mmol) were added to a dry schlenk tube. The tube was evacuated and refilled with Ar(g) (3 times). Isopropanol (3.0 mL) and ethylene glycol (0.250 mL) were injected into the schlenk tube. The schlenk tube was sealed with a teflon valve and was heated to 80° C. and stirred for over 24 hours. Subsequently the reaction mixture was allowed to reach room temperature then diluted with EtOAc (˜20 mL) and water (˜10 mL). The mixture was acidified with 1 M HCl(aq) and the organics were separated and set aside. The aqueous phase was washed with EtOAc (2×20 mL). The organic layers were combined, dried over silica gel, filtered and concentrated in vacuo affording a yellow solid. The solid was then purified via flash silica gel chromatography (gradient eluant 10 to 40% EtOAc in Hexanes) affording the title compound as a pale yellow solid (0.379 g, 1.01 mmol, 52% yield).
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:13][NH2:14]>O1CCOCC1>[CH2:7]([O:6][C:4](=[O:5])[C:3]1[CH:9]=[CH:10][CH:11]=[N:12][C:2]=1[NH:13][NH2:14])[CH3:8]
Reactant: NN
Reactant: CCOC(=O)c1cccnc1Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cccnc1NN
Temperature: 60 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
A solution of ethyl 2-chloronicotinate (10.0 g, 53.9 mmol) and anhydrous hydrazine (2.04 g, 63.8 mmol) in anhydrous 1,4-dioxane (200 mL) was stirred at 60° C. for 2 h. Analysis by LC/MS indicated the starting material was not consumed. Additional amount hydrazine (2.04 g, 63.8 mmol) was added and the reaction mixture was stirred at 60° C. overnight. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The obtained residue was triturated with MeOH (35 mL), the insoluble white solid was removed by filtration and discarded. The methanol solution was concentrated in vacuo to yield a fluffy yellow solid which was triturated in diethylether to yield the title compound as an orange solid (5.4 g, 55%). HPLC/MS (Method D): retention time=1.46 min, [M+H]+=182.3.
Reaction SMILES: ClCCl.[CH3:4][N:5]=[C:6]=[O:7].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[N:16]2[CH2:19][C:18](=[CH:20][S:21]([CH2:24][C:25]3[CH:26]=[C:27]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[CH:28]=[CH:29][CH:30]=3)(=[O:23])=[O:22])[CH2:17]2)=[CH:11][CH:10]=1>O>[CH3:4][NH:5][C:6]([N:34]1[CH2:35][CH2:36][N:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][S:21]([CH:20]=[C:18]3[CH2:17][N:16]([CH:15]([C:12]4[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=4)[C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)[CH2:19]3)(=[O:22])=[O:23])[CH:26]=2)[CH2:32][CH2:33]1)=[O:7]
Reactant: CN=C=O
Reactant: O=S(=O)(C=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)Cc1cccc(N2CCNCC2)c1
Solvent: ClCCl
Solvent: O
Product: CNC(=O)N1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1
Reaction time: 4 h
Yield: 110.1 %

Procedure:
2 cm3 of dichloromethane and then 11.5 mg of methyl isocyanate are successively added, at a temperature close to 20° C., to 54.25 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine. After stirring for 4 hours at a temperature close to 20° C., 0.05 cm3 of water is added to the mixture. After stirring for 15 minutes at the same temperature, the reaction medium is dried over magnesium sulfate, filtered on paper and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. 66 mg of 4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylic acid N-methylamide are thus obtained in the form of a beige lacquer [1H NMR spectrum (400 MHz, CDCl3), δ in ppm):
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(=O)O[C@H:25]1[CH2:29][C@@H:28]([N:30]2[CH:38]=[N:37][C:36]3[C:31]2=[N:32][C:33]([Cl:40])=[N:34][C:35]=3[Cl:39])[CH:27]=[CH:26]1)C.[CH2:42]([C:44]1[CH:48]=[N:47][NH:46][N:45]=1)[CH3:43]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:40][C:33]1[N:32]=[C:31]2[C:36]([N:37]=[CH:38][N:30]2[C@@H:28]2[CH2:29][C@H:25]([N:47]3[CH:48]=[C:44]([CH2:42][CH3:43])[N:45]=[N:46]3)[CH:26]=[CH:27]2)=[C:35]([Cl:39])[N:34]=1
Reactant: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Reactant: CCc1cn[nH]n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1cn([C@@H]2C=C[C@H](n3cnc4c(Cl)nc(Cl)nc43)C2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture comprising triphenylphosphine (0.299 g, 0.874 mmol) and Pd2(dba)3 (0.267 g, 0.291 mmol) in dry THF (5 mL) under an inert atmosphere of argon is stirred at RT for 10 minutes. This mixture is then added to a pre-stirring mixture of carbonic acid (1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl ester ethyl ester (Intermediate AA2) (2.00 g, 5.83 mmol) and 4-ethyl-2H-[1,2,3]triazole (0.594 g, 6.12 mmol) in THF (15 mL). The resulting mixture is stirred at RT overnight and then concentrated in vacuo. The crude product is purified by chromatography on silica eluting with 0-50% EtOAc in iso-hexane to afford the title compound as a white solid. (MH+ 350).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)=[O:38]>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[O:38])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC(=O)c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.1 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 2-bromo-1-(4-methoxyphenyl)ethanone (0.77 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with 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 to give the title compound as a colorless solid (0.68 g, 48%).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[N:5]2[CH2:13][CH2:14][N:15]([C:17]([O:19]C(C)(C)C)=O)[CH2:16][CH:4]2[CH2:3]1.FC(F)(F)C(O)=O.[F:31][C:32]1[CH:40]=[CH:39][C:35](C(Cl)=O)=[CH:34][CH:33]=1>C(Cl)Cl>[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:17]([N:15]2[CH2:14][CH2:13][N:5]3[C:6]4[N:12]=[CH:11][CH:10]=[CH:9][C:7]=4[NH:8][C:2](=[O:1])[CH2:3][CH:4]3[CH2:16]2)=[O:19])=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ncccc3NC(=O)CC2C1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC2CN(C(=O)c3ccc(F)cc3)CCN2c2ncccc2N1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
A solution of the product of Example 64A (0.50 g, 1.570 mmol) in CH2Cl2 (3 mL) was stirred with ice cooling as trifluoroacetic acid (2 mL) was added over 1 minute. The resulting solution was stirred at 0° C. for 50 minutes and then allowed to warm to room temperature for 1 hour. The mixture was concentrated under vacuum, and the residue was taken up in 6% NaOH (12 mL) and CH2Cl2 (5 mL), and p-fluorobenzoyl chloride (0.45 g, 2.8 mmol) was added. The mixture was stirred at room temperature for 13 hours and then filtered through diatomaceous earth with a CHCl3 (25 mL) rinse. The aqueous layer was extracted with CHCl3 (2×25 mL) and the combined extract was dried (Na2SO4) and concentrated under vacuum. The residue was purified by chromatography (SiO2, CH2Cl2-methanol-15 M NH4OH, 95:5:0.5) to provide the title compound: MS (DCI) m/z 341 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:8](F)=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[C:8]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4]
Reactant: Oc1ccccc1
Reactant: Nc1c([N+](=O)[O-])ccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1c([N+](=O)[O-])ccc(Oc2ccccc2)c1F
Temperature: 120 °C
Yield: 93.5 %

Procedure:
To a solution of 2,3-difluoro-6-nitroaniline (200 mg, 1.15 mmol) in DMF (10 ml) was added phenol (108 mg, 1.15 mmol) and potassium carbonate (317 mg, 2.30 mmol). The reaction was heated (120° C.) overnight and then cooled to rt. The reaction was diluted with ethyl acetate (200 mL) and then washed with water (2×100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-50% ethylacetate/hexane to afford the desired product (267 mg, 94%) 1H NMR (300 MHz, DMSO-d6) 7.85 (dd, J=9.8, 2.2 Hz, 1H), 7.34-7.49 (m, 4H), 7.19-7.27 (m, 1H), 7.08-7.16 (m, 2H), 6.21 (dd, J=9.7, 7.8 Hz, 1H); HPLC RT (Method A) 3.48 min.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:31])[C@H:12]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=CC=1)([O-])=O.[CH3:32][NH2:33]>C(Cl)Cl.C(O)C>[CH3:32][NH:33][C:11](=[O:31])[C@H:12]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: CN
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a stirred solution of N-benzyloxycarbonyl-L-phenylalanine p-nitrophenylester (5.0 g, 11.9 mmol) in DCM at 0° C. was slowly added a solution of 8M methylamine (1.5 ml, 11.9 mmol) in ethanol. The reaction immediately turned bright yellow and was stirred for 0.5 h. The reaction was diluted with DCM (50 ml), washed with 10% sodium carbonate (1×50 ml), brine (2×50 ml) and dried over anhydrous magnesium sulphate. Filtration and evaporation gave a white residue which was crystallised from ethyl acetate/hexane to give N-benzyloxycarbonyl-L-phenylalanine methylamide (3.0 g, 81%) as a white crystalline solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[O:14]1[C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1>>[CH3:11][Si:10]([C:9]#[C:8][C:5]1[CH:4]=[C:3]([C:21]2([OH:24])[CH2:22][CH2:23][C:18]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:19][CH2:20]2)[CH:2]=[CH:7][CH:6]=1)([CH3:13])[CH3:12]
Reactant: C[Si](C)(C)C#Cc1ccc(Br)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Product: C[Si](C)(C)C#Cc1cccc(C2(O)CCC3(CC2)OCCO3)c1

Procedure:
The title compound was prepared as a white solid from (4-bromo-phenylethynyl)-trimethyl-silane (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([C:12]1([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]1=[O:24])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:60]1(=[O:70])[NH:64][C:63](=[O:65])[C:62]2=[CH:66][CH:67]=[CH:68][CH:69]=[C:61]12>C1COCC1>[O:65]=[C:63]1[C:62]2[C:61](=[CH:69][CH:68]=[CH:67][CH:66]=2)[C:60](=[O:70])[N:64]1[CH2:2][CH2:3][CH:4]([C:12]1([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:13]1=[O:24])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)CC1(C(CCO)C(=O)OC(C)(C)C)CCN(Cc2ccccc2)C1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CC1(C(CCN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)CCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A solution of tert-butyl α-(2-hydroxyethyl)-3-(2-methylpropyl)-2-oxo-1-(phenylmethyl)-3-pyrrolidineacetate (435 mg, 1.12 mmol) in dry THF (10 mL) is treated with triphenylphosphine (323 mg, 1.23 mmol), diethylazodicarboxylate (194 μL, 1.23 mmol), and phthalimide (181 mg, 1.23 mmol). The solution is allowed to stir overnight at room temperature under N2. The reaction mixture is concentrated and purified by silica gel chromatography (25 g SG, 20% EtOAc/hexane) to give 518 mg (89%) of the title compound as an off-white, amorphous solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([N:40]4[CH2:45][CH2:44][NH:43][C:42](=[O:46])[CH2:41]4)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:47][CH2:48][CH3:49])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:52]I>CN(C)C=O>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([N:40]4[CH2:45][CH2:44][N:43]([CH3:52])[C:42](=[O:46])[CH2:41]4)[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:47][CH2:48][CH3:49])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCNC(=O)C2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCN(C)C(=O)C2)CC1
Reaction time: 0.08 h

Procedure:
4-{1-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-piperazin-2-one (61.8 mg, example 117) was dissolved in N,N-dimethylformamide (1 mL), sodium hydride (60% in mineral oil, 20 mg, Aldrich) was added. After stirring for 5 min, methyl iodide (0.03 mL, Aldrich) was added. The mixture was stirred at ambient temperature for 3 h, and the crude product was purified on a HPLC (reversed phase, eluting with acetonitrile and water) to give the title product (34 mg). HR-MS (ES, m/z) calculated for C39H49C12N6O3 [(M+H)+] 719.3238, observed 719.3242.
Reaction SMILES: [NH:1](/[C:8](/[NH:21][CH:22]([CH3:24])[CH3:23])=[CH:9]\[C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([Cl:19])=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C=O)C.O>[Cl:19][C:15]1[N:14]=[C:13]2[C:12]([C:10](=[O:11])[CH:9]=[C:8]([NH:21][CH:22]([CH3:24])[CH3:23])[N:1]2[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:17][C:16]=1[F:18]
Reactant: CC(C)N/C(=C/C(=O)c1cc(F)c(Cl)nc1Cl)Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Nc1cc(=O)c2cc(F)c(Cl)nc2n1-c1ccccc1
Temperature: 85 °C
Yield: 58.1 %

Procedure:
(2Z)-3-Anilino-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-3-(isopropylamino)-2-propen-1-one (40.0 mg, 0.109 mmol) was dissolved in 4 mL of DMF. NaH (8.70 mg, 0.217 mmol, 60% dispersion in oil) was added and the reaction was heated to 85° C. under argon for 2 h. The reaction mixture was cooled to room temperature and diluted with water and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue using Biotage silica gel chromatography eluting with 100% EtOAc to 95:5 EtOAc:MeOH provided 7-chloro-6-fluoro-2-(isopropylamino)-1-phenyl-1,8-naphthyridin-4(1H)-one (21 mg, 64%) as a white solid: LCMS RT: 2.57 min, MH+: 332.2.
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[CH2:6]([OH:10])[CH2:7][CH2:8][CH3:9].CN1C=CN=C1>>[CH3:3][Si:2]([CH3:5])([CH3:4])[O:10][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C[Si](C)(C)Cl
Reactant: CCCCO
Agent: Cn1ccnc1
Product: CCCCO[Si](C)(C)C
Temperature: 0 °C
Yield: 89.4 %

Procedure:
4.40 g (40.5 mmol) of chlorotrimethylsilane were added dropwise to a solution of 3.00 g (40.5 mmol) of 1-butanol and 11.1 g (135 mmol) of 1-methylimidazole while stirring at 0° C. The reaction mixture was stirred for another 15 minutes at 0-5° C. and for 15 minutes at 20° C., resulting in the formation of a liquid two-phase mixture. The upper phase was separated off to give 5.30 g (theory: 5.93 g) of 1-trimethylsilyloxybutane as a colorless oil having a purity of 90% (GC).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[C:4](=[O:13])[CH:3]=1.C(O[CH:19](N(C)C)[N:20]([CH3:22])[CH3:21])(C)(C)C>CN(C)C=O>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[C:4](=[O:13])[CH:3]=1
Reactant: Cc1ccn(-c2ccsc2)c(=O)c1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1ccn(-c2ccsc2)c(=O)c1
Temperature: 100 °C

Procedure:
A mixture of 4-methyl-1-(3-thienyl)pyridin-2(1H)-one (0.73 g, 3.8 mmol), tert-butoxybis(dimethylamino)methane (3 mL, 15 mmol), and N,N-dimethylformamide (4 mL) is heated in a 100° C. oil bath for 3 hours and then concentrated to dryness under reduced pressure. A quantitative yield of 4-(2-dimethylamino-vinyl)-1-thiophen-3-yl-1H-pyridin-2-one is carried on without further purification.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH:55]([C:58]1[CH:64]=[CH:63][CH:62]=[CH:61][C:59]=1[NH2:60])([CH3:57])[CH3:56]>>[Br:1][C:63]1[CH:62]=[CH:61][C:59]([NH2:60])=[C:58]([CH:55]([CH3:57])[CH3:56])[CH:64]=1
Reactant: [Br-]
Reactant: CC(C)c1ccccc1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CC(C)c1cc(Br)ccc1N
Yield: 55.5 %

Procedure:
In a manner analogous to example 9a, the process is carried out by a reaction of 89 g (185 mmol) of tetra-n-butylammonium tribromide with 25 g (185 mmol) of 2-isopropylaniline. 22 g of 4-bromo-2-isopropyl-phenylamine are obtained (yield=57%).