Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.C(Cl)Cl.[CH2:11]([N:15]1[C:23]([N:24]2[CH2:29][CH2:28][NH:27][C@@H:26]([CH3:30])[CH2:25]2)=[N:22][C:21]2[C:16]1=[N:17][C:18]([C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=1)=[N:19][C:20]=2[N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[CH:12]([CH3:14])[CH3:13].[C:44](OC(=O)C)(=[O:46])[CH3:45]>C(Cl)Cl.CO>[C:44]([N:27]1[CH2:28][CH2:29][N:24]([C:23]2[N:15]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:16]3[C:21]([N:22]=2)=[C:20]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:19]=[C:18]([C:37]2[CH:42]=[N:41][C:40]([NH2:43])=[N:39][CH:38]=2)[N:17]=3)[CH2:25][C@@H:26]1[CH3:30])(=[O:46])[CH3:45]
Reactant: CC(C)Cn1c(N2CCN[C@@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 83.3 %

Procedure:
Triethylamine (86.3 μl, 0.62 mmol) was added to a methylene chloride solution (3.0 ml) of 5-{9-isobutyl-8-[(3S)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (116.8 mg, 0.26 mmol) at room temperature followed by the addition of acetic anhydride (29.2 μl, 0.31 mmol) with ice cooling. The resulting mixture was stirred at room temperature for 70 minutes and then the reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (107.1 mg, 84%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of 0.844 g (4 mmol) of 4-chlorobenzenesulphonyl chloride in 5 ml of dichloromethane is added dropwise to a solution of 0.857 g (4 mmol) of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, 0.99 ml (6 mmol) of diisopropylethylamine and 0.024 g (0.2 mmol) of 4-dimethylaminopyridine in 9 ml of dichloromethane. The mixture is stirred at ambient temperature overnight. The organic phase is washed with 10 ml of water and then 4 ml of a 1N aqueous hydrochloric acid solution, 2 times 14 ml of water, 2 times 14 ml of a 1N aqueous sodium hydroxide solution, 3 times 14 ml of water and 14 ml of a saturated aqueous sodium chloride solution. It is dried over sodium sulphate and evaporated to dryness in order to obtain 1.371 g (3.52 mmol) of product in the form of an orange paste used as is in the following stage.
Reaction SMILES: [I-].[CH3:2][N+:3]1([CH3:13])[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH:4]1[CH3:12].[OH2:14]>>[OH-:14].[CH3:2][N+:3]1([CH3:13])[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH:4]1[CH3:12]
Reactant: O
Agent: *CC*
Agent: CC1CC2CCCCC2[N+]1(C)C
Agent: [I-]
Product: [OH-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The reaction afforded the desired quaternized salt in 88% yield (37 g) as off-white shinny powder. The obtained 1,1,2-trimethyloctahydroindolium iodide was dissolved in 130 ml of deionized water in 250 ml polyethylene plastic bottle. To the solution, 41 g of Bio-Rad AG 1-X8 ion exchange resins was added and the slurry was gently stirred at room temperature overnight. The slurry was then filtered and the resin was rinsed with additional 50 ml water (deionized). A small aliquot of the water layer was analyzed by titration with 0.1 N HCl to show 96% yield of the desired 1,1,2-trimethyloctahydroindolium hydroxide in solution.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH:10]([CH3:12])[CH3:11])[N:3]=1.[CH2:13]([NH2:15])[CH3:14].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:8][C:6]1[N:7]=[C:2]([NH:15][CH2:13][CH3:14])[N:3]=[C:4]([NH:9][CH:10]([CH3:12])[CH3:11])[N:5]=1
Reactant: CCN
Reactant: CC(C)Nc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCNc1nc(Cl)nc(NC(C)C)n1

Procedure:
To the solution of 2,4-dichloro-6-isopropylamino-s-triazine in toluene remaining in the reactor are added, under strong agitation, about 915 g of an aqueous solution containing 50% by weight of ethylamine (10.15 moles) and about 1353 g of an aqueous solution containing 30% by weight of sodium hydroxide (10.15 moles). The said solutions are added in the same manner as in the first reaction step. During the second addition the temperature rises from 25° to 50° C. and the final pH is equal to 11-12. The dense suspension thus obtained is divided into two parts as quickly as possible. One part (A) is submitted to distillation to remove the toluene in the form of an azeotropic toluene-water mixture, by operating at 85°-100° C. To the distillation residue are added 3,700 ml of water and the suspension thus obtained is filtered at 60° C. The filtered solid is washed until the sodium chloride has been removed completely. After drying for ten hours in an oven at 100° C., 2-chloro-4-ethylamino-6-isopropylamino-s-triazine is obtained with a yield of the order of 96%.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH:10]([CH2:15][NH:16]C(OCC1C=CC=CC=1)=O)[CH2:11][CH:12]([CH3:14])[CH3:13])(=[O:8])[O:5]CC)C.Cl.O1CCOCC1.C(O)(=O)C>O>[NH2:16][CH2:15][CH:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:9][P:4](=[O:3])([OH:8])[OH:5]
Reactant: CCOP(=O)(CC(CNC(=O)OCc1ccccc1)CC(C)C)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)CC(CN)CP(=O)(O)O

Procedure:
Adding the product of step f) above to a solvent selected from toluene, benzene, xylenes, or n-heptane to which methanol or tert-butanol was added to give (8) and then adding (8) to aqueous hydrochloric acid at a concentration of from 0.01 M to 12 M in the presence or absence of a solvent such as 1,4-dioxane, acetic acid or water to produce the amino acid (9); or adding the product of step f) above to a solvent selected from toluene, benzene, xylenes, or n-heptane to which benzyl alcohol was added to give (8) and then hydrogenating (8) over nickel or palladium or platinum to give lactam which was then hydrolyzed using aqueous hydrochloric acid at a concentration of from 0.01 M to 12 M in the presence or absence of a solvent such as 1,4-dioxane, acetic acid, or water to produce Example 42.
Reaction SMILES: C([Si]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][C:13]2([CH2:20][CH2:19][CH:18]([O:21][CH3:22])[CH2:17][CH2:16]2)[CH2:12][CH2:11]1)(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:22][O:21][CH:18]1[CH2:17][CH2:16][C:13]2([CH2:14][CH2:15][CH:10]([CH2:9][OH:8])[CH2:11][CH2:12]2)[CH2:20][CH2:19]1
Reactant: COC1CCC2(CCC(CO[Si](C)(C)C(C)(C)C)CC2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COC1CCC2(CCC(CO)CC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
To a solution of the crude tert-butyl-(9-methoxyspiro[5.5]undec-3-ylmethoxy)-dimethylsilane (393 mg) obtained in Step 5 in tetrahydrofuran (5 mL) was added a 1M tetrahydrofuran solution of tetra-n-butylammonium fluoride (3 mL) under ice-cooling, followed by stirring the reaction mixture at room temperature for 1.5 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:19 to 1:4) to give (9-methoxyspiro[5.5]undec-3-yl)methanol (217 mg).
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: OCCCCCBr
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N1CCN(CCCCCO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
Ethyl N-piperazinecarboxylate (25.50 g, 161.39 mmol), 5-bromo-1-pentanol (26.96 g, 161.39 mmol), potassium carbonate (55.68 g, 403.48 mmol) and anhydrous acetonitrile (200 mL) were placed in a 500 mL round-bottomed flask and heated under reflux with stirring overnight; the reaction system was cooled down to room temperature, filtered, concentrated and separated by column chromatography (eluent: dichloromethane/methanol/triethylamine system, v/v/v 100:1:0.5), to obtain a pale yellow oil 20.48 g, yield 52.0% (which was directly used in the next step reaction).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13]Cl)[CH:10]([CH2:15]Cl)[CH2:9][N:8]=[C:7]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:6]=2[CH:22]=1.[OH-].[Na+].[CH3:25][NH2:26]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][N:26]([CH3:25])[CH2:15][CH:10]3[CH2:9][N:8]=[C:7]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:6]=2[CH:22]=1
Reactant: ClCCN1c2ccc(Cl)cc2C(c2ccco2)=NCC1CCl
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CCN2c3ccc(Cl)cc3C(c3ccco3)=NCC2C1

Procedure:
3.4 g of 7-chloro-1-(β-chloroethyl)-2-chloromethyl-5-(2-furyl)-2,3-dihydro-1H -1,4-benzodiazepine in 100 ml of methanol are left to react with 0.8 g of sodium hydroxide in 1 ml of water and 2.5 g of methylamine at 95° C. in an autoclave for 5 hours. The reaction mixture is then worked up in the customary manner and the reaction product is purified by chromatography on aluminium oxide of activity level II, using methylene chloride/chloroform, and the fractions containing the product of medium polarity are separated off and the 1,2,3,4,4a,5-hexahydro-9-chloro-3-methyl-7-(2-furyl)-pyrazino[1,2-a]-[1,4]benzodiazepine obtained therefrom is dissolved in isopropanol and converted into its salt with alcoholic hydrochloric acid. This salt crystallises from isopropanol as the dihydrochloride hemihydrate with 0.1 mol of isopropanol. Melting point: >240° C., yield: 0.8 g.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[C:12]([OH:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=1.[P:17]([O:22]C)([O:20][CH3:21])[O:18][CH3:19]>>[CH3:19][O:18][P:17]([CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[C:12]([OH:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=1)(=[O:22])[O:20][CH3:21]
Reactant: COP(OC)OC
Reactant: CC(C)(O)C(=O)c1ccc(OCCBr)cc1
Product: COP(=O)(CCOc1ccc(C(=O)C(C)(C)O)cc1)OC
Temperature: 130 °C
Yield: 54.8 %

Procedure:
A mixture of 5.80 grams (0.0202 mol) of 1-[4-(2-bromoethoxy)phenyl]-2-hydroxy-2-methylpropan-1-one and 6.27 g (0.0505 mol) of trimethyl phosphite is heated to 130° C. for 16 hours. The crude product is passed through a short column of silica gel which is eluted with a mixture of 1:1 heptane:ethyl acetate followed by methanol. Evaporation of solvent gives 3.5 g (55% yield) of the title compound as a yellow oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(O[CH:14]=[C:15]([C:21]#[N:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH2:19]([O:18][C:16]([C:15]1[CH:14]=[N:10][N:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[C:21]=1[NH2:22])=[O:17])[CH3:20]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1N
Yield: 74 %

Procedure:
A stirred mixture of 11.38 g (70.0 mmole) of a commercially available sample of 4-fluorophenylhydrazine hydrochloride, 11.84 g (70.0 mmole) of ethyl (ethoxymethylene)cyanoacetate and 9.67 g (70.0 mmole) of potassium carbonate in 100 ml of ethanol was refluxed overnight and then treated with 300 ml of water. The precipitate was filtered and dried in vacuo to furnish 12.87 g (74% yield) of pale yellow crystalline solid. The sample was recrystallized from ethanol m.p. 151-2° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13].Cl.[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: O=C(Cl)CCCCCCBr
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCCCBr)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Aluminum chloride (1.23 g) was added to a solution of 7-bromoheptanoyl chloride (2 g) in benzene (20 ml) under ice-cooling, which was followed by stirring at room temperature for 1 hr. Ice water and conc. hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography to give 0.93 g of 7-bromo-1-phenyl-1-heptanone.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O.O>[CH2:11]([O:10][C:6]1[CH:5]=[C:4]([I:3])[CH:9]=[CH:8][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1cccc(I)c1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Ic1cccc(OCc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride (20 g, 0.5 mol) in dimethylformamide (300 ml), a solution of m-iodophenol (100 g, 0.454 mol}in dimethylformamide was added dropwise and then stirring was continued for 30 min at 70°±5° C. To this reaction mixture, benzyl chloride (57.4 g, 0.454 mol) was added dropwise and the reaction was continued for 2 hours at 100°±5° C. The resultant mixture was taken up in H2O (1l) and extracted with ethyl acetate. The organic extract was washed with H2O, dried over anhydrous MgSO4 and then evaporated. The residual solid was recrystallized from ethanol to give the title compound as white crystals; yield: 119.7 g; mp. 51.0°-53.0° C.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([NH:29][C:30](=[O:42])[CH2:31][C:32]([NH:34][C:35]2C=CC(F)=[CH:37][CH:36]=2)=O)[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:15]2=[C:16]([CH3:28])[C:17]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26]O[CH2:24][CH2:23]3)=[CH:18][N:14]2[N:13]=[CH:12][N:11]=1.Cl.Cl.FC1C=C(NC(NC(=O)CC2C=CC(F)=CC=2)=S)C=CC=1O[C:53]1C2=C(C)C(OCCN3CCN(C)CC3)=CN2N=C[N:54]=1.Cl>>[ClH:1].[ClH:1].[ClH:1].[F:2][C:3]1[CH:4]=[C:5]([NH:29][C:30](=[O:42])[C:31]2[CH:37]=[CH:36][CH:35]=[N:34][CH:32]=2)[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:15]2=[C:16]([CH3:28])[C:17]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][N:54]([CH3:53])[CH2:24][CH2:23]3)=[CH:18][N:14]2[N:13]=[CH:12][N:11]=1
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=O)c4cccnc4)cc3F)c12

Procedure:
Following a procedure similar to that for the synthesis of Compound D of Example 36, 3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (20 mg, 0.05 mmol, Compound B of Example 45) was converted the tile compound (10 mg, 32%) as a 3.HCl salt. 1H NMR (CD3OD) δ 9.46 (s, 1H), 9.20 (d, 1H), 9.08 (d, 1H), 8.29 (m, 1H), 7.92 (d, 1H), 7.81 (s, 1H), 7.82 (s, 1H), 7.61 (m, 1H), 7.42 (m, 1H), 4.54 (m, 2H), 3.82-4.05 (m, 10H), 3.05 (s, 3H), 2.51 (s, 3H); MS(ESI+) m/z 506.2 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)=O>C(O)C.[OH-].[OH-].[Pd+2]>[NH:8]1[CH2:13][CH2:12][C:11]2([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:10][CH2:9]1
Reactant: c1ccc(CN2CCC3(CCCCc4ccccc43)CC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Solvent: CCO
Product: c1ccc2c(c1)CCCCC21CCNCC1
Yield: 65.6 %

Procedure:
A solution of 1'-benzylspiro[6,7,8,9-tetrahydro-5H-benzocyclohepten-5,4'-piperidine] (526 mg, 1.7 mmol) in ethanol (100 ml), containing formic acid (6 ml), was hydrogenated at 50 p.s.i. in the presence of palladium hydroxide on carbon (Pearlman's catalyst) (250 mg, 50% (w/w)) for 6 hours. The solution was filtered and the solvents removed in vacuo. The residue was taken up in ethyl acetate (50 ml) and washed with 10% (w/v) potassium hydroxide in water (50 ml). The organic phase was separated and the aqueous layer extracted once more with ethyl acetate (50 ml). The combined organic layers were dried (MgSO4) and the solvents removed in vacuo to give spiro [6,7,8,9-tetrahydro-5H-benzocyclohepten-5,4'-piperidine] (240 mg, 65%), which was used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH:22][C:23](=[O:39])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[O:37][N:36]=[C:35]([CH3:38])[CH:34]=2)[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]([N:14]([CH3:15])[C:12]1[C:11]([C:20]#[N:21])=[CH:10][C:9]2[NH:22][C:23](=[O:39])[CH2:24][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[O:37][N:36]=[C:35]([CH3:38])[CH:34]=4)[CH:28]=3)=[N:7][C:8]=2[CH:13]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C#N)c(N(C)CC(C)C)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)CC(C)C)c(C#N)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (4-cyano-5-(isobutyl-methyl-amino)-2-{3-[3-(3-methyl-isoxazol-5yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M97) (0.39 g, 0.71 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (230 mg, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[N:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:13])[C:9]([F:10])([F:11])[F:12])=[N:6][CH:7]=1
Reactant: OC(c1ccc(Cl)cn1)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.5 %

Procedure:
To a solution of 1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethanol (0.643 g, 3.04 mmol) in DCM (9 mL) at 0° C. was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (1.55 g, 3.65 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 20 h before quenching with saturated NaHCO3 (10 mL) and saturated sodium thiosulfate solution. The reaction mixture was stirred for 20 min and transferred to a separatory funnel. The aqueous phase was discarded and the organic phase was washed with brine and dried over MgSO4 The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (5% to 30% EtOAc in heptane) to afford the title compound (0.545 g, 2.60 mmol, 86% yield) as a pale yellow oil. LC/MS (ESI+) m/z=209.9 (M+H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1.C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:48]=[N+:49]=[N-:50])(=O)=O)(C)C.C(O)(=O)C>O1CCCC1.C(OCC)C>[CH3:29][C:26]1[CH:25]=[CH:24][C:23]([C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH3:11])=[CH:17][CH:16]=2)([N:48]=[N+:49]=[N-:50])[C:19]([O:21][CH3:22])=[O:20])=[CH:28][CH:27]=1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: COC(=O)C(c1ccc(C)cc1)c1ccc(C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C(N=[N+]=[N-])(c1ccc(C)cc1)c1ccc(C)cc1
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
Sodium bistrimethylsilylamide (1M solution in tetrahydrofuran, 9.82 ml) was added to a solution of methyl bis(4-methylphenyl)acetate (2.08 g, 8.18 mmol) dissolved in tetrahydrofuran(10 mL) and cooled to −78° C. under a nitrogen atmosphere. The reaction was stirred for 2.5 hours and then a solution of 2,4,6-triisopropylbenzenesulfonyl azide (2.78 g, 9 mmol) in tetrahydrofuran(6 mL) was added. This mixture was stirred for 45 minutes and then warmed to room temperature and stirred for an additional two hours. Glacial acetic acid (1.5 ml) was added and the mixture was stirred for 30 minutes. The reaction was diluted with diethyl ether and washed with saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, filtered and concentrated to afford crude product. This material was chromatographed on a column of silica gel eluting with 10% ethyl acetate/hexane to give the purified title compound as an oil which was used as is.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][C:7]1=[O:12].Br[CH2:14][C:15]1[C:16]([CH3:22])=[N:17][C:18]([Cl:21])=[CH:19][CH:20]=1.Cl>C1COCC1.O>[Cl:21][C:18]1[N:17]=[C:16]([CH3:22])[C:15]([CH2:14][O:3][CH2:4][CH2:5][N:6]2[CH2:11][CH2:10][O:9][CH2:8][C:7]2=[O:12])=[CH:20][CH:19]=1
Reactant: Cc1nc(Cl)ccc1CBr
Reactant: O=C1COCCN1CCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(Cl)ccc1COCCN1CCOCC1=O
Temperature: 0 °C

Procedure:
Sodium hydride (190 mg of a 60%, 4.76 mmol) was suspended in THF (12.2 mL) and cooled to 0° C. 4-(2-Hydroxyethyl)morpholin-3-one (230 mg, 1.59 mmol) was added and the slurry was stirred for thirty minutes at 0° C. 3-(Bromomethyl)-6-chloro-2-methylpyridine (Example 421 Step 2) (350 mg, 1.59 mmol) was added and the solution was heated to 50° C. overnight. The reaction mixture was then cooled to ambient temperature, diluted with water, acidified using 1 N aqueous hydrochloric acid, and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography (0-2% methanol in ethyl acetate) to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[CH:15]=[CH:16][N:17]=[C:13]3[NH:12][C:11]([CH3:18])=[C:10]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][CH:4]=1)#[N:2].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[N:14]3[CH:15]=[CH:16][N:17]=[C:13]3[N:12]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=3)[C:11]([CH3:18])=[C:10]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7][CH:8]=1)#[N:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C1=C(C)Nc2nccn2C1c1ccc(C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nccn2C1c1ccc(C#N)cc1
Reaction time: 12 h

Procedure:
(rac)-Ethyl 5-(4-cyanophenyl)-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine-6-carboxylate (152 mg, 0.49 mmol), 3-(trifluoromethyl)phenylboronic acid (187 mg, 0.1 mmol, 2 eq.), anhydrous copper(II) acetate (181 mg, 0.1 mmol, 2 eq.) and molecular sieve (200 mg, 4 Å) were initially charged. Under an atmosphere of argon protective gas, abs. dichloromethane (5 ml), pyridine (80 μl, 0.1 mmol, 2 eq.) and triethylamine (137 μl, 0.1 mmol, 2 eq.) were added. After 12 h of stirring, more anhydrous copper(II) acetate (181 mg, 0.1 mmol, 2 eq.) and triethylamine (137 μl, 0.1 mmol, 2 eq.) were added, and the mixture was stirred for a further 48 h. The reaction was then filtered through kieselguhr, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.05% TFA). After lyophilization, the product was obtained as a solid (26 mg, 12% of theory).