Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH:11]([NH:17]C(=O)OC(C)(C)C)[C:12]([N:14]([CH3:16])[CH3:15])=[O:13].O1CCOCC1.Cl>C(#N)C>[NH2:17][CH:11]([CH2:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[C:12]([N:14]([CH3:15])[CH3:16])=[O:13]
Reactant: CN(C)C(=O)C(Cc1nc2ccccc2s1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: CN(C)C(=O)C(N)Cc1nc2ccccc2s1
Reaction time: 1 h

Procedure:
The tert-butyl 3-(benzo[d]thiazol-2-yl)-1-(dimethylamino)-1-oxopropan-2-ylcarbamate (0.13 g, 0.37 mmol) was taken up in a 4 M HCl dioxane solution (3 mL) at r.t. After stirring for 1 h. the reaction was concentrated under reduced pressure to give a residue. This was taken up in anhydrous acetonitrile and re-concentrated under reduced pressure 2 times, to finally 2-amino-3-(benzo[d]thiazol-2-yl)-N,N-dimethylpropanamide HCl salt (0.14 g, 100%) as a semisolid residue. Analytical LCMS (M+H)+: m/z=250.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[S:25][C:15]=2[N:16]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3ccccn3)nc3sc(C(F)(F)F)cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3-nitrobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([BH3-])#N.[Na+].[NH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([CH2:32][CH2:33][CH2:34][CH3:35])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=1>C(O)(=O)C.C(O)C>[CH2:32]([CH:26]([CH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][NH:15][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:20][CH:21]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:33][CH2:34][CH3:35]
Reactant: O=CCCc1ccccc1
Reactant: CCCCC(Cc1ccc(OCCN)cc1)C(=O)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCC(Cc1ccc(OCCNCCCc2ccccc2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-phenylpropionaldehyde (0.23 ml), sodium cyanoborohydride (117 mg) and acetic acid (one drop) were added to a solution of ethyl 3-[4-(2-aminoethoxy)phenyl]-2-butylpropionate (500 mg), which is the product of Reference example 6, in ethanol (10 ml). The mixture was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the layers were separated. The ethyl acetate solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified via chromatography on silica gel column using dichloromethane/methanol=19/1 as the eluant to afford the desired compound (460 mg) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1)=[O:8].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:14]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([OH:9])=[O:11])=[C:6]([C:7]([NH:23][CH2:22][CH2:21][CH2:20][CH2:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[O:8])[CH:12]=1
Reactant: NCCCCc1cccnc1
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Product: O=C(O)c1ccc(Cl)cc1C(=O)NCCCCc1cccnc1

Procedure:
When 5-chlorophthalic anhydride was reacted with 4-(3-pyridinyl)butylamine by the procedure of Example 12, the above compound, mp 152°-154° C. was obtained.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:19])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=O)[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=1>>[CH2:1]([NH:8][C:9](=[O:19])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([NH:20][C:21]2[CH:22]=[CH:23][C:24](/[CH:27]=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][CH:26]=2)=[O:18])[N:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1ccc(N)cc1
Reactant: O=C(NCc1ccccc1)Nc1nc(C(=O)O)cs1
Product: CCOC(=O)/C=C/c1ccc(NC(=O)c2csc(NC(=O)NCc3ccccc3)n2)cc1

Procedure:
2-(3-Benzyl-ureido)-thiazole-4-carboxylic acid is coupled with ethyl (E)-3-(4-amino-phenyl)-acrylate in analogy to Example 11 After chromatography on silica gel with methylene chloride-ethanol 98:2 and crystallization from ether there is obtained ethyl (E)-3-[4-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-phenyl]-acrylate, m.p. 207° C., MS: 451 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](SC)[N:9]([CH3:14])[N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[CH:21]=1.[C:22]([NH:25][NH2:26])(=O)[CH3:23]>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:22]([CH3:23])=[N:25][N:26]=[C:10]3[N:9]([CH3:14])[N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[CH:21]=1
Reactant: CC(=O)NN
Reactant: CSC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NN1C
Solvent: CCCCO
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NN2C

Procedure:
A mixture of 7.25 grams (23.0 m moles) of 7-chloro-3-methyl-(methylthio)-5-phenyl-3H-1,3,4-benzotriazepine (Example 27), 4.8 grams (65 moles) of acethydrazide, and 100 ml of n-butanol was stirred and refluxed under nitrogen for about 17 hours. The solvent was removed in vacuo on a rotary evaporator. The residue was dissolved in methylene chloride. The resulting solution was washed with water, dried with magnesium sulfate, and concentrated in vacuo. The residue was dissolved in a minimum amount of warm carbon tetrachloride. The solution was cooled and seeded with product. The precipitate was collected, washed with cold carbon tetrachloride, and air dried to yield the title compound as a yellow solid. The melting point was found to be 224.5°-227.5° C. The structure was confirmed by elemental analysis.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O1CCCC1.Cl>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]#[C:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Brc1ccc(C#Cc2ccccc2)cc1

Procedure:
In a 500-mL three-neck flask were placed 14 g (51 mmol) of p-bromoiodobenzene, 5.2 g (52 mmol) of phenylacetylene, and 98 mg (0.50 mmol) of copper(I) iodide. After the atmosphere in the flask was replaced with nitrogen, 200 mL of tetrahydrofuran and 9.0 mL of triethylamine were placed in the flask, and the mixture was degassed by being stirred under reduced pressure. To this mixture was added 0.34 mg (0.50 mmol) of bis(triphenylphosphine)palladium(II) dichloride, and the mixture was stirred under a nitrogen stream at room temperature for 20 hours. After a predetermined time, 3% hydrochloric acid was added to the mixture, and an organic substance was extracted with ethyl acetate from the aqueous phase. The extracted solution combined with the organic phase was washed with brine and dried with magnesium sulfate. The mixture was subjected to suction filtration through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), and alumina, and the filtrate was concentrated to give a solid. The obtained solid was recrystallized with hexane; thus, 7.4 g of a light-brown powder which was a product was obtained in a yield of 55%.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:11]1[CH:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH2:12]1>C1COCC1>[C:4]1([CH2:3][O:10][CH2:12][CH:13]([OH:11])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: FC(F)(F)c1cccc(OCC2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC(COCc1ccccc1)COc1cccc(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
Sodium hydride (80% dispersion in oil, 0.045 g) was added to a mixture of benzyl alcohol (4 ml) and THF (3 ml) and warmed gently until effervescence ceased. To the cooled solution was added 1,2-epoxy-3-[3-(trifluoromethyl)phenoxy]propane (2.12 g). After stirring for 3 h the mixture was poured into ER (50 ml) and washed with brine. The dried extracts were evporated and the residue distilled (b.p. 140°-144°/0.03 mm) to yield the title compound as an oil (2.25 g). I.r. (Neat) 3420 cm-1
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][C@H:25]([CH2:29][OH:30])[CH:26]([CH3:28])[CH3:27]>>[OH:30][CH2:29][C@@H:25]([NH:24][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)[C@H](N)CO
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N[C@H](CO)C(C)C)cn1
Yield: 86 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using L-valinol instead of 2-aminoethyl isopropylether, to the title compound (220 mg, 86%) which was obtained as a white solid. MS: m/e=394.2 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[C:21]([C:25](Cl)=[O:26])=[CH:20][CH:19]=[CH:18]4)[CH:5]=[CH:4][C:3]1=2.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[C:21]([C:25]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:26])=[CH:20][CH:19]=[CH:18]4)[CH:5]=[CH:4][C:3]1=2
Reactant: C1COCCN1
Reactant: CC1(C)CCC(C)(C)c2cc(Oc3ccc4c(C(=O)Cl)cccc4c3)ccc21
Product: CC1(C)CCC(C)(C)c2cc(Oc3ccc4c(C(=O)N5CCOCC5)cccc4c3)ccc21
Yield: 70.6 %

Procedure:
Utilizing a procedure analogous to that of Example 16(b), 593 mg (1.5 mmol) of 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)naphthoyl chloride were reacted with 320 μl (3.6 mmol) of morpholine to provide 470 mg (70%) of the expected amide, having a melting point of 118°-20° C.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11](OS(C(F)(F)F)(=O)=O)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][S:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.CCN(CC)CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([C:35]2[CH:36]=[CH:37][C:32]([S:31][CH3:30])=[CH:33][CH:34]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(-c2ccc(F)cc2)c(OS(=O)(=O)C(F)(F)F)cnn1Cc1ccccc1
Reactant: CSc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CSc1ccc(-c2cnn(Cc3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1
Temperature: 100 °C
Yield: 67.6 %

Procedure:
A mixture of the product from Example 8 (154 mg, 0.36 mmol), 4-(methylthio)benzeneboronic acid (67 mg, 0.4 mmol), Et3N (0.11 mmol; 0.8 mmol) and Pd(Ph3P)4 (30 mg, 0.025 mmol) in 15 mL of toluene was heated at reflux, about 100° C. for about 45 minutes. The mixture was concentrated in vacuo and the residue purified by column chromatography (hexanes-ethyl acetate 3:1) to provide the title compound (yield: 98 mg, 68%). 1H NMR (300 MHz, CDCl3) δ 2.47 (s, 3H), 5.38 (s, 2H), 6.98 (m, 4H), 7.12 (m, 2H), 7.20 (m, 2H), 7.35 (m, 3H), 7.54 (m, 2H), 7.86 (s, 1H). MS (DCI/NH3) m/z 403 (M+H)+, 420 (M+NH4)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][CH:16]=2)[NH:13][CH2:12][CH2:11][CH2:10]3)[CH:2]=1.[C:17]([N:25]=C=O)(=[O:24])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][CH:16]=2)[N:13]([C:17]([NH2:25])=[O:24])[CH2:12][CH2:11][CH2:10]3)[CH:2]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: c1cncc(-c2cnc3c(c2)CCCN3)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)N1CCCc2cc(-c3cccnc3)cnc21
Temperature: 50 °C
Yield: 55.7 %

Procedure:
6-Pyridin-3-yl-1,2,3,4-tetrahydro-[1,8]naphthyridine (50 mg, 0.24 mmol) and benzoyl isocyanate (58 mg, 0.36 mmol) are dissolved in 1.5 mL of DCM. The mixture is heated at 50° C. for 5 hrs. Then the solvent is removed in vacuum and the residue is dissolved in 1.5 mL of EtOH. K2CO3 (56 mg, 0.40 mmol) is added and the mixture is heated at 80° C. for 55 min. Then the solvent is removed and the residue is partitioned between water (35 mL) and EtOAc (55 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. To the crude product is added EtOAc (1 mL) and the white solid formed is filtered, rinsed with EtOAc/heptane (1:1) mixture and dried to give 34 mg of the titled product.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13](Cl)[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([CH2:20][OH:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([CH3:33])[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([C:23]3[C:24]([CH3:29])=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=3[CH3:33])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([CH2:20][OH:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Reactant: O=c1c(CO)nn(Cc2ccccc2)c2cccc(Cl)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2cccc3c2c(=O)c(CO)nn3Cc2ccccc2)c(C)c1
Temperature: 100 °C
Yield: 47.2 %

Procedure:
A mixture of 0.144 g (0.479 mmol) of 1-benzyl-5-chloro-3-(hydroxymethyl)cinnolin-4(1H)-one, 0.126 g (0.766 mmol) of mesityl boronic acid, 0.111 g (0.096 mmol) of tetrakis and 0.254 g (1.20 mmol) of potassium phosphate in 8 mL of DMF was heated to 100° C. for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate containing 5% hexanes. The combined organic layers were washed with brine, dried over sodium sulfate, filtered through a plug of silica gel and concentrated in vacuo onto silica gel. The crude material was purified by flash chromatography eluting with a 25% ethyl acetate/hexanes mixture to give 0.087 g (47%) of the title compound as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:27])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:25][CH3:26])=[C:16]([CH2:19][NH:20][CH2:21][CH2:22][O:23][CH3:24])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC[O:30][C:31]([C@H:33](OS(C(F)(F)F)(=O)=O)[CH3:34])=[O:32]>>[Cl:1][C:2]1[C:3]([F:27])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:25][CH3:26])=[C:16]([CH2:19][N:20]([CH2:21][CH2:22][O:23][CH3:24])[C@H:33]([C:31]([OH:32])=[O:30])[CH3:34])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Reactant: COCCNCc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC
Product: COCCN(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)[C@@H](C)C(=O)O

Procedure:
N-(3-Chloro-2-fluorophenyl)-7-methoxy-6-{[(2-methoxyethyl)amino]methyl}quinazolin-4-amine was coupled with ethyl O-trifluoromethanesulfonyl-D-lactate and hydrolysed using analogous methods to those described for the equivalent steps in Example 46 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-(2-methoxyethyl)-L-alanine; 1H NMR Spectrum: (DMSO-d6) 1.28 (d, 3H); 2.85 (t, 2H); 3.13 (s, 3H); 3.34 (m, 2H); 3.56 (q, 1H); 3.93 (m, 5H); 7.18 (s, 1H); 7.28 (t, 1H); 7.48 (t, 1H); 7.57 (m, 1H); 8.41 (m, 2H); 9.70 (brs, 1H); Mass Spectrum: (M+H)+ 463.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[N:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1>>[CH:29]1([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH:19]3[CH2:18][CH2:17][N:16]([C:14]([C:11]4[CH:10]=[CH:9][C:8]([N:1]5[CH2:5][CH2:4][CH2:3][C:2]5=[O:6])=[N:13][CH:12]=4)=[O:15])[CH2:21][CH2:20]3)=[CH:24][CH:25]=2)[CH2:30][CH2:31]1
Reactant: O=C1CCCN1
Reactant: O=C(c1ccc(Br)nc1)N1CCC(Oc2ccc(C3CC3)cc2)CC1
Product: O=C(c1ccc(N2CCCC2=O)nc1)N1CCC(Oc2ccc(C3CC3)cc2)CC1
Yield: 58.7 %

Procedure:
Using pyrrolidin-2-one (94 mg) and (6-bromopyridin-3-yl)[4-(4-cyclopropylphenoxy)piperidin-1-yl]methanone (401 mg) described in Preparation Example 192 and by the reaction and treatment in the same manner as in Example 1, the title compound (238 mg) was obtained.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:22][C:21]=1[CH:34]([CH3:38])[CH2:35][CH2:36][OH:37])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1.Cl>[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)([O:37][CH2:36][CH2:35][CH:34]([C:21]1[CH:22]=[C:23]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:25][C:20]=1[O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:38])(=[O:3])=[O:2]
Reactant: CC(CCO)c1cc(OCc2ccccc2)ccc1OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(C)c2cc(OCc3ccccc3)ccc2OCc2ccccc2)cc1
Reaction time: 18 h

Procedure:
Tosyl chloride (11.1 g., 58.1 mM) is added to a solution of 3-(2,5-dibenzyloxyphenyl)-1-butanol (20.7 g., 57 mM) in pyridine (90 ml.) at -45° C. The reaction mixture is held at -35° C. for 18 hours and is then diluted with cold 2 N hydrochloric acid (1500 ml.) and extracted with ether (5×250 ml.). The combined extracts are washed with saturated sodium chloride solution (4×250 ml.) and then dried (Na2SO4). Concentration of the dried extract affords the product which may be purified by standard methods, if desired.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@@H:17]([O:38][Si](C(C)(C)C)(C)C)[CH2:18][C@@H:19]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[CH2:20][C:21]1[CH:26]=CN=[CH:23][CH:22]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[OH:47]>ClCCl>[C:1]([NH:8][C@H:9]([C@@H:17]([OH:38])[CH2:18][C@@H:19]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[CH2:20][C:21]1[CH:22]=[CH:23][O:47][CH:26]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccncc1)NC(=O)OCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reactant: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccoc1)NC(=O)OCc1cccnc1
Yield: 60 %

Procedure:
Using the procedure of Example 4G but replacing (2S,3S,5S)-2-(Boc-amino)-5-(N-((3-pyridinyl)methoxy-carbonyl)amino)-1-phenyl-6-(4-pyridinyl)-3-(tert-butyl-dimethylsilyloxy)hexane with the resultant compound of Example 5D provided, after silica gel chromatography using 5% methanol in dichloromethane, 334.5 mg (60%) of the desired compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=2)[C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:5]=[C:4](Br)[N:3]=1.[H-].[Na+].[CH3:36][O:37][CH2:38][CH2:39][OH:40]>C1COCC1>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=2)[C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:5]=[C:4]([O:40][CH2:39][CH2:38][O:37][CH3:36])[N:3]=1
Reactant: COCCO
Reactant: CCOC(=O)N(Cc1ccc(CP(=O)(OCC)OCC)cc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccc(CP(=O)(OCC)OCC)cc1)c1cc(OCCOC)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of ethyl (2-amino-6-bromo-3-nitropyridin-4-yl)(4-((diethoxyphosphoryl)methyl)benzyl)carbamate (1 equiv.) in THF (0.30 M) was added sodium hydride (5 equiv.) in a solution of 2-methoxyethanol (0.50 M). The reaction mixture was allowed to stir at room temperature for 2 h. At this point the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH™ system using a gradient of 0-5% MeOH/DCM to provide the title compound (68%) as a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH:21][C:22]2[S:23][C:24]([CH:27]=O)=[CH:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]1>>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH:21][C:22]2[S:23][C:24]([CH2:27][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]1
Reactant: C1CCNCC1
Reactant: COc1cc(Nc2ncc(C=O)s2)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2ncc(CN3CCCCC3)s2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 57 from 16 mg (0.19 mmol) piperidine and 65 mg (0.21 mmol) 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazole-5-carbaldehyde. The reaction was not complete and the same amount of reagent was added like in example 57. The crude product was purified on silica gel with methylene chloride/methanol 9/1 yielding 36 mg (50%) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(5-piperidin-1-ylmethyl-thiazol-2-yl)-amine as a yellow oil. MS ISP (m/e): 384.3 (100) (M+H)+. 1H NMR (CDCl3, 250 MHz): δ (ppm)=7.64 (s, 1H), 7.25 (d, 1H), 7.18 (d, 1H), 7.08 (s, 1H), 6.96 (d, 1H), 6.87 (s, 1H), 3.85 (s, 3H), 3.59 (s, 2H), 2.42 (m, 4H), 2.30 (s, 3H), 1.59-1.54 (m, 4H), 1.45-1.43 (m, 2H).