Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[NH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1.C(=O)([O-])O.[Na+]>C1COCC1>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([C:16]2[CH:15]=[C:14]3[C:19]([CH2:20][CH2:21][C:12]([C:10]([NH:9][C:6]4[CH:5]=[CH:4][C:3]([CH2:2][NH:29][C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)=[CH:8][CH:7]=4)=[O:11])=[CH:13]3)=[CH:18][CH:17]=2)=[CH:23][CH:24]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Reactant: Nc1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CNc4cccnc4)cc2)CC3)cc1
Temperature: 25 °C
Yield: 8.1 %

Procedure:
In THF (7 ml) was dissolved N-[4—(chloromethyl)-phenyl]-7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150 mg), and to the mixture was added 3-aminopyridine (109 mg). The mixture was refluxed for 45 hours. The reaction mixture was cooled to room temperature, and to the mixture was added 5% sodium hydrogen carbonate solution (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=3/1) and recrystallized from ethyl acetate-hexane to give 7—(4-methylphenyl)-N-[4-[N-(3-pyridyl)aminomethyl]phenyl]-3,4-dihydronaphthalene-2-carboxamide (Compound 47) (14 mg) as colorless crystals.
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][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[OH:31]>>[OH:31][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]1[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
Reactant: NC1CCCCC1O
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCCC2O)cn1
Yield: 50 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using rac-(cis and trans)-2-aminocyclohexanol instead of 2-aminoethyl isopropylether, to the title compound (130 mg, 50%) which was obtained as a white solid. MS: m/e=408.4 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][N:5]([CH:22]([CH3:24])[CH3:23])[C:6]([C:8]1[N:9]=[C:10]([N:13]2[CH2:16][CH:15](OS(C)(=O)=O)[CH2:14]2)[S:11][CH:12]=1)=[O:7])(=[O:3])[NH2:2].[C:25]([O-:28])(=[S:27])[CH3:26].[K+]>CN(C)C=O>[C:25]([S:27][CH:15]1[CH2:14][N:13]([C:10]2[S:11][CH:12]=[C:8]([C:6](=[O:7])[N:5]([CH2:4][C:1](=[O:3])[NH2:2])[CH:22]([CH3:23])[CH3:24])[N:9]=2)[CH2:16]1)(=[O:28])[CH3:26]
Reactant: CC([O-])=S
Reactant: CC(C)N(CC(N)=O)C(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N(CC(N)=O)C(C)C)cs2)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
To a solution of 1-[4-(N-carbamoylmethyl-N-isopropyl-carbamoyl)-1,3-thiazol-2-yl]-3-methanesulfonyloxyazetidine (516 mg, 1.37 mmol) (obtained as described in Reference Example 49(5)) in dimethylformamide (15 ml) was added potassium thioacetate (939 mg, 8.22 mmol) at room temperature. The mixture was stirred in an oil bath (90° C.) for 3 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (20:1) as the eluant to afford 3-acetylthio-1-[4-(N-carbamoylmethyl-N-isopropyl-carbamoyl)-1,3-thiazol-2-yl]azetidine (347 mg, yield 71%) as a pale brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19](Cl)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29].Cl.O1CCOCC1>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([NH:29][C:28]4[CH:30]=[CH:31][CH:32]=[C:26]([F:25])[CH:27]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cnc(Cl)nc1-c1c(-c2cccc(Br)c2)nn2ccccc12
Reactant: Nc1cccc(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Fc1cccc(Nc2ncc(F)c(-c3c(-c4cccc(Br)c4)nn4ccccc34)n2)c1
Temperature: 180 °C
Yield: 76.9 %

Procedure:
A solution 2-(3-bromophenyl)-3-(2-chloro-5-fluoro-4-pyrimidinyl)pyrazolo[1,5-a]pyridine (100 mg, 0.25 mmol, obtained from composite batches) in 2-propanol (5 mL) was added 3-fluoroaniline (166 mg, 1.4 mmol) followed by 4M HCl/dioxane (0.4 ml, 1.6 mmol). The reaction mixture was heated at 180° C. in the microwave for 1 h. The solvent was removed under reduced pressure and the solids were recrystallized from EtOAc/hexanes to afford the desired product (92 mg, 77%) as a brown solid. ESIMS (M+H)+=478.
Reaction SMILES: C(Cl)CCl.[NH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:45]=[CH:44][C:13]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1.[CH2:46]([O:49][CH2:50][CH2:51][C:52](O)=[O:53])[C:47]#[CH:48].ON1C(=O)CCC1=O>C(Cl)Cl>[CH2:46]([O:49][CH2:50][CH2:51][C:52]([NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:45]=[CH:44][C:13]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1)=[O:53])[C:47]#[CH:48]
Reactant: C#CCOCCC(=O)O
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCNc1ccc(C(=O)c2ccc(OCCCN)cc2)cc1
Agent: O=C1CCC(=O)N1O
Solvent: ClCCCl
Solvent: ClCCl
Product: C#CCOCCC(=O)NCCCOc1ccc(C(=O)c2ccc(NCCOCCOCCOCCOCCC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
EDC (0.77 g, 4.00 mmol) was added to a solution of tert-butyl 1-((4-(4-(3-aminopropoxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oate (2.00 g, 3.48 mmol), 3-(prop-2-yn-1-yloxy)propanoic acid (0.45 g, 3.48 mmol) and N-hydroxysuccinimide (0.06 g, 0.52 mmol) in DCM (12 mL) at r.t. and the reaction mixture was stirred for 4 hs at room temperature. Upon completion, reaction was concentrated under reduced pressure and purified by silica gel chromatography (EtOAc toEtOAc:MeOH, gradient) to provide 2.12 g (3.10 mmol, 89% yield) of tert-butyl 1-((4-(4-(3-(3-(prop-2-yn-1-yloxy)propanamido)propoxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oate as slightly yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=O)[CH2:9][NH:10][C:11](=O)[C@@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]([CH3:15])[CH3:14])=[N:6][CH:7]=1.C([O-])(=O)C.[NH4+:30]>C1(C)C(C)=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:30]=[C:11]([C@@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]([CH3:15])[CH3:14])[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)c1ccc(Br)cn1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)c1nc(-c2ccc(Br)cn2)c[nH]1
Temperature: 130 °C
Yield: 62.9 %

Procedure:
In a sealed tube, a mixture of (S)-tert-butyl 1-(2-(5-bromopyridin-2-yl)-2-oxoethylamino)-3-methyl-1-oxobutan-2-ylcarbamate (0.1 g) and ammonium acetate (0.186 g) in xylene was heated at 130° C. for 3 hrs. The reaction was diluted with EtOAc, washed with sat. NaHCO3, water and sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield a yellow oil. The residue was purified by silica chromatography (0-100% EtOAc in hexane) to yield (S)-tert-butyl 1-(4-(5-bromopyridin-2-yl)-1H-imidazol-2-yl)-2-methylpropylcarbamate (0.06 g) as a pale yellow solid. LC/MS (Cond. N-1): [M+H]+ 395.17, RT=3.06 min.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9](O)(=[O:13])/[CH:10]=[CH:11]/[CH3:12]>[Cl-].[Zn+2].[Cl-]>[OH:2][C:1]1[CH:8]=[CH:7][C:6]2[C:9](=[O:13])[CH2:10][CH:11]([CH3:12])[O:5][C:4]=2[CH:3]=1
Reactant: C/C=C/C(=O)O
Reactant: Oc1cccc(O)c1
Agent: [Cl-]
Agent: [Zn+2]
Product: CC1CC(=O)c2ccc(O)cc2O1
Yield: 41 %

Procedure:
Resorcinol (11 g) and 17.2 g of crotonic acid were heated at 180° C. for 30 minutes together with 15 g of zinc chloride with stirring. The reaction mixture was extracted with ethyl acetate, and purified by column chromatography to give 7.3 g of 2,3-dihydro-7-hydroxy-2-methyl-4-oxobenzopyran. The OH group of the compound was benzylated in a customary manner, and then the product was reacted with CH3MgBr in tetrahydrofuran. The product was then hydrogenated in ethanol at room temperature for 13 hours in the presence of 5% palladium-carbon. The hydrogenated product was purified by column chromatography to give 4.2 g (yield 24%) of the desired product as a brown liquid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:2]1.[CH:17]([C:19]1[C:20]([F:31])=[CH:21][N:22]=[C:23]2[C:28]=1[N:27]=[C:26]([O:29][CH3:30])[CH:25]=[CH:24]2)=[CH2:18]>CCO>[C:10]1([CH2:9][O:8][C:7](=[O:16])[NH:6][CH2:5][CH:3]2[CH2:4][N:1]([CH2:18][CH2:17][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[N:27]=4)[N:22]=[CH:21][C:20]=3[F:31])[CH2:2]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=Cc1c(F)cnc2ccc(OC)nc12
Reactant: O=C(NCC1CNC1)OCc1ccccc1
Solvent: CCO
Product: COc1ccc2ncc(F)c(CCN3CC(CNC(=O)OCc4ccccc4)C3)c2n1
Reaction time: 24 h
Yield: 37.6 %

Procedure:
To a solution of phenylmethyl (3-azetidinylmethyl)carbamate (0.61 g, 2.76 mmole) in EtOH (1 mL) was added 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine (673 mg, 3.3 mmole). After 24 h at 80° C., the reaction contents were purified on silica gel (CHCl3/MeOH, 9:1, containing 5% NH4OH) to afford the title compound (440 mg, 37%) as a light yellow oil: LC-MS (ES) m/e 425 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[NH2:15][NH2:16]>CO>[CH2:6]([O:5][CH2:4][C:3]([NH:15][NH2:16])=[O:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NN
Reactant: COC(=O)COCc1ccccc1
Solvent: CO
Solvent: O
Product: NNC(=O)COCc1ccccc1
Yield: 99.7 %

Procedure:
A mixture of 70 (2.75 g, 15.3 mmol) in methanol (50 mL) and hydrazine hydrate (65% in water, 2.3 g, 30 mmol) was heated under reflux for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with benzene. The solvent was evaporated and the crude product was further dried under high vacuum (6 h) to give 71 (2.75 g), as a light yellow waxy material, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[NH:7][N:6]=[CH:5]2.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)[CH:5]=[N:6][N:7]=1
Reactant: O=c1[nH]ncc2cc(Cl)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2c(Cl)nncc2c1
Temperature: 105 °C
Reaction time: 3 h

Procedure:
A mixture of 6-chlorophthalazin-1(2H)-one (10.0 g, 55.4 mmol) and phosphoryl trichloride (50.0 mL, 538 mmol) was heated at 105° C. in an oil bath for 8 h. After cooling to RT, the mixture was concentrated by vacuum distillation. The brown residue was re-dissolved in CH2Cl2 and neutralized with saturated aq. NaHCO3. After stirring for 3 h, the organic layer was collected and the aqueous layer was extracted with CH2Cl2 (3×). The combined organics were dried over Na2SO4, filtered through a pad of silica gel, eluting with EtOAc, and concentrated to give the title compound as a tan solid. MS (ESI, pos. ion) m/z: 199.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[O:11][C:10]([NH2:12])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:15]1([CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([OH:24])=O)[CH2:20][CH2:19][CH2:18][CH2:17]C1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[O:11][C:10]([NH:12][C:22](=[O:24])[CH:21]([CH:15]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Nc1ncc(Cc2ccc(Cl)cc2)o1
Reactant: O=C(O)C(c1ccccc1)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ncc(Cc2ccc(Cl)cc2)o1)C(c1ccccc1)C1CCCC1
Reaction time: 16 h

Procedure:
5-(4-Chloro-benzyl)-oxazol-2-ylamine (42 mg, 0.20 mmol) and cyclohexyl-phenyl-acetic acid (44 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added, and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (9.6 mg, 0.023 mmol, 12%). ESI-MS m/z calc. 408.9, found 409.4 (M+1)+ Retention time 3.76 minutes.
Reaction SMILES: C([O:4][C@@H:5]1[C@:9]([CH2:18][CH:19]=[CH2:20])([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:8]([CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:7][C@H:6]1[N:30]1[CH:38]=[C:36]([CH3:37])[C:34](=[O:35])[NH:33][C:31]1=[O:32])(=O)C.C[O-].[Na+].Cl>CO>[CH2:18]([C@@:9]1([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:8]([CH2:21][O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:7][C@@H:6]([N:30]2[CH:38]=[C:36]([CH3:37])[C:34](=[O:35])[NH:33][C:31]2=[O:32])[C@@H:5]1[OH:4])[CH:19]=[CH2:20]
Reactant: C=CC[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CC[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1O

Procedure:
To a stirred solution of nucleoside 1 (11.6 g, 22.3 mmol) in methanol (110 cm3) was added sodium methoxide (3.03 g, 55.5 mmol). The reaction mixture was stirred at room temperature for 16 h and neutralised with dilute hydrochloric acid. The solvent was partly evaporated and the residue was dissolved in dichloromethane (2×400 cm3). The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (3×250 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure to give 2 as a white solid material (10.1 g, 95%). δH (CDCl3) 8.77 (1 H, br s, NH), 7.58 (1 H, d, J 1.2, 6-H), 7.41-7.25 (10 H, m, Bn), 6.14 (1H, m, 2″-H), 6.12 (1 H, d, J 7.8, 1′-H), 5.23 (1 H, m, 3″-Ha), 5.17 (1 H, br s, 3″-Hb), 4.68 (1 H, d, J 10.8, Bn), 4.59 (2 H, s, Bn), 4.55 (1 H, d, J 10.9, Bn), 4.39 (1 H, br s, 4′-H), 4.26 (1 H, dd J 7.8, 10.7, 2′-H), 3.84 (1 H, dd, J 3.1, 11.0, 5′-Ha), 3.58 (1 H, dd, J 1.4, 11.0, 5′-Hb), 3.04 (1 H, d, J 10.8, 2′-OH), 2.82-2.78 (2 H, m, 1″-Ha, 1″-Hb), 1.51 (3 H, d, J 1.0, CH3). δC (CDCl3) 163.5 (C-4), 151.1 (C-2), 137.3, 136.7 (Bn), 136.0 (C-6), 132.1 (C-2″), 128.8, 128.5, 128.3, 127.9, 127.6 (Bn), 118.4 (C-3″), 111.1 (C-5), 87.4, 82.6, 81.1, 79.3 (C-1′, C-2′, C-3′, C-4′), 73.7, 69.8 (Bn), 64.7 (C-5′), 35.1 (C-1″), 11.9 (CH3). (Found: C, 67.8; H, 6.1; N, 5.5. C27H30N2O6 requires C, 67.8; H, 6.3; N, 5.9%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([O:28][CH3:29])[CH:22]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(Cl)Cl>[CH2:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([C:42]([O:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[CH:22][C:23]=2[O:28][CH3:29])=[O:43])=[CH:45][CH:46]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: COc1cc(CC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)ccc1O
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CC(NC(=O)OCc3ccccc3)C(=O)OC(C)(C)C)cc2OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
Prepared using General Procedure 3: To a stirred solution of tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxy-3-methoxyphenyl)propanoate INT-2 (4.7 g, 11.71 mmol) and TEA (3.05 mL, 21.07 mmol) in DCM (50 mL) at 0° C. was added 4-(heptyloxy)benzoyl chloride (2.95 mL, 12.29 mmol) dropwise. After warming to room temperature and stirring for 10 min, the mixture was quenched with saturated aqueous NaHCO3 (50 mL) and water (50 mL). The organic layer was dried over MgSO4 and concentrated. The product was purified by chromatography (EA/hexanes) to afford 5.46 g (75%) of 4-(2-(((benzyloxy)carbonyl)amino)-3-(tert-butoxy)-3-oxopropyl)-2-methoxyphenyl 4-(heptyloxy)benzoate INT-3. LCMS-ESI (m/z) calculated for C36H45NO8: 619. Found 564 [M+H-tBu]+, tR=3.22 min (Method 4).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[C-:19]#[N:20].[K+]>CN(C)C=O>[C:19]([C:11]1[N:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:14]=[CH:13][N:12]=1)#[N:20]
Reactant: CS(=O)(=O)c1nccc(-c2cccc(C#N)c2)n1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2ccnc(C#N)n2)c1
Reaction time: 4 h

Procedure:
A mixture of 4-(3-cyanophenyl)-2-methylsulfonylpyrimidine and potassium cyanide in N,N-dimethylformamide is stirred for 4 hours at 100° . The reaction mixture is concentrated by evaporation, distilled water is added thereto and the whole is extracted with methylene chloride. The organic phase is dried and concentrated by evaporation to give the title compound.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:26])[C:22]([O:24]C)=O)[CH:9]=1)(=[O:3])[CH3:2].[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.ClCCl>CS(C)=O>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:11]=[C:10]([NH:20][C:21](=[O:26])[C:22](=[O:24])[N:36]2[CH2:37][CH2:38][N:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:34][CH2:35]2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COC(=O)C(=O)Nc1cc(NCCNC(C)=O)nc(-c2ccccc2)n1
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(=O)NCCNc1cc(NC(=O)C(=O)N2CCN(c3ccccc3)CC2)nc(-c2ccccc2)n1
Reaction time: 16 h

Procedure:
To a well of a 96 well microtitre plate were added methyl [(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)amino](oxo)acetate (30μl of a 0.3M solution in anhydrous DMSO) and 4-phenylpiperazine (30w1 of a 1.5M solution). This solution was left to shake on a plate shaker for 16 hrs. After this time 800 μl of dichloromethane were added, then 100 mg of PS-NCO. The plate was sealed, then mixed for 48 hrs. The slurry was filtered and the solvents removed in vacuo, to furnish the title compound.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[C:13]([O:15]C)=[O:14])=[O:8])(=O)C.[OH-].[Na+].Cl>CO>[SH:4][CH2:5][CH:6]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[C:13]([OH:15])=[O:14])=[O:8]
Reactant: COC(=O)c1ccc(N2CCCC2)c(NC(=O)C(CSC(C)=O)Cc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(N2CCCC2)c(NC(=O)C(CS)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
Metyl 3-[(2-acetylthiomethyl-3-phenylpropionyl)-amino]-4-(1-pyrrolidinyl)benzoate (compound of Example 14) (0.8 g) is dissolved in methanol (5 ml), and thereto is added 1 N aqueous sodium hydroxide solution (5.5 ml) under nitrogen, and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is acidified with hydrochloric acid and purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected and concentrated into dryness under reduced pressure to give the title compound (0.3 g).
Reaction SMILES: CS(O[CH:6]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH:17]=1)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])(=O)=O.[CH3:33][O:34][CH2:35][CH2:36][NH2:37].O>C1COCC1>[CH2:26]([O:25][C:23](=[O:24])[NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:6]([NH:37][CH2:36][CH2:35][O:34][CH3:33])[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:17]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COCCN
Reactant: CC(C)(C)[Si](C)(C)OCC(OS(C)(=O)=O)c1cccc(NC(=O)OCc2ccccc2)c1
Solvent: O
Solvent: C1CCOC1
Product: COCCNC(CO[Si](C)(C)C(C)(C)C)c1cccc(NC(=O)OCc2ccccc2)c1
Temperature: 70 °C
Yield: 29.9 %

Procedure:
1-(3-(Benzyloxycarbonylamino)phenyl)-2-(tert-butyldimethylsilyloxy)ethyl methanesulfonate (3.5 g) was dissolved in dry THF (10 mL) and methoxyethylamine (5.4 g) was added in a sealed tube and heated to 70° C. for 16 hours. Water was added and the reaction mixture extracted with DCM (2×20 mL). The organic phase was separated, dried over Na2SO4 and concentrated to give the crude product, which was purified by column chromatography to give the title compound (1 g, 30%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)=[CH:6][C:5]([C:19]([O:21][CH3:22])=[O:20])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=1>>[NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:12]([C:13](=[O:15])[NH:23][C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)[CH:11]=2)=[CH:6][C:5]([C:19]([O:21][CH3:22])=[O:20])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(N)c(C#Cc2cccc(C(=O)O)c2)c1
Reactant: Cc1cccc(N)c1
Product: COC(=O)c1cnc(N)c(C#Cc2cccc(C(=O)Nc3cccc(C)c3)c2)c1

Procedure:
In a manner similar to that described in Example 1, 3-((2-amino-5-(methoxycarbonyl)pyridin-3-yl)ethynyl)benzoic acid and m-toluidine are converted to the title compound.
Reaction SMILES: C(C1NC=CN=1)(C1[NH:4]C=CN=1)=O.[C:13]([O:17][C:18]([N:20]([CH2:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][C:31]([Cl:39])=[C:32]2[CH2:35][C:36](O)=[O:37])=[CH:27][CH:26]=1)[CH2:21][CH2:22][F:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].N>CN(C=O)C>[C:13]([O:17][C:18](=[O:19])[N:20]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]2[C:33](=[C:32]([CH2:35][C:36](=[O:37])[NH2:4])[C:31]([Cl:39])=[CH:30][CH:29]=2)[CH:34]=1)[CH2:21][CH2:22][F:23])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N(CCF)Cc1ccc2ccc(Cl)c(CC(=O)O)c2c1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCF)Cc1ccc2ccc(Cl)c(CC(N)=O)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Carbonyl diimidazole (95 mg, 0.58 mmol) was added at RT under an atmosphere of argon to a solution of (7-{[tert-butoxycarbonyl-(2-fluoro-ethyl)-amino]-methyl}-2-chloro-naphthalen-1-yl)-acetic acid (210 mg, 0.53 mmol) in DMF (2.0 ml). After 2 h at RT, concentrated aqueous ammonia (4.3 ml) is added, and the mixture is stirred for 15 minutes at RT. The emulsion is extracted with EtOAc. The organic layer is washed with brine and dried over Na2SO4. After concentration, the residue is purified by FCC (EtOAc) to yield the title compound. 1H NMR (d6-DMSO, 400 MHz): δ 1.38+1.46 (2×br s, 9H), 3.3-3.6 (br m, 2H), 4.08 (s, 2H), 4.40-4.65 (br m, 2H), 4.61 (s, 2H), 7.02 (br s, NH), 7.42 (br d, J=9 Hz, 1H), 7.48-7.58 (br m, 3H), 7.80-7.90 (br m, 2H), 7.95 (br d, J=9 Hz, 1H). ES+-MS: 412.3, 414.2 [M+H+H2O]+. ES−-MS: 393.3, 395.3 [M−H]−.