Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH3:20])[CH:14]=2)[CH2:11][CH3:12])[CH:5]=[CH:6][C:7]=1[CH3:8].[Li]C(C)(C)C.CN([CH:29]=[O:30])C>CCOCC>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH:3]=2)[CH:29]=[O:30])[CH2:11][CH3:12])=[CH:14][C:15]=1[CH3:20]
Reactant: CN(C)C=O
Reactant: CCC(Nc1ccc(C)c(Br)c1)c1ccc(Cl)c(C)c1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CCC(Nc1ccc(C)c(C=O)c1)c1ccc(Cl)c(C)c1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of INT 8 (2.20 g, 14.7 mmol) in Et2O (147 mL) at −78° C. was added tBuLi (1.7 M in pentane, 34.7 mL, 59.0 mmol) dropwise. The mixture was stirred at −78° C. for 40 min, then DMF (2.5 mL) was added. The reaction mixture was stirred at −78° C. for an additional 20 minutes. The mixture was quenched with saturated aqueous NH4Cl and extracted with Et2O (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (heptane/EtOAc) to afford INT 9.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=2)[C:6]([CH3:20])=[C:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])[C:4]=1[OH:32].I[CH3:34]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][C:12]([C:13]2[CH2:18][CH:17]=[CH:16][N:15]([CH3:34])[CH:14]=2)=[O:19])[C:6]([CH3:20])=[C:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])[C:4]=1[OH:32]
Reactant: COc1c(O)c(CCCCCCCCCCO)c(C)c(OC(=O)c2cccnc2)c1OC
Reactant: CI
Solvent: CN(C)C=O
Product: COc1c(O)c(CCCCCCCCCCO)c(C)c(OC(=O)C2=CN(C)C=CC2)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-Dimethoxy-6-(10-hydroxydecyl)-5-methyl-4-nicotinoyloxyphenol (1.1 g) was dissolved in dimethylformamide (5 ml). Iodomethane (0.3 ml) was added, and the mixture was allowed to react at room temperature for 16 hours. After concentration under reduced pressure, the residue was dissolved in ethyl acetate (20 ml). Water (20 ml) containing sodium hydrosulfite (1.74 g) and sodium bicarbonate (1.26 g) was added, and the mixture was stirred at room temperature for 1 hour. The organic layer was concentrated under reduced pressure, and the residue was subjected to column chromatography on silica gel and eluted with ethyl acetate to obtain the desired compound (1.1 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:23](=O)[CH3:24])[C:15]([O:17][CH2:18][CH:19]1[CH2:22][CH2:21][CH2:20]1)=[O:16].[NH2:26][C:27]([CH3:32])=[CH:28][C:29](=[O:31])[CH3:30]>C(O)C>[C:29]([C:28]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:14]([C:15]([O:17][CH2:18][CH:19]2[CH2:22][CH2:21][CH2:20]2)=[O:16])=[C:23]([CH3:24])[NH:26][C:27]=1[CH3:32])(=[O:31])[CH3:30]
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(=O)OCC1CCC1
Reactant: CC(=O)C=C(C)N
Solvent: CCO
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)OCC2CCC2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
960 mg (2.82 mmol) of cyclobutylmethyl 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-3-oxobutanoate are dissolved with 279 mg (2.82 mmol) of 4-aminopent-3-en-2-one in 10 ml of ethanol and heated under reflux under argon for 24 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. Concentration of the product fractions and crystallization from ethyl acetate result in 532 mg (44% of theory) of the title compound as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([OH:7])[C@H:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:9]2=[O:24])[O:4][CH:3]1[C@H:25]([OH:56])[C@@H:26]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[NH:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:48])[C@H:33]([C@@H:45]([OH:47])[CH3:46])[NH:34]C(=O)OCC1C=CC=CC=1>CO.[Pd]>[NH2:34][C@@H:33]([C@@H:45]([OH:47])[CH3:46])[C:32]([NH:31][CH2:30][CH2:29][CH2:28][NH:27][C@@H:26]([C@H:25]([CH:3]1[C@@H:2]([OH:1])[C@@H:6]([OH:7])[C@H:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:9]2=[O:24])[O:4]1)[OH:56])[C:49]([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:50])=[O:48]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](NC(=O)OCc4ccccc4)[C@H](C)O)C(=O)OC(C)(C)C)[C@@H](O)[C@H]3O)c2=O)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](N)[C@H](C)O)C(=O)OC(C)(C)C)[C@@H](O)[C@H]3O)c2=O)cc1
Yield: 92.1 %

Procedure:
tert-Butyl (5S,12S)-12-[(R)-[(3S,4R,5R)-3,4-dihydroxy-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]-(hydroxy)methyl]-5-[(1S)-1-hydroxyethyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (8 mg, 0.01 mmol, obtained from Example 44) was hydrogenated in methanol (2 ml) using 10% palladium on carbon (5 mg) under atmospheric pressure for 4 hours. The catalyst was removed and the volatiles was concentrated in vacuo to provide tert-butyl (2S,3R)-2-[(3-{[(2S,3S)-2-amino-3-hydroxybutanoyl]amino}propyl)amino]-3-[(3S,4R,5R)-3,4-dihydroxy-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-3-hydroxypropanoate (6 mg, 92%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].[CH2:27]([N:29]1[C:35](=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:28]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([N:32]4[CH2:33][CH2:34][C:35](=[O:36])[N:29]([CH2:27][CH3:28])[CH2:30][CH2:31]4)=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(Br)cc2)C1
Reactant: CCN1CCNCCC1=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCN1CCN(c2ccc(C34CC3CN(C(=O)OC(C)(C)C)C4)cc2)CCC1=O
Yield: 20.3 %

Procedure:
To a solution of 1-(4-bromo-phenyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Intermediate I, 250 mg, 0.74 mmol) in anhydrous toluene (5 mL) were added Pd2(dba)3 (1.65 mg, 0.002 mmol), BINAP (3.42 mg, 0.006 mmol), sodium tert-butoxide (106.56 mg, 1.11 mmol) and 4-ethyl-[1,4]diazepan-5-one (210.2 mg, 1.48 mmol, prepared by the procedure as described in WO2008136754) at r.t. and reaction mixture was refluxed for 3 h. Reaction mixture was then concentrated and the crude product was purified by column chromatography (silica gel, 0.3:9.7 MeOH:CHCl3) to afford the title compound as viscous liquid (60 mg, 20.3%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:39])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:23](=[O:32])[C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:16]=1>>[CH3:12][O:13][C:14](=[O:39])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)/[C:24](=[C:25](/[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)\[C:2]3[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:9])[NH2:11])=[CH:4][CH:3]=3)/[C:23]2=[O:32])[CH:16]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Reactant: NS(=O)(=O)c1ccc(I)cc1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(S(N)(=O)=O)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 4-iodo-benzenesulfonamide (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.90 (s, 3H), 4.95 (s, 2H), 5.02 (s, 2H), 6.41 (d, 1H), 6.65-6.71 (m, 2H), 7.09 (t, 1H), 7.26-7.33 (m, 2H), 7.35-7.42 (m, 6H), 7.58-7.60 (m, 3H), 7.99 (d, 1H), 8.07 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[S:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)(=[O:14])(=[O:13])[NH2:12]>>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N:19][C:18]1[CH:20]=[CH:21][C:15]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(F)cc1F
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(N=Cc2ccc(F)cc2F)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 2,4-difluorobenzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a pale yellow powder (yield 52%).
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:15][C:14](=[O:16])[O:13][C@@H:12]1[O:17][CH2:18][CH3:19])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[NH2:10][C@@H:11]1[C@@H:12]([O:17][CH2:18][CH3:19])[O:13][C:14](=[O:16])[CH2:15]1
Reactant: CCO[C@H]1OC(=O)C[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCO[C@H]1OC(=O)C[C@@H]1N
Temperature: 25 °C
Yield: 93.9 %

Procedure:
To a suspension of (2S,3S)-(2-Ethoxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid benzyl ester (0.43 g, 1.54 mmol) in Ethyl acetate (50 mL) at room temperature was added 10 mol % Pd/C (˜0.05 g). The reaction flask was purged between H2 (1atm) and vacuum three times before stirring under H2 (1atm) at room temperature. After stirring at room temperature for 3 hrs, the reaction mixture was filtered through celite and then evaporated to dryness to give the title compound (0.21 g, 94%) as a clear oil. 1HNMR (CDCl3) δ 5.17 (d, J=1.2 Hz, 1H), 3.93–3.82 (dq, J=9.6, 7.2 Hz, 1H), 3.67–3.57 (dq, J=9.3, 6.9 Hz, 1H), 2.95–287 (dd, J=17.7, 6.9 Hz, 1H), 2.56–2.19 (dd, J=17.4, 2.7 Hz, 1H), 1.26–1.21 (t, J=7.2 Hz, 3H). MS(ES) for C6H11NO3 (MW=145.16): positive 146 ([MH+]).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[OH:9][C:10]1[CH:17]=[CH:16][C:15]([N:18]2[N:22]=[N:21][CH:20]=[N:19]2)=[CH:14][C:11]=1[CH:12]=[O:13]>CN(C)C=O.O>[CH3:1][O:9][C:10]1[CH:17]=[CH:16][C:15]([N:18]2[N:22]=[N:21][CH:20]=[N:19]2)=[CH:14][C:11]=1[CH:12]=[O:13]
Reactant: O=Cc1cc(-n2ncnn2)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1ccc(-n2ncnn2)cc1C=O
Reaction time: 2 h
Yield: 42.4 %

Procedure:
Potassium carbonate (1.06g) and methyl iodide (0.5 ml) were added to a solution of 2-hydroxy-5-tetrazol -2yl-benzaldehyde (930 mg) in dimethylformamide (6 ml ) at room temperature. The mixture was stirred for 2 h then evaporated to give an orange solid. This was dissolved in water (40 ml), extracted with dichloromethane (3×30 ml), dried (Na2 SO4) and evaporated. The residue was purified by FCC (dichloromethane) to give the title compound as a yellow solid (423 mg).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][N:8]=1.C([O-])([O-])=O.[Na+].[Na+]>O.Cl[Pd]Cl>[NH2:6][C:7]1[N:8]=[CH:9][C:10](/[CH:3]=[CH:2]/[C:1]([OH:5])=[O:4])=[CH:11][CH:12]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C=CC(=O)O
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Nc1ccc(/C=C/C(=O)O)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.5 %

Procedure:
Acrylic acid (23 mL, 0.33 mole) was added carefully to a solution of 2-amino-5-bromopyridine (25.92 g, 0.15 mole) and Na2CO3 (55.64 g, 0.53 mole) in H2O (600 mL). PdCl2 (0.53 g, 0.003 mole) was then added, and the mixture was heated at reflux. After 24 hr, the reaction was cooled to RT and filtered, and the filtrate was adjusted to pH 6 with aqueous HCl. Additional H2O (0.5 L) was added to improve mixing, and the mixture was stirred for 1 hr. The pH was readjusted to 6, then the solid was collected by suction filtration. The filter pad was washed sequentially with H2O (2×0.5 L), cold absolute EtOH (100 mL), and Et2O (2×250 mL). Drying in high vacuum at elevated temperature gave the title compound (15.38 g, 62%) as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J=2.0 Hz, 1H), 7.75 (dd, J=8.7, 2.0 Hz, 1H), 7.43 (d, J=15.8 Hz, 1H), 6.53 (s, 2H), 6.45 (d, J=8.7 Hz, 1H), 6.22 (d, J=15.8 Hz, 1H); MS (ES) m/e 165 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.Br[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=1>>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=2)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]3)=[CH:16][CH:17]=1)([CH3:22])([CH3:24])[CH3:23]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Product: Cc1ccc(-n2c(C(=O)O)cc3cc(-c4ccc(C(C)(C)C)cc4)ccc32)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared in accordance with Example 1 using 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester and 4-bromo-1-methyl-2-nitrobenzene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4](Br)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[I:13][C:14]1[CH:34]=[CH:33][CH:32]=[CH:31][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1)=[O:17].C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[I:13][C:14]1[CH:34]=[CH:33][CH:32]=[CH:31][C:15]=1[C:16]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:26][CH2:27][N:28]([CH:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]([O:2][CH3:1])=[O:12])[CH2:29][CH2:30]2)=[CH:23][CH:24]=1)=[O:17]
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1I
Reactant: COC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)c3ccccc3I)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
α-Bromo-benzeneacetic acid methyl ester (0.0123 mol) was added at room temperature to a mixture of intermediate (28) (0.0123 mol) and Na2CO3 (0.0123 mol) in DMF (50 ml). The mixture was stirred at room temperature for 2 hours. Water was added. The mixture was stirred at room temperature for 15 minutes. The precipitate was filtered, washed with diethyl ether and dried, yielding 5.8 g of 4-[4-[(2-iodobenzoyl)amino]phenyl]-α-phenyl-1-piperazine-acetic acid, methyl ester (intermediate 29).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[CH:31]=[CH:32][C:33](O)=[O:34])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1/[CH:31]=[CH:32]/[C:33]([NH:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[N:9][N:8]2[CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:12][CH:13]=1)=[O:34])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Reactant: O=C(O)C=Cc1cnccc1Oc1ccccc1
Product: O=C(/C=C/c1cnccc1Oc1ccccc1)Nc1ccc2cnn(CCN3CCCC3)c2c1

Procedure:
According to the procedure for Example 49, 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine and 3-(4-phenoxy-pyridin-3-yl)-acrylic acid were processed to provide the title compound. MS (DCI/NH3) MS m/z 454 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ ppm 1.84 (m, 2 H), 2.01 (m, 2 H), 3.07 (m, 2 H), 3.54 (m, 2 H), 3.73 (m, 2 H), 4.71 (t, J=6.08 Hz, 2 H), 6.88 (m, 1 H), 7.20 (m, 5 H), 7.45 (m, 2 H), 7.62 (m, 1 H), 7.75 (m, 1 H), 8.13 (m, 2 H), 8.40 (m, 2 H), 9.62 (br s, N H).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[C:11]([N:16]2[C:20](=[O:21])[O:19][N:18]=[C:17]2[C:22]2[C:23]([NH:27][CH2:28][CH2:29][NH:30][S:31]([NH:34]C(=O)OC(C)(C)C)(=[O:33])=[O:32])=[N:24][O:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[F:15]>O>[Br:8][C:9]1[CH:10]=[C:11]([N:16]2[C:20](=[O:21])[O:19][N:18]=[C:17]2[C:22]2[C:23]([NH:27][CH2:28][CH2:29][NH:30][S:31]([NH2:34])(=[O:32])=[O:33])=[N:24][O:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 22 L flask containing 98:2 trifluoroacetic acid:water (8.9 L) was added tert-butyl ({[2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)ethyl]amino}sulfonyl)carbamate (1931 g, 3.42 mol) in portions over 10 minutes. The resulting mixture was stirred at room temperature for 1.5 h, the solvents removed in vacuo, and chased with dichloromethane (2 L). The resulting solid was treated a second time with fresh 98:2 trifluoroacetic acid:water (8.9 L), heated for 1 h at 40-50° C., the solvents removed in vacuo, and chased with dichloromethane (3×2 L). The resulting white solid was dried in a vacuum drying oven at 50° C. overnight. A total of 5409 g was processed in this manner (4990 g, quant. yield). LCMS for C12H12BrFN7O5S (M+H)+: m/z=463.9, 465.9. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (dd, J=6.2, 2.5 Hz, 1H), 7.72 (m, 1H), 7.59 (t, J=8.7 Hz, 1H), 6.67 (t, J=5.9 Hz, 1H), 6.52 (t, J=6.0 Hz, 1H), 3.38 (dd, J=12.7, 6.3 Hz, 2H), 3.11 (dd, J=12.3, 6.3 Hz).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[NH2:20][CH:21]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:22][C:23]([NH2:25])=[O:24]>>[C:23]([CH2:22][CH:21]([NH:20][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])[CH2:26][CH:27]([CH3:29])[CH3:28])(=[O:24])[NH2:25]
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: CC(C)CC(N)CC(N)=O
Agent: Cl
Product: CC(C)CC(CC(N)=O)NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 63b, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 3-amino-5-methylhexanamide hydrochloride (CAN 93169-29-0) as starting materials to yield the racemate mixture. The racemate was separated into its enantiomers by preparative chiral HPLC (Chiralpak AD, isopropanol/heptane) and the title compound was the first enantiomer collected and isolated as colorless oil; MS (ESI, m/z): 388.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:21][CH:22]([CH3:25])[CH2:23][OH:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:21][CH:22]([CH3:25])[CH2:23][OH:24])=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(N)CO
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(CO)NC(=O)c1cccc(-c2ccc3ncnc(N)c3n2)c1

Procedure:
Following the same reaction and purification procedure, the acid 14 (80 mg, 0.30 mmol) was reacted with 2-aminopropan-1-ol (CAS 78-91-1) (0.05 mL, 0.6 mmol), HATU (141 mg, 0.36 mmol) and DIPEA (0.26 mL, 1.5 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-(1-hydroxypropan-2-yl)benzamide 17. LC/MS (ESI+): m/z 323 (M+H). 1H NMR (400 MHz, DMSO) δ 8.70 (s, 1H), 8.61 (t, J=13.5 Hz, 1H), 8.57-8.48 (m, 1H), 8.43 (s, 1H), 8.29 (d, J=7.9 Hz, 1H), 8.19 (dd, J=8.8, 3.1 Hz, 1H), 8.05 (d, J=30.8 Hz, 2H), 7.97 (d, J=7.7 Hz, 1H), 7.63 (t, J=7.8 Hz, 1H), 4.76 (s, 1H), 4.18-4.00 (m, 1H), 3.52 (dd, J=10.5, 5.7 Hz, 1H), 3.46-3.35 (m, 1H), 1.19 (d, J=6.7 Hz, 3H).
Reaction SMILES: [NH2:1]CC1C=CC(CCC(O)=O)=CC=1.[CH3:14][C:15]([CH3:32])([CH3:31])[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]C(N)=O)=[CH:22][CH:21]=1)=[O:17].FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O>>[CH3:14][C:15]([CH3:32])([CH3:31])[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH2:1])=[CH:22][CH:21]=1)=[O:17]
Reactant: NCc1ccc(CCC(=O)O)cc1
Reactant: CC(C)(C)C(=O)NCc1ccc(CCC(N)=O)cc1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Product: CC(C)(C)C(=O)NCc1ccc(CCN)cc1

Procedure:
4-Cyanocinnamic is catalytically hydrogenated to form 4-(aminomethyl)-benzenepropanoic acid, the amino function is then protected by a tert.butoxycarbonyl group and the carboxylic acid function is converted into the primary carboxamide; the resulting 4-[[(2,2-dimethyl-1-oxopropyl)amino]methyl]benzenepropanamide when reacted with I,I-bis-(trifluoroacetoxy)iodobenzene, yields 4-[[(2,2-dimethyl-1-oxopropyl)amino]methyl]benzeneethanamine (see also: A. S. Radhakrishna, M. E. Parham, R. M. Riggs and G. M. Loudon, J. Org. Chem. 44: 1746-1747 (1979) and K. Seraminathan and N. Venkatasubramanian, J. Chem. Soc. Perkim Trans. II 1975, 1161), which may be converted into the corresponding urea in the usual way, e.g. by treating the hydrochloride with sodium cyanate; cleaving the tert.butoxycarbonyl group with suitable acids, e.g. trifluoroacetic acid, finally yields the desired 4-[2-(aminocarbonylamino)ethyl]phenylmethanamine.
Reaction SMILES: COC1C=CC=CC=1O.[C:10]([O:14][CH2:15][CH2:16][CH2:17][Si:18]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])(=[O:13])[CH:11]=C>>[C:10]([O:14][CH2:15][CH2:16][CH2:17][Si:18]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])[O:25][CH2:26][CH3:27])(=[O:13])[CH3:11]
Reactant: C=CC(=O)OCCC[Si](OCC)(OCC)OCC
Agent: COc1ccccc1O
Product: CCO[Si](CCCOC(C)=O)(OCC)OCC
Yield: 96 %

Procedure:
The same procedure as in Example 1 was followed to conduct a reaction, except that 0.02 g of methoxyphenol was further added. After completion of the reaction, the reaction product was analyzed by GC. As a result, it was thus found that triethoxysilylpropyl acrylate as the objective compound had been obtained in a yield of 96% (in terms of triethoxysilylpropyl acetate).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:41])[C@@H:10]([NH:25][C:26]([C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([N:38]([CH3:40])[CH3:39])[CH:34]=2)[CH:29]=1)=[O:27])[CH2:11][CH2:12][CH2:13][NH:14]C(=O)OCC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[NH2:14][CH2:13][CH2:12][CH2:11][C@H:10]([NH:25][C:26]([C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([N:38]([CH3:40])[CH3:39])[CH:34]=2)[CH:29]=1)=[O:27])[C:9]([NH:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:41]
Reactant: CN(C)c1ccc2cc(C(=O)N[C@@H](CCCNC(=O)OCc3ccccc3)C(=O)NCc3ccccc3)ccc2c1
Agent: [Pd]
Solvent: CO
Product: CN(C)c1ccc2cc(C(=O)N[C@@H](CCCN)C(=O)NCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of (S)-benzyl 5-(benzylamino)-4-(6-(dimethylamino)-2-naphthamido)-5-oxopentylcarbamate (80 mg, 0.145 mmol) in methanol (10 ml) of was added Pd/C (10%) 10 mg. The reaction mixture was stirred under H2 balloon for 8 hr at rt. After filtration the filtrate was evaporated in vacuo and the residue was triturated with ether repeatedly to provide (S)—N-(5-amino-1-(benzylamino)-1-oxopentan-2-yl)-6-(dimethylamino)-2-naphthamide as colorless powder.