Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC.[CH3:58][N:59]1[CH:63]=[C:62]([NH2:64])[CH:61]=[N:60]1>C1COCC1.CCCCCCC.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:64][C:62]4[CH:61]=[N:60][N:59]([CH3:58])[CH:63]=4)=[O:20])=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Reactant: Cn1cc(N)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(NC(=O)c2ccc(OCc3c(-c4ccc(F)cc4)noc3CO)nc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.29 mmol) in THF (3 mL) were added 1-hydroxybenzotriazole hydrate (45.3 mg, 0.29 mmol), N-ethyldiisopropylamine (127 μL, 0.73 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (56.7 mg, 0.29 mmol) and 1-methyl-1H-pyrazol-4-ylamine (28.2 mg, 0.29 mmol). The reaction mixture was stirred overnight at room temperature. Chromatography (silica, ethyl acetate:heptane=2:1 to 9:1) afforded the title compound (70 mg, 57%) as a white solid. MS: m/e=424.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]2[C:7]([O:9][C:10](=[O:11])[C:3]=2[CH:2]=1)=[O:8].[Al+3].[Cl-].[Cl-].[Cl-].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][C:3]=2[C:10]([OH:9])=[O:11])=[O:8])=[CH:19][CH:18]=1
Reactant: Fc1ccccc1
Reactant: O=C1OC(=O)c2cnccc21
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)c1cnccc1C(=O)c1ccc(F)cc1

Procedure:
To a solution of pyridine-3,4-dicarboxylic anhydride (56.04 g, 0.38 mol) in 950 mL of fluorobenzene is added AlCl3 (126.67 g, 0.95 mol) over 45 min. from a powder addition funnel. The mixture is heated to reflux for 12 hours, then allowed to cool and quenched with ice water. Addition of a concentrated NaOH solution results in a solid precipitate which is filtered. The basic aqueous fraction of the biphasic filtrate is separated, washed with Et2O (3×150 mL), and acidified to pH 2.5 with concentrated HCl to generate a white solid which is collected by vacuum filtration. The solid is washed with several portions of hot MeOH to generate pure 3-(4-fluorobenzoyl)pyridine-4-carboxylic acid. M.P. 308.5° C. The combined methanolic filtrates are evaporated and recrystallized from MeOH to generate 4-(4-fluorobenzoyl)-pyridine-3-carboxylic acid. M.P. 231°-232.5° C.
Reaction SMILES: CCCCC[CH2:6][CH2:7][C:8]1C=[C:12]([O:14][C:15]([C:17]2[C:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:21][C:20]([OH:30])=[CH:19][C:18]=2[O:31][C@@H]2OC([C@H](O)CO)[C@H](O)[C@H]2O)=[O:16])[CH:11]=[C:10](O)[CH:9]=1.CCCCCCCC1C(C(OC2C=C(CCCCCCC)C(C(O)=O)=C(O)C=2)=O)=C(O[C@@H]2OC([C@H](O)CO)[C@H](O)[C@H]2O)C=C(O)C=1>>[OH:31][C:18]1[CH:19]=[C:20]([OH:30])[CH:21]=[C:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:17]=1[C:15]([O:14][CH2:12][C:11]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:16]
Reactant: CCCCCCCc1cc(O)cc(OC(=O)c2c(CCCCCCC)cc(O)cc2O[C@@H]2OC([C@H](O)CO)[C@H](O)[C@H]2O)c1
Agent: CCCCCCCc1cc(OC(=O)c2c(CCCCCCC)cc(O)cc2O[C@@H]2OC([C@H](O)CO)[C@H](O)[C@H]2O)cc(O)c1C(=O)O
Product: CCCCCCCc1cc(O)cc(O)c1C(=O)OCc1ccccc1

Procedure:
Assembly of Synthesized Intermediates into KS-501, ent-KS-501, KS-502 and ent-KS-502.
Reaction SMILES: S1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]3[C:14]([C:15]4[CH:16]=[C:17]([CH:38]=[CH:39][CH:40]=4)[CH2:18][NH:19][C:20]([C:22]4[C:23](=[O:37])[N:24]([CH2:28][C:29]5[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=5)[CH:25]=[CH:26][CH:27]=4)=[O:21])=[CH:13][NH:12][C:9]3=[N:10][CH:11]=2)=[CH:2]1.[N:41]1C=CC=C(B(O)O)[CH:42]=1.B(O)O>>[N:41]1[CH:42]=[CH:5][CH:4]=[C:3]([C:6]2[CH:7]=[C:8]3[C:14]([C:15]4[CH:16]=[C:17]([CH:38]=[CH:39][CH:40]=4)[CH2:18][NH:19][C:20]([C:22]4[C:23](=[O:37])[N:24]([CH2:28][C:29]5[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=5)[CH:25]=[CH:26][CH:27]=4)=[O:21])=[CH:13][NH:12][C:9]3=[N:10][CH:11]=2)[CH:2]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C(NCc1cccc(-c2c[nH]c3ncc(-c4ccsc4)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Agent: OBO
Product: O=C(NCc1cccc(-c2c[nH]c3ncc(-c4cccnc4)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
Except where indicated, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide was synthesized as per Example 91, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide (Scheme 10) using 3-Pyridylboronic acid as boronic acid to yield the product. 1H NMR (400 MHz, DMSO-d6) d ppm 12.153 (s, 1H) 10.089 (t, J=5.8 Hz, 1H) 9.177 (s, 1H) 8.714 (d, J=4.9 Hz, 1H) 8.670 (s, 1H) 8.603 (s, 1H) 8.546 (d, J=7.3 Hz, 1H) 8.374 (d, J=7.3 Hz, 1H) 8.197 (d, J=6.8 Hz, 1H) 7.954 (s, 1H) 7.797 (s, 1H) 7.813-7.742 (m, 1H) 7.684 (d, J=7.3 Hz, 1H) 7.440-7.307 (m, 3H) 7.220 (d, J=7.3 Hz, 1H) 7.142-7.083 (m, 1H) 6.555 (t, J=6.8 Hz, 1H) 5.147 (s, 2H) 4.594 (d, J=5.8 Hz, 2H); MS m/z=548.07 M+H.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:39])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31]CC3C=CC=CC=3)=[O:30])[CH2:24]2)[O:12]1>C(O)C.[Pd]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:39])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:24]2)[O:12]1
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)O)C1
Reaction time: 18 h
Yield: 85.8 %

Procedure:
Benzyl 3-[3-({[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]methyl}(methyl)amino)cyclobutyl]propanoate (1.19 g, 2.22 mmol) was dissolved in ethanol (24 ml) and 10% palladium on charcoal (50% wet paste) (0.24 g) added. The suspension was stirred under an atmosphere of hydrogen for 18 h. It was then filtered and the solid washed with ethanol (10 ml). As the reaction was incomplete, further palladium on charcoal (0.21 g) was added and the reaction continued under hydrogen for a further 24 h. Filtered through double glass fibre, washed with ethanol and evaporated to dryness to give the desired compound as a white foam (mix of diastereomers) (0.85 g, 86%): MS (ESI+) for C21H30N6O5 m/z 447.5 [M+H]+; LC purity 86% (ret. time, 1.08 min); 1H NMR (500 MHz, d4-MeOD) δH 8.18-8.35 (m, 2H), 6.14-6.30 (m, 1H), 5.25-5.56 (m, 1H), 5.01-5.11 (m, 1H), 4.35-4.52 (m, 1H), 3.63-3.81 (m, 1H), 3.24-3.30 (m, 1H), 2.98-3.16 (m, 1H), 2.89 (ddd, J=17.2, 13.4, 3.7 Hz, 1H), 2.36 (m, 2H), 2.17-2.26 (m, 1H), 1.98-2.17 (m, 3H), 1.67-1.92 (m, 3H), 1.49-1.64 (m, 4H), 1.39 (s, 3H), 1.20-1.33 (m, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3(O)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:13]1[CH2:12][CH2:11][CH:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH:2]=[CH:3][C:4]=3[CH:9]=2)[CH2:15][CH2:14]1
Reactant: OC1(c2ccc3occc3c2)CCOCC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2cc(C3CCOCC3)ccc2o1
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a solution of 4-(benzofuran-5-yl)-tetrahydro-2H-pyran-4-ol (109 mg, 0.5 mmol) in DCM (5 mL) at 0° C. under nitrogen atmosphere was added triethylsilane (175 mg, 1.5 mmol) followed by TFA (570 mg, 5.0 mmol). After stirring for 15 min at the same temperature, the cooling bath was removed, and allowed the reaction mixture to reach room temperature. It was further stirred at room temperature for 6 h and then poured into crushed ice-water mixture (10 mL). It was extracted with DCM (3×10 mL), and the combined organic layer was washed with brine (10 mL), dried and evaporated. The crude compound was purified by column chromatography using 5% EtOAc-hexanes to afford the desired product (88%). 1H NMR (400 MHz, CDCl3) δ 7.61 (d, 1H), 7.44 (d, 2H), 7.15 (d, 1H), 6.73 (d, 1H), 4.11 (dd, 2H), 3.56 (t, 2H), 2.89-2.81 (m, 1H), 1.93-1.79 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:18][C:19]([C:21]1[CH:26]=[CH:25][N:24]=[C:23](Cl)[CH:22]=1)=[O:20].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:18][C:19]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([N:14]2[CH2:15][CH2:16][CH2:11][CH2:12][CH2:13]2)[CH:22]=1)=[O:20]
Reactant: C1CCNCC1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccnc(Cl)c2)c1)c1ccnc(Cl)c1
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccnc(N3CCCCC3)c2)c1)c1ccnc(N2CCCCC2)c1
Yield: 96 %

Procedure:
Using an analogous procedure to that described in Example 21, N-[2-chloro-5-(2-chloropyrid-4-ylcarbonylamino)phenyl]-2-chloropyridine-4-carboxamide was reacted with piperidine to give the title compound in 96% yield; NMR Spectrum: (DMSOd6) 1.6 (m, 12H), 3.58 (m, 8H), 7.01 (m, 2H), 7.24 (d, 2H), 7.54 (d, 1H), 7.73 (d, 1H), 8.02 (s, 1H), 8.13 (m, 2H), 10.09 (br s, 1H), 10.44 (br s, 1H); Mass Spectrum: M+H+ 519.
Reaction SMILES: C([Li])CCC.[CH:6]1[C:14]2[C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.C1C[O:22]CC1>>[OH:22][C:9]1[C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[C:14]=2[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc2c(c1)sc1ccccc12
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: Oc1cccc2c1sc1ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
n-Butyllithium (26.25 g, 406 mmols, 175 ml of 2.4M solution in hexane) was added to a stirred solution of dibenzothiophene (25 g, 135.7 mole) in dry THF (200 ml) at 0° C. over a period of 1 hr under dry N2 atmosphere. This reaction mixture was stirred overnight at room temperature and dry oxygen gas was bubbled into the reaction mixture over 5 hrs. This reaction mixture was poured slowly over cold 1N HCl (500 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×500 ml). Organic layers were mixed together and concentrated to dryness to get crude product (32 g). The crude product was purified by silica gel column chromatography.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:20])=[C:6]([CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:12]=1)[C:7]([OH:9])=[O:8])[CH:2]=[CH2:3].[OH-].[K+]>O>[CH:1]([C:4]1[C:5]([OH:20])=[C:6]([CH:10]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH:12]=1)[C:7]([OH:9])=[O:8])=[CH:2][CH3:3]
Reactant: C=CCc1cc(-c2ccc(F)cc2)cc(C(=O)O)c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC=Cc1cc(-c2ccc(F)cc2)cc(C(=O)O)c1O

Procedure:
A mixture of 2 g. of 3-allyl-5-(4'-fluorophenyl)2-hydroxy-benzoic acid, 5 g. of potassium hydroxide pellets and 2 ml. of water was heated under nitrogen in an oil bath at 170° C. for 1 hour with occasional stirring. The reaction mixture was cooled, dissolved in water, and the solution acidified. The product was extracted into ether. After drying the ether solution, and removing the ether, the product was recrystallized from benzene to yield 1.37 g., m.p. 196° -200° C. One more recrystallization from benzene raised the m.p. to 198° -201° C.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][CH2:15][CH:16]([C:18](OC)=[O:19])[N:17]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.COC(=O)[C@H](CO)[NH:28]C(=O)C1C=CC(OC2C=CC(F)=CC=2)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(Cl)(Cl)(Cl)Cl>C(#N)C>[F:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][CH:15]=[C:16]([C:18]([NH2:28])=[O:19])[N:17]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CO)NC(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: COC(=O)C1COC(c2ccc(Oc3ccc(F)cc3)cc2)=N1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: NC(=O)c1coc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89 %

Procedure:
Methyl 4,5-dihydro-2-[4-(4-fluorophenoxy)phenyl]oxazole-4-carboxylate. To a solution of N-[4-(4-fluorophenoxy)benzoyl]-L-serine methyl ester (assumed to be 37 mmol from the previous reaction) and triphenylphosphine (0.38 g, 6.8 mmol) in acetonitrile (40 mL) was added diisopropylethyl amine (1.2 ml, 6.8 mmol) and carbon tetrachloride (0.66 mL, 6.8 mmol). The resulting solution was stirred at room temperature for 48 hours when TLC analysis indicated incomplete reaction. Triphenylphosphine (1.9 g, 7.2 mmol), diisopropylethyl amine (1.2 mL, 6.8 mmol) and carbon tetrachloride (0.66 mL, 6.8 mmol) was added to the reaction. The solution was stirred at room temperature for 16 hours and concentrated to dryness. The resulting solid was purified by column chromatography affording 910 mg (89%) of the desired product. 1H NMR (DMSO-d6): 7.88 (d, J=8.7 Hz, 2H), 7.29 (t, J=9.3 Hz, 2H), 7.20-7.17 (m, 2H), 7.03 (d, J=8.7 Hz, 2H), 4.95 (dd, J=8.1 Hz, 1H), 4.64-4.25 (m, 2H), 3.71 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19].C(N(CC)CC)C>CN(C)C=O>[CH2:18]([NH:20][C:21]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)=[O:22])[CH3:19]
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: CCN=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reaction time: 16 h
Yield: 97.9 %

Procedure:
A suspension of 9.2 g (40 mmol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 100 ml of dimethylformamide, 4.8 ml (60 mmol) of ethyl isocyanate and 5.6 ml (40 mmol) of triethylamine is stirred at 25° for 16 hrs. The dimethylformamide is evaporated under reduced pressure and the residue is treated with 200 ml of water and the pH is adjusted to 2.0 with 1 N hydrochloric acid. The solid is filtered and washed with methanol, ether and dried to give 11.8 g of 6-[4-(N-ethylcarbamoylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)(=O)=O.[CH3:20][C:21]1[CH:22]=[C:23]([SH:27])[CH:24]=[CH:25][CH:26]=1.CCN(C(C)C)C(C)C>O1CCOCC1.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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:20][C:21]1[CH:22]=[C:23]([S:27][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]3)[CH:24]=[CH:25][CH:26]=1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: Cc1cccc(S)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Sc2ccc3c(c2)CCCC3=O)c1
Yield: 110 %

Procedure:
The suspension of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (1.8 g, 6.1 mmol), 3-methylbenzene-1-thiol (0.76 g, 6.1 mmol), Pd2(dba)3 (142 mg, 0.153 mmol), Xantphos (177 mg, 0.306 mmol) and DIEA (1.58 g, 12.2 mmol) in 1,4-dioxane (60 mL) was stirred at reflux overnight under N2. The reaction was filtered and concentrated. Purification by silica gel chromatography (PE:EtOAc=5:1) gave 1.8 g (100%) of the title compound as an orange oil. [M+H] Calc'd for C17H16OS, 269. Found, 269.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:10](=[O:13])[CH2:11][CH3:12])[CH:7]=[CH:8][CH:9]=1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][CH:11]([CH3:12])[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=1)=[O:13]
Reactant: BrBr
Reactant: CCC(=O)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(Br)C(=O)c1cccc(Cl)c1
Yield: 60 %

Procedure:
Bromine (6.07 ml, 0.12 mol) was added to a solution of 3′-chloropropiophenone (20 g, 0.12 mol) in chloroform (250 ml) at room temperature. The reaction was followed by TLC in DCM. When all of the starting material was consumed the mixture was washed with a saturated solution of sodium bicarbonate. The organic phase was dried over magnesium sulphate, filtered and evaporated. Recrystallisation from chloroform gives the desired compound in 60% yield as a pale yellow solid (18 g, 73 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@@H:13]([C:22]([OH:24])=O)[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][N:26](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C(N(CC)CC)C>CN(C=O)C.O>[C:18]([O:17][C:15]([NH:14][CH:13]([C:22]([NH:26][CH3:25])=[O:24])[CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:16])([CH3:19])([CH3:20])[CH3:21]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCc1ccccc1)C(=O)O
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CNC(=O)C(CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of 3-{[(benzyloxy)carbonyl]amino}-N-(tert-butoxycarbonyl)alanine (10.0 g, 30.0 mmol) in DMF (100 mL) was added HATU (14.0 g, 36.0 mmol). After 2 hours, methylamine (4.1 g, 60 mmol) and triethylamine (15.0 g, 149 mol) were added. After 16 hours, the reaction mixture was diluted with water and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to give benzyl {2-[(tert-butoxycarbonyl)amino]-3-(methylamino)-3-oxopropyl}carbamate. MS ESI calc'd. for C17H26N3O5 [M+H]+ 352. found 352. 1H NMR (300 MHz, CDCl3) δ 7.33-7.31 (m, 5H), 6.59-6.57 (m, 1H), 5.69-5.66 (m, 1H), 5.42-5.39 (m, 1H), 5.14-5.05 (m, 2H), 4.19-4.16 (m, 1H), 3.63-3.41 (m, 2H), 2.78 (d, J=4.8 Hz, 3H), 1.43 (s, 9H).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:15])[C:10](=[O:14])[C:11]([CH3:13])([CH3:12])[C:6]2=[CH:5][CH:4]=1.Cl.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1>>[CH3:15][N:9]1[C:7]2=[N:8][C:3]([NH:2][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=3)=[CH:4][CH:5]=[C:6]2[C:11]([CH3:12])([CH3:13])[C:10]1=[O:14]
Reactant: O=C(Cl)c1cccnc1
Reactant: CN1C(=O)C(C)(C)c2ccc(N)nc21
Agent: Cl
Product: CN1C(=O)C(C)(C)c2ccc(NC(=O)c3cccnc3)nc21

Procedure:
Prepared in analogy to example 2 using 6-amino-1,3,3-trimethyl-1H-pyrrolo[2,3-b]pyridin-2-one hydrochloride (example 76c) and nicotinoyl chloride hydrochloride. The title compound was obtained as light yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH2:6]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:5][O:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24]([O:31][C:32]([NH:34][C@@H:35]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C:36]([OH:38])=[O:37])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[I-].[Na+]>O.CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH2:6][O:37][C:36](=[O:38])[C@@H:35]([NH:34][C:32]([O:31][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:33])[CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:5][O:4][CH2:3]1
Reactant: CC(C)(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)OCC1(C)COC1
Reaction time: 8 h
Yield: 89.6 %

Procedure:
Toluene-4-sulfonic acid 3-methyloxetan-3-ylmethyl ester (18.6 g, 66 mmol) was added to a solution of cesium carbonate (13.04 g, 39 mmol) in water (15 ml) and stirred until the solution became clear. The solution was lyophilized overnight to give flaky white solid. The solid was dissolved in DMF (50 ml) and 2(S)-benzyloxycarbonylamino-4,4-dimethylpentanoic acid (15.99 g, 66 mmol) and sodium iodide (2 g, 13.2 mmol) were added. After 48 h, the solution was diluted with 500 ml of ethyl acetate, washed with water, saturated solution of sodium bicarbonate solution (50 ml) and brine. The ethyl acetate layer was separated and dried over MgSO4. The solvent was evaporated and the crude was column chromatographed on a silica gel column using 20:80 EtOAc:Hexane as eluent to give 2(S)-benzyloxycarbonylamino-4,4-dimethylpentanoic acid 3-methyloxetan-3-ylmethyl ester (21.5 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@@H:27]([CH3:32])[C:28]([O:30]C)=O)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:36][NH:37][CH3:38]>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@@H:27]([CH3:32])[C:28]([N:37]([CH3:38])[CH3:36])=[O:30])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Reactant: CNC
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C(=O)N(C)C
Yield: 56 %

Procedure:
A solution of methyl (2S)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.42 mmol) in 6N methanolic dimethylamine (10 ml) was stirred for 18 hours. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 2% methanol in dichloromethane) to give the title compound as a beige solid (115 mg, 56%); NMR Spectrum 1.59 (d, 3H), 2.94 (s, 3H), 3.15 (s, 3H), 5.71 (s, 2H), 5.86 (q, 1H), 7.07 (m, 3H), 7.30 (d, 1H), 7.36 (m, 2H), 7.74 (m, 2H), 7.84 (m, 1H), 8.17 (s, 1H), 8.51 (s, 1H), 8.55 (s, 1H); Mass spectrum 485.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:14]SC)=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].O>C(O)C.[Ni]>[NH2:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1ccc(Cl)c(N)c1CSC
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(Cl)c(N)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
A solution of ethyl 3-amino-4-chloro-2-(methylsulphenylmethyl)benzoate (50 g) in ethanol was added to a stirred suspension of Raney Nickel (300 g) in ethanol. After stirring overnight at room temperature, a further addition of Raney Nickel was made and the mixture stirred for 2 hours. Water was added, the mixture filtered and the residue washed with dichloromethane. The filtrate was evaporated, re-extracted with ethyl acetate, dried (magnesium sulphate) and evaporated to give ethyl 3-amino-4-chloro-2-methylbenzoate (29.7 g) as a brown oil, NMR (CDCl3) 1.25 (t,3H), 2.25 (s,3H), 4.3 (q,2H), 7.05 (m,2H).