Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([CH:20]=[O:21])=[CH:18][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:36]([N:49]1[CH2:52][CH:51](OS(C)(=O)=O)[CH2:50]1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[CH:36]([N:49]1[CH2:52][CH:51]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=3)[C:6]([C:11]3[N:12]=[C:13]4[C:19]([CH:20]=[O:21])=[CH:18][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]4=[N:15][CH:16]=3)=[N:7]2)[CH2:50]1)([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3n[nH]c4cc(F)ccc34)cnc21
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3nn(C4CN(C(c5ccccc5)c5ccccc5)C4)c4cc(F)ccc34)cnc21
Temperature: 100 °C
Yield: 38.1 %

Procedure:
In a microwave vial 2-(6-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (300 mg, 0.73 mmol) was dissolved in DMF (6 ml) and cesium carbonate (713 mg, 2.19 mmol) and methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (347 mg, 1.09 mmol) were added. The vial was sealed and heated in a microwave reactor at 100° C. 3 h. The reaction was cooled, quenched with water and extracted with EtOAc (2×). The combined organics were washed with water and brine then dried over MgSO4 and concentrated. The crude residue was purified by silica gel chromatography with 20% to 30% EtOAc/hexanes to provide 176 mg (38%) of 2-[1-(1-benzhydryl-azetidin-3-yl)-6-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as an orange foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18].S1C=CC=C1C(Cl)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([O:13][CH3:12])[CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C(Cl)c1cccs1
Product: COc1cccc(C(=O)Nc2ccc(F)c([N+](=O)[O-])c2)c1

Procedure:
4-Fluoro-3-nitro-phenylamine was reacted with 3-methoxybenzoyl chloride according to the procedure of Example 256a substituting 3-methoxybenzoyl chloride for thiophene-2-carbonyl chloride to provide N-(4-Fluoro-3-nitro-phenyl)-3-methoxy-benzamide which was then reacted according to the procedures of Examples 256b and 256c to provide the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Reactant: OB(O)c1cccnc1
Product: COc1cc(Nc2cncc(-c3cccnc3)n2)cc(OC)c1OC
Yield: 52.2 %

Procedure:
Using Method C with 200 mg (0.68 mmol) 2a and 100 mg (0.82 mmol) 3-pyridylboronic acid, 120 mg (52.1%) pure title compound were obtained after purification of the whole batch by column chromatography (Kieselgel 60, 0.040-0.063; eluent: AcOEt:MeOH 1:1). Reaction time: 3 hours. 1H-NMR (DMSO), δ (ppm), J (Hz): 3.67 (s, 3H, CH3O(4′)), 3.85 (s, 6H, CH3O(3′+5′)), 7.26 (s, 2H, Harom(2+6)), 7.59 (m, 1H, Harom 5′), 8.25 (s, 1H, HP5), 8.49 (d, 1H, Harom 6′, J=7.90), 8.63 (s, 1H, HP3), 8.69 (d, 1H, Harom 4′, J=3.18), 9.51 (d, 1H, Harom 2′, J=2.21), 9.51 (s, 1H, NHamine); MS, (C18H18N4O3), m/z: 339.1 [M++1, 100].
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][C:14]=3[O:19][CH3:20])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CN(C)C(N(C)C)=N>CS(C)=O.C(OCC)(=O)C>[CH3:20][O:19][C:14]1[CH:13]=[C:12]([O:21][CH3:22])[CH:11]=[C:10]2[C:15]=1[C:16](=[O:18])[NH:17][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([N:30]3[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH2:28][CH2:29]3)[N:7]=1)=[N:9]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(F)n3)nc2c1
Reactant: COCCN1CCNCC1
Agent: CN(C)C(=N)N(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COCCN1CCN(c2cccc(-c3nc4cc(OC)cc(OC)c4c(=O)[nH]3)n2)CC1
Temperature: 80 °C
Yield: 49.9 %

Procedure:
A mixture of 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.100 g, 0.33 mmol), 1-(2-methoxyethyl)piperazine (0.072 g, 0.49 mmol) and 1,1,3,3-tetramethylguanidine (0.096 g, 0.83 mmol) in dry DMSO (2 mL) was heated at 80° C. for 17 h. After that time the reaction mixture was cooled to rt and diluted with ethyl acetate (30 mL). The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol to 95:5 dichloromethane/methanol) to give 5,7-dimethoxy-2-(6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one (0.070 g, 49%) as a yellow solid: mp 99-101° C.; 1H NMR (400 MHz, CDCl3) δ 10.32 (s, 1H), 7.85 (d, J=7.42 Hz, 1H), 7.61-7.71 (m, 1H), 6.77-6.87 (m, 2H), 6.48 (d, J=1.95 Hz, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.64-3.71 (m, 4H), 3.59 (t, J=5.47 Hz, 2H), 3.40 (s, 3H), 2.61-2.71 (m, 6H); ESI MS m/z 426 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6](S(C)=O)[N:7]=1.[CH3:24][CH:25]1[CH2:30][CH2:29][N:28]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:27][CH2:26]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6]([N:34]2[CH2:35][CH2:36][CH:31]([N:28]3[CH2:29][CH2:30][CH:25]([CH3:24])[CH2:26][CH2:27]3)[CH2:32][CH2:33]2)[N:7]=1
Reactant: CC1CCN(C2CCNCC2)CC1
Reactant: CS(=O)c1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCN(C2CCN(c3nc(Cl)c4ccc(=O)n(-c5c(F)cccc5F)c4n3)CC2)CC1
Temperature: -20 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To the compound 4-chloro-8-(2,6-difluorophenyl)-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one (1.39 g, 3.9 mmol) in dichloromethane (80 mL) were added 4-methyl-1,4′-bipiperidine (0.75 g, 5.85 mol) and triethylamine (1.03 mL, 11.7 mmol). The mixture was stirred at −20° C. overnight. Filtration followed by concentration, the crude was purified with flash chromatography to afford the title compound (0.904 g, 51%). LC-MS m/z 474 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH:27][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:12][CH:13]=3)[CH:5]=[CH:4][N:3]=2)=[CH:21][CH:20]=1
Reactant: CC(=O)c1cccc(-c2ccnc(Cl)n2)c1
Reactant: COc1ccc(CCN)cc1
Product: COc1ccc(CCNc2nccc(-c3cccc(C(C)=O)c3)n2)cc1

Procedure:
Intermediate 38 was coupled with 2-(4-Methoxy-phenyl)-ethylamine following procedure F. LC-MS showed the product had the expected M+H+ of 348.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:34])=[O:12])[N:7]([CH3:35])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH2:37].Cl.Cl>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:37][CH3:36])[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:34])=[O:12])[N:7]([CH3:35])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(C(C)(C)C)nn4C)c3)c(=O)n(C)c2n1
Reactant: CN
Agent: Cl
Product: CNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(C(C)(C)C)nn4C)c3)c(=O)n(C)c2n1
Yield: 26 %

Procedure:
Using a procedure analogous to Example A1, 1-(3-t-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.180 g, 0.363 mmol) and MeNH2.HCl (0.0502 g, 0.743 mmol, 2.00 eq) were combined to afford 1-(3-t-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.0451 g, 24% yield) as the HCl salt. 1H NMR (400 MHz, DMSO-d6): δ 9.49 (brs, 1H), 9.07 (s, 1H), 8.44-8.41 (m, 1H), 7.97 (brs, 1H), 7.92 (s, 1H), 7.33-7.27 (m, 2H), 6.23 (s, 1H), 3.71 (s, 3H), 3.63 (brs, 3H), 2.94 (s, 3H), 1.24 (s, 9H); MS (ESI) m/z: 479.2 (M+H+).
Reaction SMILES: [S:1]1[C:5]([C:6]([NH2:8])=[NH:7])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[Cl:13][C:14]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:15]=1[CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19]>>[NH2:21][CH2:20][C:17]1[C:18]([NH2:19])=[N:7][C:6]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[N:8][C:16]=1[C:15]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:14]=1[Cl:13]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: N=C(N)c1cc2ccccc2s1
Product: NCc1c(N)nc(-c2cc3ccccc3s2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=400.9 (M+H+), was prepared from benzo[b]thiophene-2-carboxamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH2:11][N:10](C(OCC3C=CC=CC=3)=O)[C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:8]2)=[CH:3][CH:2]=1.I[Si](C)(C)C>C(#N)C>[C:1]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:2]=[CH:3][C:4]([C@@:7]2([S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH2:11][NH:10][C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:8]2)=[CH:5][CH:6]=1
Reactant: CCCS(=O)(=O)[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CCCS(=O)(=O)[C@]1(c2ccc(-c3ccccc3)cc2)CN[C@H](C(=O)OC)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a solution of (2S,4R)-1-benzyl 2-methyl 4-(biphenyl-4-yl)-4-(propylsulfonyl)pyrrolidine-1,2-dicarboxylate (1.85 g, 3.55 mmol) in acetonitrile (30 mL) was added iodotrimethylsilane (1.211 mL, 8.51 mmol) at 0° C. The formed light brown solution was stirred at room temperature for 2 h. Cooled with ice bath, quenched with methanol. Removed the volatiles in vacuo. The residual brown oil was triturated with 2M HCl in ether (20 mL). The formed brown solid was filtered. Washed the cake with ether thoroughly. The collected light brown solid was pumped to afford the desired product (2S,4R)-methyl 4-(biphenyl-4-yl)-4-(propylsulfonyl)pyrrolidine-2-carboxylate (1.54 g, 3.19 mmol, 90% yield). 1H NMR (500 MHz, MeOD) δ ppm 0.97 (t, J=7.32 Hz, 3 H) 1.57-1.71 (m, 2 H) 2.96 (dd, J=9.16, 5.49 Hz, 1 H) 3.22-3.39 (m, 2 H) 3.65 (dd, J=15.72, 4.73 Hz, 1 H) 3.94 (s, 1 H) 4.14 (d, J=13.12 Hz, 1 H) 4.70 (d, J=13.12 Hz, 1 H) 7.37-7.44 (m, 1 H) 7.45-7.54 (m, 2 H) 7.66 (dd, J=19.99, 7.78 Hz, 4 H) 7.79 (d, J=8.55 Hz, 2 H). LC-MS (retention time: 1.42 min, method A), MS m/z 388 (M+H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[C:11]1[C:10]([OH:17])=[CH:9][C:8]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:7][C:6]=1[O:5]2.[CH2:24]([OH:27])[CH2:25][OH:26].[H-].[Na+]>CN(C=O)C>[OH:17][C:10]1[C:11]2[C:12](=[O:16])[C:13]3[C:4](=[CH:3][C:2]([O:26][CH2:25][CH2:24][OH:27])=[CH:15][CH:14]=3)[O:5][C:6]=2[CH:7]=[C:8]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:9]=1
Reactant: O=c1c2ccc(F)cc2oc2cc(N3CCOCC3)cc(O)c12
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2ccc(OCCO)cc2oc2cc(N3CCOCC3)cc(O)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.3 %

Procedure:
A solution of 6-fluoro-1-hydroxy-3-morpholin-4-yl-xanthen-9-one (30.0 mg, 0.095 mmol) and ethylene glycol (59.1 mg, 0.951 mmol) in anhydrous DMF (1 mL) was treated with NaH (40.0 mg, 0.951 mmol). The bubbling reaction was stirred for 15 minutes at room temperature, then heated at 80° C. for 1 hour. The reaction mixture was quenched with water and extracted with EtOAc (3×50 mL). The combined organics were washed with water (3×15 mL), dried (MgSO4), and concentrated to produce an oil. The oil was purified via Biotage chromatography using a gradient of 2.5%-5% MeOH/CH2Cl2 as eluent to yield 12 mg (35%) of 1-hydroxy-6-(2-hydroxyethoxy)-3-morpholin-4-yl-xanthen-9-one as a white powder. Rf=0.55 (5% MeOH/CH2Cl2). 1H NMR (DMSO-d6, 400 MHz) δ: 12.91 (s, 1H), 8.05 (d, 1H), 7.10 (m, 2H), 6.48 (s, 1H), 6.34 (s, 1H), 4.98 (m, 1H), 4.18 (t, 2H), 3.78 (t, 2H), 3.70 (m, 4H), 3.38 (m, 4H). LRMS (APCI, positive): Da/e 358.4 (m+1).
Reaction SMILES: C([O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[C:10]([Br:15])[C:11]2=[O:14])=[CH:7][CH:6]=1)(=O)C.C(OC1C=C2C(C(C3C=CC=CC=3)=C(Br)C2=O)=CC=1)(=O)C>>[Br:15][C:10]1[C:11](=[O:14])[C:12]2[C:8]([C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[CH:7][CH:6]=[C:5]([OH:4])[CH:13]=2
Reactant: CC(=O)Oc1ccc2c(c1)C(=O)C(Br)=C2c1cccc(F)c1
Agent: CC(=O)Oc1ccc2c(c1)C(=O)C(Br)=C2c1ccccc1
Product: O=C1C(Br)=C(c2cccc(F)c2)c2ccc(O)cc21
Yield: 96 %

Procedure:
The procedure of Step 5 of Example 1 was repeated except for using 2-bromo-3-(3-fluorophenyl)-1-oxo-1H-inden-6-yl acetate obtained in Step 4 as a starting material instead of 2-bromo-1-oxo-3-phenyl-1H-inden-6-yl acetate to obtain the title compound (96%).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4](O)[CH:3]=1.C(OCC1(O)C=CCC(C)(C)C1)(=O)C>>[CH2:1]=[C:2]1[CH:3]=[CH:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7]1
Reactant: CC1=CC(O)CC(C)(C)C1
Agent: CC(=O)OCC1(O)C=CCC(C)(C)C1
Product: C=C1C=CCC(C)(C)C1

Procedure:
1-Methylene-3,3-dimethyl-cyclohex-5-ene was prepared by the procedure given in Bull. Soc. Chim. France 4170 (1972) starting from isophorol. Its conversion into (1-hydroxy-3,3-dimethyl-cyclohex-5-en-1-yl)-methyl acetate was performed as follows:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1>C(#N)C.CO.[Pt]>[NH2:12][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:15][NH:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=2
Reactant: CC(C)(C)OC(=O)NNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Agent: [Pt]
Solvent: CO
Solvent: CC#N
Product: CC(C)(C)OC(=O)NNc1c(N)cnc2cc(Br)ccc12
Reaction time: 4 h
Yield: 80.2 %

Procedure:
A suspension of tert-butyl N′-(7-bromo-3-nitroquinolin-4-yl)hydrazinecarboxylate (50.0 g, 131 mmol) in 320 mL of acetonitrile (MeCN) and 80 mL of methanol was treated with platinum on carbon (5.0 g, 1.3 mmol, 5% w/w) and shaken under an atmosphere of hydrogen (3.8×105 Pa). After 4 h, the reaction mixture was filtered through a pad of CELITE filter agent and rinsed with portions of MeCN:MeOH (1:1) until the filtrate ran clear. The filtrate was concentrated under reduced pressure to yield 37.1 g of tert-butyl N′-(3-amino-7-bromoquinolin-4-yl)hydrazinecarboxylate as a tan solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=[O:20])[CH2:6][C:7]([CH:9]1[C:18](=O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:11][CH2:10]1)=[O:8])C.O1C2C(=CC=CC=2)C(=O)C(C(=O)CC(=O)C(O)=O)C1>>[CH3:1][O:3][C:4]([C:5]1[O:20][C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH2:10][C:9]=2[C:7](=[O:8])[CH:6]=1)=[O:21]
Reactant: CCOC(=O)C(=O)CC(=O)C1COc2ccccc2C1=O
Agent: O=C(O)C(=O)CC(=O)C1COc2ccccc2C1=O
Product: COC(=O)c1cc(=O)c2c(o1)-c1ccccc1OC2

Procedure:
In the same manner as described above in (c) but replacing 4-(4-chromanone-3-yl)-2,4-dioxobutyric acid ethyl ester with an equivalent amount of the corresponding acid, 4-(4-chromanone-3-yl)-2,4-dioxobutyric acid [described above in (b)], the title compound is obtained.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH:25]([N:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[NH:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]([OH:44])=O)=[CH:40][CH:39]=1)([CH3:27])[CH3:26].[NH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58].C(N(CC)C(C)C)(C)C>>[CH:25]([N:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[NH:37][C:38]1[CH:39]=[CH:40][C:41]([C:42]([NH:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[NH:54][C:55](=[O:61])[O:56][C:57]([CH3:59])([CH3:58])[CH3:60])=[O:44])=[CH:45][CH:46]=1)([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: CC(C)n1c(Nc2ccc(C(=O)O)cc2)nc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1c(Nc2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 62 mg, 0.16 mmol) was added to a solution of 4-(1-isopropyl-1H-benzo[d]imidazol-2-ylamino)benzoic acid (40 mg, 0.13 mmol), tert-butyl 2-aminophenylcarbamate (34 mg, 0.16 mmol) and N,N-diisopropylethylamine (0.047 mL, 0.27 mmol. The reaction may be stirred at room temperature for an appropriate time period such as 2 hrs and quenched by water. The mixture may be extracted with any appropriate agent, such as ethyl acetate, and concentrated. The residue may be purified by any appropriate method, including Biotage column chromatography to give tert-butyl 2-(4-(1-isopropyl-1H-benzo[d]imidazol-2-ylamino)benzamido)phenylcarbamate (58 mg)
Reaction SMILES: [CH2:1]([C@@:4]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[CH:15][C:14]=1[Cl:30])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3]>C(OCC)(=O)C>[C:35]([O:34][C:32]([NH:31][C@:4]([CH2:1][CH2:2][CH3:3])([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)=[CH:15][C:14]=1[Cl:30])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: C=CC[C@](CCCc1ccc(Sc2cccc(C(F)(F)F)c2)cc1Cl)(NC(=O)OC(C)(C)C)C(=O)OCC
Solvent: CCOC(C)=O
Product: CCC[C@](CCCc1ccc(Sc2cccc(C(F)(F)F)c2)cc1Cl)(NC(=O)OC(C)(C)C)C(=O)OCC
Yield: 73 %

Procedure:
To a solution of the compound of Example 14 (400 mg) in ethyl acetate (20 mL) was added palladium-carbon/ethylene diamine complex (100 mg), and the resultant solution was stirred at room temperature for 24 hours under hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was evaporated. The resultant residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to obtain the target product (293 mg) as a colorless oil.
Reaction SMILES: CO.O1[CH2:8][CH2:7][O:6][CH2:5]C1.Cl.[Cl:10]C1[N:16]=[CH:15][N:14]=[C:13]([N:17]2[C:21](=[O:22])[C:20]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)=[CH:19][NH:18]2)C=1>C1COCC1>[ClH:10].[CH3:5][O:6][C:7]1[N:16]=[CH:15][N:14]=[C:13]([N:17]2[C:21](=[O:22])[C:20]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)=[CH:19][NH:18]2)[CH:8]=1
Reactant: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(-n2[nH]cc(-n3ccnn3)c2=O)ncn1

Procedure:
0.3 ml (6.6 mmol) methanol are initially introduced into 15 ml dioxane. 1.3 ml (2.7 mmol) of a 2 M solution of the phosphazene base P2-tert-butyl in THF are added slowly, while stirring, and the mixture is stirred at RT for 15 min 350 mg (1.3 mmol) of the compound from Example 52A are subsequently added and the mixture is reacted in a single mode microwave (CEM Explorer) at 150° C. for 2 h. A further 2 ml (49.2 mmol) methanol are then added and the mixture is reacted again in a single mode microwave (CEM Explorer) under the same conditions for 2 h. After cooling, the reaction mixture is concentrated and the residue is purified via preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions are combined and the mixture is concentrated on a rotary evaporator. The residue is dried under a high vacuum and 3 ml of a 4 N solution of hydrogen chloride in dioxane is subsequently added. The mixture is stirred at RT for 30 min and the solid is then filtered off and dried under a high vacuum.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]1([S:19]([CH2:22][CH2:23][S:24][C:25]2[N:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=O)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:37]=[C:38]([CH:42]([NH2:44])[CH3:43])[CH:39]=[CH:40][CH:41]=1.C(OCC)(=O)C.CCCCCC>C(Cl)Cl>[C:13]1([S:19]([CH2:22][CH2:23][S:24][C:25]2[N:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([NH:44][CH:42]([C:38]2[CH:39]=[CH:40][CH:41]=[C:36]([C:35]([F:34])([F:45])[F:46])[CH:37]=2)[CH3:43])=[O:29])(=[O:20])=[O:21])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1cccnc1SCCS(=O)(=O)c1ccccc1
Reactant: CC(N)c1cccc(C(F)(F)F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(NC(=O)c1cccnc1SCCS(=O)(=O)c1ccccc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
264 mg (1.62 mmol) of CDI were added to a solution of 500 mg (1.55 mmol) of 2-(2-(phenylsulfonyl)ethylthio)nicotinic acid in DCM (12 ml), and the mixture was stirred for 1 h at RT. A solution of 292 mg (1.55 mmol) of 1-(3-(trifluoromethyl)phenyl)ethylamine in DCM (12 ml) was then added, and stirring was continued for a further 16 h at RT. The reaction solution was then washed in each case three times with sat. aq. ammonium chloride solution and saturated aqueous NaCl solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. CC with the residue (ethyl acetate/hexane 1:1) yielded 462 mg (0.93 mmol, 60%) of 2-(2-(phenylsulfonyl)ethylthio)-N-(1-(3-(trifluoromethyl)phenyl)ethyl)nicotinamide. MS: m/z 495.1 [M+H]+.
Reaction SMILES: C(C[C@H](O[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]Br)=[CH:9][CH:8]=1)C)C.[CH3:16][C@H:17]([NH2:26])[C@H:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:8]([CH2:9][C@H:10]([CH2:13][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][NH:26][C@@H:17]([CH3:16])[C@H:18]([OH:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:11][CH:12]=1)[CH3:11])[CH3:7]
Reactant: CCC[C@@H](C)Oc1ccc(CCBr)cc1
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC[C@@H](C)Cc1ccc(CCN[C@@H](C)[C@H](O)c2ccccc2)cc1

Procedure:
A compound ethyl(R)-2-[4-(2-bromoethyl)phenoxy]propane (450 mg, 1.5 mM) and (1R,2S)-Norephedrine in DMF (5 ml) it is maintained in agitation in nitrogen atmosphere at a temperature of 70° C. for 72 hours. Then the reaction mixture is diluted with ethyl acetate, washed with a saturated solution of NaCl and dried with anhydrous Na2SO4. The solvent is removed at reduced pressure and the product is isolated from the residue by column chromatography (silica gel; mobile phase: dichloromethane/ethanol=40:1). 145 mg of ethyl (R)-2-[4-[2-((1R,2S)-1-hydroxy-1-phenylpropan-2-yl-amino)ethyl]benzyl]propane is obtained as clear yellow oil (52% of yield). [α]D=−0.6 (c 1.1, CHCl3). FT-IR (neat): 3262, 3055, 2986, 2930, 1748, 1613, 1559, 1511, 1451, 1270, 1241, 1196, 1136, 1098, 1051, 1016, 743, 703 cm−1. 1NMRs (500 MHz, CDCl3, δ): 7.32-7.22 (m, 5H, aromatic protons); 7.11-7.09 (2H, aromatic protons); 6.80-6.78 (2H, aromatic protons); 5.15-5.14 (d, 1H, J=4.0 Hz, CHOH); 4.76 (bs, 2H, OH and NH: exchanged with D2O); 4.71-4.67 (q, 1H, J=6.7 Hz, CH3CHCO); 4.22-4.18 (q, 1H, J=7.2 Hz, CH2CH3); 3.71-3.67 (q, 1H, J=7.0 Hz, CH3CHNH); 3.20-2.91 (m, 4H, CH2CH2); 1.60-1.59 (d, 3H, J=6.7 Hz, OCHCH3); 1.25-1.20 (m, 3H, CH3CH2); 0.96-0.94 (m, 3H, J=7.0 Hz, CH3CHNH). 13C NMRs (125 MHz CDCl3, δ): 172.23, 161.34, 156.25, 129.69, 128.13, 127.60, 127.17, 126.10, 125.88, 115.22, 75.80, 72.62, 72.40, 61.23, 58.98, 49.72, 48.09, 34.28, 18.51, 14.08. MS-ESI m/z (%): 372 [M+H]+ (100). MS-MS (372): 354 (100), 221 (55), 147 (24), 121 (7).