Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:5]1([C:18]([NH2:20])=[O:19])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][NH:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3)(C)(C)C.[CH2:21]([O:28][C:29]([NH:31][C@@H:32]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@@H:33]1[O:35][CH2:34]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[CH2:21]([O:28][C:29]([NH:31][C@@H:32]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:33]([OH:35])[CH2:34][N:6]1[CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:5]1[C:18]([NH:20][C:9]([CH3:17])([CH3:10])[CH3:8])=[O:19])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)C1(C(N)=O)NCCc2c1[nH]c1ccccc21
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Solvent: CO
Product: CC(C)(C)NC(=O)C1c2[nH]c3ccccc3c2CCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
A solution of 0.60 g of tert.butyl 1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxamide and 0.66 g of 3(S)-(benzyloxyformamido)-1,2(S)-epoxy-4-phenylbutane in 20 ml of methanol was heated at reflux under argon for 16 hours and then evaporated to give a clear oil. The two diastereomeric products were separated by flash chromatography on silica gel using n-hexane/ethyl acetate (3:1) for the elution. There were obtained 268 mg of isomer A of 2-[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxamide, MS: m/e 569 [M+H]+, and 65 mg of isomer B of the same compound; MS: m/e 569 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C1C(=O)N([O:17][C:18]([CH2:20][I:21])=O)C(=O)C1.C(N(CC)C(C)C)(C)C>ClCCl>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:18](=[O:17])[CH2:20][I:21])=[CH:4][CH:3]=1
Reactant: O=C(CI)ON1C(=O)CCC1=O
Reactant: NCc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(CNC(=O)CI)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
FIG. 11 illustrates the synthesis of Mass Tag (2). 4-Amino-benzylamine (Aldrich, 1 mmol), N-succinimidyl iodoacetate (Pierce, 1 mmol), and N,N-diisopropyl ethylamine (DIEA, 100 μL) were mixed in dichloromethane (10 mL) and stirred at room temperature for 1 hr. Solvent was removed under reduced pressure. The product was purified by silica gel column chromatography, eluting with hexane, ethyl acetate (20%-60%), to give 4-amino-N-iodoacetylbenzylamine (62.2% yield). 1H NMR (MeOD): 7.1 (d, 2H), 6.75 (d, 2H), 4.21 (s, 2H), 3.65 (s, 2H). [M+H]+ in MS: 291.0, calculated; 291.0, found.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]([NH2:23])=[O:22].[CH3:24][C:25]1[S:26][C:27]([CH2:31][NH2:32])=[C:28]([CH3:30])[N:29]=1.O>C(#N)C>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:32][CH2:31][C:27]4[S:26][C:25]([CH3:24])=[N:29][C:28]=4[CH3:30])=[C:3]([C:21]([NH2:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: Cc1nc(C)c(CN)s1
Reactant: COc1cc2c(Cl)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Solvent: CC#N
Solvent: O
Product: COc1cc2c(NCc3sc(C)nc3C)c(C(N)=O)cnc2cc1-c1c(C)noc1C

Procedure:
To a solution of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 0.5 g,) in acetonitrile (50 ml) was added a solution of [(2,4-dimethyl-1,3-thiazol-5-yl)methyl]amine (0.64 g, dihydrochloride available from Matrix Scientific) in acetonitrile (10 ml). The reaction mixture was heated at reflux for 3 h, whereupon another portion of amine (0.5 g) was added. The reaction mixture was refluxed overnight and was then poured into water. The mixture phase was extracted with DCM and the organic dried over Na2SO4 and concentrated to dryness to give a yellow sticky solid. The latter was recrystallised in acetonitrile to give 7-(3,5-dimethyl-4-isoxazolyl)-4-{[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]amino}-6-(methyloxy)-3-quinolinecarboxamide (0.33 g) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]3[CH2:13][CH2:14][C:15]([CH2:21][CH3:22])([C:17]([O:19][CH3:20])=[O:18])[CH2:16][C:11]3(N3CCCC3)[O:10][N:9]=2)=[CH:4][CH:3]=1>Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][C:15]([CH2:21][CH3:22])([C:17]([O:19][CH3:20])=[O:18])[CH2:16][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCC1(C(=O)OC)CCC2C(c3ccc(Cl)cc3)=NOC2(N2CCCC2)C1
Agent: Cl
Product: CCC1(C(=O)OC)CCc2c(-c3ccc(Cl)cc3)noc2C1
Yield: 41.2 %

Procedure:
A solution of 4.7 g (12 mmol) of methyl 3-(4-chlorophenyl)-6-ethyl-3a,4,5,6,7,7a-hexahydro-7a-pyrrolidino-1,2-benzisoxazole-6-carboxylate in 200 ml of 2N hydrochloric acid was heated under reflux for 6 hours. The mixture was extracted with diethyl ether and the extracts were dried over magnesium sulfate and evaporated. After crystallization from methylcyclohexane, there were obtained 1.58 g of methyl 3-(4-chlorophenyl)-6-ethyl-4,5,6,7-tetrahydro-1,2-benzisoxazole-6-carboxylate of melting point 101°-102.5° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][N:26]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[C:27]1[CH3:37]>C(#N)C>[F:16][C:14]1[CH:13]=[CH:12][C:11]2[C:7]([CH:4]3[CH2:3][CH2:2][N:1]([CH2:24][CH2:25][N:26]4[C:35](=[O:36])[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=[C:27]4[CH3:37])[CH2:6][CH2:5]3)=[N:8][O:9][C:10]=2[CH:15]=1
Reactant: Cc1nc2ccccc2c(=O)n1CCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc2ccccc2c(=O)n1CCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of 3-(4-piperidinyl)-6-fluorobenzisoxazole (4 g, 18.2 mmol), K2CO3 (3.76 g, 27.2 mmol) and 3-(2-chloroethyl)-2-methyl-3H-4-quinazolinone (6.0 g, 27 mmol) in acetonitrile (300 ml) was heated at reflux for 16 hours. The reaction was complete as judged by TLC. The solids were filtered and the solvent was evaporated. The residue was purified over a flash chromatography column (SiO2, 75 gm, eluted with dichloromethane and MeOH in dichloromethane). The pure product thus obtained weighed 6.5 gm. Recrystallization from ethanol yielded white crystals, 3.94 gm (53%), m.p. 164°-165° C. This material appeared pure by TLC over silica gel plates.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][CH:11]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[C:37]1[CH2:42][CH2:41][C:40]([C:48]([O:50][CH2:51][CH3:52])=[O:49])([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH:38]=1)(=O)=O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:37]3[CH2:42][CH2:41][C:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:39][CH:38]=3)=[CH:14][CH:15]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC1(C)OB(c2ccc(-c3ccc([N+](=O)[O-])cn3)cc2)OC1(C)C
Reactant: CCOC(=O)C1(C(=O)OCC)CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C1(C(=O)OCC)CC=C(c2ccc(-c3ccc([N+](=O)[O-])cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.5 %

Procedure:
A flask was charged with 5-nitro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine (3.9 g, 10.73 mmol) and potassium carbonate (6.77 g, 48.3 mmol) in dioxane (60 ml) and Water (25 ml), and stirred at room temperature for 10 minutes under nitrogen. Then Pd(PPh3)4 (1.240 g, 1.073 mmol) and diethyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1,1-dicarboxylate (4.22 g, 11.27 mmol) were added to the reaction mixture. The flask was sealed, flushed with nitrogen for three times and heated at 100° C. for 1 hour. The organic solvent was evaporated under vacuum and EtOAc (3×100 ml) was used to extract and the combined organic solvent was washed by saturated aqueous sodium bicarbonate solution, brine, and dried over Na2SO4, then concentrated. The residue was purified by flash chromatography (heptanes/acetone 1/2) to afford diethyl 4′-(5-nitropyridin-2-yl)-5,6-dihydro-[1,1′-biphenyl]-4,4(3H)-dicarboxylate (2.8 g, 61%) as yellow solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.25 (t, J=7.20 Hz, 6H) 2.30 (dt, J=6.28, 3.24 Hz, 2H) 2.53 (dd, J=4.67, 1.77 Hz, 2H) 2.76 (dd, J=3.98, 2.08 Hz, 2H) 4.20 (q, J=7.20 Hz, 4H) 6.19 (s, 1H) 7.06-8.88 (m, 7H).
Reaction SMILES: [C:1]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([Cl:18])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][CH:20](C(OCC)=O)[C:21]([O:23]CC)=[O:22]>>[C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH:20]([CH3:19])[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=[C:13]([Cl:18])[CH:12]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: O=C(c1ccccc1)c1cc2ccc(Cl)cc2[nH]1
Product: CC(C(=O)O)c1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 4 of Example 2 (Method B) from 2-benzoyl-6-chloroindole (step 3 of Example 2, Method B) and diethyl methylmalonate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si](C)(C)C)=[C:4]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[C:4]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:3]=1
Reactant: C[Si](C)(C)C#Cc1ccc(Cl)cc1C1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc(Cl)cc1C1CCCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
16.6 g (57.1 mmol) of 8 are dissolved in 154 ml of tetrahydrofuran, cooled to 0° C., and a 1 M solution of tetra-n-butylammonium fluoride (68.48 mmol) is added dropwise. The batch is stirred at room temperature overnight, water is added, the mixture is extracted with methyl t-butyl ether, the organic phase is dried over sodium sulfate and filtered, the solvent is removed in vacuo, and the residue is filtered through silica gel with heptane/toluene, giving the product 9, which is employed in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:14]=[C:13](Cl)[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][N:10]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:8][C:9]1[CH:14]=[C:13]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][N:10]=1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCN(c2cc(Cl)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
1-methylpiperazine (298.5 mg, 330.6 μL, 2.980 mmol) in THF (5 mL) was added to a stirred solution of 2,4-dichloro-5-nitro-pyridine (500 mg, 2.591 mmol) and DIPEA (401.8 mg, 541.5 μL, 3.109 mmol) in THF (10 mL) at 0° C. under an atmosphere of nitrogen. The reaction was allowed to stir at ambient temperature for 1 hour then the solvent removed in vacuo. The residue was purified by column chromatography (ISCO Companion, 40 g column, eluting with 0 to 10% MeOH/DCM solutions) to give 1-(2-chloro-5-nitropyridin-4-yl)-4-methylpiperazine as a yellow solid (638 mg, 96% Yield). MS (ES+) 257.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])[CH:5]=[CH:6][CH:7]=1.[C:25](=[O:27])=[O:26]>C1COCC1>[OH:12]/[N:11]=[C:10](/[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)\[CH2:9][CH:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:25]([OH:27])=[O:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C=O
Reactant: O/N=C(\CC(c1ccccc1)c1cccc(Br)c1)c1ccncc1
Solvent: C1CCOC1
Product: O=C(O)c1cccc(C(C/C(=N\O)c2ccncc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 29 %

Procedure:
At −78° C., to a solution of (E)-3-(3-bromo-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (60 mg, example 12) in THF (1.5 mL) n-BuLi (1.6 M in hexane, 0.11 mL) was added dropwise. After stirring for 30 mins at that temperature carbon dioxide gas was bubbled into the solution for 5 min at −78° C. The reaction mixture was then warmed up to 0° C. and stirred for 15 min. The reaction was quenched by adding 1N aqueous KHSO4 solution, the phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Column chromatography on silica gel (CH2Cl2/MeOH 97:3) yielded 3-{3-[(E)-hydroxyimino]-1-phenyl-3-pyridin-4-yl-propyl}-benzoic acid (16 mg, 29%) as a yellow foam, MS (ESI+): m/z=347.1391 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[C:13]([O:16][C@@H:17]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@@H:25]([O:31][C:32](=[O:34])[CH3:33])[C@@H:24]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[O:23][C@H:18]1[O:19][CH2:20][CH2:21]Br)(=[O:15])[CH3:14].C1(S)C=CC=CC=1>CN(C)C=O.CCOCC.C(OCC)(=O)C.C(CC(C)(C)C)(C)C>[C:13]([O:16][C@@H:17]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@@H:25]([O:31][C:32](=[O:34])[CH3:33])[C@@H:24]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[O:23][C@H:18]1[O:19][CH2:20][CH2:21][S:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC[C@H]1O[C@@H](OCCBr)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CC(C)CC(C)(C)C
Product: CC(=O)OC[C@H]1O[C@@H](OCCSc2ccc([N+](=O)[O-])cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 0 °C

Procedure:
p-Nitrothiophenol (50 mg; 0.32 mmol) was added to a suspension of sodium hydride (oil-free; 11 mg; 0.46 mmol) in dimethylformamide (3 ml) at room temperature and with stirring. 2-Bromoethyl 2,3,4,6-tetra-O-acetyl-β-D-galactopyranoside (1) (110 mg; 0.24 mmol) in dimethylformamide (3 ml) was added during 10 min to the thiophenol solution and the reaction mixture was stirred for another 75 min (TLC: SiO2, ethyl acetate:isooctane 1:1). The reaction mixture was poured into ice-cold water (20 ml) and ether (40 ml). The aqueous phase was extracted further with ether (40 ml) and the combined organic phases were washed with cold water (20 ml) and dried (sodium sulfate). Evaporation and chromatography (SiO2, ethyl acetate:isooctane 1:1) gave the title compound (25) as a light yellow oil. Yield: 80 mg (62%). [α]D23 -15.2° (c 1.1; CDCl3); 1H-NMR (CDCl3, TMS) δ 8.14, 7.36 (ABq, 4H, JAB =9.2 Hz, aromatic H), 5.40 (dd, 1H, J4,5 =1.0 Hz, H4), 5.22 (dd, 1H, J2,3 =10.5 Hz, H2), 5.01 (dd, 1H, J3,4 =3.4 Hz, H3), 4.52 (d, 1H, J1,2 =7.8 Hz, H1), 3.25 (t, 2H, J=6.5 Hz, S--CH2), 2.17, 2.05, 2.04, 1.99 (s, 3H each, CH3CO) ppm. 13C-NMR (CDCl3, TMS) δ 170.4, 170.2, 170.1, l69.4 (CO), 146.6, 145.3, 126.5, 124.1 (aromatic C), 101.4 (Cl), 70.9, 70.8, 68.5, 66.9 (C2-C5), 67.9 (CH2 --O) 61.2 (C6), 31.8 (S--CH2), 20.8, 20.7, 20.6 (CH3CO) ppm.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][CH:13]=[CH:14][N:15]=2)[CH:8]=[CH:7][C:6]=1[C:16]1[C:17]([S:22]([NH:25][C:26]2[O:30][N:29]=[C:28]([CH3:31])[C:27]=2[CH3:32])(=[O:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=O)=[CH:36][CH:35]=1.C(N(CC)CC)C.ON1C2N=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C>C(Cl)Cl>[CH3:31][C:28]1[C:27]([CH3:32])=[C:26]([NH:25][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[O:12][CH:13]=[CH:14][N:15]=3)=[CH:10][C:5]=2[CH2:4][N:3]([CH3:2])[C:38](=[O:40])[C:37]2[CH:36]=[CH:35][C:34]([F:33])=[CH:42][CH:41]=2)(=[O:24])=[O:23])[O:30][N:29]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)c2ccc(F)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 2'-[(methylamino)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide, monohydrochloride (100 mg, 0.21 mmol, prepared as described in Step (A) of Example 28) and 4-fluorobenzoic acid (29.5 mg, 0.21 mmol) in 0.3 ml of CH2Cl2, triethylamine (43 mg, 0.42 mmol) and 1-hydroxy-7-azabenzotriazole (31.6 mg, 0.23 mmol) were added and followed by 1,3-diisopropylcarbodiimide (29.3 mg, 0.23 mmol). The reaction was stirred at room temperature for 3 hrs and concentrated. The residue was purified by preparative HPLC on an ODS S10 O column using 31% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 69% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (60 mg, 51%) as a white solid, m.p. 125°-135° C. (amorphous).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=[CH2:30])[C:21]3[C:20](=[O:31])[N:19]([CH2:32][O:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[C:18](=[O:40])[NH:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=[CH2:30])[C:21]3[C:20](=[O:31])[N:19]([CH2:32][O:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[C:18](=[O:40])[N:17]([CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: C=Cc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(=O)n(COC(=O)C(C)(C)C)c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2CC(=O)OCC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4-[1-(2,2-Dimethylpropionyloxymethyl)-2,6-dioxo-7-(2-vinylphenyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (80 mg) was dissolved in N,N-dimethylformamide (2 ml), ethyl bromoacetate (19 μl) and potassium carbonate (22 mg) were added to the solution, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 89 mg of the title compound
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([CH:18]1[CH2:22][CH2:21][C:20](=[O:23])[O:19]1)[CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH:13]=C(C)C)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=[O:26].[Na+].O=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O=O.CO.C(Cl)Cl>[C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([CH:18]1[CH2:22][CH2:21][C:20](=[O:23])[O:19]1)[CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH:13]=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)=CCCC(C)C[C@@H](NC(=O)OC(C)(C)C)C1CCC(=O)O1
Reactant: O=C([O-])O
Agent: O=O
Agent: O=[O+][O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(CCC=O)C[C@@H](NC(=O)OC(C)(C)C)C1CCC(=O)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 5.4 g (15.9 mmol) of [(R)-3,7-dimethyl-1-(5-oxo-tetrahydro-furan-2-yl)oct-6-enyl]-carbamic acid tert-butyl ester (preparation of aldehyde in step g of example 6) in a mixture 200 ml DCM and 10 ml MeOH is cooled to −70° C. After addition of 0.63 g (7.5 mmol) NaHCO3 a stream of O3 in O2 is passed through the stirred mixture till a blue color persists. The excess ozone is removed by passing through more oxygen. After addition of 5.0 g (19 mmol) triphenylphosphine the mixture is allowed to warm up at rt and stirred for 4 h. The mixture is filtered and concentrated in vacuo. Chromatography on silica gel (EtOAc/Hexane 1:1) gives the title aldehyde.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH2:11])[CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>O>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(N)ncc1[N+](=O)[O-]
Solvent: O
Product: CC(=O)Nc1cc(C)c([N+](=O)[O-])cn1
Temperature: 130 °C
Reaction time: 1.5 h

Procedure:
4-Methyl-5-nitro-2-pyridinamine (3.69 g, 2.41 mmol) was added with acetic anhydride (10 ml) and stirred at 130° C. for 1.5 hours. The reaction mixture was left stand for cooling, and then added with distilled water (5.4 ml) at 0° C., heated to 130° C., and stirred for 45 minutes. The reaction mixture was left stand for cooling and concentrated, and the deposited crystals were collected by filtration and washed with distilled water to obtain the title compound (4.71 g, quantitative).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:14]3[CH:25]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][CH:32]=[N:31]2.C(N(C(C)C)CC)(C)C>CS(C)=O.C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N:19]4[CH2:24][CH2:23][N:22]([CH2:27][C:28]5[CH:29]=[C:30]6[C:35](=[CH:36][CH:37]=5)[N:34]=[CH:33][CH:32]=[N:31]6)[CH2:21][CH2:20]4)[N:14]3[CH:25]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2cn3c(N4CCNCC4)cccc3n2)cc1
Reactant: BrCc1ccc2nccnc2c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(-c2cn3c(N4CCN(Cc5ccc6nccnc6c5)CC4)cccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.4 %

Procedure:
2-(4-tert-Butyl-phenyl)-5-piperazin-1-yl-imidazo[1,2-a]pyridine (0.086 g, 0.258 mmol) was dissolved in DMSO (1 mL) and treated with 6-bromomethyl-quinoxaline (0.072 g, 0.323 mmol) followed by diisopropylethylamine (0.046 mL, 0.258 mmol). The mixture was stirred at room temperature overnight and diluted with ethyl acetate (10 mL). The solution was washed with water and saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield the crude product. Purification by flash silica gel chromatography (40-50% acetone/hexanes) gave 0.0362 g (29%) of the title compound. HPLC (Method B): r.t.=9.6 min., purity 100% at 210-370 nm, 96.0% at 238 nm. HRMS: calcd for C30H32N6+H+, 477.27612; found (ESI, [M+H]+), 477.2786.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:17][C:11]3[C:12](=[O:16])[NH:13][CH:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.Br[C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:29][CH2:28][C@@H:27]([N:30]3[CH2:34][CH2:33][C@@H:32]([F:35])[CH2:31]3)[CH2:26]2)=[N:23][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CNCCNC.[NH4+].[OH-]>O1CCOCC1.[Cu]I.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:17][C:11]3[C:12](=[O:16])[N:13]([C:19]4[CH:24]=[N:23][C:22]([N:25]5[CH2:29][CH2:28][C@@H:27]([N:30]6[CH2:34][CH2:33][C@@H:32]([F:35])[CH2:31]6)[CH2:26]5)=[CH:21][CH:20]=4)[CH:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]ccc2cc(-c3ccc(Cl)cc3)sc12
Reactant: F[C@@H]1CCN([C@@H]2CCN(c3ccc(Br)cn3)C2)C1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=c1c2sc(-c3ccc(Cl)cc3)cc2ccn1-c1ccc(N2CC[C@@H](N3CC[C@@H](F)C3)C2)nc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
Degass a mixture of 2-(4-chloro-phenyl)-6H-thieno[2,3-c]pyridin-7-one (458 mg, 1.75 mmol), (3R,3′R)-1′-(5-bromo-pyridin-2-yl)-3-fluoro-[1,3′]bipyrrolidinyl (550 mg, 1.75 mmol) and cesium carbonate (1.14 g, 3.50 mmol) in 1,4-dioxane (20 mL). Add copper (I) iodide (133 mg, 700 μmol) and sym-dimethylethylene diamine (99 μL, 928 μmol). Heat the mixture at 100° C. overnight. Add to the cooled mixture concentrated NH4OH (5 mL). After 10 min, pour the mixture into water (20 mL). Filter the resulting solid and rinse with water (2×), followed by rinsing with Et2O (2×). Purify using chromatography (0 to 5% MeOH/CH2Cl2) to afford 610 mg (71%) of the title compound. 1H NMR (400 MHz, CDCl3) δ: 1.95 (m, 1H), 2.24 (m, 3H), 3.59 (m, 8H), 5.18 (d, 1H), 5.40 (brs, 1H), 6.44 (d, 1H), 6.65 (d, 1H), 7.22 (d, 1H), 7.38 (t, 3H), 7.60 (m, 3H), 8.13 (s, 1H).