Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N(CC)CC)C.[CH2:20]([N:22]([CH2:26][CH3:27])[C:23](Cl)=[O:24])[CH3:21]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH2:20]([N:22]([CH2:26][CH3:27])[C:23]([N:11]([OH:12])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:24])[CH3:21]
Reactant: CCN(CC)C(=O)Cl
Reactant: CCCCCCCCCCNO
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCN(O)C(=O)N(CC)CC
Reaction time: 2 h

Procedure:
To a stirred solution of N-decylhydroxylamine (2.60 g, 15.0 mmol) and triethylamine (2.3 ml) in tetrahydrofuran (hereinafter THF) (30 ml) at 0° C. was added dropwise N,N-diethylcarbamyl chloride (1.92 ml). After two hours, 4-(dimethylamino)pyridine (1.3 g) was added. After 18 hours, the reaction mixture was quenched with 1N hydrochloric acid (hereinafter HCl), extracted with hexane, and the organic solution was dried over MgSO4, filtered and evaporated. Trituration of the residue with hexane at -30° C. gave the title compound as a while solid (3.1 g, mp 35°-37° C.).
Reaction SMILES: ClC([O:4][C:5](Cl)(Cl)Cl)=O.[CH2:9]([NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH2:10][CH2:11][CH2:12][CH3:13]>C(#N)C>[CH2:9]([NH:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]([N:24]=[C:5]=[O:4])=[CH:22][CH:23]=1)(=[O:17])=[O:16])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCCCCNS(=O)(=O)c1ccc(N)cc1
Solvent: CC#N
Product: CCCCCNS(=O)(=O)c1ccc(N=C=O)cc1
Temperature: 65 °C

Procedure:
Under argon, trichloromethyl chloroformate (135 μL, 1.118 mmol) is added to N-(pentyl)-4-aminobenzenesulfonamide (Example 26, 0.572 mmol) in anhydrous acetonitrile (4 mL). The solution is heated to 65° C. for 5 hours and the solvent removed at reduced pressure. The formation of the isocyanate is confirmed by infrared spectroscopy of the residue, then immediately used without further purification in the next reaction.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:30]4[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CN1CCNCC1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCN(C)CC4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.33 (d, J=2.53 Hz, 3 H) 2.84 (s, 3H) 3.17 (s, 8 H) 7.63 (d, J=7.58 Hz, 1 H) 7.70-7.79 (m, 1 H) 8.04-8.57 (m, 3 H) 8.59 (d, J=1.52 Hz, 1 H). ESI-MS m/z [M+H]+ 421.3.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:15]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19]C)=[O:18])=[C:14]([CH3:24])[N:13]=[C:12]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:15]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([OH:19])=[O:18])=[C:14]([CH3:24])[N:13]=[C:12]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2occc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc2occc2c1
Yield: 85.3 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-(benzofuran-5-yl)-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.114 g; 0.285 mmol), sodium hydroxide 10N (0.285 mL; 2.85 mmol) in methanol (3 mL) to afford 0.094 g (81%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][N:35]([CH:47]2[CH2:49][CH2:48]2)[C:36]([O:38][CH2:39][C:40]([C:43]([O:45]C)=[O:44])([CH3:42])[CH3:41])=[O:37])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>O.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][N:35]([C:36]([O:38][CH2:39][C:40]([C:43]([OH:45])=[O:44])([CH3:42])[CH3:41])=[O:37])[CH:47]2[CH2:48][CH2:49]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)OCC(C)(C)C(=O)OC)C2CC2)C(C)C)ccc1OC
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)OCC(C)(C)C(=O)O)C2CC2)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of (3S*,4R*)-3-{[cyclopropyl-(2-methoxycarbonyl-2-methyl-propoxycarbonyl)-amino]-methyl}-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (290 mg, 0.42 mmol) and LiOH•H2O (44 mg, 1.05 mmol) in H2O (2 mL) and THF (6 mL) is stirred at RT for 3 d. After evaporation of the solvent 1N HCl is added and the mixture is extracted with ethyl acetate. Drying (Na2SO4) of the combined extracts, filtration and evaporation of the solvent affords the title compound which is used without further purification. MS (LC-MS): 578.0 [M+H-Boc]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H20/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.44 min.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:10]([F:18])=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:14])=O)[CH2:5][CH2:4]1)[CH3:2].P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([N:3]1[CH2:4][CH2:5][CH:6]([C:9]2[C:10]([F:18])=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]#[N:14])[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCC(c2cccc(C(N)=O)c2F)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCN1CCC(c2cccc(C#N)c2F)CC1
Reaction time: 1 h

Procedure:
To a solution of 3-(1-ethylpiperidin-4-yl)-2-fluorobenzamide (0.46 g, 1.83 mmol) in dry N,N-dimethylformamide (4 ml) was added freshly distilled phosphoryl trichloride (0.42 ml, 4.57 mmol) and the reaction mixture was stirred for 1 h. The solution was poured on to ice and was made basic by addition of aqueous sodium carbonate (10%, 50 ml). Ethyl acetate (50 ml) was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×50 ml) and the combined organic phases was dried (MgSO4) and evaporated under reduced pressure to give an oil. Purification by flash column chromatography (ethyl acetate/methanol, 1:1) gave the title compound: 0.32 g (75%). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether: M.p. 156-158° C. MS m/z (relative intensity, 70 eV) 232 (M+, 12), 218 (14), 217 (bp), 147 (10), 134 (13).
Reaction SMILES: CON(C)[C:4]([CH:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5].[CH3:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][Mg]Cl>C1COCC1>[CH3:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:4]([CH:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:7]1)=[O:5]
Reactant: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Reactant: COCCCC[Mg]Cl
Solvent: C1CCOC1
Product: COCCCCC(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
A stirred solution of (±)-tert-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (1.73 g, 6.4 mmol) in dry THF (40 mL) was cooled in an ice-salt bath and 1.34 M 4-methoxybutylmagnesium chloride in THF (10 mL, 1.34 mmol) was added dropwise over 3 min. The cooling bath was allowed to expire and the mixture was stirred at rt for 6 h, poured into ice cold 3% aq HCl (100 mL) and extracted with ether (2×100 mL). The combined ether extracts were washed with satd aq NaHCO3 (35 mL), dried over MgSO4 and concentrated to afford (±)-tert-butyl 2-(5-methoxypentanoyl)morpholine-4-carboxylate (1.78 g, 93%) as an oil.
Reaction SMILES: [CH2:1]([N:5]([CH2:49][CH2:50][C:51](O)=[O:52])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:36])[NH:22][S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])=[CH:17][C:16]=2[C:37]([N:39]2[CH2:48][CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40]2)=[O:38])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[NH2:54][CH:55]([CH2:58][OH:59])[CH2:56][OH:57]>>[CH2:1]([N:5]([CH2:49][CH2:50][C:51]([NH:54][CH:55]([CH2:58][OH:59])[CH2:56][OH:57])=[O:52])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:36])[NH:22][S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])=[CH:17][C:16]=2[C:37]([N:39]2[CH2:48][CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40]2)=[O:38])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCC(=O)O)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Reactant: NC(CO)CO
Product: CCCCN(CCC(=O)NC(CO)CO)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Yield: 23.2 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 124, 3-(N-butyl-4-chloro-5-methyl-1-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazole-3-carboxamido)propanoic acid (Intermediate 158B, 20 mg, 0.026 mmol) and 2-amino-1,3-propanediol (Aldrich, 8 mg, 0.088 mmol) were converted to the title compound (5 mg, 21%). 1H NMR (CD3OD, 1:1 mixture of amide rotamers) δ 8.72 (br s, 1H), 8.15-7.94 (m, 6.5H), 7.76-7.62 (m, 3.5H), 7.25-7.03 (m, 3.5H), 6.94-6.81 (m, 0.5H), 4.75-4.00 (m, 2H), 3.97-3.70 (m, 2H), 3.65-3.43 (m, 7H), 2.94-2.64 (m, 3H), 2.58-2.12 (m, 5H), 1.58-1.14 (m, 4H), 1.13-0.85 (m, 3H), 0.76 (t, J=7.3 Hz, 1H), 0.68 (t, J=7.5 Hz, 1H); MS(ESI+) m/z 829.4 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:41])[C:5](F)=[C:6]([C:8](=O)[CH:9]([CH:17]([C:21]2[CH:38]=[CH:37][C:24]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])=[O:26])=[CH:23][CH:22]=2)[CH2:18][CH2:19][CH3:20])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:7]=1.O.[NH2:43][NH2:44]>CS(C)=O>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([CH:9]([C:8]2[C:6]3[C:5](=[C:4]([F:41])[CH:3]=[C:2]([C:3]4[CH:2]=[CH:7][C:6]([CH3:8])=[CH:5][CH:4]=4)[CH:7]=3)[NH:44][N:43]=2)[CH:17]([C:21]2[CH:38]=[CH:37][C:24]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:22]=2)[CH2:18][CH2:19][CH3:20])=[CH:15][CH:14]=1
Reactant: NN
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(C(=O)c1cc(Br)cc(F)c1F)c1ccc(Cl)cc1
Solvent: CS(C)=O
Solvent: O
Product: CCCC(c1ccc(C(=O)NCCC(=O)O)cc1)C(c1ccc(Cl)cc1)c1n[nH]c2c(F)cc(-c3ccc(C)cc3)cc12

Procedure:
To a solution of the product of Step F (600 mg, 0.925 mmol) in DMSO (10 mL) was added hydrazine hydrate (60 wt %, 2.0 mL, 24 mmol). The mixture was stirred at room temperature until all starting ketone had been consumed by LC-MS analysis. The mixture was diluted with ethyl acetate then washed with saturated NaCl (aq). The organic layer was dried over sodium sulfate, filtered, then concentrated. The resulting residue was purified by silica gel chromatography eluting with 0-50% EtOAc/hexanes to afford the title compound as a solid. LC2 1.40 min. (M+H)+644.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].CCN(CC)CC.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33]>C1COCC1>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:33])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[CH:4][C:3]=1[CH3:16]
Reactant: O=C=Nc1ccccc1F
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methylphenylacetate (1.09 g, 4.93 mmol) and Et3N (755 ml, 5.42 mmol) in THF (10 ml) was added 2-fluorophenyl isocyanate (610 μl, 5.44 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to a small volume and diluted with n-hexane. Resulting precipitate was collected under a reduced pressure and the filtrate was washed with n-hexane to give tert-butyl 4-[N′-(2-fluorophenyl)ureido]-3-methylphenylacetate (1.31 g, 74%) as a white crystalline powder. mp 89–91° C.; 1H-NMR (CDCl3) δ 1.47 (s, 9 H), 2.06 (s, 3 H), 3.49 (s, 2 H), 6.62 (s, 1 H), 6.92–7.09 (m, 5 H), 7.21 (br s, 1 H), 7.49–7.51 (m, 1 H), 8.10–8.15 (m, 1 H); Anal. Calcd for C20H23FN2O3: C, 67.02; H, 6.47; N, 7.82; F, 5.30. Found: C, 66.74; H, 6.35; N, 7.85; F, 5.69.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:14][OH:15])[C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)[OH:4].Br[CH2:17][CH2:18][CH2:19][N:20]1C(=O)C2=CC=CC=C2C1=O>>[NH2:20][CH2:19][CH2:18][CH2:17][NH:1][C@H:2]([CH2:14][OH:15])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[OH:4]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: N[C@@H](CO)[C@@H](O)c1ccc([N+](=O)[O-])cc1
Product: NCCCN[C@H](CO)[C@H](O)c1ccc([N+](=O)[O-])cc1
Yield: 66.7 %

Procedure:
By using (1S,2S)-(+)-2-amino-1-(4-nitrophenyl)-1,3-propanediol (3.0 g) and N-(3-bromopropyl)phthalimide (4.53 g) as starting materials, the title compound (2.54 g) was obtained in the same manner as that of Reference Example 139.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]([C:16]1[CH:33]=[CH:32][C:19]([CH2:20][NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:12]([C:16]1[CH:33]=[CH:32][C:19]([CH2:20][N:21]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)[C:4](=[O:6])[C:3]2[CH:7]=[C:8]([Cl:11])[CH:9]=[N:10][C:2]=2[Cl:1])=[CH:18][CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)c(Cl)c2)C(=O)c2cc(Cl)cnc2Cl)cc1
Yield: 95.6 %

Procedure:
A solution of 2,5-dichloronicotinic acid (300 mg, 1.56 mmol), (4-tert-butyl-benzyl)-[2-(3,4-dichloro-phenyl)-ethyl]-amine (578 mg, 1.72 mmol), 4-methylmorpholine (474 mg, 7.81 mmol), and HBTU (889 mg, 2.34 mmol) in DMF (9 mL) was stirred at RT for 16 h, then partitioned between heptane, ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (761 mg, 95%). White foam, MS (ISP) 509.0 (M+H)+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Si:11]([O:18][C@@H:19]([CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:20][OH:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[Si:11]([O:18][C@@H:19]([CH2:22][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)[CH:20]=[O:21])([C:14]([CH3:16])([CH3:17])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)O[C@H](CO)CC1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H](C=O)CC1CCCCC1
Reaction time: 0.17 h

Procedure:
1.5 ml (21.1 mmol) of dimethyl sulfoxide were added dropwise over a period of 2 minutes to a solution of 1.0 ml (11.5 mmol) of oxalyl chloride in 20 ml of methylene chloride at -78° C. The mixture was allowed to stand for 10 minutes, after which a solution of 2.54 g (9.32 mmol) of (S)-2-t-butyldimethylsilyloxy-3-cyclohexylpropyl alcohol [prepared as described in step (iii) above] in 12 ml of methylene chloride was added dropwise over a period of 5 minutes. The resulting mixture was then stirred for 20 minutes at the same temperature, after which 6.5 ml (46.6 mmol) of triethylamine were added. The mixture was then allowed to stand for 7 minutes, and the cooling bath was removed. After a further 10 minutes, the reaction was stopped by adding an aqueous solution of ammonium chloride. The reaction mixture was then extracted with diethyl ether. The extract was washed twice with water and once with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under reduced pressure, to give 2.55 g (a quantitative yield) of the title aldehyde compound as a colorless oil.
Reaction SMILES: BrC1C=C2C(=CC=1)N(C(=O)C)[C@@H](C)CN2.ClC(OCC)=O.[C:22]([N:25]1[C:34]2[C:29](=[CH:30][C:31]([Br:35])=[CH:32][CH:33]=2)[N:28]([C:36]([O:38][CH:39](C)[CH3:40])=[O:37])[CH2:27][C@@H:26]1[CH3:42])(=[O:24])[CH3:23]>>[C:22]([N:25]1[C:34]2[C:29](=[CH:30][C:31]([Br:35])=[CH:32][CH:33]=2)[N:28]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:27][C@@H:26]1[CH3:42])(=[O:24])[CH3:23]
Reactant: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Agent: CC(=O)N1c2ccc(Br)cc2NC[C@@H]1C
Agent: CCOC(=O)Cl
Product: CCOC(=O)N1C[C@H](C)N(C(C)=O)c2ccc(Br)cc21

Procedure:
Ethyl (S)-4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1 (2H)-carboxylate was prepared from (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone and ethyl chloroformate according to the procedure outlined above for (S)-isopropyl 4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 341, 343 [M+1]+.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[CH:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][C:34]1=[O:39])([CH3:32])[CH3:31].CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:36]4[CH2:37][CH2:38][N:33]([CH:30]([CH3:32])[CH3:31])[C:34](=[O:39])[CH2:35]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CC(C)N1CCNCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)C)C(=O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.8 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.15 g, 0.39 mmol), 1-isopropylpiperazin-2-one (0.082 g, 0.58 mmol) and 4 Å molecular sieves (0.718 g) in DCE (5 mL) and MeOH (1 mL) was stirred for 5 h at room temperature. Sodium triacetoxyborohydride (0.163 g, 0.77 mmol) was added and the reaction mixture was stirred for 72 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 5:95) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 469 as an off-white solid (0.044 g, 22%). LCMS (Method I): RT=3.31 min, [M+H]+ 518.3. 1H NMR (400 MHz, DMSO-d6): δ 8.04-8.00 (m, 1 H); 7.65-7.61 (m, 1 H); 7.28-7.21 (m, 2 H); 4.64-4.58 (m, 1 H); 4.28-4.25 (m, 4 H); 3.86 (s, 2 H); 3.81 (s, 3 H); 3.80-3.77 (m, 4 H); 3.27 (q, 7.5 Hz, 2 H); 3.17 (t, J=5.3 Hz, 2 H); 3.13 (s, 2 H); 2.73 (t, J=5.3 Hz, 2 H); 1.34 (t, J=7.5 Hz, 3 H); 1.05 (d, J=6.8 Hz, 6 H)
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([CH:13]1[CH2:15][CH2:14]1)=[O:12].[O-]CC.[Na+]>C(O)C>[CH:13]1([C:11](=[O:12])[CH:10]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:15][CH2:14]1
Reactant: CC(=O)C1CC1
Reactant: O=Cc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(C=Cc1ccc(F)cc1)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
A mixture of 4-fluorobenzaldehyde (9.30 g, 75.00 mmol, Aldrich) and cyclopropyl methyl ketone (6.30 g, 75.00 mmol) in absolute ethanol (100 ml) was treated with a solution of sodium ethoxide in ethanol (21% by weight solution; 2.79 ml, 7.50 mmol). After stirring for 2 hours at room temperature, additional 4-fluorobenzaldehyde was added (1.86 g, 15.00 mmol). The reaction mixture was stirred for 2 hours, concentrated to 1/3 volume and partitioned between 50% saturated NH4Cl/EtOAc (100 ml/250 ml). The layers were separated and the aqueous portion was extracted with EtOAc (twice) and the combined organics were washed with H2O (twice) and brine, dried (Na2SO4) and concentrated. The yellow oily residue was distilled (Vigroux column, bp 115°-120° C., 0.6 mm Hg) to afford the title compound as a colorless oil (12.8 g, 89.7%).
Reaction SMILES: Br[C:2]1[C:7]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][C:5]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:4][C:3]=1[S:16]([OH:19])(=[O:18])=[O:17].[Na:20].[Br:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1.N1C=CC=CC=1C1C=CC=CN=1>CC(N(C)C)=O.[Cu].O>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:7]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][C:5]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:4][C:3]=2[S:16]([OH:19])(=[O:18])=[O:17])=[CH:24][CH:23]=1.[Na:20]
Reactant: O=S(=O)(O)c1cc(S(=O)(=O)O)c(Br)c(S(=O)(=O)O)c1
Reactant: Brc1ccc(I)cc1
Agent: [Cu]
Agent: [Na]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=S(=O)(O)c1cc(S(=O)(=O)O)c(-c2ccc(Br)cc2)c(S(=O)(=O)O)c1
Temperature: 80 °C

Procedure:
A solution of 2-bromo-benzene-1,3,5-trisulfonic acid, sodium salt and 1-bromo-4-iodo-benzene (1 equivalent) in DMAc can be treated with activated copper bronze (2.2 equivalents) and 2,2′-bipyridine (0.2 equivalents) then heated to 80° C. for 4 hours. The cooled mixture can be poured into water, the solids filtered off, and the filtrate evaporated and then dried under vacuum. The crude product can be isolated by extracting the solids with moist ethanol, filtering off the solids, and evaporating the filtrate to give 4′-bromo-biphenyl-2,4,6-trisulfonic acid, sodium salt.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[Br:15]N1C(=O)CCC1=O.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:15])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c([N+](=O)[O-])c1
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 61 %

Procedure:
To a solution of 4-methyl-3-nitrobenzoic acid (5.52 g, 30.5 mmol) in MeOH (100 mL) was added 98% sulfuric acid (2 mL) and the resultant mixture was refluxed overnight, then cooled to room temperature. The mixture was concentrated and the residue was dissolved in CH2Cl2 (50 mL) and water (20 mL). Solid Na2CO3 was added until the aqueous phase was basic to litmus paper. The phases were separated and the aqueous phase was extracted with CH2Cl2 (5×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated and provided 5.79 g (97%) of 4-methyl-3-nitrobenzoic acid methyl ester as a white solid. To a solution of 4-methyl-3-nitrobenzoic acid methyl ester (5.01 g, 25.7 mmol) in CCl4 (65 mL) was added N-bromosuccinimide (5.04 g, 28.3 mmol) followed by 1,1′-azobis(cyclohexanecarbonitrile) (1.21 g, 4.96 mmol). The resultant mixture was refluxed for 24 hours then cooled to room temperature, filtered through filter paper, and concentrated. Purification of the crude material by column chromatography on silica gel (9:1 :hexanes-EtOAc) provided 4.30 g (61%) of 4-bromomethyl-3-nitrobenzoic acid methyl ester as a yellow oil. 1H NMR (CDCl3) δ 3.98 (s, 3H), 4.85 (s, 2H), 7.67 (d, 1H, J=7.8 Hz), 8.25 (d, 1H, J=7.8, 1.5 Hz), 8.66 (d, 1H, J=1.5 Hz).