Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1C=C(C=CC=1O)C[N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)C.Cl.Cl.COC(=O)C1C(C(F)(F)F)=CC(NC2CCNCC2)=NC=1.[CH3:55][O:56][C:57]1[CH:64]=[CH:63][C:60]([CH:61]=O)=[CH:59][C:58]=1[O:65][CH2:66][CH2:67][CH3:68]>>[CH3:55][O:56][C:57]1[CH:64]=[CH:63][C:60]([CH2:61][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[CH:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[CH:59][C:58]=1[O:65][CH2:66][CH2:67][CH3:68]
Reactant: CCCOc1cc(C=O)ccc1OC
Reactant: CCOc1cc(CN2CCC(Nc3cc(C(F)(F)F)c(C(=O)O)cn3)CC2)ccc1O
Agent: COC(=O)c1cnc(NC2CCNCC2)cc1C(F)(F)F
Agent: Cl
Product: CCCOc1cc(CN2CCC(Nc3cc(C(F)(F)F)c(C(=O)O)cn3)CC2)ccc1OC

Procedure:
The title compound was prepared in analogy to the synthesis of 6-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinic acid (example 201) from 6-(piperidin-4-ylamino)-4-trifluoromethyl-nicotinic acid methyl ester dihydrochloride (intermediate B7) and 4-methoxy-3-propoxy-benzaldehyde (intermediate E11) in a yield of 16.4 mg (23%). MS (ISP): 468.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:19][CH2:20][CH2:21][OH:22]>CC(CC)=O>[Cl-:19].[CH2:11]([N+:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([CH3:10])[CH2:20][CH2:21][OH:22])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCN(C)CCCCCCCC
Reactant: OCCCl
Solvent: CCC(C)=O
Product: CCCCCCCC[N+](C)(CCO)CCCCCCCC
Product: [Cl-]

Procedure:
Initially a hydroxyethyl quat was made by reacting 100 grams of dioctyl methyl amine with 42 mLs of 2-chloroethanol in 200 grams of methylethyl ketone solvent at reflux for 5 hours to obtain a methylethyl ketone solution of dioctyl methyl hydroxyethyl ammonium chloride. To this was added dropwise, 59.04 grams of glutaryl dichloride over a 1 hour period while sparging the mixture with nitrogen. This was held at reflux (90° C.) for 30 minutes to give a brown solution of di(dioctyl methyl ammonium ethyl)glutarate dichloride which could be recovered by evaporation of the methylethyl ketone under vacuum.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][N:6]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[C:7]=1[CH3:8].CN(C=O)C.S(Cl)([Cl:22])=O.O>ClCCl>[Cl:22][CH2:2][C:3]1[N:4]=[CH:5][N:6]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[C:7]=1[CH3:8]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CO)ncn1S(=O)(=O)N(C)C
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(CCl)ncn1S(=O)(=O)N(C)C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
A suspension of 4-(hydroxymethyl)-N,N,5-trimethyl-1H-imidazole-1-sulphonamide (2.86 g) in dry dichloromethane (200 ml) containing DMF (0.5 ml) was treated dropwise with a solution of thionyl chloride (1.178 g) in dichloromethane (10 ml). The reaction mixture was cooled in ice during the addition and blanketed with nitrogen. When addition was complete (ca. 5 min), stirring was continued at 0° for a further 30 min. Water (200 ml) was then added and the organic phase was separated, washed with 8% sodium bicarbonate (100 ml), dried and concentrated to give the title compound (2.3 g) as a solid, m.p. 115°-118°.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.C(N(CC)CC)C.Cl[CH2:42][CH2:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[CH:43]([S:44]([N:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1)(=[O:46])=[O:45])=[CH2:42]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Reactant: O=S(=O)(Cl)CCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)N1CC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)C1
Reaction time: 1 h
Yield: 82 %

Procedure:
To a mixture of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (100 mg, 0.2 mmol) in dry DCM (2 mL) was added triethylamine (60 μL, 0.4 mmol) and the reaction mixture was stirred for 1 hour. The mixture was washed with water followed by brine, dried (Na2SO4) and then treated with triethylamine (30 μL, 0.2 mmol) followed by 2-chloroethane-sulfonyl chloride (42 μL, 0.4 mmol) in dry DCM (1 mL). The reaction mixture was stirred at RT for 18 hours then diluted with DCM and washed with water followed by brine, dried (Na2SO4) and concentrated in vacuo to give 8-(1-Ethenesulfonyl-azetidin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene as a light brown oil (75 mg, 82%). 1H NMR δ (ppm) (CDCl3): 8.39 (1 H, d, J=8.22 Hz), 7.93 (1 H, s), 7.16 (1 H, dd, J=8.22, 1.98 Hz), 7.02 (1 H, d, J=1.91 Hz), 6.61 (1 H, dd, J=16.50, 9.95 Hz), 6.39 (1 H, d, J=16.66 Hz), 6.18 (1 H, d, J=9.95 Hz), 5.93-5.87 (1 H, m), 4.45-4.39 (2 H, m), 4.28-4.22 (2 H, m), 4.07-3.97 (2 H, m), 3.81 (1 H, t, J=7.81 Hz), 3.46-3.40 (2 H, m), 1.64 (6 H, d, J=6.65 Hz)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][NH:12][CH3:13].CO>CO>[CH3:11][N:12]([CH3:13])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CO
Product: CN(C)c1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (317.08 mg, 2 mmol) in 1 ml of methanol was added of 2 M dimethylamine/MeOH (5 ml, 10 mmol) in a sealed tube at 0° C. The reaction mixture was warmed up to room temperature and stirred over night. After evaporating the solvent, the residue was diluted with EtOAc (20 ml), washed with saturated NaHCO3 aq., brine, dried over Na2SO4, filtered and concentrated by vacuum, yielding 334 mg (100%) of yellow solids. 1H NMR (CDCl3): 9.06 (d, J=2.7 Hz, 1H), 8.22-8.18 (m, 1H), 6.46 (d, J=9.3 Hz, 1H), 3.23 (s, 6H).
Reaction SMILES: CS(O)(=O)=O.C(OC([NH:13][C@:14]1([C:19]([OH:21])=[O:20])[CH2:16][C@H:15]1[CH:17]=[CH2:18])=O)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[NH2:13][C@:14]1([C:19]([OH:21])=[O:20])[CH2:16][C@H:15]1[CH:17]=[CH2:18]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C[C@@H]1C[C@]1(N)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulfonic acid (576 mg, 6 mmol) was added to a solution of (1R,2S)-1-(tert-butoxycarbonylamino)-2-vinyl-cyclopropanecarboxylic acid (1135 mg, 5 mmol) and methylene chloride (5 mL), and the mixture was stirred at 25° C. for 3 hours. When triethylamine (708 mg, 7 mmol) was added thereto, a solid was precipitated. The solid was sufficiently precipitated, and then the solution was stirred at 25° C. for 30 minutes. Thereafter, the solid was separated by filtration under reduced pressure. The solid was washed with methylene chloride (5 mL), and then was subjected to vacuum drying. Thereby, the titled compound was produced as a white solid (665 mg, yield of 100%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:30]([CH2:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)[CH3:31])[CH3:29]>>[CH2:28]([N:30]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([NH:37]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:38][CH:39]=1)[CH3:31])[CH3:29]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CCN(C)Cc1ccc(N)cc1
Product: CCN(C)Cc1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-ethyl-N-methyl-aminomethyl)-aniline Rf value: 0.3 (silica gel, methylene chloride/methanol=10:1) C27H27N3O3
Reaction SMILES: [C:1](Cl)(=O)[O:2]C1C=CC([N+]([O-])=O)=CC=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]([OH:46])([C:42]([F:45])([F:44])[F:43])[C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=3)[CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1.[CH:47]1([CH:50]([NH2:52])C)[CH2:49][CH2:48]1.O>ClCCl>[CH:47]1([CH2:50][NH:52][C:1]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([N:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]([OH:46])([C:38]([F:39])([F:40])[F:41])[C:42]([F:45])([F:44])[F:43])=[CH:35][CH:36]=4)[CH2:28][CH2:29]3)(=[O:22])=[O:23])=[CH:19][CH:20]=2)=[O:2])[CH2:49][CH2:48]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(S(=O)(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reactant: CC(N)C1CC1
Solvent: ClCCl
Solvent: O
Product: O=C(NCC1CC1)Nc1ccc(S(=O)(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reaction time: 1 h

Procedure:
4-Nitrophenyl carbonochloridate (0.126 mmol, 0.02549 g) was added to a stirred solution of 2-(4-((4-(4-aminophenylsulfonyl)piperazin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.126 mmol, 0.0629 g) in dichloromethane (1 mL). After 1 hour, cyclopropylethanamine (0.380 mmol, 0.027 g) was added and stirring was continued for 1 hour. Water (5 mL) was added and the organic layer was separated, washed with water (3×10 mL), dried over magnesium sulphate and concentrated under reduced pressure to give a yellow gum. Purification was achieved by preparative HPLC, giving after filtration through a silica carbonate column in methanol, the title compound as a pale gum (15.2 mg). MS (ESI) m/z 595.0 [M+H]+
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][C:19]([OH:21])=[O:20])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2].[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH2:24]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][CH3:17])[C:7]2[CH2:6][CH2:5][O:4][C:3]([CH2:18][C:19]([OH:21])=[O:20])([CH2:1][CH3:2])[C:8]1=2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)O)OCC3
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cccc2c3c(n(Cc4ccccc4)c12)C(CC)(CC(=O)O)OCC3
Temperature: 50 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
To a solution of (1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid (0.51 g, 1.8 mmol) in tetrahydrofuran at room temperature was added sodium hydride (60% dispersion in mineral oil, 0.4 g). After being heated at 50° C. for 2 hours, benzyl bromide (0.6 g, 3.5 mmol) was added and the solution was stirred for another 2 hours. It was quenched with ethyl acetate and washed with water. The ethyl acetate layer was dried over magnesium sulfate and evaporated to dryness. Flash chromatography on silica gel provided 0.486 g (73%) of the title compound as a solid. 1H NMR (500 MHz, CDCl3) δ 7.13 (m, 3H), 6.97 (d, 1H), 6.74 (d, 1H), 6.68 (t, 1H), 6.21 (d, 1H), 3.90 (s, 1H), 3.63 (m, 1H), 3.35 (td, 1H), 3.18 (d, 1H), 3.00 (d, 1H), 2.67 (q, 2H), 2.44 (q, 2H), 2.10 (m, 1H), 1.85 (d, 1H), 1.52 (m, 1H), 1.41 (m, 1H), 1.16 (t, 3H), 0.75 (t, 3H); ESI (+) MS m/e=278 (MH+).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:12]=[CH:11][C:10]2[CH:9]=[CH:8][C:7]3[C:13]([C:23]([NH2:25])=[O:24])=[N:14][N:15]([CH2:16][CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:6]=3[C:5]=2[N:4]=1.C(O)(=O)C.O=[CH:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37].[BH3-]C#N.[Na+]>CO.CN(C=O)C>[C:36]([O:35][C:34](=[O:40])[NH:33][CH2:32][CH2:31][N:20]1[CH2:21][CH2:22][CH:17]([CH2:16][N:15]2[C:6]3[C:5]4[N:4]=[C:3]([S:2][CH3:1])[N:12]=[CH:11][C:10]=4[CH:9]=[CH:8][C:7]=3[C:13]([C:23](=[O:24])[NH2:25])=[N:14]2)[CH2:18][CH2:19]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CSc1ncc2ccc3c(C(N)=O)nn(CC4CCNCC4)c3c2n1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CSc1ncc2ccc3c(C(N)=O)nn(CC4CCN(CCNC(=O)OC(C)(C)C)CC4)c3c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a solution of 8-(methylsulfanyl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide 26 mg (0.073 mmol) in methanol (1.5 ml) and DMF (1 ml), acetic acid 13 μl (0.219 mmol), tert-butyl (2-oxoethyl)carbamate 69.6 mg (0.438 mmol) and NaCNBH3 28 mg (0.438 mmol) were added. The mixture was stirred at r.t. for 18 hours, consequently the volatiles were removed in vacuo. The residue was dissolved with ethyl acetate and portioned with water; the organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude was purified by flash chromatography (DCM/MeOH 95/5) to give tert-butyl[2-(4-{[3-carbamoyl-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazolin-1-yl]methyl}piperidin-1-yl)ethyl]carbamate 27 mg as a white solid (75%). LC/MS (254) HPLC method 2 Rt 3.86 min. 1H NMR (401 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.28 (d, J=8.67 Hz, 1H), 7.81 (s, 1H), 7.74 (d, J=8.79 Hz, 1H), 7.54 (br. s., 1H), 6.56 (br. s., 1H), 5.08 (d, J=7.32 Hz, 2H), 2.93-3.05 (m, 2H), 2.76-2.84 (m, J=10.25 Hz, 2H), 2.71 (s, 3H), 2.27 (br. s., 1H), 2.14 (br. s., 1H), 1.75-1.94 (m, 2H), 1.12-1.49 (m, 17H). HRMS (ESI) calcd for C24H33N7O3S [M+H]+ 500.2439 found 500.2436.
Reaction SMILES: F[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9]C=[C:7]([F:11])[CH:6]=1.[F:12]C1C(F)=CC=CC=1C1C=CC(OCCCCCCC)=CC=1.B([O:39][CH3:40])(OC)OC.OO.O>C(O)(=O)C>[CH2:3]([O:4][C:5]1[CH:10]=[CH:9][C:40]([OH:39])=[C:7]([F:11])[C:6]=1[F:12])[CH3:2]
Reactant: FCCOc1cccc(F)c1
Reactant: CCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Reactant: COB(OC)OC
Agent: OO
Solvent: CC(=O)O
Solvent: O
Product: CCOc1ccc(O)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.02 mol of 2,3-difluoroethoxybenzene are metalated according to 1b. Subsequently, 0.02 mol of trimethyl borate are added dropwise at a temperature of about -55° to -60° C. during the course of 0.5 h. The resulting suspension is subsequently stirred for a further 0.5 h, the temperature climbing to about -20°. 1.5 ml of 98% acetic acid are added. After about 15 min, the mixture is cooled to about -35° and a solution of 30% H2O2 /H2O (5 ml/2 ml) is added dropwise. After stirring for 2 h while slowly warming to room temperature, the organic phase is separated and the aqueous phase is extracted with methyl tert.butyl ether. Finally, the mixture is washed with saturated NaCl solution, dried and evaporated.
Reaction SMILES: C([BH3-])#N.[Na+].[C@H]12C[C@H](NC1)CN2[C:12]1[CH:25]=[CH:24][C:15]2[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:17]S[C:14]=2[CH:13]=1.[CH2:26]([O:28]C1(O[Si](C)(C)C)CC1)C.C([OH:39])C>O>[CH3:26][O:28][C:12]1[CH:25]=[CH:24][C:15]2[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:17][O:39][C:14]=2[CH:13]=1
Reactant: CCO
Reactant: CCOC(=O)c1nsc2cc(N3C[C@@H]4C[C@H]3CN4)ccc12
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1noc2cc(OC)ccc12
Temperature: 60 °C
Yield: 56 %

Procedure:
Sodium cyanoborohydride (8.57 mmol) was added to a solution of ethyl 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-1,2-benzisothiazole-3-carboxylate (0.260 g, 0.857 mmol) and 1-ethoxy-1-(trimethylsilyloxy)cyclopropane (8.57 mmol) in ethanol (11.2 mL) and the reaction mixture was heated at 60° C. for 6 h. The reaction mixture was diluted with water (50 mL) and was extracted with ethyl acetate (2 ×50 mL). The combined organic layers were washed with brine (25 mL), dried (magnesium sulfate), and were concentrated. The residue was purified by chromatography (ethyl acetate) to yield the ester. A 5.0 M solution of sodium hydroxide in water (4.00 mL) was added to a solution of the ester in ethanol (10.0 mL) and the reaction mixture was maintained for 16 h. The reaction was neutralized with acetic acid and was loaded onto a SCX column. The column was flushed with water (200 mL) and methanol (100 mL) and the product was eluted with 2.0 M ammonia in methanol (60 mL) to provide the acid in 56% yield. The acid was used without further purification.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][N:5]=C(C(O)=O)[CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.P(Cl)(Cl)([Cl:19])=O.[C:22](Cl)(=O)[C:23]([Cl:25])=[O:24]>ClCCl.CN(C=O)C>[Cl:19][C:2]1[N:7]=[CH:6][N:5]=[C:22]([C:23]([Cl:25])=[O:24])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(O)ncn1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(Cl)ncn1
Temperature: 0 °C

Procedure:
A stirred mixture of 6-hydroxypyrimidine-4-carboxylic acid (10.0 g, 71.4 mmol, prepared according to the method described by Daves, G. C.; Baiocchi, F.; Robins, R. K.; Cheng, C. C. in J. Org. Chem. 1961, 26, 2755-2763) and phosphorus pentachloride (58.0 g, 0.27 mol) was treated with phosphorus oxychloride (100 mL, 1.07 mol) and the resultant mixture was refluxed for 16 hours under nitrogen. The excess phosphorus oxychloride was distilled off and the residue was azeotroped three times with toluene and dried in vacuo. The solid product obtained was suspended in dry dichloromethane (100 mL), cooled (0° C.) and treated with dry DMF (2 mL) and oxalyl chloride (7.9 mL, 91 mmol). The resultant mixture was stirred at room temperature for 15 hours and evaporated in vacuo to afford 6-chloropyrimidine-4-carbonyl chloride as a brown liquid, which was used for the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Br:22][C:23]1[CH:24]=[C:25]2[C:30](=O)[O:29][C:27](=[O:28])[C:26]2=[CH:32][CH:33]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl.O>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:30](=[O:29])[C:25]3[C:26](=[CH:32][CH:33]=[C:23]([Br:22])[CH:24]=3)[C:27]2=[O:28])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(N2C(=O)c3ccc(Br)cc3C2=O)cc1)NC(=O)OC(C)(C)C
Reaction time: 15 h

Procedure:
To a suspension of 4-amino-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (6.78 mmol, 1.99 g) in dichloromethane (90 mL) was added a solution of 4-bromophthalic anhydride (6.78 mmol, 1.54 g) in dichloromethane (30 mL) and 1,1′-carbonyldiimidazole (6.78 mmol, 1.1 g) at room temperature. The resulting solution was stirred for 15 h at which time TLC analysis of the mixture indicated the absence of starting material. The mixture was diluted with water (100 mL) and layers were separated. The aqueous layer was extracted with dichloromethane (2×100 mL) and the combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum gave a crude product which was purified by silica gel column chromatography to obtaine 2.4 g (70%) of a white solid: mp 168-170° C. HR MS C23H23BrN2O6): Obs mass, 525.0656. Calcd mass, 525.0637 (M+Na).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7](Cl)=[O:8].C(N(CC)CC)C.[SH2:17]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:8])=[S:17]
Reactant: S
Reactant: COCCOCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOCC(O)=S
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
A solution of 2-methoxyethoxyacetyl chloride (700 mg.; 4.59 mmoles) in methylene chloride (10 ml.; dried over molecular sieves) was added dropwise at 0°-5° to a stirred solution of triethylamine (0.7 ml.; 508 mg.; 5.04 mmoles) in methylene chloride (20 ml.) which had been saturated at 0°-5° with H2S (ca. 30 min.). The light yellow mixture was stirred at 0°-5° for 30 min. and then at room temperature for 30 min. The mixture was washed with 1N HCl (10 ml.×2) and then brine. The CH2Cl2 layer was dried (Na2SO4) and evaporated yielding 2-methoxyethoxythioacetic acid (480 mg.; 3.20 mmoles; yield 69.7%) as a light yellow liquid: nmr (CDCl3): δppm 3.42 (3H, s, --OCH3), 3.4-3.9 (4H, m, --CH2CH2 -), 4.10 (2H, s, -OCCH2O), 5.0 (1H, br, -COSH); ir (neat): 2550 cm-1 (νS-H), 1770 (νc=o, thio acid).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=O)C.CO.C1COCC1.CO.[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:44][C:45]2[N:46]=[C:47]([N+:50]([O-])=O)[NH:48][CH:49]=2)[CH2:40][CH2:39]1>[Ni].C(Cl)Cl.CO>[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:44][C:45]2[N:46]=[C:47]([NH:50][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=4[F:27])=[CH:14][CH:15]=3)=[O:3])[NH:48][CH:49]=2)[CH2:40][CH2:39]1
Reactant: CN1CCN(Cc2c[nH]c([N+](=O)[O-])n2)CC1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3nc(CN4CCN(C)CC4)c[nH]3)c3nccnc23)c1F

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2, and 1-methyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine (Step 20.1) instead of 2-nitroimidazole in Step 14.3. Title compound: ESI-MS: 524.1 [M+H]+; tR=3.03 min (System 1); TLC: Rf=0.22 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH:34]=O)=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:36][O:37][C:38](=[O:40])[CH3:39])(=[O:3])[CH3:2].N1C=CC=CC=1.Cl.[CH3:48][O:49][NH2:50]>C(O)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([CH2:33][CH:34]=[N:50][O:49][CH3:48])=[CH:31][CH:32]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:36][O:37][C:38](=[O:40])[CH3:39])(=[O:3])[CH3:2]
Reactant: CON
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(CC=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=CCc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Yield: 21.7 %

Procedure:
To a solution of (2R,3 R,4R,5S,65)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(2-oxoethyl)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.35 mg, 0.61 mmol), in ethanol (10 mL) under nitrogen atmosphere, were added pyridine (0.24 mL, 3.04 mmol), and O-methylhydroxylamine hydrochloride (151 mg, 1.82 mmol). The reaction mixture was refluxed for 2 h. After completion of the reaction as confirmed by TLC, the solvent was evaporated. The crude compound was diluted with ethyl acetate (25 mL). The organic layer was washed with water (3×10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1.0:9.0 Acetone:Pet. Ether) to afford the title compound (80 mg, 22%).