Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:43]=[CH:42][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([NH:32][C:33]([O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:34])[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44][O:45][NH2:46]>>[CH3:44][O:45][N:46]=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:43]=[CH:42][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH:27]([NH:32][C:33]([O:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[O:34])[C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:25]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1
Reactant: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)NC(=O)Oc1ccccc1
Reactant: CON
Product: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC(NC(=O)Oc2ccccc2)C(=O)OC)cc1

Procedure:
Starting from the compound obtained in Step A, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[CH3:14][C@@H:15]([CH2:23][CH2:24][CH3:25])[CH:16]([CH2:19][C:20](=O)[CH3:21])[CH:17]=O.Cl.C(=O)(O)[O-].[Na+]>O.O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][N:7]1[CH:14]=[C:15]([C@@H:16]([CH3:17])[CH2:19][CH2:20][CH3:21])[CH:23]=[C:24]1[CH3:25])=[O:5]
Reactant: CSc1ccc(C(=O)NN)c(Cl)c1
Reactant: CCC[C@H](C)C(C=O)CC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC[C@H](C)c1cc(C)n(NC(=O)c2ccc(SC)cc2Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.9 %

Procedure:
The compound prepared in Example 76 (1.65 g) and (3S)-3-methyl-2-(2-oxopropyl)hexanal (1.86 g) were dissolved with tetrahydrofuran (10 mL), and 5N hydrochloric acid (0.2 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 6 hours. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The obtained organic layer was washed by water and a saturated aqueous solution of sodium chloride. The organic layer was dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=85/15→65/35) to obtain the title compound (1.6 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH3:15])([C:12]([OH:14])=O)[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Li].[C:17]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:22]=[CH:21][C:20]([CH:23]([NH:30][CH3:31])[CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:17]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:22]=[CH:21][C:20]([CH:23]([N:30]([CH3:31])[C:12](=[O:14])[C:10]([CH3:11])([CH3:15])[NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:19][CH:18]=1
Reactant: CC(C)(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: CNC(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C(=O)C(C)(C)Nc1ccc(Cl)c(Cl)c1)C(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
N-(3,4-dichlorophenyl)-2-methylalanine, lithium salt (100 mg, 0.4 mmol), [1-(4-biphenylyl)-2-(1-pyrrolidinyl)ethyl]methylamine (124 mg, 0.44 mmol), triethylamine (246 uL, 1.77 mmol), and (1 H-1,2,3-benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate (BOP Reagent, 215 mg, 0.486 mmol) were added in that order to a 4 mL screw capped vial that contained 2 mL of anhydrous DMF. The reaction mixture was stirred for 20 hours at room temperature, then filtered through a 0.45 um PTFE Acrodisk, and purified by reverse-phase HPLC (Xterra Prep RP C-18, 30×150 mm, 50 mL/min, A: acetonitrile B: water, pH 10 w/NH4OH, A: 20 to 99% over 9 min, UV detection at 214 nm) to give the title compound as a white solid. MS (ES) m/e 510 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([S:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[C:16]([C:18]3[CH2:19][CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][CH:23]=3)=[CH:17][C:10]=12>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([S:31]([C:34]3[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=3)(=[O:33])=[O:32])[C:16]([C:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=3)=[CH:17][C:10]=12
Reactant: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(Cl)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c(C3=CCNCC3)cc3c(Cl)ccnc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of P-5-I (2.4 g) in CH2Cl2 (20 mL) at 0° C. and the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, solvents were removed under reduced pressure and saturated NaHCO3 (60 mL) solution was added to the residue. Extraction was carried out using EtOAc (50 mL×3); the combined organic layers were washed with water (100 mL); brine (100 mL); dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained (1.9 g, quantitative) was used without any purification. LCMS: m/z; 388.2 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][N:3]=1.[Br-].[CH:18]1([CH2:24][Zn+])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1.CCOC(C)=O>[C:13]([O:12][C:10]([NH:9][CH2:8][C:5]1[CH:4]=[N:3][C:2]([CH2:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:7][CH:6]=1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: [Zn+]CC1CCCCC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)nc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(CC2CCCCC2)nc1
Temperature: 60 °C
Yield: 68 %

Procedure:
Dissolve 2-bromo-5-tert-butoxycarbonylaminomethyl-pyridine (500 mg, 1.74 mmol) in anhydrous THF (5 mL) in a sealed tube. Degas the solution, purge with nitrogen and add 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (127 mg, 0.174 mmol) and 0.5 M cyclohexylmethylzinc bromide in THF (10.4 mL, 5.22 mmol). Heat the mixture at 60° C. overnight. Cool to room temperature and dilute the reaction mixture with EtOAc. Add water and filter the precipitate over Celite®. Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (4:1, 3:2) to give the desired intermediate as an oil (359 mg, 68%). MS (ES+) m/z: 305 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[C:15](B(O)O)=[CH:14][CH:13]=[CH:12][N:11]=1.COCCOC.C([O-])(O)=O.[Na+]>CCOC(C)=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>[Cl:1][C:2]1[N:7]=[C:6]([C:15]2[C:10]([Cl:9])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1cccnc1Cl
Reactant: Clc1ccnc(Cl)n1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Clc1nccc(-c2cccnc2Cl)n1
Temperature: 90 °C

Procedure:
To 2,4-dichloropyrimidine (2.00 g, 13.4 mmol), 2-choropyridine-3-boronic acid (3.16 g, 20.1 mmol) and Pd(PPh3)4 (1.55 g, 1.30 mmol), was added DME (30.0 ML) and 1 M NaHCO3 (13.0 mL). The resulting mixture was heated to 90° C. for 17 hours, then diluted with EtOAc and extracted with saturated sodium carbonate, water, and brine. The organics were dried over sodium sulfate, filtered and concentrated. The resulting solid was triturated with ether and dried to yield the desired product. MS m/z=226 [M+H]+. Calc'd for C9H5Cl2N4: 225.12.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([NH2:13])=O)=[CH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[S:23])[NH2:13])=[CH:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1cc(C(N)=O)c2ccccc21
Solvent: Cc1ccccc1
Product: Cn1cc(C(N)=S)c2ccccc21

Procedure:
1-Methylindole-3-carboxamide (0.6 g) was suspended in toluene (20 ml); Lawesson's Reagent (0.7 g) was added and the mixture was heated at reflux under nitrogen for 30 min until dissolution occurred. The solution was cooled and toluene was removed under reduced pressure. The orange residue was purified by column chromatography on alumina using CH2Cl2 as eluant. This afforded an orange crystalline material, (0.5 g). δH (360 MHz, DMSO-d6) 3.82 (3H, s, NCH3), 7.18 and 7.23 (2H, 2×dt, J=7.1, 1.1 Hz, H-5 and H-6), 7.49 (1H, d, J=7.5 Hz, H-7), 8.08 (1H, s, H-2), 8.59 (1H, d, J=7.5 Hz, H-4), 8.76 (2H, brs, NH2); m/z 190 (M+, 100%), 174 (20), 157 (80).
Reaction SMILES: [S:1]1[C:5]([C:6]([C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[O:7])=[CH:4][C:3]2[CH:21]=[CH:22][CH:23]=[CH:24][C:2]1=2.[CH3:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][Mg]Cl.[NH4+].[Cl-]>C1COCC1>[S:1]1[C:5]([C@:6]([C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)([OH:7])[CH2:30][CH2:29][CH2:28][CH2:27][O:26][CH3:25])=[CH:4][C:3]2[CH:21]=[CH:22][CH:23]=[CH:24][C:2]1=2
Reactant: COCCCC[Mg]Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cc3ccccc3s2)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1cc2ccccc2s1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
A solution of (R)-tert-butyl 3-(benzo[b]thiophene-2-carbonyl)piperidine-1-carboxylate (146 mg, 0.423 mmol) in dry THF (5 mL) was cooled to −70° C. A solution of 1.34 M 4-methoxybutylmagnesium chloride in THF (630 μL, 2 equiv) was added slowly. After 10 min, the reaction mixture was allowed to warm up to rt slowly and stirred for another 2 h. Sat'd aq NH4Cl (20 mL) was added and the mixture was extracted with ether (2×40 mL). The combined ether layers were washed with brine (20 mL) and dried over Na2SO4. After concentration, the crude product was purified by chromatography on a 12-g silica cartridge eluted with a gradient from 0 to 35% EtOAc in hexanes to afford (R)-tert-butyl 3-((S)-1-(benzo[b]thiophen-2-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (160.7 mg, 88%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[CH3:23])=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O>C1COCC1>[Br:24][C:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]=1[CH3:23]
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Cc1c(Br)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole (Example 1) (3.3 g, 10 mmol) in THF (80 ml) at -70° C., N-bromosuccinimide (1.78 g, 10 mmol) was added over 10 minutes. The reaction was warmed to 20° C. over 3 hours and stirred for 18 hours. After dilution with aqueous sodium bicarbonate, the mixture was extracted with ethyl acetate. The organic fractions were washed with water, dried (MgSO4), filtered and concentrated. The crude yellowish liquid (4.52 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 7/3) to give 3-bromo-1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole (3.6 g, 88%): mp (DSC) 153° C. Anal Calc'd. for C18H15NSBrFO2 : C, 52.95; H, 3.70; N, 3.43; S, 19.53. Found: C, 53.01; H, 3.93; N, 3.39; S, 19.06.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[N:6]=[C:5]2[CH3:11]
Reactant: Cc1n[nH]c2ccc(Br)cc12
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nn(CCN2CCCC2)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.9 %

Procedure:
A solution of 5-bromo-3-methyl-1H-indazole (4.23 g, 20.0 mmol) in DMSO (150 mL) was treated with Cs2CO3 (19.55 g, 60.00 mmol) and 1-(2-chloroethyl)pyrrolidine hydrochloride (5.27 g, 31.0 mmol). After stirring for 16 hours at room temperature, the mixture was diluted with water (300 mL) and extracted with EtOAc (3×200 mL). The combined organics were washed with water (200 mL) and brine (200 mL), dried over Na2SO4, filtered and concentrated to dryness. Purification by flash column chromatography (silica gel, MeOH/EtOAc/hexanes, 1.4:5) gave the title compound (0.67 g, 11%) as an orange oil. 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J=1.5 Hz, 1H), 7.42 (dd, J=9.0, 1.5 Hz, 1H), 7.26 (d, J=9.0, 1H, overlapping with solvent peak), 4.43 (t, J=7.5 Hz, 2H), 2.96 (t, J=7.5 Hz, 2H), 2.58-2.55 (m, 4H), 2.53 (s, 3H), 1.79-1.74 (m, 4H).
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.CC1(C)O[C:31](=[O:33])[C:30](=[CH:34][NH:35][C:36]2[C:40]([CH3:41])=[CH:39][S:38][CH:37]=2)C(=O)O1>>[CH3:41][C:40]1[C:36]2=[N:35][CH:34]=[CH:30][C:31]([OH:33])=[C:37]2[S:38][CH:39]=1
Reactant: Cc1cscc1NC=C1C(=O)OC(C)(C)OC1=O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1csc2c(O)ccnc12
Temperature: 235 °C
Reaction time: 0.08 h
Yield: 101.9 %

Procedure:
A solution of Dowtherm A (7 mL) was heated in oil bath at 235° C. under nitrogen. 2,2-dimethyl-5-((4-methylthiophen-3-ylamino)methylene)-1,3-dioxane-4,6-dione (5.0 g, 19 mmol) was added in portions over a 20 minutes period. After the last portion was added, the solution stirred at 235° C. for another 5 minutes. The solution was removed from the oil bath and allowed to cool to room temperature. Upon cooling, the product precipitated out of solution. Diethyl ether was added and the solid was filtered and dried to give the title compound (3.2 g) with residual amounts of Dowtherm A remaining.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH2:7][OH:8].N1C=CN=C1.Cl[Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH2:7][O:8][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1c(F)cc(Br)cc1CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(F)cc(Br)cc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
907 mg of 5-bromo-3-fluoro-2-methoxybenzyl alcohol was dissolved in 10 ml of N,N-dimethylformamide. 400 mg of imidazole and 1.06 g of chloro(t-butyl)diphenylsilane were added, followed by stirring for 1 hour at room temperature and for 0.5 hours at 50° C. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated, to give 1.882 g of [(5-bromo-3-fluoro-2methoxybenzyl)oxy](t-butyl)diphenylsilane.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[O-:27][CH2:28][CH3:29].[Na+]>C(O)C>[CH2:28]([O:27][CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:5][CH2:4]1)[CH3:29]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOCC1(O)CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Yield: 55 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol) with sodium ethoxide (1.6 mmol) in ethanol (10 ml) at a temperature 60° C. for 6 hours and by purifying the compound by silica gel column chromatography in 55% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=O.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][C:4]=1[C:5](=[N:16][OH:17])[O:7][CH3:8]
Reactant: NO
Reactant: COC(=O)c1cc(C=O)ccc1OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=NO)c1cc(C=O)ccc1OC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Combine methyl 2-methoxy-5-formylbenzoate (5.0 g, 25.9 mmol), hydroxylamine hydrochloride (8.55 g, 133 mmol), and sodium acetate (10.25 g, 125 mmol) in ethanol/water (200 mL, 1/1). Heat to 50° C. After 1 hour, pour the reaction mixture onto ice to give a solid. Collect the solid by filtration to give methyl 2-methoxy-5-formylbenzoate oxime: Rf =0.76 (silica gel, 9/1 dichloromethane/methanol).
Reaction SMILES: C[O:2][C:3]1[C:12]([O:13]C)=[N:11][C:10]2[C:5](=[CH:6][C:7]([N+:25]([O-:27])=[O:26])=[CH:8][C:9]=2[CH2:15][N:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:17])[N:4]=1.[BrH:28]>C(O)(=O)C.C(OCC)C>[BrH:28].[O:2]=[C:3]1[C:12](=[O:13])[NH:11][C:10]2[C:5](=[CH:6][C:7]([N+:25]([O-:27])=[O:26])=[CH:8][C:9]=2[CH2:15][N:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:17])[NH:4]1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CN(C)Cc3ccccc3)c2nc1OC
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CN(Cc1ccccc1)Cc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
213 mg (0.53 mmol) of N-(2,3-dimethoxy-7-nitro-quinoxalin-5-ylmethyl)-N-methylbenzylamine are dissolved in 4 ml of an approximately 25% solution of hydrogen bromide in acetic acid, and the solution is stirred at room temperature for 20 hours. The mixture is diluted with diethyl ether and then stirred for 10 minutes, and the solid is filtered off and washed with diethyl ether and a small amount of water. After drying under a high vacuum, the title compound is obtained in the form of a beige solid.
Reaction SMILES: [CH3:1][NH:2][N:3]=[C:4]([CH3:6])[CH3:5].C(N(CC)CC)C.[CH2:14]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH2:23][CH3:24])[C:17]=1[C:25](=[O:29])[C:26](Cl)=[O:27])[CH3:15]>C(#N)C>[CH2:14]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH2:23][CH3:24])[C:17]=1[C:25](=[O:29])[C:26]([N:2]([CH3:1])[N:3]=[C:4]([CH3:6])[CH3:5])=[O:27])[CH3:15]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)Cl
Reactant: CNN=C(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)C
Temperature: 1 °C

Procedure:
To a 1000 ml volume four-necked flask, 1-methyl-2-(2-propylidene)hydrazine (17-a) (9.61 g), acetonitrile (280 ml), and triethylamine (17 ml) were added under a nitrogen atmosphere and cooled to about 1° C. To the mixture, 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl chloride (6-a) (27.12 g) dissolved in acetonitrile (77 ml) was added dropwise over 30 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:13])[NH:4][C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH2:14](O)[CH3:15]>C(O)(=O)C>[CH3:14][C:15]1[NH:1][C:2]2[C:3](=[O:13])[NH:4][C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: CCCn1c(N)c(N)c(=O)[nH]c1=O
Reactant: CCO
Solvent: CC(=O)O
Product: CCCn1c(=O)[nH]c(=O)c2[nH]c(C)nc21

Procedure:
A solution of 22.6 g of 5,6-diamino-1-propyl-2,4-(1H,3H)-pyrimidinedione in 50 ml of acetic acid was refluxed for 2 hours. 30 ml of ethanol was added. The received crystals were filtered off. Yield 19.8 g. The amide was refluxed in 80 ml of 2N NaOH for 2 hours and then neutralized with 5N HCl. The crystals were filtered off and recrystallized from 2.1 l ethanol. Yield 9.8 g (38%) (XXXXVI) NMR (see Table I).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:3]=1.[NH:19]1[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]1.C1(O)C=CC=CC=1>O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[CH:3]=[C:2]([N:19]3[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Reactant: NC(=O)C1CCNCC1
Solvent: Oc1ccccc1
Solvent: O
Product: NC(=O)C1CCN(c2cc(-c3ccc(F)cc3)nc3ccccc23)CC1

Procedure:
A mixture of 1.44 g of 4-chloro-2-(4-fluorophenyl)quinoline 1.3 g (10 mmol) of isonipecotamide, and 3 g of phenol was stirred and heated in an oil bath at 165°-170° for 4.5 hr. It was then cooled and diluted with water. It wa made alkaline with 3N sodium hydroxide, and crystallization was induced by the addition of ether and scratching. The solid was collected and washed with ether to give 1.6 g of crude product. Recrystallization from ethanol/water gave white needles (0.42g). mp 218°-220° dec.
Reaction SMILES: [O:1]=[C:2]([NH:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])/[C:3](/[CH2:17][S:18][C:19](=[O:21])[CH3:20])=[CH:4]/[C:5]1C=C[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.NCCC(OCC1C=CC=CC=1)=O>>[O:1]=[C:2]([NH:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])/[C:3](/[CH2:17][S:18][C:19](=[O:21])[CH3:20])=[CH:4]/[C:5]1[C:12]2[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)SC/C(=C\c1ccc(-c2ccccc2)cc1)C(=O)NCCC(=O)OCc1ccccc1
Agent: NCCC(=O)OCc1ccccc1
Product: CC(=O)SC/C(=C\c1cccc2ccccc12)C(=O)NCCC(=O)OCc1ccccc1
Yield: 57 %

Procedure:
The above (Z) acid is coupled with benzyl β-alaninate according to the experimental procedure described in Example 1 (step D). Yield: 57% (after flash chromatography, eluent ether/petroleum ether 60/40). m.p. 81° C. IR (nujol): 3290, 1740, 1695, 1640, 1620 cm-1 1H NMR (CDCl3 /TMS): 8.20 (s, 1H); 8.00 to 7.70 (m, 3H); 7.65 to 7.00 (m, 10H); 5.20 (s, 2H); 3.90 (s, 2H); 3.65 to 3.45 (m, 2H); 2.65 (t, 2H, J=6 Hz); 2.35 (s, 3H). Microanalysis: C26H25O4NS Calc. % C=69.78 H=5.63 N=3.13 Found. % C=69.86 H=5.68 N=3.17
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1.[CH3:20][O:21][C:22](=[O:32])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([O:30][CH3:31])[CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C>[CH3:20][O:21][C:22](=[O:32])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:2]2[N:3]=[CH:4][C:5]3[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)[C:6]=3[N:19]=2)=[C:25]([O:30][CH3:31])[CH:24]=1
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COC(=O)c1ccc(N)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Product: COC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CCC(=O)N3C)c(OC)c1
Yield: 38.3 %

Procedure:
2-Chloro-9-cyclopentyl-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (Intermediate 1; 500 mg, 1.78 mmol), methyl4-amino-3-methoxybenzoate (324 mg, 1.78 mmol) and p-toluenesulfonic acid (847 mg, 4.45 mmol) were suspended in (2R/S)-4-methyl-2-pentanol (10 mL) and heated at reflux for 5 h. The reaction mixture was cooled and loaded onto an SCX-2 column and washed with MeOH (20 mL). The crude product was then eluted from the SCX-2 column with NH3 (40 mL, 7M in MeOH) and the volatiles removed under reduced pressure. Purification by column chromatography (SiO2, eluent gradient 0-10% MeOH in DCM) afforded the title compound (290 mg, 38%) as a solid.