Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]O)[CH3:2].C1C=CC(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:26]([CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[S:3][CH2:1][CH3:2])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCSc1ccccc1CO
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCSc1ccccc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 2-(ethylthio)benzyl alcohol (3.98 g, 23.6 mmol) in THF (48 mL) at 0° C. under Ar was added DPPA (6.1 mL, 28.4 mmol) followed by DBU (4.0 mL, 26.0 mmol). The reaction was allowed to warm to room temperature and stirred for 2 days. The solution was concentrated to an oil, which was taken up in EtOAc, and washed successively with 10% aqueous citric acid, saturated aqueous NaHCO3 solution and brine. The organic layer was dried over Na2SO4 and concentrated to an oil which was purified by silica gel chromatography (gradient elution with 100% hexanes to 5% EtOAc-hexanes). Concentration of the product fractions at reduced pressure afforded a pale yellow oil which was dried on a high vacuum line overnight to afford the title compound:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]=O)=[C:16]2[CH3:26])=[CH:11][C:10]=1[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].CO>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]=[N:29][OH:30])=[C:16]2[CH3:26])=[CH:11][C:10]=1[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1c(C=O)c2ccccc2n1-c1ccc(OCc2ccccc2)c(F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: Cc1c(C=NO)c2ccccc2n1-c1ccc(OCc2ccccc2)c(F)c1
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
To a stirred solution of 1-(4-benzyloxy-3-fluorophenyl)-2-methyl-1H-indole-3-carbaldehyde (0.81 g, 2.3 mmol), hydroxylamine hydrochloride (0.25 g, 3.6 mmol) and methanol (25 mL) was added pyridine (1 mL). The reaction mixture was heated to reflux and held for 30 min. The mixture was cooled, the methanol removed by evaporation and the residue taken up in ethyl acetate/water. The product was extracted into ethyl acetate (2×50 mL), the ethyl acetate washed with water and brine and dried over MgSO4. The solvent was evaporated, and the crude product was purified by silica gel chromatography (25% ethyl acetate-hexanes) to provide a white solid (0.7 gr, 83%): mp 167-168° C.; 1H NMR (DMSO-d6): δ 2.32 (3H, s), 5.29 (2H, s), 6.99-7.01 (1H, m), 7.10-7.17 (2H, m), 7.25-7.28 (1H, m), 7.37-7.42 (1H, m), 7.43-7.49 (3H, m), 7.49-7.54 (2H, m), 8.01-8.04 (1H, m), 8.41 (1H, s), 10.67 (1H, s); MS m/z (M+H)+ 375: Anal. for C23H19FN2O2: Calc'd: C, 73.78; H, 5.11; N, 7.48. Found: C, 73.53; H, 5.06; N, 7.32
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](O)=[O:23])[CH:4]=1)#[N:2].[CH3:25][C:26]([NH2:34])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27]>>[CH3:25][C:26]([NH:34][C:22]([C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@:18]1([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]1)=[CH:6][CH2:7]3)=[O:23])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27]
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: CC(C)(N)c1ccccc1
Product: CC(C)(NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C)c1ccccc1
Yield: 74 %

Procedure:
Following a procedure similar to that described in Preparation 16a, but using 3-cyanoandrosta-3,5-diene-17β-carboxylic acid [prepared as described in Example 1(b)] and 1-methyl-1-phenylethylamine as starting materials, in relative proportions similar to those used in that Preparation, the title compound was obtained in a yield of 74%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[C:2]1=[O:14].C([O-])(=O)C.[Na+].[Br:20]Br.C(=O)([O-])O.[Na+]>C(O)(=O)C>[Br:20][CH:13]1[C:3]2([C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: O=C1Nc2ccccc2C12CCCC2
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2C12CCCC2Br
Yield: 105 %

Procedure:
A solution of spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one (0.27 g, 1.4 mmol) and sodium acetate (0.12 g, 1.46 mmol) in acetic acid (10 cm3) was treated with bromine (0.24 g, 1.51 mmol) in acetic acid (2 cm3). After 30 min. the mixture was poured into sat. sodium hydrogen carbonate solution and extracted with EtOAc (×2), the combined organic layers were washed with water, sat. sodium hydrogen carbonate solution, water, dried (MgSO4), and evaporated to give the subtitled compound (0.37 g, 1.47 mmol, 96%) as an off-white solid which was used without further purification: 1H NMR (CDCl3) δ 1.8-2.27 (m, 8H), 6.79 (d, J=8 Hz, 1H), 7.30-7.39 (m, 2H), 8.63 (br s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][O:27][C:26]1=[O:30]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:23][CH2:24][N:25]2[CH2:29][CH2:28][O:27][C:26]2=[O:30])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OCCN1CCCl
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1OCCN1CCN1CCN(Cc2ccccc2)CC1

Procedure:
744 g of 1-benzyl-piperazine are treated, together with 590 g of powdered potassium carbonate, 10 g of potassium iodide and 5 litres of toluene, with 450 g of 3-(2-chloroethyl)-2 -oxazolidinone and the mixture is heated to reflux for 21 hours. The mixture is cooled, filtered and concentrated under reduced pressure. The residue is distilled under reduced pressure. There is obtained 3-[2-(4-benzyl-1-piperazinyl)-ethyl]-2- oxazolidinone which boils at 225° - 235° C under a pressure of 2- 2.5 mm. The compound is recrystallised from ethyl acetate; melting point 82° - 84° C. The dihydrochloride of melting point 243° - 245° C is obtained by treatment with an excess of hydrochloric acid in ethanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:10]2[CH:9]=[C:8]3[NH:11][C:12](=O)[NH:13][C:7]3=[CH:6][C:5]=2[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]1=[O:20].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:12]1[NH:11][C:8]2=[CH:9][C:10]3[C:2]([CH3:21])([CH3:1])[C:3](=[O:20])[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:5]=3[CH:6]=[C:7]2[N:13]=1
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(=O)[nH]c3cc21
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(Cl)nc3cc21
Temperature: 25 °C

Procedure:
7,7-Dimethyl-5-pentyl-5,7-dihydro-1H,3H-imidazo[4,5-f]indole-2,6-dione (3.80 g) is suspended in phosphoryl chloride (39 ml) and heated under reflux for 5 h. After re-cooling to RT the dark reaction mixture is poured into ice-water (1 l) and heavily stirred. The aqueous phase is made alkaline and extracted with CH2Cl2. The combined organic layer is washed with brine, dried over MgSO4 and evaporated to give F1 (2.85 g) as a dark oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)[CH3:2].F[C:15]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=1[CH:17]=[O:18]>>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:15]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=2[CH:17]=[O:18])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Product: CCOC(=O)Cc1cccc(Oc2ccc([N+](=O)[O-])cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 2, using the following starting materials: (3-hydroxy-phenyl)-acetic acid ethyl ester and 2-fluoro-5-nitrobenzaldehyde.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[CH2:19]([N+:26](C)(C)C)[C:20]1C=CC=C[CH:21]=1>C(#N)C=C>[O:1]=[C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:21][CH2:20][C:19]#[N:26]
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: O=c1cc(-c2ccccc2)c2ccccc2[nH]1
Agent: [OH-]
Solvent: C=CC#N
Product: N#CCCn1c(=O)cc(-c2ccccc2)c2ccccc21
Reaction time: 12 h

Procedure:
6.9 g of 1,2-dihydro-2-oxo-4-phenylquinoline are suspended in 45 ml of acrylonitrile, and 3 ml of benzyltrimethylammonium hydroxide are added at 40° to 45° C. During this addition, the mixture starts to boil. After boiling for ten minutes, the acrylonitrile is largely distilled off in vacuo. The residue is heated with 300 ml of ethanol to the boiling point, undissolved material is filtered off and the filtrate is treated with active charcoal and concentrated to 200 ml. The mixture is left to stand for 12 hours and the title compound which has separated out (6.4 l g of m. 162°-165° C.) is filtered off.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.P([O-])([O-])([O-])=[O:19].[Na+].[Na+].[Na+]>>[OH:19][CH2:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1
Reactant: O=P([O-])([O-])[O-]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)nc1N
Agent: [Na+]
Product: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1CO
Temperature: 75 °C
Reaction time: 4 h

Procedure:
5-Hydroxymethyldeoxycytidine is synthesized according to the published procedure of Itahara et al. (Chem. Lett. 1591-1594, 1991). To 5-methyl-2'-deoxycytidine (0.5 mmol, available from Sigma Chemical Company) in 100 mL of sodium phosphate buffer (pH 7.0) Na2S2O8 (0.5 mmol) is added and the reaction mixture stirred at 75° C. for 4 hours under argon. The reaction mixture is then concentrated and the crude 5-hydroxymethyldeoxycytidine is purified on a LiChroprep reversed-phase HPLC column by eluting with 0.05 M sodium phosphate (pH 7.0) and evaporation of the appropriate fractions.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[NH:12][CH2:11][C:10]=2[CH:20]=1)(=[O:5])=[O:4].[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23].Cl>N1C=CC=CC=1>[CH3:1][N:2]([CH3:21])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[N:12]([C:29](=[O:30])[C:28]3[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:33][CH:32]=3)[CH2:11][C:10]=2[CH:20]=1)(=[O:4])=[O:5]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CNc1ccccc1O2
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1O2
Reaction time: 7 h
Yield: 82 %

Procedure:
A mixture of 0.9 g of 10,11-dihydro-N,N-dimethyldibenz[b,f][1,4]oxazepine-2-sulfonamide and 0.55 g of 4-nitrobenzoyl chloride in 3 ml of pyridine is stirred for 7 hours. To the mixture is added 20 ml of 2N hydrochloric acid and the mixture is extracted with ethyl acetate. The extract is washed with 5 ml of 2N HCl and three times with 5 ml of 2N Na2CO3. The extract is dried (MgSO4) and filtered through a thin pad of hydrous magnesium silicate. The pad is washed with ethyl acetate and the filtrate concentrated to give 1.1 g of a yellow solid. Crystallization from dichloromethane-diisopropylether gives 0.62 g of crystals, m.p. 177°-178° C.
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH2:40][C:41]3[S:42][C:43]([C:46]4[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=4)=[CH:44][CH:45]=3)[CH:34]=2)([O:31]C)[O:11][C:10]1([CH2:55]O)[CH2:53][OH:54])C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[F:52][C:49]1[CH:48]=[CH:47][C:46]([C:43]2[S:42][C:41]([CH2:40][C:35]3[CH:34]=[C:33]([C@@:12]45[O:11][C@@:10]([CH2:53][OH:54])([CH2:55][O:31]4)[C@@H:9]([OH:8])[C@H:14]([OH:15])[C@H:13]5[OH:23])[CH:38]=[CH:37][C:36]=3[CH3:39])=[CH:45][CH:44]=2)=[CH:51][CH:50]=1
Reactant: CO[C@@]1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc([C@]23OC[C@](CO)(O2)[C@@H](O)[C@H](O)[C@H]3O)cc1Cc1ccc(-c2ccc(F)cc2)s1
Reaction time: 16 h
Yield: 13.7 %

Procedure:
[(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 9j (130 mg, 0.17 mmol) was dissolved in 10 mL methanol, followed by addition of a solution (4 mL) of 2 M hydrochloric in ethyl acetate and Palladium/carbon (260 mg, 20%). The mixture was exchanged with H2 three times and stirred for 16 hours. Thereafter, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by HPLC to obtain the title compound (1S,2S,3S,4R,5S)-5-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol 9 (11 mg, white solid), yield: 13.8%. MS m/z (ESI): 473.2 [M+1]; 1H NMR (400 MHz, CD3OD): δ 7.57-7.56 (m, 2H), 7.48 (d, 1H), 7.39-7.37 (m, 1H), 7.19 (d, 1H), 7.15 (d, 1H), 7.10-7.06 (m, 2H), 6.67 (d, 1H), 4.18 (d, 3H), 3.88-3.81 (m, 2H), 3.73-3.68 (m, 2H), 3.65-3.62 (m, 2H), 2.33 (s, 3H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[CH3:27]O>>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:27])=[O:24])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: CO
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Agent: Cl
Product: COC(=O)CCc1ccc(-c2ccc(CCN3CCC[C@H]3C)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (14.0 mg, 0.041 mmol, see Example 1.46 for preparation) was added 1.25M hydrogen chloride in methanol (0.996 mL, 1.245 mmol). The reaction was stirred at 60° C. for 2 h. The resulting mixture was concentrated and triturated with acetonitrile to give the title compound. LCMS m/z=352.4 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.24 (d, J=6.9 Hz, 0.5H), 1.56 (d, J=6.4 Hz, 2.5H), 1.76-1.90 (m, 1H), 1.99-2.14 (m, 2H), 2.23-2.38 (m, 1H), 2.68 (t, J=7.6 Hz, 2H), 2.97 (t, J=7.6 Hz, 2H), 3.00-3.21 (m, 3H), 3.30-3.41 (m, 2H), 3.45-3.55 (m, 1H), 3.65 (s, 3H), 3.69-3.80 (m, 1H), 7.33 (d, J=8.1 Hz, 2H), 7.40 (d, J=8.2 Hz, 2H), 7.58 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.2 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=O)[CH2:11]1)=[O:9].F[B-](F)(F)F.C([O+](CC)CC)C.[N:29]1[CH:34]=[CH:33][C:32]([C:35]([NH:37][NH2:38])=O)=[N:31][CH:30]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]2[C:35]([C:32]3[CH:33]=[CH:34][N:29]=[CH:30][N:31]=3)=[N:37][N:38]=[C:12]2[CH2:11]1)=[O:9]
Reactant: O=C1CN(C(=O)c2ccccc2Cl)CCN1
Reactant: NNC(=O)c1ccncn1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccccc1Cl)N1CCn2c(nnc2-c2ccncn2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title compound was prepared in a method analogous to the example E111. To a solution of 4-[(2-chlorophenyl)carbonyl]-2-piperazinone (I4) (269 mg, 1.127 mmol,) in Dichloromethane (5 ml) stirred under argon at room temp was added solid triethyloxonium tetrafluoroborate (214 mg, 1.127 mmol). The reaction mixture was stirred at RT for 1 hr. Solid 4-pyrimidinecarbohydrazide (I71 mg, 1.240 mmol, commerically available from e.g. Anichem, J&W PharmLab or Bepharm) was added and the reaction mixture stirred at RT for 18 hr. The solvent was evaporated in vacuo, and the residue dissolved in n-butanol (5 ml) and stirred at 120° C. for 3 hr. The reaction mixture was cooled to room temperature and partitioned between Dichloromethane (˜50 ml) and saturated brine (˜25 ml). The aqueous phase was extracted with Dichloromethane (2×25 ml) and the combined organic extracts washed with saturated brine (2×25 ml), dried over sodium sulphate and evaporated in vacuo to afford the crude product (−Z1) as a dark orange oil. This was dissolved in 1:1 MeOH:DMSO and purified by Open Access Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier. The solvent was evaporated in vacuo, and the residue washed with ether (˜10 ml) and dried overnight in a vacuum oven at 40° C. to afford the required product as a yellow solid in 74.1 mg.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][CH:18]([N:20]1[C:29]2[C:24](=[CH:25][C:26]([C:30](=O)[CH3:31])=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1)[CH3:19].O>CN(C)C=O>[CH3:19][CH:18]([N:20]1[C:29]2[C:24](=[CH:25][C:26](/[C:30](/[CH3:31])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1)[CH3:17]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(=O)c1ccc2c(c1)CCCN2C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C(\C)c1ccc2c(c1)CCCN2C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
2.0 g (60%, 51 mmol) of sodium hydride was suspended in 10 ml of N,N-dimethylformamide, and 11.3 g (51 mmol) of ethyl diethylphosphonoacetate was dropped into the suspension under cooling with ice. The obtained mixture was stirred at room temperature for one hour, followed by the addition of 5.5 g (25 mmol) of 1-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]ethanone. The obtained mixture was stirred at 60° C. for 48 hours, followed by the addition of water. The mixture thus obtained was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated in a vacuum. The residue was purified by silica gel column chromatography (4% ethyl acetate/n-hexane) to give 4.0 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5]O.[NH:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19]
Reactant: COc1ccc(CO)c(OC)c1
Reactant: O=C1CCC(=O)N1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)CCC2=O)c(OC)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To 2,4-dimethoxybenzyl-alcohol (4.3 g, 25.6 mmol) and pyrrolidine-2,5-dione (succinimide, 1.2 g, 12.2 mmol) dissolved in tetrahydrofuran (25 ml) and dichloromethane (25 ml) was added triphenyphosphine (6.4 g, 24.4 mmol). After cooling to 0° C., diethylazidodicarboxylate (DEAD, 4.25 g, 24.4 mmol) was added dropwise to the reaction mixture. The reaction mixture was then allowed to warm to room temperature and kept at room temperature with stirring overnight. Following concentration in vacuo, 100 ml of a (1:1)hexane/ether solution was added and this mixture was stored at 0° C. overnight. The resulting solid precipitate was filtered off and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (3/1—ethyl acetate/hexane) to afford 1-(2,4-dimethoxy-benzyl)-pyrrolidine-2,5-dione 299 (1.4 g, 5.6 mmol, 46%). 1H NMR (CDCl3) δ 7.07 (d, 1H), 6.38 (m, 2H), 4.60 (s, 2H), 3.76 (s, 3H), 2.62 (s, 4H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:33])[C:9]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:11]=2)[C:6](=[O:34])[C:5]([C:35](O)=[O:36])=[CH:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:71]1([CH2:76][CH2:77][NH2:78])[CH2:75][CH2:74][CH2:73][CH2:72]1>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:33])[C:9]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH:11]=2)[C:6](=[O:34])[C:5]([C:35]([NH:78][CH2:77][CH2:76][N:71]2[CH2:75][CH2:74][CH2:73][CH2:72]2)=[O:36])=[CH:4]1)[CH3:2]
Reactant: NCCN1CCCC1
Reactant: CCn1cc(C(=O)O)c(=O)c2c(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1cc(C(=O)NCCN2CCCC2)c(=O)c2c(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a solution of 1-ethyl-5-fluoro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydro quinoline-3-carboxylic acid (Example 36h) (5 g, 9.85 mmol) in N,N-Dimethylformamide (DMF) (5 mL) was added HATU (5.62 g, 14.78 mmol) and DIPEA (5.16 mL, 29.6 mmol), the resulting mixture was stirred at r.t. for 30 min. Then 2-(pyrrolidin-1-yl)ethanamine (1.861 mL, 14.78 mmol) was added and the resulting mixture was stirred at r.t. overnight. The mixture was concentrated and the residue was purified by normal phase automatic silica column chromatography (Combiflash RF) eluting with MeOH/DCM (0-20%). The product was further purified by reverse phase automatic chromatography (Combinflash RF), using a 150 g golden C18 column and eluting with acetonitrile/Water (0%-100%) to afford 1-ethyl-5-fluoro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-N-(2-(pyrrolidin-1-yl)ethyl)-1,4-dihydroquinoline-3-carboxamide (3.8 g, 6.29 mmol, 63.9% yield) as pale yellow solid. LCMS: (M+H)+: 604.4.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:34])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:34])[CH2:12][CH2:13]1
Reactant: COc1cc(-c2ccncc2)c2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2ccncc2)c2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2 mL of a chloroform solution containing 280 mg of tert-butyl(1-(2-(7-methoxy-5-(pyridin-4-yl)-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 0.84 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, chloroform and water were added thereto, the resultant solution was adjusted to pH about 12 with a 2 mol/L aqueous sodium hydroxide solution, and the organic layer was separated. The organic layer was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 230 mg of a yellow oily substance, 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-5-(pyridin-4-yl)quinoxalin-2(1H)-one.