Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1[C:19]2[CH:18]([CH2:20][O:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[C:29]([OH:31])=[O:30])=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.C(N(C(C)C)C(C)C)C.O[C@H:42]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:43]([OH:45])=[O:44]>C(Cl)Cl.CN(C)C=O>[CH:16]1[C:17]2[CH:18]([CH2:20][O:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[C:29]([O:31][C@H:42]([CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:43]([OH:45])=[O:44])=[O:30])=[O:23])[C:19]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)[C@H](O)Cc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(O)[C@@H](Cc1ccccc1)OC(=O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Yield: 74.1 %

Procedure:
Oxalyl chloride (1.17 mL, 13.3 mmol) was added dropwise to a solution of (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carboxylic acid (Fmoc-Pro-OH) (3.00 g, 8.89 mmol) and N,N-dimethylformamide (34 μL, 0.445 mmol) in methylene chloride (36 mL) with stirring at 0° C. under a nitrogen atmosphere, and the reaction mixture was then stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the resulting residue was mixed with methylene chloride (36 mL), N-ethyldiisopropylamine (DIPEA) (2.33 mL, 13.3 mmol) and (R)-2-hydroxy-3-phenylpropanoic acid (2.22 g, 13.3 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was washed with 1 N hydrochloric acid twice and a saturated aqueous sodium chloride solution twice, dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (R)-2-(((S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carbonyl)oxy)-3-phenylpropanoic acid (Fmoc-Pro-D-PhLac-OH) (Compound SP635) (3.20 g, 6.59 mmol, 74%).
Reaction SMILES: [C:1]1([N:13]2[CH2:17][CH2:16][CH:15]([NH:18]C(=O)OC(C)(C)C)[CH2:14]2)[N:5]2[C:6]3[CH:12]=[CH:11][NH:10][C:7]=3[N:8]=[CH:9][C:4]2=[CH:3][N:2]=1.Cl.CCN(C(C)C)C(C)C.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]1([N:13]2[CH2:17][CH2:16][CH:15]([NH:18][S:39]([CH:36]3[CH2:38][CH2:37]3)(=[O:41])=[O:40])[CH2:14]2)[N:5]2[C:6]3[CH:12]=[CH:11][NH:10][C:7]=3[N:8]=[CH:9][C:4]2=[CH:3][N:2]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncc3cnc4[nH]ccc4n23)C1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NC1CCN(c2ncc3cnc4[nH]ccc4n23)C1)C1CC1
Reaction time: 4 h
Yield: 70.6 %

Procedure:
To a solution of tert-butyl 1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-ylcarbamate (0.175 g, 0.511 mmol, Example #D.1.42) in DCM (10 mL) was added HCl (4 N in 1,4-dioxane, 1.28 mL, 5.11 mmol). After about 4 h at ambient temperature, the reaction mixture was concd in vacuo. The residue was suspended in DCM (10 mL) and DIEA (0.446 mL, 2.56 mmol) was added to the reaction mixture resulting in a nearly homogeneous mixture. To the mixture was added cyclopropanesulfonyl chloride (0.079 g, 0.56 mmol). After about 2 h at ambient temperature, additional cyclopropane-sulfonyl chloride (0.079 g, 0.56 mmol) was added. After about 6 h at ambient temperature, saturated aqueous NaHCO3 (10 mL) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were concd in vacuo and purified by chromatography on silica gel (40 g) eluting with 50-90% MeCN in DCM to provide N-(1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)cyclopropane-sulfonamide (0.125 g, 70%) as a tan solid: LC/MS (Table 1, Method a) Rt=1.42 min; MS m/z: 347 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9](=[O:31])[NH:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.[C:32](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1nc(Cl)cc2c1c(=O)[nH]n2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3(2H)-one (Intermediate 4B; 406 mg, 0.953 mmol) in DMF (3 mL) was charged with potassium carbonate (348 mg, 2.52 mmol) and methyl iodide (0.089 mL, 1.430 mmol) and stirred at room temperature for 1 h. The reaction mixture was diluted with water, filtered, and dried under vacuum to give 6-chloro-3-methoxy-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridine, which was carried onto the next step without further purification. MS ESI calc'd. for C27H22ClN3O [M+1]+ 440. found 440.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[CH2:11]Br)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH2:14][C:15]([NH2:17])=[S:16]>C(O)C>[NH2:17][C:15]1[S:16][CH:11]=[C:10]([CH:7]2[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]2)[N:14]=1
Reactant: NC(N)=S
Reactant: CC(=O)N1CCC(C(=O)CBr)CC1
Solvent: CCO
Product: CC(=O)N1CCC(c2csc(N)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
1-(1-acetylpiperidin-4-yl)-2-bromoethanone (2.37 g, 9.561 mmol) and thiourea (0.728 g, 9.561 mmol) were dissolved in ethanol (40 mL) and agitated at ambient temperature for 30 minutes. The mixture was heated to 80° C. and agitated an additional 1 hour. Upon cooling solvent was evaporated and the residue was distributed between 20 mL of 2M NaOH and 20 mL of chloroform. The organic phase was separated and discarded. The remaining aqueous phase (white slurry) was extracted with chloroform until all solids were extracted (4×200 mL). The organic extracts were combined, dried over magnesium sulfate and evaporated to give the desired product (1.600 g, 74.27% yield) as white solid.
Reaction SMILES: S(O[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+].[Na+].[I-]>CN(C=O)C>[N:26]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)=[N+:27]=[N-:28]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(CN=[N+]=[N-])C1
Temperature: 70 °C
Yield: 93.3 %

Procedure:
tert-butyl 3-((tosyloxy)methyl)piperidine-1-carboxylate (8.85 g, 24 mmol) was dissolved in DMF (100 ml), and then NaN3 (6.24 g, 96 mmol) and NaI (0.36 g, 2.40 mmol) were added, followed by stirring at 70° C. for hours. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (EA:Hex=1:10), to give tert-butyl 3-(azidomethyl)piperidine-1-carboxylate (5.38 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[C:42]1([S:48]([NH2:51])(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.ClCCCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[CH:28][CH:27]=[C:23]([C:24](=[O:25])[NH:51][S:48]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)(=[O:50])=[O:49])[CH:22]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NS(=O)(=O)c4ccccc4)c3)cc12
Yield: 67.3 %

Procedure:
In a 1 dram vial with stir bar were combined 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (35 mg, 0.090 mmol), DMAP (33 mg, 0.27 mmol), EDC hydrochloride (26 mg, 0.14 mmol), and benzenesulfonamide (43 mg, 0.27 mmol). 1,2-Dichloroethane (1 mL) and DMF (0.3 mL) were added, the vial was capped, and the suspension was stirred at r.t. overnight, over which time the solids dissolved. The reaction was concentrated, filtered, purified by prep HPLC, and concentrated to give 32 mg (67% yield) of the title compound as a white powder. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.78 (br. s., 1H) 8.52 (q, J=4.48 Hz, 1H) 8.24 (s, 1H) 7.97-8.06 (m, 4H) 7.90-7.97 (m, 2H) 7.85 (d, J=7.94 Hz, 1H) 7.74-7.81 (m, 2H) 7.66-7.73 (m, 1H) 7.63 (t, J=7.63 Hz, 2H) 7.58 (t, J=7.63 Hz, 1H) 7.40 (t, J=8.85 Hz, 2H) 2.87 (d, J=4.58 Hz, 3H). LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=1.77 min, (ES+) m/z (MH+)=529. Analytical HPLC were performed using a Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: solvent A=5% CH3OH/95% H2O/10 mM NH4HCO3, solvent B=95% CH3OH/5% H2O/10 mM NH4HCO3, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: Phenomenex Gemini C18, 4.6 mm, 3 μm, Rt=15.70 min, purity=100%; column: Waters Xbridge Phenyl 4.6×150 mm, 3.5 μm, Rt=14.90 min, purity=99%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[N:11]([C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[C:17]([CH3:24])[N:18]=[CH:19]2)=[C:12]=[O:13].N(C1C=CC=C2C=1C=CN=C2)=C=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:12]([NH:11][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH:16]=[C:17]([CH3:24])[N:18]=[CH:19]3)=[O:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Reactant: C[C@H](N)c1ccc(Br)cc1
Agent: O=C=Nc1cccc2cnccc12
Product: Cc1cc2c(NC(=O)N[C@@H](C)c3ccc(Br)cc3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 61B using (1S)-1-(4-bromophenyl)ethanamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16](B(O)O)=[CH:17][C:18]2[C:19]([CH3:28])([CH3:27])[CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[C:23]=2[CH:24]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.I/[C:45](/[CH3:51])=[CH:46]\[C:47]([O:49][CH3:50])=[O:48]>O.C(COC)OC>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16](/[C:45](/[CH3:51])=[CH:46]\[C:47]([O:49][CH3:50])=[O:48])=[CH:17][C:18]2[C:19]([CH3:28])([CH3:27])[CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[C:23]=2[CH:24]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)/C=C(/C)I
Reactant: CC1(C)CCC(C)(C)c2cc(B(O)O)c(OCCCCCO[Si](C)(C)C(C)(C)C)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COC(=O)/C=C(/C)c1cc2c(cc1OCCCCCO[Si](C)(C)C(C)(C)C)C(C)(C)CCC2(C)C

Procedure:
A mixture of tetrakis(triphenyl-phosphine)palladium (155 mg), 3-[5-(tert-butyldimethylsilyloxy)pentyloxy]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaleneboronic acid (300 mg, 0.67 mmol), a 2M solution of potassium carbonate in water (0.67 ml) and methyl (Z)-3-iodo-2-butenoate (Ma, S. & Lu, X.; J. Chem. Soc. Chem. Com., pp. 1643-1644 (1990)) (182 mg) in dimethoxyethane (DME) (10 ml) was heated to reflux for 24 h. The solution was poured into a mixture of water and ethyl acetate. The organic phase was washed twice with water, dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40° C. The desired compound was purified by flash chromatography on a silica column.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:19])[C@:15]([NH2:18])([O:16][CH3:17])[C@H:12]2[S:11][CH2:10][C:9]=1[C:20]([CH2:30][PH:31]([O:33]C(C)(C)C)=[O:32])([S:24][C:25]1[NH:29][N:28]=[N:27][N:26]=1)[O:21][CH2:22][CH3:23])=[O:7])(C)(C)C.C(N(CC)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)C>C(Cl)Cl>[C:15]([NH:18][C@:15]1([O:16][CH3:17])[C:14](=[O:19])[N:13]2[C:8]([C:6]([OH:5])=[O:7])=[C:9]([C:20]([CH2:30][PH:31]([OH:33])=[O:32])([S:24][C:25]3[NH:26][N:27]=[N:28][N:29]=3)[O:21][CH2:22][CH3:23])[CH2:10][S:11][C@H:12]12)(=[O:16])[C@@H:14]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[OH:19]
Reactant: CCN(CC)c1ccccc1
Reactant: CCOC(C[PH](=O)OC(C)(C)C)(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)[C@](N)(OC)[C@H]2SC1
Solvent: ClCCl
Product: CCOC(C[PH](=O)O)(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@](NC(=O)[C@H](O)c3ccccc3)(OC)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.16 g (2 mmol) of 7β-amino-7α-methoxy-3-(1-ethoxy-t-butoxyphosphinylmethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid t-butyl ester and 0.30 g (2 mmol) of N,N-diethylaniline in 100 ml of dry methylene chloride is stirred at 0°-5° while 0.56 g (2 mmol) of D-O-dichloroacetylmandeloyl chloride in 10 ml of methylene chloride is added dropwise over 10 minutes. The mixture is stirred in the cold for 30 minutes then warmed to room temperature and stirred for an additional 30 minutes. The solution is washed with 50 ml of cold dilute hydrochloric acid and 50 ml of cold 5% aqueous sodium bicarbonate, dried and evaporated to dryness. The residue is dissolved in a mixture of 10 ml of trifluoroacetic acid and 2 ml of m-dimethoxybenzene and stirred at ambient temperature for 2 hours. The excess trifluoroacetic acid is evaporated under vacuum and the residue is partitioned between 50 ml of ether and 50 ml of water and adjusted to pH 9.3-9.5 with 5% aqueous sodium carbonate. The organic phase is separated and discarded. The aqueous phase is stirred at pH 9.3-9.5 for 30 minutes, layered with ethyl acetate and adjusted to pH 3.0 with dilute hydrochloric acid. After separation of the layers, the aqueous phase is adjusted to pH 7 with sodium bicarbonate and passed through a XAD-7 resin column. The product-containing fractions are combined, stirred with Amberlite IR-120H ion-exchange resin and lyophilized to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:29].[K+].[K+].C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:27])=[O:29])=[CH:22][CH:21]=3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1ccc(-c2nc(-c3cccc(C)c3)c(-c3ccnc(C)c3)s2)cc1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc(-c2nc(-c3ccc(S(C)=O)cc3)sc2-c2ccnc(C)c2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 26.5 %

Procedure:
To a solution of 4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-[4-(methylthio)phenyl]-1,3-thiazole (0.55 g, 1.4 mmol) in acetic acid (15 mL) was added a solution of potassium persulfate (0.43 g, 1.6 mmol) in water (8 mL), and the mixture was stirred for 14 hours at room temperature. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and extracted with ethyl acetate. The extracts were washed with water, dried, then, the solvent was distilled off. The residue was purified by column chromatography (filler: Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical Ltd.), hexane-ethyl acetate=1:4), and recrystallized from ethyl acetate-hexane to obtain a title compound (0.15 g, yield 26%).
Reaction SMILES: [CH:1]([N:4]([CH3:29])[C:5]1[C:6]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[N:23]=[CH:22]3)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[OH-].[Na+].O>CO.C(Cl)(Cl)Cl>[CH:1]([N:4]([CH3:29])[C:5]1[C:6]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[N:23]=[CH:22]3)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc4c(cnn4C)c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2c(cnn2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2-(1-methyl-1H-indazol-5-yl)quinoxaline-6-carboxylate (110 mg, 0.28 mmol) in methanol (20 mL) and CHCl3 (6 mL) was added sodium hydroxide (20 mg, 0.50 mmol) and water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (10 mL) and adjusted to pH 6 with hydrochloric acid (3N). The solids were collected by filtration to afford 3-(isopropyl(methyl)amino)-2-(1-methyl-1H-indazol-5-yl)quinoxaline-6-carboxylic acid (50 mg, 47%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClS([N:29]=[C:30]=O)(=O)=O.CN(C=O)C.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH2:10][C:9]1([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2([CH3:24])[CH3:23])[C:30]#[N:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C(C)(C)C(=O)N2
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C=CCC1(C#N)c1ccc2c(c1)C(C)(C)C(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.5 %

Procedure:
To a solution 2-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyrrole-1-carboxylic acid tert-butyl ester (0.39 g, 1.2 mmol) in THF (anhydrous, 9 mL) at −78° C. was added chlorosulfonyl isocyanate (1.15 eq, 0.12 mL, 1.4 mmol). After 120 min, DMF (20 eq, 1.8 mL, 23 mmol) was added and the reaction was allowed to warm to room temperature. The reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (2×50 mL). The organic layers were combined, washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash column chromatography on silica gel (1:3 ethyl acetate/hexane) gave 2-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-cyanopyrrole-1-carboxylic acid tert-butyl ester (0.21 g, 50%) as a white solid: mp 158.6. 1H NMR (DMSO-d6; 300 MHz) δ 1.27 (s, 6H), 1.33 (s, 9H), 6.40 (d, 1H, J=3.8 Hz), 6.90 (d, 1H, J=8.0 Hz), 7.19 (dd, 1H, J=1.8, 8.0 Hz), 7.30 (d, 1H, J=1.5 Hz), 10.50 (s, 1H). MS m/z 350 (M−H)−. Calcd for C19H22N2O3: C, 68.36; H, 6.02; N, 11.96. Found: C, 66.79; H, 6.03; N, 11.02.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]([CH3:20])[C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[CH3:28][O:29][C:30]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][N:38]=[C:37]2Cl)=[O:31]>C(#N)C>[CH3:28][O:29][C:30]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][N:38]=[C:37]2[NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]([C:10](=[O:19])[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH3:20])[CH:4]=1)=[O:31]
Reactant: COc1ccc(C(=O)N(C)c2cccc(CN)c2)cc1
Reactant: COC(=O)c1cccc2c(Cl)ncnc12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2c(NCc3cccc(N(C)C(=O)c4ccc(OC)cc4)c3)ncnc12
Reaction time: 8 h

Procedure:
101 mg (0.37 mmol) N-(3-Aminomethyl-phenyl)-4-methoxy-N-methyl-benzamide were dissolved in 3 ml acetonitrile and 260 μl (1.87 mmol) triethylamine. 130 mg (0.37 mmol) 4-Chloro-quinazoline-8-carboxylic acid methyl ester were added and the mixture was stirred overnight. The solvent was removed, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude product was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[N:6]=2)[CH2:2]1.C(N(CC)CC)C.[CH3:23][NH:24][C:25]1[N:30]2[CH:31]=[CH:32][N:33]=[C:29]2[N:28]=[C:27]([C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[C:26]=1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[CH3:23][NH:24][C:25]1[N:30]2[CH:31]=[CH:32][N:33]=[C:29]2[N:28]=[C:27]([C:34]2[CH:41]=[CH:40][C:37]([CH2:38][N:1]3[CH2:4][CH:3]([C:5]4[N:6]=[C:7]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=5)[NH:8][N:9]=4)[CH2:2]3)=[CH:36][CH:35]=2)[C:26]=1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CNc1c(-c2ccccc2)c(-c2ccc(C=O)cc2)nc2nccn12
Reactant: c1ccc(-c2n[nH]c(C3CNC3)n2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CNc1c(-c2ccccc2)c(-c2ccc(CN3CC(c4n[nH]c(-c5ccccn5)n4)C3)cc2)nc2nccn12
Reaction time: 1 h
Yield: 37.3 %

Procedure:
257 mg (0.94 mmol) 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-pyridine×2HCl are dissolved in 7.3 mL NMP. After addition of 0.26 mL (1.88 mmol) triethylamine the reaction mixture is stirred for one hour. 280 mg (0.85 mmol) 4-(5-Methylamino-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-benzaldehyde and 0.12 mL (2.05 mmol) acetic acid are added. The reaction mixture is stirred for 24 hours at room temperature. 469.9 mg (2.2 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature over night. The reaction mixture is treated with saturated NaHCO3. The precipitate is filtered off, washed with water, dried and purified by chromatography (silicagel, eluents: dichloromethane/methanol) yielding 163 mg (33.5%) of the desired title compound.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[Br:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O>>[Br:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]1[C:3]2[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=2[NH:1][C:2]2[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]1=2
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: O=Cc1ccccc1Br
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccccc1Br

Procedure:
3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 2-bromobenzaldehyde in an analogous manner to that described in Example 1 to give 9-(2-bromophenyl)-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from dimethylformamide/water gave a yellow powder of melting point >285° C. (decomposition).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[CH:4]=[N:3][CH:2]=1.[N+:10]([O-])([OH:12])=[O:11].C(=O)(O)[O-].[Na+]>O>[N+:10]([C:9]1[C:5]2[CH:4]=[N:3][CH:2]=[N:1][C:6]=2[NH:7][CH:8]=1)([O-:12])=[O:11]
Reactant: c1ncc2cc[nH]c2n1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1c[nH]c2ncncc12
Temperature: 0 °C

Procedure:
5-Nitro-7H-pyrrolo[2,3-d]pyrimidine (8) is prepared by adding 7H-pyrrolo[2,3-d]pyrimidine (6) to fuming nitric acid while cooling (e.g. 0° C.). After stirring for one to several hours, water is carefully added and the mixture neutralized with saturated sodium bicarbonate. The solids are collected by filtration and dried to provide 5-nitro-7H-pyrrolo[2,3-d]pyrimidine 8.