Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH2:4].[CH:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[BH4-].[Na+]>CO.ClCCl>[CH2:5]([NH:1][CH2:2][CH2:3][NH2:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCN
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: NCCNCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
60.0 g (998 mmol) of 1,4-diazabutane is dissolved in 750 ml of absolute methanol and cooled to 0° C. At this temperature, the drop-by-drop addition of 20.0 g (188 mmol) of benzaldehyde, dissolved in 100 ml of absolute methanol, is carried out. After a reaction time of 2 hours at 0° C., the addition in portions of a total of 7.13 g (188 mmol) of sodium borohydride is carried out. After 12 hours at 25° C., the reaction solution is suctioned off on diatomaceous earth, and the solvent is drawn off in a vacuum. The remaining oily residue is taken up in 500 ml of dichloromethane and washed three times with 100 ml of water in each case. After the organic phase is dried on sodium sulfate, the solvent is drawn off in a vacuum. The oily residue that is thus obtained is chromatographed on silica gel (eluant: methanol/aqueous ammonia solution 20:1).
Reaction SMILES: C[Si]([CH2:5][C:6]1(O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:8][C:7]1=[O:21])(C)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:5]=[C:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:8][C:7]1=[O:21]
Reactant: CCOC(=O)C1CCCCCCC(O)(C[Si](C)(C)C)C(=O)N1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: C=C1CCCCCCC(C(=O)OCC)NC1=O
Temperature: 25 °C
Reaction time: 26 h

Procedure:
Ethyl 3-(trimethylsilylmethyl)-3-hydroxy-2-oxo-1-azacyclodecane-10-carboxylate (0.98 g, 2.98 mmol) is dissolved in methylene chloride (50 mL), and boron trifluoride etherate (1.8 mL, 15 mmol) is added. The reaction is stirred at room temperature for 26 hours. The reaction is then quenched with saturated ammonium chloride and extracted several times with methylene chloride. The combined organic layers are dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (20% ethyl acetate/hexane) to give ethyl 3-methylidene-2-oxo-1-azacyclodecane-10-carboxylate, m.p. 91°-92° C.
Reaction SMILES: CNN(CCC)NC.[CH3:9][C:10]1([CH3:30])[O:17][CH2:16][CH2:15][C@H:14]2[N:11]1[C:12](=[O:29])[C@@H:13]2[N:18]1C(=O)C2=CC=CC=C2C1=O>CO.ClCCl>[NH2:18][C@H:13]1[C:12](=[O:29])[N:11]2[C@@H:14]1[CH2:15][CH2:16][O:17][C:10]2([CH3:30])[CH3:9]
Reactant: CC1(C)OCC[C@@H]2[C@@H](N3C(=O)c4ccccc4C3=O)C(=O)N21
Agent: CCCN(NC)NC
Solvent: CO
Solvent: ClCCl
Product: CC1(C)OCC[C@@H]2[C@@H](N)C(=O)N21
Reaction time: 2 h
Yield: 59.5 %

Procedure:
N,N-Dimethylaminopropylamine (91 μl) was added to a solution of (6R,7R)-2,2-dimethyl-7-phthalimido-1-aza-3-oxabicyclo[4.2.0]octan-8-one (80 mg) in a mixture of methanol (1.4 ml) and dichloromethane (0.7 ml) at 0° C. under a nitrogen atmosphere. The solution was stirred at the same temperature for two hours and left at ambient temperature for 24 hours. The mixture was evaporated and the residue was chromatographed on silica gel (1.5 g; eluting with 3 to 5% methanol in dichloromethane) to give 27 mg (59.5%) of (6R,7R)-7-amino-2,2-dimethyl-1-aza-3-oxabicyclo[4.2.0]octan-8-one: IR (CH2Cl2): 3100-3600 (broad) and 1735 cm-1 ; NMR (CDCl3) δ: 1.41 (s, 3H), 1.72 (s, 3H), 1.5-2.1 (m, 4H), 3.34 (ddd, J=2, 5 and 10 Hz, 1H), and 3.7-3.9 (m, 3H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[CH2:10][C:11]([OH:13])=O.[CH2:14]([C@H:21]1[CH2:25][NH:24][C@H:23]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)=[CH:31][CH:30]=2)=[O:27])[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C@H:21]1[CH2:25][N:24]([C:11](=[O:13])[CH2:10][C:4]2[C:5]([F:9])=[CH:6][CH:7]=[CH:8][C:3]=2[F:2])[C@H:23]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)=[CH:31][CH:30]=2)=[O:27])[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)Cc1c(F)cccc1F
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)Cc1c(F)cccc1F
Yield: 37.6 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2,6-difluorophenyl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 95, (2S,4R)-4-benzyl-1-(2-(2,6-difluorophenyl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (12.3 mg, 37.6%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): a 9.92 (s, 1H), 7.53 (m, 3H), 7.28 (m, 3H), 7.24-7.14 (m, 6H), 6.97-6.91 (m, 4H), 4.46 (m, 1H), 3.82 (m, 1H), 3.70 (m, 2H), 3.37 (m, 1H), 2.70 (m, 3H), 1.19 (m, 2H). MS (EI) for C32H27F3N2O3. found 545.6 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:42]=[CH:41][C:7]([CH2:8][O:9][C:10](=[O:40])[CH:11]([N:13]2[CH:16]([S:17][C:18](=[O:36])[CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])[CH:15]([CH2:37][CH3:38])[C:14]2=[O:39])Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:43]1([P:49]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O1CCCC1.C(Cl)Cl>[N+:1]([C:4]1[CH:42]=[CH:41][C:7]([CH2:8][O:9][C:10](=[O:40])[C:11]([N:13]2[CH:16]([S:17][C:18](=[O:36])[CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])[CH:15]([CH2:37][CH3:38])[C:14]2=[O:39])=[P:49]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCC1C(=O)N(C(Cl)C(=O)OCc2ccc([N+](=O)[O-])cc2)C1SC(=O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(c2ccccc2)(c2ccccc2)c2ccccc2)C1SC(=O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The resulting crude 2-[3-ethyl-4-(4-p-nitrobenzyloxycarbonylaminobutyrylthio)-2-oxoazetidin-1-yl]-2-chloroacetic acid p-nitrobenzyl ester is dissolved in a minimum amount of tetrahydrofuran, 9 g of triphenylphosphine are added and the mixture is stirred overnight at room temperature under nitrogen. The reaction mixture is diluted with 250 ml of methylene chloride, washed with saturated aqueous sodium bicarbonate solution, dried and concentrated by evaporation in vacuo. The residue is chromatographed over silica gel with toluene/ethyl acetate (1:1) and yields the title compound with the following physico-chemical properties:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:29])[CH2:24][CH2:25][C:26](O)=[O:27].ClC(OCC(C)C)=O.C(N(CC)CC)C.C(O)(=O)C(O)=O.[CH2:51]([O:53][P:54]([CH2:59][CH2:60][NH2:61])(=[O:58])[O:55][CH2:56][CH3:57])[CH3:52]>C1COCC1>[CH2:56]([O:55][P:54]([CH2:59][CH2:60][NH:61][C:26](=[O:27])[CH2:25][CH2:24][C:23]([CH3:29])=[CH:22][CH2:21][C:4]1[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:18])[CH3:20])=[C:6]2[C:10](=[C:11]([CH3:12])[C:3]=1[O:2][CH3:1])[CH2:9][O:8][C:7]2=[O:13])(=[O:58])[O:53][CH2:51][CH3:52])[CH3:57]
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CCC(=O)O)C(=O)OC2
Reactant: CCOP(=O)(CCN)OCC
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(=O)(CCNC(=O)CCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
To a solution of 6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid (50 mg, 0.12 mmol) in THF (1 mL) was added isobutyl chloroformate (17 μL, 0.13 mmol) and triethylamine (50 μL, 0.36 mmol) at 0° C. After stirring at 0° C. for 2 hours, diethyl(aminoethyl)phosphonate oxalate (62 mg, 0.26 mmol) was added and stirred at room temperature was continued for one hour. After removal of solvent, the residue was purified by preparative reverse-phase HPLC to afford 37 mg (54%) of the desired product as a white solid. 1H NMR (300 MHz, CDCl3) δ 0.03 (s, 9H), 1.15-1.22 (m, 2H), 1.31 (t, 6H), 1.81 (s, 3H), 1.85-1.93 (m,2H), 2.18 (s, 3H), 2.30 (m, 4H), 3.41 (d, 2H, J=7 Hz), 3.48-3.54 (m, 2H), 3.77 (s, 3H), 3.77-4.16 (m, 4H), 4.26-4.32 (m,2H), 5.12 (s, 2H), 5.17-5.19 (m, 1H), 6.30 (bs, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 29.91 ppm; MS (m/z) 584 [M+H]+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:3]=1[C:4]#[N:5].C(O)(=O)C.[CH:22]([NH2:24])=[NH:23]>CN(C)C(=O)C>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:24]=[CH:22][N:23]=1
Reactant: N=CN
Reactant: N#Cc1c(F)cccc1Oc1ccc(F)cc1
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: Nc1ncnc2cccc(Oc3ccc(F)cc3)c12
Temperature: 162 °C
Yield: 10.7 %

Procedure:
A mixture of 2-fluoro-6-(4-fluorophenoxy)benzonitrile (2.5 g, 11 mmol) and formamidine acetate (Aldrich) (2.3 g, 22 mmol) in 50 ml of N,N-dimethylacetamide was heated at 162° C. under nitrogen for 9 hours. After cooling to room temperature the reaction mixture was evaporated under reduced pressure. The product was suspended in 80 ml of cold water and the pH adjusted to 8.5 with concentrated ammonium hydroxide. After cooling the suspension overnight, the precipitate was isolated by filtration, washed with water (25 ml), dried and recrystallized from 30 ml of ethanol at 4° C. The precipitate was collected by filtration, washed with ethanol and dried at 50° C. in vacuo to give 4-amino-5-(4-fluorophenoxy)quinazoline (0.3 g, 10.7%, m.p. 188-190° C.):
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)([CH3:5])[CH2:3][OH:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:40]1[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:5][C:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)([CH3:1])[CH2:3][O:4][C:40]1[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)(CO)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCC(C)(C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 34.6 %

Procedure:
305 mg of 2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propanol dissolved in 15 ml THF were treated with 338 mg of triphenylphosphine, 196 mg of methyl 4-hydroxybenzoate and 0.21 ml of diethyl azodicarboxylate. The reaction mixture was heated to reflux for 6 hours. The mixture was partitioned in 100 ml of 1:1 ethyl acetate/sat. aq. sodium chloride solution. The phases were separated and the organic phase was dried over MgSO4. The solvents were removed in vacuo and the resulting oil was purified by flash chromatography (SiO2, 20% ethyl acetate/hexanes), giving 160 mg of methyl 4-[2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propyloxy]-benzoate as a colorless oil. The ester (160 mg), dissolved in 4 ml THF/0.8 ml H2O, was treated with 50 mg of lithium hydroxide hydrate. The mixture was heated at 60° C. for two hours. The mixture was acidified to pH 2 with 1N hydrochloric acid then partitioned in 10 ml ethyl acetate/10 ml sat. aq. sodium chloride solution. The phases were separated and the organic phase was dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by preparation tlc (SiO2, 40% ethyl acetate/hexanes), giving a white foam. 1H NMR (CDCl3): 8.03 (d, J=8.8 Hz, 2H), 7.35 (d, J=2.1 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.17 (dd, J=8.4, 2.1 Hz, 1H), 6.91 (d, J=8.8 Hz, 2H), 3.96 (s, 2H), 1.67 (s, 4H), 1.46 (s, 6H), 1.27 (s, 12H).
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH2:8][CH3:9])[C:5]([CH3:11])([CH3:10])[S:4]1)[OH:2].[CH3:12][N:13]=[C:14]=[O:15]>>[CH3:12][NH:13][C:14]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH2:8][CH3:9])[C:5]([CH3:10])([CH3:11])[S:4]1)=[O:15]
Reactant: CN=C=O
Reactant: CCC1=NC(=NO)SC1(C)C
Product: CCC1=NC(=NOC(=O)NC)SC1(C)C

Procedure:
2-oxo-4-ethyl-5,5-dimethyl-3-thiazoline-oxime was reacted with methyl isocyanate as described in Example 4 to yield 2-oxo-4-ethyl-5,5-dimethyl-3-thiazoline-O-(methylcarbamoyl)-oxime, m.p. 98°-100° C. The 2-oxo-4-ethyl-5,5-dimethyl-3-thiazoline-oxime starting material (m.p. 178°-180° C.) was prepared from 2-methyl-2-thiocyanato-3-pentanone (b.p. [0.03 mm] 56°-58° C.).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.C1(CC([NH:16][C@@H:17]2[C:66](=[O:67])[N:19]3[C:20]([C:50]([O:52][CH:53]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)[C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)=[O:51])=[C:21]([S:24][CH2:25][C:26]4[CH:27]=[N:28][N:29](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:30]=4)[CH2:22][S:23][C@H:18]23)=O)C=CC=CC=1.Cl.[OH-].[Na+]>ClCCl.C(OCC)(=O)C.O.CO.N1C=CC=CC=1>[NH2:16][C@@H:17]1[C:66](=[O:67])[N:19]2[C:20]([C:50]([O:52][CH:53]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[O:51])=[C:21]([S:24][CH2:25][C:26]3[CH:30]=[N:29][NH:28][CH:27]=3)[CH2:22][S:23][C@H:18]12
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3cnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3)CS[C@H]12
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3cn[nH]c3)CS[C@H]12
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
Pyridine (1.3 ml) was added to a suspension of phosphorus pentachloride (3.37 g) in dichloromethane (47.6 ml) at −10° C., and the mixture was stirred at between −15 to −5° C. for 30 minutes. Diphenylmethyl 7β-phenylacetamido-3-[(1-tritylpyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (6.8 g) was added to the above mixture at −10° C. and the reaction mixture was stirred under ice-cooling for 1 hour. Then, methanol (5.2 ml) was added to the reaction mixture at −20° C. and the resulting solution was stirred under ice-cooling for 1 hour. Water (40 ml) was added to the above mixture under ice-cooling, and stirred for 30 minutes at the same temperature. The aqueous layer was separated and the dichloromethane layer was reextracted with 1 mol hydrochloric acid (30 ml). The aqueous layer and 1 mol hydrochloric acid layer were combined ethyl acetate (50 ml) was added to the aqueous layer and then the mixture was adjusted to pH 3.5 with 30% aqueous sodium hydroxide under stirring. The organic layer was separated, washed with brine (20 ml) and dried over magnesium sulfate. The solvent was distilled off and the residue was pulverized with IPE (50 ml), collected by filtration, washed with IPE (20 ml) and dried over phosphorus pentoxide to give powder of diphenylmethyl 7β-amino-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (2.1 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[Cl-].[CH2:32]1COCC1>C(=O)(O)[O-].[Na+].C(OCC)(=O)C.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>[OH:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([CH3:32])=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: C1CCOC1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3cnccc3c2ncn1[C@H]1CCCC[C@@H]1O
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: [Cl-]
Solvent: CCOC(C)=O
Product: Cc1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccncc23)cn1
Temperature: 90 °C

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]pyrido[3,4-h]quinazolin-4(3H)-one (Example 1, 0.030 g, 0.071 mmol) in 1 mL of THF under an atmosphere of nitrogen was added methylzine chloride (2 M in THF, 0.107 mL, 0.214 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.0 mg, 0.0026 mmol). The reaction was heated at 90° C. for 3 h, cooled to rt, and diluted with saturated aqueous sodium bicarbonate and ethyl acetate. The layers were partitioned, and the organic solution was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-10% methanol in dichloromethane, to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 401.0 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 8.43 (s, 2H), 8.19 (s, 2H), 7.86 (s, 1H), 7.34-7.32 (m, 1H), 7.04 (s, 1H), 5.30 (s, 2H), 4.53-4.49 (m, 2H), 4.22 (br s, 1H), 2.49 (s, 3H), 2.32-2.29 (m, 1H), 2.04-2.01 (m, 1H), 1.91-1.89 (m, 1H), 1.58-1.46 (m, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:15]=[C:16]([NH:20][S:21]([C:24]4[CH:29]=[CH:28][C:27]([NH:30]C(=O)C)=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4].Cl>[OH-].[Na+].O>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:11]3[N:12]=[C:13]4[C:5]([C:3](=[O:4])[C:2]([CH3:34])([CH3:1])[CH3:35])=[CH:6][NH:7][C:8]4=[N:9][CH:10]=3)[CH:15]=2)(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2cccc(-c3cnc4[nH]cc(C(=O)C(C)(C)C)c4n3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(NS(=O)(=O)c4ccc(N)cc4)c3)nc12
Temperature: 100 °C
Yield: 74 %

Procedure:
In a flask N-(4-{3-[7-(2,2-Dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenylsulfamoyl}-phenyl)-acetamide 0.034 gm (0.069 mM), 1 ml water and 10 drops 3M aqueous sodium hydroxide was added and the mixture heated to 100° C. for two hours. Water (20 ml) was added and the pH adjusted to 8 with hydrochloric acid and much solid formed. The mixture was extracted three times with ethyl acetate, the ethyl acetate dried over magnesium sulfate to give 4-Amino-N-{3-[7-(2,2-dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-benzenesulfonamide 0.023 gm (0.051 mM, 74% yield) M+1 450 m.p. 285-286° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.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.Br.[O:52]=[C:53]1[C:62]2[CH2:61][CH2:60][NH:59][CH2:58][C:57]=2[NH:56][C:55]2[CH:63]=[CH:64][CH:65]=[C:66]([C:67]([O:69][CH3:70])=[O:68])[C:54]1=2>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([N:59]1[CH2:58][C:57]2[NH:56][C:55]3[CH:63]=[CH:64][CH:65]=[C:66]([C:67]([O:69][CH3:70])=[O:68])[C:54]=3[C:53](=[O:52])[C:62]=2[CH2:61][CH2:60]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCNC3
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCN(C(=O)C(C)(C)NC(=O)OCc1ccccc1)C3
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.9 %

Procedure:
To a solution of 2-(((benzyloxy)carbonyl)amino)-2-methylpropanoic acid (385 mg, 1.62 mmol) in DMF (8.0 mL) were added HATU (1.1 g, 2.94 mmol), DIPEA (0.75 g, 5.87 mmol), and methyl 5-oxo-1,2,3,4,5,10-hexahydrobenzo[b][1,7]naphthyridine-6-carboxylate hydrobromide (410 mg, 1.6 mmol). The mixture was then stirred at room temperature for 24 h. Then the reaction was quenched by water (20 mL). The mixture was extracted with THF/EtOAc (10 ml/60 ml) three times. The organic layers were combined, dried, concentrated, and chromatographed on silica gel using gradient eluant of 0-50% methanol in dichloromethane to give the desired compound as pale solid (114 mg, 14%). MS (ESI) m/e [M+1]+478.
Reaction SMILES: [Tl].[Tl].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])=[O:13])=[O:11].[CH3:21][N:22]([CH3:28])[CH2:23][CH:24]([CH3:27])[CH2:25]Cl>C1(C)C=CC=CC=1>[CH3:21][N:22]([CH3:28])[CH2:23][CH:24]([CH3:27])[CH2:25][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:25][CH:24]([CH3:27])[CH2:23][N:22]([CH3:28])[CH3:21])=[O:13])=[O:11]
Reactant: CC(CCl)CN(C)C
Reactant: O=C(C(=O)c1ccccc1O)c1ccccc1O
Agent: [Tl]
Solvent: Cc1ccccc1
Product: CC(COc1ccccc1C(=O)C(=O)c1ccccc1OCC(C)CN(C)C)CN(C)C

Procedure:
A suspension of 15 g. (0.023 M) of 2,2'-dihydroxybenzil dithallium salt in 500 ml. of dry toluene was stirred vigorously while adding dropwise a solution of 8.8 g. (0.05 M) of 3-dimethylamino-2-methyl propyl chloride in 91.5 ml. of toluene. The mixture was gradually heated to reflux during the addition, and the resulting mixture was stirred and refluxed for 12 hours before a color change was observed. After cooling to 25°, the pale yellow solid was filtered off and washed with toluene. The material was resuspended in toluene and filtered off again. The combined filtrates were washed with 10% sodium hydroxide solution, saturated brine solution, and finally dried over MgSO4. Evaporation of the dry toluene extract with heating up to 70° at 11 mm resulted in an oily residue. Various salts were prepared but failed to solidify. The free base was regenerated and the crude material began to crystallize. The product was recrystallized from hexane. After cooling to +5° overnight, the material was filtered off and dried in vacuo over P2O5 and paraffin wax to obtain 3.8 g. of the title compound; m.p. 69°-70°; λmaxKBr 3.55, 5.88, 6.10, 6.55, 6.72 μ.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[CH:30][CH:31]=3)[NH:26][CH2:25][CH2:24]2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].O.[OH-].[Li+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:30][CH:31]=3)[NH:26][CH2:25][CH2:24]2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: CCOC(=O)CCc1ccc2c(c1)NCCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(CC(=O)N2CCNc3cc(CCC(=O)O)ccc32)ccc1NC(=O)Nc1ccccc1C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
A solution of ethyl 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro -quinoxalin-6-yl)-propanoate (0.16 g, Reference Example 1) in anhydrous ethanol (3 ml), at 25° C., was treated dropwise with a solution of lithium hydroxide monohydrate (22 mg) in distilled water (1 ml). After stirring for 4 hours at 25° C. a further portion (10 mg) of lithium hydroxide monohydrate was added and stirring was continued for 16 hours at 25° C. The reaction mixture was evaporated under reduced pressure (2.7 kPa) at 40° C. and the residue was treated with distilled water (40 ml). The resulting solution was washed twice with diethyl ether (20 ml), then acidified to pH 3 by addition of hydrochloric acid (1.3 ml, 1N) and then extracted three times with ethyl acetate (25 ml). The combined organic extracts were washed twice with water (5 ml), then dried over magnesium sulphate and then evaporated under reduced pressure (2.7 kPa) at 40° C. to give the title compound (132 mg) as a foamy solid. 1H NMR [400 Hz, (CD3)2SO]: δ2.2 (s, 3H); 2.5 (bq, 2H); 2.7 (broad t, 2H); 3.2 (broad s, 2H); 3.65 (broad s, 2H); 3.8 (s, 5H); 6.1 (broad s, 1H); 6.4 (broad s, 1H); 6.45 (broad s, 1H); 6.7 (very broad s, 1H); 6.9 (t, J=8 Hz, 1H); 7.15 (m, 3H); 7.8 (d, J=8 Hz, 1H); 8 (broad s, 1H); 8.45(s, 1H); 8.6(s, 1H); 12.1 (broad s, 1H. MS (LSIMS: glycerol+thioglycerol): 503 (MH+).