Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][C:2]=12.Br[C:14]1[CH:15]=[C:16]([N:20]([CH3:22])[CH3:21])[CH:17]=[CH:18][CH:19]=1>>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([N:20]([CH3:22])[CH3:21])[CH:17]=[CH:18][CH:19]=3)[CH:8]=[CH:9][C:2]=12
Reactant: OB(O)c1ccc2nonc2c1
Reactant: CN(C)c1cccc(Br)c1
Product: CN(C)c1cccc(-c2ccc3nonc3c2)c1

Procedure:
Starting from 5-benzo[1,2,5]oxadiazoleboronic acid and (3-bromo-phenyl)-dimethyl-amine. Orange-yellow powder. MS(ES+): 240 (M+1).
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[N+:36]([C:39]1[CH:40]=[CH:41][CH:42]=[C:43]2[C:47]=1[NH:46][C:45]([C:48]([NH:50][CH2:51][CH2:52][S:53]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)=[CH:44]2)([O-:38])=[O:37]>ClCCl>[S:53]1[CH2:52][CH2:51][N:50]=[C:48]1[C:45]1[NH:46][C:47]2[C:43]([CH:44]=1)=[CH:42][CH:41]=[CH:40][C:39]=2[N+:36]([O-:38])=[O:37]
Reactant: O=C(NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)c1cc2cccc([N+](=O)[O-])c2[nH]1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc2cc(C3=NCCS3)[nH]c12
Reaction time: 0.17 h
Yield: 81.3 %

Procedure:
To a solution of triphenylphosphine oxide (16.7 g) in dichloromethane (30 mL) was slowly added trifluoromethanesulfonic anhydride (5.0 mL) at 0° C., and the mixture was stirred for 10 min and 7-nitro-N-[2-(tritylthio)ethyl]-1H-indole-2-carboxamide (10.1 g) was added. The reaction mixture was stirred at room temperature for 8 hr and concentrated. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:3) to give the title compound (4.0 g, yield 81%) as yellow crystals.
Reaction SMILES: FC1C=NN([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)C=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][C:14]1=[O:19]>>[O:19]=[C:14]1[N:13]([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH2:18][CH2:17][O:16][CH2:15]1
Reactant: O=C(O)C1(n2cc(F)cn2)CC1
Reactant: O=C1COCCN1
Product: O=C1COCCN1C1(C(=O)O)CC1

Procedure:
The title compound was prepared by a method analogous to the one used for Intermediate 4, but using morpholin-3-one in Step 1. MS (ES+) (M+H) 186.3; LCMS retention time: 0.59 minutes (Method M).
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH3:15])=O)(C)(C)C.C(OC(NC1C=CN=CC=1)=O)(C)(C)C.C([Li])CCC.CI>O1CCCC1>[NH:8]1[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[CH:15]=[CH:6]1
Reactant: Cc1cnccc1NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)Nc1ccncc1
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: c1cc2[nH]ccc2cn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
4-tert-Butoxycarbonylamino-3-methylpyridine A solution of 4-tert-butoxycarbonylaminopyridine (10.0 g, 51.5 mmol) in tetrahydrofuran (150 ml) was cooled to -30° C. and n-butyllithium (45.3 ml, 2.5M in hexane, 113.3 mmol) was added at such a rate as to keep the temperature below -20° C. The mixture was stirred at 0° C. for 3 hours, the slurry cooled to -70° C. and a solution of methyl iodide (8.77 g, 61.8 mmol) in tetrahydrofuran (25 ml) added. The mixture was warmed to 20° C. and stirred for 1 hour. The mixture was quenched with water (100 ml) and extracted with ethyl acetate (2×100 ml). The combined ethyl acetate fractions were washed with saturated brine (100 ml), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was chromatographed on silica gel (95% methylene chloride/5% methanol) and then swished in hot hexane to afford the title compound as a pale yellow solid; yield: 5.75 g (54%). mp 124°-126° C.; Analysis Found: C, 63.35; H, 7.72; N, 13.44. C11H16N2O2 : requires C, 63.44; H, 7.74; N, 13.45%; 1H NMR (CD2Cl1 /TMS) δ1.52 (9H, s), 2.22 (3H, s), 6.92 (1H, br.s), 7.97 (1H, d, J=5.6 Hz), 8.28 (1H, s), 8.33 (1H, d, J=5.6 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[N:3]=1.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:9][C:4]1[N:3]=[C:2]([N:13]2[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(F)nc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(F)nc(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 80 °C
Yield: 61 %

Procedure:
2-Bromo-6-fluoro-4-methylpyridine (380 mg, 2 mmol), tert-butyl piperazine-1-carboxylate (466 mg, 2.5 mmol), Pd2(DBA)3 (40 mg, 0.044 mmol), sodium tert-butoxide (317 mg, 3.3 mmol) and BINAP (80 mg, 0.032 mmol) were dissolved in anhydrous THF (6 ml) under argon and heated at 80° C. under microwave heating. The mixture was diluted with ethyl acetate, filtered, the filtrate was evaporated under reduced pressure. The residue was dissolved in DCM and filtered through a pad of silica. The silica was washed with a mixture of DCM and diethylether, the combined filtrates were concentrated under reduced pressure to yield 360 mg (1.22 mmol, yield 61%) MS (multi-mode) m/z=296.2 [M+1]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:16])[NH:12][CH2:13][CH2:14][OH:15])[N:10]=2)[CH2:3]1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].N1C=CN=C1.CO>CN(C)C=O>[Si:17]([O:15][CH2:14][CH2:13][NH:12][C:11]([C:9]1[N:10]=[C:6]([N:4]2[CH2:5][CH:2]([OH:1])[CH2:3]2)[S:7][CH:8]=1)=[O:16])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: O=C(NCCO)c1csc(N2CC(O)C2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCNC(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of 3-hydroxy-1-(4-hydroxyethylcarbamoyl-1,3-thiazol-2-yl)azetidine (481.2 mg, 1.98 mmol) (obtained as described in Reference Example 33(3)) in dimethylformamide (24.0 ml) were added t-butyldimethylsilyl chloride (352 mg, 2.3 mmol) and imidazole (116.3 mg, 2.4 mmol) in an ice bath, and the mixture was stirred in the ice bath for 4 hours. After checking the completion of the reaction, methanol was added thereto and the reaction mixture was stirred for 30 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (2:3) as the eluant to afford 1-{4-[2-(t-butyldimethylsilyloxy)-ethylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (531.1 mg, yield 75%) as a colorless and transparent syrup.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][CH2:7][C:6]=2[CH:12]=1.[Cl:13][C:14]1[CH:15]=[C:16]([S:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([S:21][CH2:22][CH2:23][CH2:24][CH2:25][O:1][C:2]2[CH:3]=[CH:4][C:5]3[NH:10][C:9](=[O:11])[O:8][CH2:7][C:6]=3[CH:12]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C1Nc2ccc(O)cc2CO1
Reactant: Clc1ccc(SCCCCBr)cc1Cl
Product: O=C1Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc2CO1

Procedure:
Prepared analogously to Example 5 from 6-hydroxy-4H-3,1-benzoxazin-2-one and 4-(3,4-dichloro-phenylmercapto)-butylbromide (prepared from 3,4-dichlorothiophenol and 1,4-dibromo-butane, B.p. 0.1 mb : 153°-160° C.).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[F:20][CH:21]([F:31])[O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=1>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:30][CH2:29][C:26]2[CH:25]=[CH:24][C:23]([O:22][CH:21]([F:20])[F:31])=[CH:28][CH:27]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCc1ccc(OC(F)F)cc1
Product: CCCCN1C(=O)C(NCc2ccc(OC(F)F)cc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1-[4-(difluoromethoxy)phenyl]methanamine in a similar manner as described for e.g. Example 6 and 7. 1H NMR (CD3CN) δ 7.46-7.41 (m, 1H), 7.39-7.33 (m, 2H), 7.29-7.25 (m, 2H), 6.98-6.93 (m, 2H), 6.86-6.81 (m, 2H), 6.72 (t, J=74.4 Hz, 1H), 6.48-6.39 (m, 1H), 4.16 (d, J=6.6 Hz, 2H), 3.67 (t, J=7.2 Hz, 2H), 1.81-1.72 (m, 2H), 1.49-1.38 (m, 2H), 0.98 (t, J=7.3 MHz, 3H); Mass spectrum: M+H+ 437.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:14])[CH2:10][NH:11]C=O.[ClH:15].C(OCC)(=O)C.C(OCC)(=O)C>CO>[ClH:15].[NH2:11][CH2:10][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[OH:14]
Reactant: O=CNCC(O)c1ccc(F)cc1F
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: NCC(O)c1ccc(F)cc1F
Temperature: 60 °C
Reaction time: 3 h

Procedure:
N-[2-(2,4-difluorophenyl)-2-hydroxy-ethyl]-formamide (1.0 g) was dissolved in methanol (2 mL), 4N hydrochloric acid/ethyl acetate (60 mL) was added. After stirring at 60° C. for 3 hours, the solution was allowed to cooled down to room temperature, and the solid that were generated by adding ethyl acetate (50 mL) was collected by filtration, washed with ethyl acetate, and the title compound (770 mg) was obtained as a colorless solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH2:18][C@@H:17](O)[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10]1.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH:18]=[CH:17][C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10]1
Reactant: O[C@@H]1CC[C@@H](c2cccc(F)c2F)Cc2cccnc21
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: c1ccccc1
Product: Fc1cccc([C@@H]2CC=Cc3ncccc3C2)c1F
Temperature: 85 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
In an oven-dried 250 mL round-bottom flask was mixed (6R,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (1.93 g, 7.01 mmol) and (methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt (2.005 g, 8.41 mmol) in benzene (60 mL) to give a suspension. It was heated at 85° C. with stirring under nitrogen for 1 h (color quickly changed to deep red). LCMS showed desired MW. TLC (1/1 ethyl acetate/hexanes) showed only a trace of SM left and a major, more polar component. Benzene was removed in vacuo and the residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated to give a tan oil. Purification by FCC up to 80% ethyl acetate/hexane afforded the desired product (0.81 g, 45%) as a light yellow oil. MS(ESI)[M+H+]=258.16, 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.45 (dd, J=4.78, 1.51 Hz, 1H) 7.35 (d, J=7.55 Hz, 1H) 6.92-7.09 (m, 4H) 6.77 (dt, J=12.53, 1.92 Hz, 1H) 6.20 (dt, J=12.59, 4.53 Hz, 1H) 3.43-3.58 (m, 1H) 3.22 (dd, J=14.10, 9.57 Hz, 1H) 2.96 (d, J=14.35 Hz, 1H) 2.69 (td, J=5.29, 2.01 Hz, 2H); 13C NMR (101 MHz, CHLOROFORM-d) δ ppm 154.90 (s, 1C) 151.94-149.34 (dd, J=13.10 and 249.47 Hz, 1C) 149.43-146.86 (dd, J=12.33 and 247.45 Hz, 1C) 147.31 (s, 2C) 136.93 (s, 2C) 135.63 (d, J=11.56 Hz, 1C) 134.74 (s, 1C) 133.74 (s, 2C) 131.83 (s, 2C) 123.95-124.47 (m, 2C) 122.61 (t, J=3.47 Hz, 2C) 121.44 (s, 2C) 115.15 (d, J=16.96 Hz, 2C) 40.28 (s, 2C) 38.53 (s, 2C) 37.70 (s, 1C); 19F NMR (376 MHz, CHLOROFORM-d) δ ppm −138.33-−137.90 (m, 1F) −144.07-−143.71 (m, 1F).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH2:20][NH:21][CH:22]3[CH2:27][CH2:26][CH:25]([N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24][CH2:23]3)[CH:13]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[Cl:37][C:38]1[C:39]2[C:49]([F:50])=[CH:48][CH:47]=[C:46]([F:51])[C:40]=2[S:41][C:42]=1[C:43](Cl)=[O:44]>>[Cl:37][C:38]1[C:39]2[C:49]([F:50])=[CH:48][CH:47]=[C:46]([F:51])[C:40]=2[S:41][C:42]=1[C:43]([N:21]([CH2:20][C:14]1[CH:13]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][CH:8]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19])[CH:22]1[CH2:27][CH2:26][CH:25]([N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:24][CH2:23]1)=[O:44]
Reactant: COc1ccc(-c2ccc(CS(C)(=O)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: COc1ccc(-c2ccc(CS(C)(=O)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Crude biaryl amine 198 (362 mg) is treated with acid chloride 8 (224 mg, 0.84 mmol) using Method D to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[C@H:10]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[NH:11][C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:27](=O)([O-])[O-].[K+].[K+].CN(C)C=O>ClCCl>[CH2:1]([O:8][C:9](=[O:24])[C@H:10]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:27])=[CH:19][CH:18]=1)[NH:11][C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: ClCCl
Product: COC(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.8 %

Procedure:
A mixture of N-methoxycarbonyl-L-tyrosine benzyl ester (22.0 g), methyl iodide (10.8 ml), potassium carbonate (24.0 g), and N,N-dimethylformamide (87 ml) was stirred at ambient temperature for 5 hours. The mixture was diluted with dichloromethane (87 ml) and filtered. The filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The crude product was purified by pulverization with petroleum ether to give N-methoxycarbonyl-O-methyl-L-tyrosine benzyl ester (16.0 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[C:11](=[O:22])[C:12](=[O:21])[C:13]=2[NH:14][CH:15]([CH3:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:21]=[C:12]1[C:11](=[O:22])[C:10](/[CH:9]=[CH:8]/[C:5]2[CH:6]=[CH:7][C:2]([C:30]#[N:31])=[CH:3][CH:4]=2)=[C:13]1[NH:14][CH:15]([CH3:20])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(Nc1c(/C=C/c2ccc(Br)cc2)c(=O)c1=O)C(C)(C)C
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: CC(Nc1c(/C=C/c2ccc(C#N)cc2)c(=O)c1=O)C(C)(C)C
Temperature: 100 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
The title compound was prepared via cyano-debromination (Tschaen, Synth. Comm. 1994, 24, 887) of the title compound of Example 26. To a mixture of 3-[(E)-2-(4-bromo-phenyl)-vinyl]-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione (400 mg, 1.10 mmol) and zinc (II) cyanide (77.8 mg, 0.662 mmol) in DMF (1.20 mL) was added tetrakis(triphenylphosphine) palladium (0) (76.6 mg, 0.0662) under an atmosphere of Argon. The reaction mixture was heated to 100° C., stirred 18 hours, then worked up by dilution with toluene (150 mL), followed by consecutive extraction with ammonium hydroxide (3×50 mL) and brine (50 mL). The organic phase was further diluted with ethyl acetate (300 mL), dried over MgSO4, filtered through a short pad of diatomaceous earth, and then concentrated onto silica gel. Submission to flash chromatography (multiple gradient elution with ether-petroleum ether) afforded a yellow solid which was triturated with ether-hexanes. Drying under high vacuum at 60° C. yielded the title compound (248 mg, 73%) as a hydroscopic yellow solid (1H NMR in DMSO-d6 suggested the presence of amide rotamers in a ratio of approximately 4:1): m.p. 240.2-241.0° C.; 1H NMR (DMSO-d6) δ8.96(d,1H), 7.83(m,4H), 7.64(d,1H), 7.48(d,1H), 4.03(dq,1H), 1.20(d,3H), 0.90(s,9H); IR (KBr) 3450, 3250, 3290, 2960, 1770, 1725, 1620, 1600, 1500, 1480, 1440, 1405, 1170, 1140, 1080, 980, 825, 755; MS (m/z) 309 [(M+H)+], 331 [(M+Na)+].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[S:13][CH2:14][C:15]([OH:17])=O)([O-])=O.O.O.[Sn](Cl)Cl>C(O)C>[NH2:10][C:8]1[CH:7]=[CH:6][C:5]2[S:13][CH2:14][C:15](=[O:17])[NH:1][C:4]=2[CH:9]=1
Reactant: O=C(O)CSc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)NC(=O)CS2
Yield: 61.7 %

Procedure:
A solution of 2-(2,4-dinitrophenylthio)-acetic acid (2.3 g, 9 mmol) and tin (II) chloride dihydrate (22.6 g, 0.1 mol) in ethanol (30 mL) was refluxed overnight. After removal of the solvent under reduced pressure, the residual slurry was diluted with water (100 mL) and basified with 10% Na2CO3 solution to pH 8. The resulting suspension was extracted with ethyl acetate (3×100 mL). The ethyl acetate extract was washed with water and brine, dried over Na2SO4, and concentrated. The residue was washed with CH2Cl2 to yield 6-amino-2H-benzo[b][1,4]thiazin-3(4H)-one (DC-7) as a yellow powder (1 g, 52%). 1H NMR (DMSO-d6) δ 10.24 (s. 1H), 6.88 (d, 1H, J=6 Hz), 6.19-6.21 (m, 2H), 5.15 (s, 2H), 3.28 (s, 2H); ESI-MS 181.1 m/z (MH+).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)[CH:21]=[C:22]([N:28]1[CH:33]=[CH:32][C:31](=[O:34])[CH:30]=[CH:29]1)[C:23](OCC)=[O:24]>>[CH2:1]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:23]([OH:24])=[C:22]([N:28]3[CH:29]=[CH:30][C:31](=[O:34])[CH:32]=[CH:33]3)[CH:21]=[N:17]2)=[N:12][CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccc(C(=O)NCc2ccccc2)cn1
Reactant: CCOC(=O)C(=CN(C)C)n1ccc(=O)cc1
Product: O=C(NCc1ccccc1)c1ccc(-n2ncc(-n3ccc(=O)cc3)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 188 using N-benzyl-6-hydrazinylnicotinamide and ethyl 3-(dimethylamino)-2-(4-oxopyridin-1(4H)-yl)acrylate. MS m/z 388 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.53 (d, J=5.6 Hz, 2H) 6.68 (br. s., 2 H) 7.27 (dq, J=8.5, 4.2 Hz, 1 H) 7.30-7.41 (m, 4 H) 8.29 (br. s., 2 H) 8.37-8.54 (m, 3 H) 8.97 (s, 1 H) 9.27 (t, J=5.8 Hz, 1 H).
Reaction SMILES: [Br-:1].[Br-].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][CH:14]([N+:17]3[CH:21]=[CH:20][N:19]([CH2:22][CH2:23][CH2:24][N+:25]4[CH:29]=[CH:28][N:27]([CH:30]5[CH2:34][CH2:33][N:32]([C:35]6[CH:40]=[CH:39][C:38]([N+:41]([O-])=O)=[CH:37][CH:36]=6)[CH2:31]5)[CH:26]=4)[CH:18]=3)[CH2:13]2)=[CH:8][CH:7]=1)([O-])=O>O.C(O)C.[Pd]>[Br-:1].[Br-:1].[NH2:3][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][CH:14]([N+:17]3[CH:21]=[CH:20][N:19]([CH2:22][CH2:23][CH2:24][N+:25]4[CH:29]=[CH:28][N:27]([CH:30]5[CH2:34][CH2:33][N:32]([C:35]6[CH:36]=[CH:37][C:38]([NH2:41])=[CH:39][CH:40]=6)[CH2:31]5)[CH:26]=4)[CH:18]=3)[CH2:13]2)=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(N2CCC(n3cc[n+](CCCn4cc[n+](C5CCN(c6ccc([N+](=O)[O-])cc6)C5)c4)c3)C2)cc1
Agent: [Pd]
Agent: [Br-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(N2CCC(n3cc[n+](CCCn4cc[n+](C5CCN(c6ccc(N)cc6)C5)c4)c3)C2)cc1

Procedure:
3.2 g (0.0044 mol) of derivative (4) above dissolved in a mixture of 60 ml of water/300 ml of ethanol were hydrogenated in the presence of palladium-on-charcoal under a hydrogen pressure of 9 bar and at 75° C. After filtering off the catalyst, the expected derivative (5) was isolated in the form of the hydrobromide. 3.4 g of white powder were obtained; 94% yield.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:7][N:8]=[C:9]([NH2:11])[CH:10]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21].CN(C=O)C>C(OCC)(=O)C>[NH2:11][C:9]1[N:8]([CH2:19][C:20]([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:26][CH2:27]2)=[O:21])[N:7]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:10]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: Nc1cc(-c2ccco2)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc(-c2ccco2)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 3-Furan-2-yl-2H-pyrazol-5-ylamine, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using 100% ethyl acetate afforded the title compound as a white solid. 1H NMR (400 MHz, CD6CO); 7.48–7.52 (m, 1H), 6.98–7.06 (m, 2H), 6.52–6.56 (m, 2H), 6.44–6.48 (m, 2H), 5.74 (s, 1H), 4.98 (s, 2H), 3.68–3.88 (m, 4H), 3.12–3.24 (m, 4H). MS (ES) M+H) expected=369.4, found 370.1.
Reaction SMILES: [C:1]1([C:7]2[N:8]([NH2:22])[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=2[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[C:16]1([C:9]2[N:8]([N:22]([S:24]([CH3:23])(=[O:26])=[O:25])[S:24]([CH3:23])(=[O:26])=[O:25])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:15]3[C:10]=2[CH2:11][CH2:12][CH2:13][CH2:14]3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nn1c(-c2ccccc2)c2c(c1-c1ccccc1)CCCC2
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N(n1c(-c2ccccc2)c2c(c1-c1ccccc1)CCCC2)S(C)(=O)=O

Procedure:
1,3-Diphenyl-4,5,6,7-tetrahydro-2H-2-isoindolamine (Example 11) is treated with 2 equivalents of methanesulphonyl chloride.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2=[N:9][C:10](S(C)=O)=[N:11][CH:12]=[C:7]2[CH2:6][N:5]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:17]=2[F:26])[C:4]1=[O:27])[CH3:2].[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31][CH2:30]1>O1CCOCC1>[CH2:1]([N:3]1[C:8]2=[N:9][C:10]([NH:28][CH:29]3[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]3)=[N:11][CH:12]=[C:7]2[CH2:6][N:5]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:17]=2[F:26])[C:4]1=[O:27])[CH3:2]
Reactant: CCN1C(=O)N(c2cc(OC)cc(OC)c2F)Cc2cnc(S(C)=O)nc21
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: C1COCCO1
Product: CCN1C(=O)N(c2cc(OC)cc(OC)c2F)Cc2cnc(NC3CCC(O)CC3)nc21
Temperature: 95 °C
Yield: 61.1 %

Procedure:
A flask was charged with 0.312 g (0.79 mmol) of 1-Ethyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-methanesulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 15 mL dioxane, and 0.273 g (2.37 mmol) of trans-4-Aminocyclohexanol, and the mixture was heated 48 hours at 95° C. The dioxane was removed under reduced pressure, and the crude residue was purified directly via column chromatography (20:1 dichloromethane/methanol). This procedure gave 0.215 g (66%) of 1-Ethyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-(4-hydroxy-cyclohexylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a white solid: mp=198° C.–204° C.; MS (APCI) m+1/z 462.