Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[CH3:9][C:10]([CH3:12])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:9][C:10]1([CH3:12])[N:7]2[C:6](=[O:8])[CH2:5][CH2:4][C@@H:3]2[CH2:2][O:1]1
Reactant: CC(C)=O
Reactant: O=C1CCC(CO)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)OC[C@H]2CCC(=O)N21

Procedure:
A mixture of 5-hydroxymethyl-2-pyrrolidone (0.4 g), acetone (5 ml) and p-toluenesulfonic acid (ca. 10 mg) was refluxed in 20 ml of benzene for 20 hours with a Dean-Stark water separator. After working up the reaction mixture, distillation (boiling point 70°-75° C. at 0.5 mm of Hg) yielded 0.2 g or (R)-tetrahydro-3,3-dimethyl-3H,5H-pyrrolo[1,2-c]oxazol-5-one as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)=O)[N:5]=[C:4]2[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:12](=[O:15])[NH:13][CH2:14][C:3]=12.[N:24]1([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([N:32]2[CH2:33][CH2:34][CH:29]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:30][CH2:31]2)[N:5]=[C:4]2[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:12](=[O:15])[NH:13][CH2:14][C:3]=12
Reactant: CS(=O)c1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: C1CCN(C2CCNCC2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1NCc2c(Cl)nc(N3CCC(N4CCCC4)CC3)nc2N1c1c(F)cccc1F
Yield: 80.5 %

Procedure:
To a solution of 5-chloro-1-(2,6-difluorophenyl)-7-(methylsulfinyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (250 mg, 0.70 mmol) in DCM (10 mL) were added 4-(1-pyrrolidinyl)piperidine (323 mg, 2.1 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.7 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (253 mg, 81%). LC-MS m/z 449 (M+H)+
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[OH:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:7]([O:6][C:5]([NH:4][CH2:3][CH2:2][O:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])=[O:11])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCCNC(=O)OC(C)(C)C)c1
Reaction time: 12 h
Yield: 45.5 %

Procedure:
To a solution of tert-butyl 2-bromoethylcarbamate (5 g) and methyl 3-hydroxybenzoate (3.4 g) in dimethylformamide (60 ml) was added caesium carbonate (14.5 g) and the reaction stirred for 12 hours before partitioning between water and ethyl acetate. The organic layer was separated, dried with MgSO4 and the solvent removed by evaporation. Purification by flash chromatography (ethyl acetate:isohexane 92.5:7.5) gave the sub-title product as a colourless oil (3 g).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]([O:11]CC)=[O:10])[S:7][CH:8]=1)([CH3:3])[CH3:2].[OH-].[Li+]>CO.C1COCC1.O>[CH:1]([C:4]1[N:5]=[C:6]([C:9]([OH:11])=[O:10])[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1nc(C(C)C)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1csc(C(=O)O)n1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
A solution of ethyl 4-isopropylthiazole-2-carboxylate (example 53, step a) (2.2 g) in a mixture of methanol (10 mL) and THF (20 mL) was treated with a solution of lithium hydroxide (0.264 g) in water (20 mL). The reaction mixture was stirred at 20° C. for 24 hours. The organic solvent was removed under reduced pressure and the remaining aqueous mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 2M hydrochloric acid and extracted twice with ethyl acetate, the combined organics were washed with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was triturated with cyclohexane to afford the subtitled compound. Yield 0.93 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][NH:18][C:17](=[O:21])[CH2:16]1)(=[O:14])=[O:13].[F:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:24]=1[C:38]1[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=1>>[NH2:44][C:41]1[N:42]=[CH:43][C:38]([C:24]2[CH:25]=[CH:26][C:27]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=3[S:12]([N:15]3[CH2:20][CH2:19][NH:18][C:17](=[O:21])[CH2:16]3)(=[O:14])=[O:13])=[CH:28][C:23]=2[F:22])=[CH:39][N:40]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: O=C1CN(S(=O)(=O)c2cc(C(F)(F)F)ccc2Br)CCN1
Product: Nc1ncc(-c2ccc(-c3ccc(C(F)(F)F)cc3S(=O)(=O)N3CCNC(=O)C3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 4-((2-bromo-5-(trifluoromethyl)phenyl)-sulfonyl)-piperazin-2-one and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amine. MS (ESI): mass calcd. for C21H17F4N5O3S, 495.10; m/z found, 496.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.70-8.61 (d, J=1.2, 2H), 8.40 (s, 1H), 8.10-8.03 (d, J=157.7, 1H), 7.71-7.64 (d, J=7.9, 1H), 7.64-7.58 (m, 1H), 7.39-7.37 (m, 1H), 7.36 (s, 1H), 3.34 (s, 2H), 3.22-3.17 (m, 2H), 3.17-3.12 (m, 2H).
Reaction SMILES: [I-:1].[CH3:2][C:3]([C:6]1[CH:15]=[CH:14][C:13]2[N:12]3[C:16]4[CH:25]=[CH:24][C:23]5[CH:22]=[C:21](F)[CH:20]=[CH:19][C:18]=5[N+:17]=4[CH:27]=[C:11]3[CH:10]=[CH:9][C:8]=2[CH:7]=1)([CH3:5])[CH3:4].[CH3:28][N:29]([CH3:31])[NH2:30].CN1CCCC1=O>C(OCC)(=O)C>[I-:1].[CH3:2][C:3]([C:6]1[CH:15]=[CH:14][C:13]2[N:12]3[C:16]4[CH:25]=[CH:24][C:23]5[CH:22]=[C:21]([NH:30][N:29]([CH3:31])[CH3:28])[CH:20]=[CH:19][C:18]=5[N+:17]=4[CH:27]=[C:11]3[CH:10]=[CH:9][C:8]=2[CH:7]=1)([CH3:5])[CH3:4]
Reactant: CC(C)(C)c1ccc2c(ccc3c[n+]4c5ccc(F)cc5ccc4n32)c1
Reactant: CN(C)N
Agent: [I-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CN(C)Nc1ccc2c(ccc3n4c(ccc5cc(C(C)(C)C)ccc54)c[n+]23)c1

Procedure:
A mixture of 1.46 g. of 10-(1,1-dimethylethyl)-3-fluoroimidazo-[1,2-a:3,4-a']diquinolin-15-ium iodide, 1.64 ml. of 1,1-dimethylhydrazine and 25 ml. of N-methyl-2-pyrrolidinone is heated at reflux for 15 hours, then cooled and diluted with 300 ml. of ethyl acetate. The precipitate is collected and stirred with 1% aqueous triethylamine hydroiodide. The solid is collected, washed with water and dissolved in 150 ml. of hot methanol. The methanol solution is treated with activated charcoal, filtered, evaporated to a volume of about 25 ml. and cooled. The resulting precipitate of 10-(1,1-dimethylethyl)-3-(2,2-dimethylhydrazino)imidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration, washed with cold methanol and dried; m.p. 347°-350° C., after two crystallizations from 2-propanol/ethanol.
Reaction SMILES: [H-].[Na+].CC1C(C)=C(O)C2C(=CC(F)=C(F)C=2)N=1.[CH2:18]([C:20]1[C:29]([CH3:30])=[C:28]([O:31][C:32]([CH:34]2CC2)=[O:33])[C:27]2[C:22](=[CH:23][C:24]([F:38])=[C:25]([F:37])[CH:26]=2)[N:21]=1)C.C(C1C(C)=C(OC(C2CC2)=O)C2C(=CC=C(F)C=2F)N=1)C>O1CCCC1.O>[CH3:18][C:20]1[C:29]([CH3:30])=[C:28]([O:31][C:32](=[O:33])[CH3:34])[C:27]2[C:22](=[CH:23][C:24]([F:38])=[C:25]([F:37])[CH:26]=2)[N:21]=1
Reactant: CCc1nc2cc(F)c(F)cc2c(OC(=O)C2CC2)c1C
Agent: CCc1nc2ccc(F)c(F)c2c(OC(=O)C2CC2)c1C
Agent: Cc1nc2cc(F)c(F)cc2c(O)c1C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Oc1c(C)c(C)nc2cc(F)c(F)cc12
Reaction time: 1 h

Procedure:
In 10 ml of tetrahydrofuran was suspended 230 mg of 60% sodium hydride. The mixture (1 g) of 2,3-dimethyl-4-hydroxy-6,7-difluoroquinoline with 2,3-dimethyl-4-hydroxy-5,6-difluoroquinoline (starting material 1) prepared as described in Example 4 was suspended in 20 ml of tetrahydrofuran, and this suspension of starting material 1 was added dropwise to the above suspension under ice cooling. The reaction mixture was stirred for one hr. Acetyl chloride (starting material 2) (450 mg) was added thereto, and the mixture was then stirred at room temperature for 15 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (200 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 262.5 mg of 2,3-dimethyl-4-acetyloxy-6,7-difluoroquinoline (compound 17). 1H-NMR data are shown in Table 3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[CH:13]=[C:12]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=3[O:20][CH3:21])[CH:13]=[C:12]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: COc1cc(OC)c2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1cc(OC)c2c(Oc3ccc(F)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 400 was used, starting from 4-Fluorophenol and (1-Chloro-6,8-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-Fluoro-phenoxy)-6,8-dimethoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 395(MH+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[C:24]([CH2:28][C:29](Cl)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:29](=[O:30])[CH2:28][C:24]([CH3:27])([CH3:26])[CH3:25])[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: CC(C)(C)CC(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(CNC(=O)CC(C)(C)C)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.1 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.49 g, 1.5 mmol) in acetonitrile (10 mL), was added t-butylacetyl chloride (0.31 mL, 2.2 mmol) and N,N-diisopropyl ethylamine (0.60 mL, 3.7 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-3,3-dimethyl-butyramide as a light yellow solid (120 mg, 22% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 5.74 min (98.4%); mp, 212-214° C.; 1HNMR (DMSO-d6)0.96 (s, 9H, 3CH3), 2.08 (s, 2H, CH2Me3), 2.12-2.19 (m, 1H, CHH), 2.57-2.86 (m, 6H, CHCH2, CH3), 4.68-4.85 (m, 2H, CH2NH), 5.24 (dd, J=6, 11 Hz, 1H, CH), 7.34-7.76 (m, 3H, Ar), 8.11 (t, J=6 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.76, 23.28, 29.69, 30.47, 30.58, 41.43, 48.76, 56.47, 117.65, 124.64, 125.42, 133.77, 141.19, 148.42, 154.75, 160.93, 169.51, 170.97, 172.60. LCMS MH=399; Anal Calcd For C21H26N4O4+0.1H2O: C, 63.02; H, 6.60; N, 14.00. Found: C, 62.86; H, 6.70; N, 13.92.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])O[C:8](=[O:9])[C:7]=12.[NH:14]([CH2:16]C(O)=O)[CH3:15]>>[Br:1][C:2]1[C:7]2[C:8](=[O:9])[N:14]([CH3:16])[CH2:15][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cccc(Br)c2c(=O)o1
Reactant: CNCC(=O)O
Product: CN1CC(=O)Nc2cccc(Br)c2C1=O

Procedure:
4.84 g (0.02 mol) of 6-bromoisatoic acid anhydride and 1.78 g (0.02 mol) of sarcosine are finely rubbed together and subsequently heated to 260° under a protective gas for 6 minutes. After cooling, the crude product is chromatographed on silica gel using chloroform/methanol (20:1) for the elution. After recrystallization from chloforom/hexane, there is obtained 6-bromo-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione of melting point 232°-233°.
Reaction SMILES: [H-].[Na+].[CH:3]1([SH:6])[CH2:5][CH2:4]1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1>C1COCC1.O>[CH:3]1([S:6][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4]1
Reactant: SC1CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(SC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
1.78 g (44.6 mmol) of sodium hydride (60%) was added in portions to a solution of 3.00 g (40.5 mmol) of cyclopropane thiol (preparation according to: E. Block et al., J. Am. Chem. Soc. 1992, 114, 3492) in 100 ml THF/100 ml diethyl ether and was stirred for 30 minutes at room temperature. Then 6.00 g (38.7 mmol) of 1-fluoro-4-nitrobenzene was added in portions. The mixture was stirred for 2 hours at 40° C. After it had cooled, the mixture was put in water and was extracted with benzene (3×). The combined organic phases were concentrated by evaporation and the residue was purified chromatographically (hexane/ethyl acetate 95:5). 4.6 g (23.6 mmol; yield: 61%) of the product was obtained.
Reaction SMILES: C(OC([N:11]([C:17]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)[C:12](=[O:16])[CH2:13][NH:14][CH3:15])=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[CH3:15][NH:14][CH2:13][C:12]([NH:11][C:17]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:16]
Reactant: CCOC(=O)C1(N(C(=O)CNC)C(=O)OCc2ccccc2)CCc2ccccc2C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(NC(=O)CNC)CCc2ccccc2C1
Yield: 95.7 %

Procedure:
A solution of ethyl 2-(N-benzyloxycarbonyl-N-methylaminoacetylamino)tetralin-2-carboxylate (750 mg, 1.8 mmol) in ethanol (20 ml) was subjected to hydrogenation in the presence of 10% palladium-carbon (200 mg) for 5 hours. After the catalyst was filtered off, the mother liquid was concentrated under reduced pressure to yield 500 mg (96%) of the title compound as a crude substance.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Si:11]([O:28][CH2:29][CH2:30][C:31]([CH3:49])([CH3:48])[CH2:32][C@@H:33]([C@H:42]1[O:46][C:45](=[O:47])[CH2:44][CH2:43]1)[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1.C(Br)C=CC>[CH2:17]([C@@H:44]1[CH2:43][C@@H:42]([C@@H:33]([NH:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:32][C:31]([CH3:49])([CH3:48])[CH2:30][CH2:29][O:28][Si:11]([C:24]([CH3:26])([CH3:27])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:46][C:45]1=[O:47])[CH:12]=[CH:13][CH3:14]
Reactant: CC(C)(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CCC(=O)O1
Agent: CC=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC=CC[C@@H]1C[C@@H]([C@H](CC(C)(C)CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)NC(=O)OC(C)(C)C)OC1=O
Reaction time: 5 h

Procedure:
4.6 ml of a 1M lithium bis-(trimethylsilyl)amide solution in tetrahydrofuran and 0.26 ml of crotyl bromide (89%, 5.7:1 E:Z) are added to 1.22 g of 5(S)-[5-tert-butyl-diphenylsilyloxy-1(S)-tert-butoxycarbonylamino-3,3-dimethyl-pentyl]-2-oxo-tetrahydrofuran analogously to Example 74d). Working up after 5 h and subsequent purification by means of FC over silica gel (mobile phase C) gives the title compound, of uniform (R) configuration on C-3, as a 2E/2Z isomer mixture which cannot be separated: (Rf (C)=0.62; FAB-MS: (M+H)+ =608).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[C:11]([NH:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=3)=[N:10][CH:9]=[N:8][C:7]=2[S:6][CH:5]=1.Cl[C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=1>CS(C)=O.O>[Cl:3][C:4]1[C:12]2[C:11]([NH:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:26]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=4)=[C:18]([O:23][CH3:24])[CH:17]=3)=[N:10][CH:9]=[N:8][C:7]=2[S:6][CH:5]=1
Reactant: COc1cc(CCNc2ncnc3scc(Cl)c23)ccc1O
Reactant: FC(F)(F)c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(CCNc2ncnc3scc(Cl)c23)ccc1Oc1cc(C(F)(F)F)ccn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To a solution of 60 percent sodium hydride / oil dispersion (31 mg, 0.78 mmol) in DMSO (3 mL) was added 4-{2-[(5-chlorothieno[2,3-d]pyrimidin-4-yl)amino]ethyl}-2-methoxyphenol (250 mg, 0.75 mmol). After stirring for 30 min, 2-chloro-4-(trifluoromethyl)pyridine (141 mg, 0.78 mmol) was added and the reaction heated at 80° C. overnight. The reaction mixture was diluted with H2O and the precipitate collected by filtration. The filter cake washed with H2O and then dissolved in CH2Cl2. The organics were dried with (Na2SO4), filtered and the stripped in vacuo. The solid residue was triturated with a mixture of ether and pentane leaving a brown solid, 120 mg, 0.25 mmol, 33 percent yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:24])[CH2:9][CH:10]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl>[Fe].C(O)C.O>[NH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:4]2[CH:5]=[CH:6][C:7]([C:8](=[O:24])[CH2:9][CH:10]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:2]([CH3:1])[CH:3]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)C(CCc1ccccc1)CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)CC(=O)c1ccc(-c2ccc(N)cc2)cc1C

Procedure:
A mixture of ethyl 4-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate (3.40 g, 7.60 mmol), iron powder (4.20 g, 76.00 mmol), 2 N aqueous hydrochloric acid (3.80 mL, 7.60 mmol), and 85/15 ethanol/water (100 mL) was stirred at reflux for 2.5 h. The reaction mixture was filtered through a pad of Celite®, and concentrated to give ethyl 4-(4′-amino-3-methyl-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate as a light, brown solid (2.94 g, 93% yield). LC-MS ret. time 3.23 min, m/z 416.1 (MH+); 1H NMR (CDCl3) δ 1.32 (t, 3H), 1.82-2.17 (m, 2H), 2.58 (s, 3H), 2.68-2.77 (m, 2H), 2.98-3.09 (m, 2H), 3.49 (dd, 1H), 3.74 (br s, 2H), 4.10 (q, 2H), 6.79 (d, 2H), 7.12-7.37 (m, 5H), 7.38-7.54 (m, 4H), 7.78 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].[CH2:12]([O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:25])=[CH:27][CH:28]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: COc1cccc(CCN)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1cccc(CCNC(=O)c2ccc(OCc3ccccc3)cc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A mixture of 3-methoxyphenethylamine (16.557 g, 109.5 mmol), 4-benzyloxybenzoic acid (25.000 g, 109.5 mmol), 1-hydroxybenzotriazole hydrate (22.202 g, 164.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.047 g, 115.0 mmol) in anhydrous CH2Cl2 (300 ml) was stirred at 0° C. under N2 for 1 hr, then warmed to rt and stirred at rt for 19 hr. The reaction mixture was washed sequentially with 1M NaOH (150 ml), 1M HCl (150 ml), and H2O (150 ml), then dried over MgSO4 and concentrated in vacuo to give 39.00 g (99% yield) of yellow solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH2:38]([SH:52])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]>>[CH2:38]([S:52][C:18](=[O:19])[CH2:17][S:14](=[O:15])(=[O:16])[NH:13][C:5]1[C:6]([CH:10]([CH3:11])[CH3:12])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Reactant: CCCCCCCCCCCCCCS
Product: CCCCCCCCCCCCCCSC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with tetradecanethiol.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:18]=[CH:17][C:12]3[B:13]([OH:16])[O:14][CH2:15][C:11]=3[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[ClH:21]>CO>[ClH:21].[NH2:1][C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:18]=[CH:17][C:12]3[B:13]([OH:16])[O:14][CH2:15][C:11]=3[CH:10]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)COB3O)cc1
Agent: Cl
Solvent: CO
Product: Nc1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 25 mL round-bottom flask fitted with magnetic stirring bar was added 5-(4-nitro-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (310 mg, 1.1 mmol, 1.0 eq.), followed by addition of MeOH (10 mL). The flask was evacuated and recharged with N2 twice. To the stirring solution was added 5% Pd/C (60 mg) and the flask was evacuated and recharged with H2 three times. The resulting suspension was stirred under a H2 balloon at room temperature overnight. The mixture was filtered through a short pack of celite and washed with MeOH (3×10 mL). The combined filtrate was concentrated under reduced pressure to give a light yellow oil. The oil was dissolved in minimum amount of MeOH and carefully treated with HCl (conc.). The precipitate was collected by filtration, washed with heptanes to give 5-(4-amino-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride salt as a white solid. LCMS (m/z) 242 (M+H); 1H NMR (DMSO-d6) δ: 9.03 (br. s., 1H), 7.64 (d, J=8.0 Hz, 1H), 6.77-6.89 (m, 4H), 6.64-6.77 (m, 2H), 4.86 (s, 2H), 3.30 (br. s., 2H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:24][C:23]([CH3:26])([CH3:25])[C:22]2[C:17](=[CH:18][C:19]([NH:27][C:28]([C:30]3[C:31]([NH:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][N:39]=4)=[N:32][CH:33]=[CH:34][CH:35]=3)=[O:29])=[CH:20][CH:21]=2)[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH3:25][C:23]1([CH3:26])[C:22]2[C:17](=[CH:18][C:19]([NH:27][C:28](=[O:29])[C:30]3[CH:35]=[CH:34][CH:33]=[N:32][C:31]=3[NH:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][N:39]=3)=[CH:20][CH:21]=2)[CH2:16][NH:15][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3NCc3ccc(F)cn3)ccc2C(C)(C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CNCc2cc(NC(=O)c3cccnc3NCc3ccc(F)cn3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 ml of TFA was added to a solution of 7-({2-[(5-fluoro-pyridin-2-ylmethyl)-amino]-pyridine-3-carbonyl}-amino)-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.20 g, 0.40 mmol) in 2.5 ml of CH2Cl2. The mixture was stirred at RT for 1 h. The volatiles were removed under reduced pressure, and the residue was purified by flash column chromatography (2 to 5% of MeOH in CH2Cl2 with 2% of NH4OH). The titled compound was obtained as an off-white solid. MS: (ES+) 406.1 (M+H). Calc'd. for C23H24FN5O—405.47.