Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C@H:6]3[CH2:20][O:21][CH2:22][CH2:23][N:5]3[C:4]=2[N:3]=1.[NH:24]1[C:32]2[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[C:27]=2[CH:26]=[CH:25]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.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>[NH:24]1[C:32]2[C:27](=[C:28]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C@H:6]5[CH2:20][O:21][CH2:22][CH2:23][N:5]5[C:4]=4[N:3]=3)[CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)CN1C[C@H]2COCCN2c2nc(Cl)ncc21
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: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CN1C[C@H]2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc21
Temperature: 120 °C
Yield: 90.7 %

Procedure:
A mixture of (S)-tert-butyl 2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetate (PREPARATION x80, 100 mg, 0.293 mmol), indole-4-boronic acid (70.8 mg, 0.440 mmol), tetrakis(triphenylphosphine)palladium(0) (33.9 mg, 0.029 mmol), and sodium carbonate (62.2 mg, 0.587 mmol) in 1,4-dioxane (1 mL) and water (0.5 mL) was heated to 120° C. for 1 hour in a microwave. After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered through Celite, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography (silica-NH, gradient 10-80% EtOAc/hexane) to afford the title compound as an off-white solid (112 mg, 91%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38-1.48 (m, 9H), 2.98-3.09 (m, 1H), 3.15-3.40 (m, 3H), 3.52-3.64 (m, 2H), 3.87-4.11 (m, 3H), 4.28 (d, J=17.94 Hz, 1H), 4.52-4.60 (m, 1H), 7.12 (t, J=7.71 Hz, 1H), 7.29-7.44 (m, 3H), 7.51-7.68 (m, 1H), 7.93 (dd, J=7.45, 0.88 Hz, 1H), 11.12 (br s, 1H); ESI-MS m/z [M+H]+ calc'd for C23H27N5O3, 422.22. found 422.3.
Reaction SMILES: [S:1]([N:11]1[CH2:16][CH2:15][N:14]2[CH:17]=[CH:18][CH:19]=[C:13]2[CH:12]1[CH2:20][C:21](O)=[O:22])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:57]([NH:61][CH2:62][C:63]1[CH:64]=[C:65]2[C:70](=[CH:71][CH:72]=1)[C@H:69]([NH2:73])[CH2:68][CH2:67][CH2:66]2)([CH3:60])([CH3:59])[CH3:58]>C1COCC1.C(OCC)(=O)C>[C:57]([NH:61][CH2:62][C:63]1[CH:64]=[C:65]2[C:70](=[CH:71][CH:72]=1)[C@H:69]([NH:73][C:21](=[O:22])[CH2:20][CH:12]1[N:11]([S:1]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=3)(=[O:2])=[O:3])[CH2:16][CH2:15][N:14]3[CH:17]=[CH:18][CH:19]=[C:13]13)[CH2:68][CH2:67][CH2:66]2)([CH3:60])([CH3:58])[CH3:59]
Reactant: Cc1ccc(S(=O)(=O)N2CCn3cccc3C2CC(=O)O)cc1
Reactant: CC(C)(C)NCc1ccc2c(c1)CCC[C@H]2N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N2CCn3cccc3C2CC(=O)N[C@@H]2CCCc3cc(CNC(C)(C)C)ccc32)cc1
Reaction time: 0.25 h
Yield: 19 %

Procedure:
To a solution of 2-(2-tosyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid (S11) (300 mg, 0.898 mmol, 1.0 eq.) in THF (5 ml) were added DIPEA (0.47 ml, 2.694 mmol, 3.0 eq.) and HATU (410 mg, 1.08 mmol, 1.2 eq.) at 0° C. and the mixture was stirred for 15 min at the same temperature. A solution of (R)-6-((tert-butylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-amine (A50) (0.898 mmol, 1.0 eq.) in THF (5 ml) was added to the reaction mixture and it was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with sat. NH4Cl solution (20 ml), sat. NaHCO3 solution (20 ml), water (20 ml) and brine (20 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to get the crude product which was purified by column chromatography (silica gel; 1.5% MeOH/DCM) to yield the desired product as an off-white solid. Yield: 19% (94 mg, 0.171 mmol); MS, Rt=3.2 min; m/z=549.1 [MH]+
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16](Cl)[N:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.C(O)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccnc(Cl)n2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccncn2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 395 mg [1-(2-Chloro-pyrimidin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester in 10 mL ethanol and 0.3 mL acetic acid, 20 mg Pd/C (10%) were added and the mixture purged with argon for 10 min. Then the mixture was stirred under a hydrogen atmosphere for 5 h at RT. After addition of 10 mL ethyl acetate the reaction mixture was filtered through a pad of celite. The solvent was evaporated under reduced pressure and the residue codistilled twice with toluene to give the product as a white solid. Yield: 468 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[O:13][C:12]2[CH:14]=[C:15]([F:25])[C:16]([C:18]([N:20]3[CH2:24][CH:23]=[CH:22][CH2:21]3)=[O:19])=[CH:17][C:11]=2[O:10]1.[OH2:33].C[N+]1([O-])CCOCC1.[OH2:42].O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O.O.O.[O-][Os]([O-])(=O)=O.[K+].[K+]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[O:13][C:12]2[CH:14]=[C:15]([F:25])[C:16]([C:18]([N:20]3[CH2:21][C@H:22]([OH:33])[C@H:23]([OH:42])[CH2:24]3)=[O:19])=[CH:17][C:11]=2[O:10]1
Reactant: O=C(c1cc2c(cc1F)OC(c1ccc(F)cc1)(c1ccc(Cl)cc1Cl)O2)N1CC=CC1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: O=[Os](=O)([O-])[O-]
Agent: C[N+]1([O-])CCOCC1
Solvent: CC(C)=O
Product: O=C(c1cc2c(cc1F)OC(c1ccc(F)cc1)(c1ccc(Cl)cc1Cl)O2)N1C[C@@H](O)[C@@H](O)C1
Temperature: 20 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
To a solution of [2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(2,5-dihydro-pyrrol-1-yl)-methanone (70 mg, 0.15 mmol) in acetone (3.7 mL) and water (1.5 mL), 4-methylmorpholine-4-oxide monohydrate (23 mg, 0.16 mmol), osmium tetroxide (0.02 mL, 0.0015 mmol) and potassium osmate (VI) dihydrate (2.4 mg, 0.0065 mmol) were added and the reaction stirred 24 h at 20° C. Sodium thiosulfate pentahydrate was added, the reaction mixture was stirred 30 min. and poured onto crushed ice. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with brine, dried over sodium sulfate, filtered and the volatiles removed in vacuo. Purification by flash chromatography afforded the title product as a black oil (56 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[CH2:45][C@@H:46]1[NH:50][C:49](=[O:51])[CH2:48][CH2:47]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:45][C@H:46]4[CH2:47][CH2:48][C:49](=[O:51])[NH:50]4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=C1CC[C@H](CO)N1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CC[C@H](Cn2nc3c(-c4ccc(Cl)cc4)c(-c4ccc(Cl)cc4)cnn3c2=O)N1
Yield: 60.5 %

Procedure:
The title compound was prepared using 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (50 mg, 0.14 mmol), prepared as described in Example 1, Ph3P (110 mg, 0.42 mmol) and (R)-5-(hydroxymethyl)pyrrolidin-2-one (17 mg, 0.14 mmol) in THF (1.0 mL) and by following the procedure described in Example 2. The title compound, (R)-7,8-bis(4-chlorophenyl)-2-((5-oxopyrrolidin-2-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (38.5 mg, 85%) was obtained as yellow powder. MS M+H=454; 1H NMR (CDCl3) δ 8.15 (1H, s), 7.24-7.36 (6H, m), 7.09 (2H, d, J=10.0 Hz), 6.59 (1H, s), 4.17-4.20 (1H, m), 4.03-4.10 (2H, m), 2.25-2.35 (3H, m), 1.92-2.02 (1H, m).
Reaction SMILES: [CH:1]([C:3]1[C:24]([CH3:25])=[CH:23][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])=[C:5]([CH3:26])[CH:4]=1)=[O:2].[CH2:27]([Mg]Br)[CH3:28].Cl>O1CCCC1>[OH:2][CH:1]([C:3]1[C:24]([CH3:25])=[CH:23][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])=[C:5]([CH3:26])[CH:4]=1)[CH2:27][CH3:28]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(C)c(C=O)cc1C
Reactant: CC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCC(O)c1cc(C)c(OCc2ccccc2/C(=C\OC)C(=O)OC)cc1C
Yield: 79 %

Procedure:
A solution of 0.2 g (0.56 mmol) of (E)-methyl 2-(2-((4-formyl-2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate obtained in Step 1 in 15 mL of tetrahydrofuran (THF) was cooled to −78° C. and reacted with ethyl magnesium bromide (0.22 mL, 1.2 eq) at −78° C. for 2 hours. After completion of the reaction, the reaction mixture was adjusted to pH 7 with 1N-HCl at 0° C. and concentrated in a vacuum. The residue was stirred in water (10 mL) and extracted twice with 10 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in a vacuum. The concentrate was purified using silica gel chromatography to afford (E)-methyl 2-(2-((4-(1-hydroxypropyl)-2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate as a white oil (0.17 g, yield 79%).
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:9]([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])=[CH:10][CH3:11].Cl.C(OCC)(=O)C>C1COCC1>[OH:13][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH:9]=[CH:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C[Zn]Br
Reactant: CC=CC(=O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC=CC(O)(CC(=O)OCC)c1ccccc1
Yield: 93 %

Procedure:
Under nitrogen atmosphere, 15 mL of THF was added to 3.05 g (5 mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.73 g (5 mmol) of phenyl propenyl ketone in 2.5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 3 hours. 7.5 mL of 1N hydrochloric acid was added at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, purification with silica gel column (developing solvent; ethyl acetate/n-hexane=1/3) afforded 1.09 g of the desired product (yield 93%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[CH2:38][NH:39][CH2:40][CH2:41][CH2:42][OH:43]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:39]([CH2:40][CH2:41][CH2:42][OH:43])[CH2:38][C:29]2[CH:30]=[CH:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:28]=2)=[O:26])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: OCCCNCc1ccc2ccccc2n1
Product: CN(C)c1cccc(N(CC(=O)N(CCCO)Cc2ccc3ccccc3n2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with 3-[(quinolin-2-ylmethyl)-amino]-propan-1-ol
Reaction SMILES: Cl.CCO.C(OC([N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[C:22]([CH3:23])=[C:21]([C:24]3[CH:33]=[N:32][C:31]4[C:26](=[C:27]([C:34]5[CH:39]=[C:38]([F:40])[C:37]([CH2:41][N:42]6[CH2:47][CH2:46][O:45][CH2:44][CH2:43]6)=[C:36]([F:48])[CH:35]=5)[CH:28]=[CH:29][CH:30]=4)[N:25]=3)[CH:20]=[N:19]2)[CH2:14][CH2:13]1)=O)(C)(C)C>>[F:40][C:38]1[CH:39]=[C:34]([C:27]2[CH:28]=[CH:29][CH:30]=[C:31]3[C:26]=2[N:25]=[C:24]([C:21]2[CH:20]=[N:19][N:18]([CH:15]4[CH2:16][CH2:17][NH:12][CH2:13][CH2:14]4)[C:22]=2[CH3:23])[CH:33]=[N:32]3)[CH:35]=[C:36]([F:48])[C:37]=1[CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1
Reactant: Cc1c(-c2cnc3cccc(-c4cc(F)c(CN5CCOCC5)c(F)c4)c3n2)cnn1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Product: Cc1c(-c2cnc3cccc(-c4cc(F)c(CN5CCOCC5)c(F)c4)c3n2)cnn1C1CCNCC1
Temperature: 60 °C

Procedure:
A 1.25 M solution of HCl in EtOH (5 ml, 6.26 mmol) is added to 4-{4-[8-(3,5-Difluoro-4-morpholin-4-ylmethyl-phenyl)-quinoxalin-2-yl]-5-methyl-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (Example 121, 239 mg, 0.368 mmol) and the reaction mixture is heated at 60° C. for 4 h. After cooling, the yellow suspension is concentrated under vacuo and the residue is diluted with EtOAc, poured onto a saturated solution of NaHCO3 and extracted 3× with EtOAc. The combined organic layers are washed with NaHCO3, brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is dissolved in CH2Cl2 and purified by chromatography on a 40 g silica gel column on a Combiflash Companion™ (Isco Inc.) apparatus (gradient CH2Cl2/(CH2Cl2:EtOH:NH3 85:13.5:1.5) from 1:0=>1:9) to afford the title compound as a pale orange foam. Rt=0.703 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 505 (M+1)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([N:28]([C:32]2[CH:42]=[C:41]([CH3:43])[C:35]3[N:36]([CH3:40])[C:37](=[O:39])[O:38][C:34]=3[CH:33]=2)[C:29](=[O:31])[CH3:30])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[CH3:40][N:36]1[C:35]2[C:41]([CH3:43])=[CH:42][C:32]([N:28]([C:24]3[CH:23]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[N:27]=[CH:26][N:25]=3)[C:29](=[O:31])[CH3:30])=[CH:33][C:34]=2[O:38][C:37]1=[O:39]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: CC(=O)N(c1cc(C)c2c(c1)oc(=O)n2C)c1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(N(C(C)=O)c4cc(C)c5c(c4)oc(=O)n5C)ncn3)CC1)C(=O)N2
Temperature: 80 °C

Procedure:
59 mg (0.21 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 65 mg (0.19 mmol) N-(6-chloro-pyrimidin-4-yl)-N-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-acetamide and 81 mg (0.59 mmol) potassium carbonate in 1.5 mL NMP were combined and stirred at 80° C. The reaction mixture was purified by preparative HPLC. The product-containing fractions were combined and evaporated down. The solid obtained was washed with diethyl ether and dried.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1)[CH3:2].[CH:19]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:29][C:30]([CH3:36])=[C:31]([CH2:33][CH2:34]O)[N:32]=2)=[CH:24][CH:23]=1)([CH3:21])[CH3:20].COC(=O)CC(=O)C(Br)C.C(C1C=CC(C(N)=S)=CC=1)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:34][CH2:33][C:31]2[N:32]=[C:28]([C:25]3[CH:24]=[CH:23][C:22]([CH:19]([CH3:20])[CH3:21])=[CH:27][CH:26]=3)[S:29][C:30]=2[CH3:36])=[C:9]([CH3:14])[CH:8]=1)[CH3:2]
Reactant: Cc1sc(-c2ccc(C(C)C)cc2)nc1CCO
Reactant: CCOC(=O)C(Cc1ccc(O)c(C)c1)OCC
Agent: CC(C)c1ccc(C(N)=S)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COC(=O)CC(=O)C(C)Br
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(C(C)C)cc3)sc2C)c(C)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(4-hydroxy-3-methyl-phenyl)-propionic acid ethyl ester (example 4 c]) was reacted with 2-[2-(4-isopropyl-phenyl)-5-methyl-thiazol-4-yl]-ethanol (prepared from [rac]-4-bromo-3-oxo-pentanoic acid methyl ester [PCT Int. Appl. (2001), WO 01/79202] and 4-isopropyl-thiobenzamide in analogy to the procedures described in examples 12 a] and 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-isopropyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3-methyl-phenyl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-isopropyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3-methyl-phenyl)-propionic acid as light yellow solid.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[O:8][B:7]([OH:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:14].C(OOC(=O)C1C=CC=CC=1)(=[O:22])C1C=CC=CC=1.C1C(=O)N(Br)C(=O)C1.C([O-])([O-])=O.[Na+].[Na+].Cl>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:10]2[C:9]([CH3:11])([CH3:12])[O:8][B:7]([OH:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:14]=[O:22]
Reactant: Cc1ccc2c(c1F)C(C)(C)OB2O
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OB(O)c2ccc(C=O)c(F)c21
Temperature: 25 °C
Yield: 661.6 %

Procedure:
To a solution of 4-fluoro-3,3,5-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol (970 mg, 5 mmol) in CCl4 (50 mL) at rt was added benzoyl peroxide (121 mg, 0.5 mmol) followed by NBS (1.958 g, 11.0 mmol). The reaction mixture was heated under reflux for 16 h, cooled to rt and treated with Na2CO3. The aqueous layer was acidified with 3 N HCl to pH 3 and extracted three times with ethyl acetate. The combined extracts were washed with water and brine, dried over with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with PE-EA (2:1) to give 4-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde (688 mg, 68%) as a light yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH3:6])[CH:4]=O)[CH3:2].[Cl-].[P+]=O.[Cl:10][C:11]1[CH:31]=[CH:30][C:14]([O:15][C:16]2[N:21]=[C:20]([CH3:22])[C:19]([NH2:23])=[CH:18][C:17]=2[C:24]#[C:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:13][C:12]=1[C:32]([F:35])([F:34])[F:33].[OH-].[Na+]>ClCCl>[Cl:10][C:11]1[CH:31]=[CH:30][C:14]([O:15][C:16]2[N:21]=[C:20]([CH3:22])[C:19]([N:23]=[CH:4][N:3]([CH2:1][CH3:2])[CH3:6])=[CH:18][C:17]=2[C:24]#[C:25][Si:26]([CH3:29])([CH3:27])[CH3:28])=[CH:13][C:12]=1[C:32]([F:34])([F:33])[F:35]
Reactant: Cc1nc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(C#C[Si](C)(C)C)cc1N
Reactant: CCN(C)C=O
Agent: O=[P+]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CCN(C)C=Nc1cc(C#C[Si](C)(C)C)c(Oc2ccc(Cl)c(C(F)(F)F)c2)nc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a 10 ml single-necked round-bottomed flask, 3.1 mg. of ethylmethylformamide is solubilized in 0.25 ml of dry dichloromethane at ambient temperature (colourless solution). Under stirring, 0.0032 ml of phosphorous oxide chloride is added dropwise by syringe. Stirring at ambient temperature is continued for 1.0 hour, whereupon a pink-orange solution is obtained. To this solution, 7.0 mg of 6-(4-chloro-3-trifluoromethyl-phenoxy)-2-methyl-5-trimethylsilanylethynyl-pyridin-3-ylamine dissolved in 0.75 ml of dry dichloromethane is added dropwise by syringe, giving a yellow solution. Stirring is continued at room temperature for 2.5 hours. The mixture is then poured into ice/water (pH=2, water phase). 2 M aqueous NaOH is then added to get a pH of about 11 and stirring is continued for 15 minutes. The mixture is then extracted with two 10 ml portions of diethyl ether. The combined organic phases are then dried over sodium sulfate, filtered and the solvent is removed in vacuo to obtain 6.0 mg of the compound as a yellow oil. RP HPLC: retention time of compound: 1.61 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][S:16][CH3:17])[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][OH:19]>O1CCOCC1.C(OCC)(=O)C>[OH:19][NH:18][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][CH2:15][S:16][CH3:17]
Reactant: NO
Reactant: COC(=O)[C@H](CCSC)NC(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)NO
Yield: 33 %

Procedure:
A solution of (S)-methyl 2-(tert-butoxycarbonylamino)-4-(methylthio)butanoate (1 g, 3.8 mmol) in dioxane (10 mL) and hydroxylamine (50% in water, 10 mL) was stirred at room temperature for 2 days. The solution was diluted with ethyl acetate (200 mL). The organic layer was washed with 1N HCl, brine, and dried over sodium sulfate, filtered and concentrated to give a residue, which was purified on silica gel column (hexane:ethyl acetate, 1:1 to pure acetate) to give (S)-tert-butyl 1-(hydroxyamino)-4-(methylthio)-1-oxobutan-2-ylcarbamate as a white solid (0.33 g, 33%). MS calcd for (C10H20N2O4S+H)+: 265.1; MS found: (M+H)+=266.2, 166.2 (-Boc).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][C:6]=2[CH:13]=1.[Na]>[Na].[Hg].[Hg].[OH-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([OH:12])=[O:11])[CH2:7][C:6]=2[CH:13]=1
Reactant: O=C(O)c1cc2cc(F)ccc2o1
Agent: [Hg]
Agent: [Na+]
Agent: [Na]
Product: O=C(O)C1Cc2cc(F)ccc2O1
Reaction time: 2 h

Procedure:
5-Fluorobenzofuran-2-carboxylic acid (2.4 g) was added to aqueous sodium hydroxide solution (3.3 g of sodium hydroxide in 50 ml of water). Sodium amalgam was added over 20 minutes (prepared from 1.1 g of sodium and 42 g of mercury). After a further 21/2 hours the solution was left to stand over the amalgam overnight. The mercury was separated and the solution filtered and then treated with excess 4 M sulphuric acid. The precipitated acid was filtered off and dried over P2O5 in vacuo (1.5 g) I.R. νmax 1720 cm-1.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12])#[N:2].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[NH:24][CH2:23][CH2:22][CH2:21]2)[CH:14]=1>>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:24]2[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:20]([CH2:19][C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)[CH2:21][CH2:22][CH2:23]2)=[O:9])=[CH:5][C:4]=1[CH3:12])#[N:2]
Reactant: c1cncc(CN2CCCNc3ccccc32)c1
Reactant: Cc1cc(C(=O)O)ccc1C#N
Product: Cc1cc(C(=O)N2CCCN(Cc3cccnc3)c3ccccc32)ccc1C#N

Procedure:
The carboxylic acid from Example C (0.31 g, 1.93 mmol) was reacted with 1-(3-pyridyl)methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine from Example 16A (0.39 g, 1.61 mmol) according to the procedure in Example 1A. The product was purified by flash chromatography on silica (eluant EtOAc); yield 0.28 g (45%).