Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[N:5]([CH:10]=[C:11]([CH3:13])[N:12]=2)[N:6]=[C:7]([CH3:9])[CH:8]=1)[CH3:2].[CH2:14]([CH:16]([C:19]1[C:20]2[N:21]([C:26](I)=[C:27]([CH3:29])[N:28]=2)[N:22]=[C:23]([CH3:25])[CH:24]=1)[CH2:17][CH3:18])[CH3:15]>>[CH2:14]([CH:16]([C:19]1[C:20]2[N:21]([C:26]([C:10]3[N:5]4[N:6]=[C:7]([CH3:9])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]4=[N:12][C:11]=3[CH3:13])=[C:27]([CH3:29])[N:28]=2)[N:22]=[C:23]([CH3:25])[CH:24]=1)[CH2:17][CH3:18])[CH3:15]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: CCc1cc(C)nn2cc(C)nc12
Product: CCc1cc(C)nn2c(-c3c(C)nc4c(C(CC)CC)cc(C)nn34)c(C)nc12
Yield: 37.4 %

Procedure:
Using a procedure analogous to Example 16B, 8-ethyl-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.30 g, 1.71 mmol) and 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.59 g, 1.71 mmol) give the title compound (0.25 g, 0.64 mmol, 38%). 1H NMR (CDCl3): δ 0.90 (t, J=7.5 Hz, 6H), 1.43 (d, J=1.4 Hz, 3H), 1.78-1.92 (m, 4H), 2.42 (s, 3H), 2.43 (s, 3H), 2.44 (s, 3H), 2.45 (s, 3H), 3.11 (q, J=7.5 Hz, 2H), 3.34-3.42 (m, 1H), 6.67 (s, 1H), 6.74 (s, 1H) ppm. ES-MS (m/z): calcd for C23H30N6 (M+H)+: 391.5. found: 391.3.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[O:5].Cl.[CH3:19][CH2:20]O>>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([O:17][CH2:19][CH3:20])=[O:16])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CCO
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Agent: Cl
Product: CCOC(=O)c1ccc2[nH]c(C(=O)OCC)cc2c1
Reaction time: 24 h
Yield: 99 %

Procedure:
A suspension of 1H-Indole-2,5-dicarboxylic acid 2-ethyl ester (20.0 g, 85.75 mmole) in a saturated HCl/EtOH (200 ml) was stirred at 55 C. for 24 h and evaporated in vacuo to dryness. The residue was freeze-dried from dioxane to give 22.18 g (99%) of 1H-indole-2,5-dicarboxylic acid diethyl ester, 16 as white powder. MS: 262.12 (M+H). 1-NMR (DMSO-d6): 12.23 (s, 1H, H-1, indole); 8.34 (m, 1H, H-4, indole); 7.83 (m, 1H, H-6, indole); 7.49 (m, 1H, H-7, indole); 7.30 (s, 1H, H-3, indole); 4.31 (m, 4H, —OCH2CH3); 1.32 (m, 4H, —OCH2CH3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:28]1[CH2:33][CH2:32][CH:31](O)[CH2:30][CH2:29]1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)[CH:3]=1
Reactant: Oc1cncc(Br)c1
Reactant: OC1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Brc1cncc(OC2CCOCC2)c1
Temperature: 25 °C
Yield: 64.6 %

Procedure:
To a mixture of 5-bromo-3-pyridinol (5.22 g, 30 mmol), toluene (150 mL), triphenylphosphine (11.8 g, 45 mmol) and tetrahydropyran-4-ol (4.7 g, 45 mmol) was slowly added diethyl azodicarboxylate (7.1 mL, 45 mmol). The mixture was heated at reflux for 20 h, then cooled to room temperature, washed with water (3×100 mL) and then brine (100 mL), then dried (MgSO4), filtered and concentrated by rotary evaporation. The crude oil was treated with diisopropyloxide (50 mL) and the solid thus obtained was filtered and washed with diisopropyloxide (20 mL). The combined filtrates were concentrated by rotary evaporation and purified by column chromatography on silica gel, eluting with ethyl acetate/cyclohexane (20/80, v/v). Selected fractions containing the product were concentrated via rotary evaporation to give 5 g (65%) of a yellow oil.
Reaction SMILES: [C:1]1([N:7]2[CH:15]=[C:14]3[C:9]([N:10]=[CH:11][C:12]([NH2:16])=[CH:13]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC#N>[C:1]1([N:7]2[CH:15]=[C:14]3[C:9]([N:10]=[CH:11][C:12]([NH:16][S:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:31])=[O:30])=[CH:13]3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cnc2nn(-c3ccccc3)cc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CC#N
Product: O=S(=O)(Nc1cnc2nn(-c3ccccc3)cc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
To a solution of 3C (305 mg, 1.458 mmol) and pyridine (0.7 mL) in CH3CN (30 mL) cooled to 0° C. was added bezenesulfonyl chloride (274 mg, 1.550 mmol). After addition, the reaction mixture was stirred at RT for 1 hour, then concentrated under reduced pressure. The resultant residue was dissolved in CH2Cl2 (100 mL), washed with water (2×50 mL), saturated NaCl (50 mL). The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 2% of 2 M NH3 in MeOH/CH2Cl2 to give the title compound as a light brown solid (200 mg, 40% yield). LC/MS (method A): retention time=2.78 min, (M+H)+=351.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22](/[CH:27]=[CH:28]/[C:29](O)=[O:30])[CH:23]=[CH:24][C:25]=1[F:26]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:22]3[CH:23]=[CH:24][C:25]([F:26])=[C:20]([Cl:19])[CH:21]=3)=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(F)c(Cl)c1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccc(F)c(Cl)c3)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(3-chloro-4-fluoro-phenyl)-acrylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1nc(-c2ccccn2)sc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.4 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.30 g, 1.1 mmol), benzyl bromide (0.61 g, 3.5 mmol) and potassium carbonate (0.32 g, 2.3 mmol) and DMF (10 ml) was stirred at room temperature for 2 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-hexane to give the titled compound (0.39 g, 95%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.B(F)(F)F>>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:1](=[O:3])[CH3:2])=[CH:8][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Fc1ccccc1
Agent: FB(F)F
Product: CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 89.6 %

Procedure:
Into a 250 ml stainless steel reactor equipped with a magnetic stirring system, 100 ml of anhydrous HF, 20.8 g (0.25 mole) of acetyl chloride and 20 g (0.21 mole) of fluorobenzene were introduced at about 0° C. The reactor was closed, after which gaseous boron trifluoride (BF3) was introduced until a constant pressure of 10 bars was achieved. The reaction was then allowed to proceed with stirring for 23 hours at ambient temperature. After reaction, the reactor was decompressed to atmospheric pressure, and the reaction mixture poured onto 200 g of crushed ice. The heterogeneous mixture was extracted three times with 200 ml of methylene chloride. The organic phases were washed three times with 200 ml of water, once with 200 ml of 3% aqueous potassium hydroxide solution and twice with 200 ml of water. The organic phase was dried over magnesium sulfate and the solvent eliminated by distillation under reduced pressure. 26 g (yield: 98%) of p-fluoroacetophenone (90% purity) was recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:10]([OH:30])[C:11]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([S:28][CH3:29])[N:23]=2)=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][CH3:21])[CH:15]=2)[N:13]=1.ClC1C=CC=C(C(OO)=[O:39])C=1>ClCCl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[N:10]([OH:30])[C:11]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([S:28]([CH3:29])=[O:39])[N:23]=2)=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][CH3:21])[CH:15]=2)[N:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cccc(-c2nc(-c3c(Cl)cccc3Cl)n(O)c2-c2ccnc(SC)n2)c1
Solvent: ClCCl
Product: CSc1cccc(-c2nc(-c3c(Cl)cccc3Cl)n(O)c2-c2ccnc(S(C)=O)n2)c1
Reaction time: 6 h

Procedure:
To a solution of 480 mg (1 mmol) E16.1 in 3 ml dichloromethane a solution of 246 mg (1 mmol) 3-chloroperbenzoic acid in 7 ml dichloromethane was added at 0° C. and stirred at this temperature for 6 hours. After washing with 5% aqueous sodium hydrogencarbonate and water (each 0° C.) the organic layer was dried over sodium sulfate and evaporated to dryness to yield 470 mg G16.1.1 (96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][N:3]=1.[OH-].[K+].[N+:12]([CH2:14][C:15]([N:17]1[CH2:21][CH:20]=[CH:19][CH2:18]1)=[O:16])#[C-:13]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C@@H:8]2[O:9][CH:13]=[N:12][C@H:14]2[C:15]([N:17]2[CH2:21][CH:20]=[CH:19][CH2:18]2)=[O:16])[CH:5]=[CH:4][N:3]=1
Reactant: [C-]#[N+]CC(=O)N1CC=CC1
Reactant: O=Cc1ccnc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1ccnc(Cl)c1)N1CC=CC1
Reaction time: 2 h
Yield: 84 %

Procedure:
SLA 07158 was prepared in accordance with method D using 2-chloropyridine-4-carbaldehyde SLA 07156 (0.47 g, 3.31 mmol), KOH (0.184 g, 3.33 mmol) in methanol (10 mL) and 2-Isocyano-1-(2H-pyrrol-1(5H)-yl)ethanone SLA 07178 (0.410 g, 3.01 mmol). The solution was stirred 2 h with continued cooling. After work-up and column chromatography on florisil (EtOAc), trans-(5-(2-chloropyridin-4-yl)-4,5-dihydrooxazol-4-yl)(2H-pyrrol-1(5H)-yl)methanone SLA 07158 was obtained as a yellow solid (0.597 g, 84
Reaction SMILES: [K].[C:2]([CH:10]([CH2:34][CH3:35])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[S:22](=[O:24])(=[O:23])[NH:21][C:20](=[O:25])[CH2:19]2)=[C:14]([O:26]CC2C=CC=CC=2)[CH:13]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CCO.O.[Pd]>[C:2]([CH:10]([CH2:34][CH3:35])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[S:22](=[O:24])(=[O:23])[NH:21][C:20](=[O:25])[CH2:19]2)=[C:14]([OH:26])[CH:13]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCC(Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)C(=O)c1ccccc1
Agent: [Pd]
Agent: [K]
Solvent: CCO
Solvent: O
Product: CCC(Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1)C(=O)c1ccccc1

Procedure:
A solution of 5-[4-(2-benzoylbutyl)-2-benzyloxyphenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one potassium salt (45 mg) in 4 mL of EtOH/water (1:1) is hydrogenated over Degussa 5% Pd/C (7 mg) at 1 atm for 6 h. The catalyst is filtered and the solvent is removed under reduced pressure to give the title compound: (M−1)−=387. HPLC retention time=0.60 min (Method C).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH:25]([O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][C:30]=1[O:37][CH3:38])([CH3:27])[CH3:26]>C(Cl)Cl.[Zn]>[Br:2][C:1]([Br:5])=[CH:33][C:32]1[CH:35]=[CH:36][C:29]([O:28][CH:25]([CH3:27])[CH3:26])=[C:30]([O:37][CH3:38])[CH:31]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(C=O)ccc1OC(C)C
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(C=C(Br)Br)ccc1OC(C)C
Temperature: 0 °C
Reaction time: 22 h
Yield: 100.5 %

Procedure:
Carbon tetrabromide (51.3 g, 154.7 mmol) was added portion-wise to a magnetically stirred mixture of zinc dust (10.1 g, 154.5 mmol) and PPh3 (40.5 g, 159.4 mmol) in CH2Cl2 (350 ml) maintained at 0° C. on an ice-salt bath. This suspension was allowed to warm to room temperature and then stirred at for a further 22 h. After this time the reaction mixture was re-cooled to 0° C. and vanillin isopropyl ether (15.0 g, 77.3 mmol) was added dropwise over 2 min. and allowed to stir at room temperature for 1 h. After dilution with hexane (200 ml) the resulting mixture was filtered through a sintered glass funnel and the filtrate concentrated on to silica gel (30 g). The resulting solid was added to the top of a flash chromatography column (silica gel: 20 cm long×10 cm wide) which was subjected to gradient elution (2:1, 1:1 and then 1:2 hexane/CH2Cl2). Concentration of the appropriate fractions (Rf 0.5 in 1:1 hexane/CH2Cl2) then afforded the title compound (27.2 g, 99.8%) as white crystalline masses, m.p. 36–38° C. IR (KBr disc, cm−1) 2976, 2973, 1599, 1510, 1464, 1418, 1383, 1373, 1267, 1235, 1141, 1110, 1036. 1H NMR (300 MHz, CDCl3) δ 7.41 (s, 1H), 7.21 (d, J=2.1 Hz, 1H), 7.07 (dd, J=2.1, 8.4 Hz, 1H), 6.87 (d, J=8.4 Hz), 4.58 (septet, J=6.0 Hz, 1H), 3.87 (s, 3H), 1.39 (d, J=6.0 Hz, 6H). 13C NMR+APT (75.5 MHz, CDCl3) δ 149.7 (C), 147.7 (C), 136.5 (CH), 127.9 (C), 121.9 (CH), 114.4 (CH), 111.8 (CH), 87.1 (CH), 71.1 (CH), 56.0 (CH3), 22.1 (CH3). MS (70 eV) m/z (%): 352 (28), 350 (49), 448 (31) (M+•), 310 (51), 308 (100), 306 (54) (M+•-CH2CHCH3), 295 (34), 293 (38), 291 (36) (M+•-CH2CHCH3—CH3). Anal. Calcd for C12H14O2Br2, 41.17; H, 4.03; Br, 45.65. Found: C, 41.21; H, 3.92; Br, 45.47.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:31][O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)=[O:34].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:31][O:32][C:33](=[O:34])[C:35]1[CH:40]=[CH:39][C:38]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]2)=[O:9])=[CH:37][CH:36]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc32)cc1
Yield: 40 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 4-methoxycarbonylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (40%).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:22]3[S:21][CH:25]=[CH:24][N:23]=3)[CH:27]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2nccs2)c1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2nccs2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 3-(thiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions I): tR=1.29 min.; [M+H]+: 423.10 g/mol.
Reaction SMILES: [CH:1]1([C:7](=[O:9])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:10]Br.S([O-])([O-])=O.[Na+].[Na+]>CO>[Br:10][CH2:8][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9]
Reactant: CC(=O)C1CCCCC1
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(CBr)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution (50 mL) of 1-cyclohexylethanone (25.0 g) in methanol was added bromine (10.1 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. Saturated sodium sulfite aqueous solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-10% ethyl acetate/hexane) to give the title object compound (25.8 g, 63%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[C:5]([CH3:7])=O.[C:19]1([N:25]2[C:29]([NH2:30])=[CH:28][C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH3:1][O:2][C:3]([C:4]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:28]2[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:26][N:25]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:29]=2[NH:30][C:5]=1[CH3:7])=[O:18]
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: Nc1cc(-c2ccccc2)nn1-c1ccccc1
Solvent: CCO
Product: COC(=O)C1=C(C)Nc2c(c(-c3ccccc3)nn2-c2ccccc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
Methyl-2-(3-nitrobenzyliden)acetoacetate is added to 1,3-diphenyl-5-pyrazolamine (0.010 mol) in ethanol (16 ml) and refluxed for 90 minutes under nitrogen. After cooling to room temperature, the solvent is evaporated under reduced pressure, the residue is taken up in ethyl ether, discarding the insolubles, and then the solvent is evaporated. Upon crystallization from methanol, the product of the title is obtained. M.p. 186°-189° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21](=[O:23])[CH3:22]>CC(C)=O>[O:23]=[C:21]([CH3:22])[CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8](=[O:12])[O:9][C:10]=2[CH:11]=1
Reactant: O=c1ccc2ccc(O)cc2o1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc2ccc(=O)oc2c1
Temperature: 0 °C
Yield: 96.2 %

Procedure:
To a solution of 7-hydroxycoumarin (1.62 g, 10 mmol) in acetone (20 ml) were added potassium carbonate (5.53 g, 40 mmol) and chloroacetone (1.38 g, 15 mmol). The resulting mixture was refluxed for 4 h. (monitored by TLC). Evaporation of the solvent gave a residue which was poured into ice water (50 ml). The resulting solid was collected and crystallized from ethyl acetate to afford 7-(2-oxopropoxy)-2H-1-benzopyran-2-one (3a) (2.10 g, 96.1%) as a white needle crystal. mp: 165°-167° C.; IR(KBr) νmax : 1709, 1620; UV(CHCl3) λmax (log ε): 308 (4.14), 244 (3.52); 1H-NMR (CDCl3): δ2.31 (s, 3H, CH3), 4.65 (s, 2H, OCH2), 6.29 (d, 1H, 3-H), 6.76 (d, 1H, 8-H), 6.88 (dd, 1H, 6-H), 7.42 (d, 1H, 5-H), 7.65 (d, 1H, 4-H). Anal. Calcd for C12H10O4 : C, 66.05; H, 4.62. Found: C, 65.98; H, 4.61.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:27][CH3:28])=[O:4].[CH:35]1([CH2:40][CH2:41]O)[CH2:39][CH2:38][CH2:37][CH2:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH:35]1([CH2:40][CH2:41][O:25][C:22]2[CH:21]=[CH:20][C:19]([C@H:17]3[CH2:16][O:15][C:11]4=[CH:12][C:13]5[CH2:14][C@@H:5]([C:3]([OH:2])=[O:4])[N:6]([C@H:26]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)[CH2:27][CH3:28])[CH2:7][C:8]=5[CH:9]=[C:10]4[O:18]3)=[CH:24][CH:23]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2CC1C(=O)OC)OC[C@H](c1ccc(O)cc1)O3
Reactant: OCCC1CCCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCCC2CCCC2)cc1)O3
Temperature: 25 °C

Procedure:
(S)-3-(4-Hydroxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (20 mg) was dissolved in DCM and cyclopentane-ethanol (5 eq.), triphenyl phosphine (5 eq.) and DIAD (4.5 eq.) added. The reaction mixture stirred at room temperature and was directly purified over silica (hexanes to 9:1 hexanes EtOAc to 7:3 hexanes EtOAc). This ester was hydrolyzed according to General Procedure AB to give (3S,8S)-3-[4-(2-cyclopentyl-ethoxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid. This acid was coupled with (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester dihydrochloride according to General Procedure L to give (S)-2-{[(3S,8S)-3-[4-(2-cyclopentyl-ethoxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester. This ester was hydrolyzed according to General Procedure B to give the title compound (5 mg). LCMS (m/z): 811.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.B(O)(O)[C:30]1[CH:35]=[N:34][C:33]([O:36][CH3:37])=[N:32][CH:31]=1>>[OH:21][C@@H:19]([CH3:20])[C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:3][C:2]([C:30]4[CH:31]=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)=[O:22]
Reactant: COc1ncc(B(O)O)cn1
Reactant: C[C@H](O)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(=O)[C@H](C)O)CC4)cc3n2)cn1
Yield: 46.5 %

Procedure:
(S)-1-(4-((2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (61 mg) was reacted with 35 mg of 2-methoxypyrimidin-5-yl-5-boronic acid via General Procedure A to give 33.3 mg of 209. MS (Q1) 500.3 (M)+
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].N1C=CC=CC=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[Cl:31]>ClCCl>[Cl:31][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][C:21]=1[NH:20][C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3])[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of 5.43 g of 4-nitrophenyl chloroformate in 100 mL of dichloromethane was added 2.4 mL of pyridine under ice-cooling, and 5 g of methyl 4-amino-3-chlorobenzoate was added to the obtained mixture, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue, followed by washing with 1 M hydrochloric acid, water, a saturated aqueous sodium hydrogen carbonate solution, water, and a saturated aqueous sodium chloride solution in this order. The organic layer was dried over anhydrous sodium sulfate, and after filtration, the filtrate was concentrated under reduced pressure. The obtained solid was dissolved in 200 mL of toluene under heating, and left to be cooled to room temperature, and further cooled in an ice bath. The precipitated solid was collected by filtration, and dried under reduced pressure to obtain 5.59 g of methyl 3-chloro-4-{[(4-nitrophenoxy)carbonyl]amino}benzoate as a white solid.