Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:18])[S:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:38]1([N:44]=[C:45]=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[NH:44]([C:45]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[O:18])[S:10][N:9]=2)=[CH:6][CH:7]=1)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NC(=O)c1c(-c2ccc(N)cc2)nsc1NC(=O)NCCCN1CCOCC1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1c(-c2ccc(NC(=O)Nc3ccccc3)cc2)nsc1NC(=O)NCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 76.4 %

Procedure:
A mixture of 3-(4-aminophenyl)-5-(3-(3-morpholinopropyl)ureido)isothiazole-4-carboxamide (12 mg, 0.030 mmol), N,N-diisopropylethylamine (0.021 mL, 0.120 mmol), and phenyl isocyanate (0.0056 mL, 0.051 mmol) in 1.0 mL THF was stirred at rt for 19 hours. The reaction was quenched with 0.2 mL aqueous Na2CO3 solution, stirred 5 min at rt, and then partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated to a white solid. The solid was chromatographed eluting with CHCl3, then gradient 2.5% to 10% MeOH in CHCl3. The resulting solid was subjected to an EtOAc/NaHCO3 work-up to remove the presence of any silica gel impurity. Upon evaporation of the EtOAc layer the title compound was obtained as a white solid (12 mg, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([S:48]([N:51]2[CH2:56][CH2:55][N:54]([CH2:57][CH3:58])[CH2:53][CH2:52]2)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=1>>[CH2:57]([N:54]1[CH2:53][CH2:52][N:51]([S:48]([C:44]2[CH:43]=[C:42]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=6)[CH2:30][C:31]6[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=6)=[N:14][CH:13]=5)[C:16]=4[CH2:29][CH2:28]3)[CH:47]=[CH:46][CH:45]=2)(=[O:49])=[O:50])[CH2:56][CH2:55]1)[CH3:58]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CCN1CCN(S(=O)(=O)c2cccc(Br)c2)CC1
Product: CCN1CCN(S(=O)(=O)c2cccc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)c2)CC1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and 1-(3-bromo-benzenesulfonyl)-4-ethyl-piperazine (prepared from 3-bromo-benzenesulfonyl chloride and N-ethylpiperazine in acetonitrile, 68 mg) instead of 4-bromobenzoic acid methyl ester in Example 1-D-08, in the same manner as Example 1-D-08, a crude product of (5-{7-[3-(4-ethyl-piperazine-1-sulfonyl)-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl)-bis-(4-methoxy-benzyl)-amine was obtained, and then the PMB groups were removed according to the above Deprotection method 1, to obtain the desired compound (D-96) as an ivory powder (45 mg, 43%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].O.[I:19]Cl.C1(C)C=CC=CC=1>Cl>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[C:15]([I:19])[CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: ClI
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(Cc1ccc(O)c(I)c1)OCC
Yield: 98.13 %

Procedure:
To stirred solution of racemic ethyl 2-ethoxy-3-(4-hydroxyphenyl)propionate of the formula (13a) (20 g) obtained according to the procedure described in step (v) above and dimineralised water (100 ml), ICl (13.6 g, 4.4 ml) in HCl (80 ml) was added dropwise at room temperature for 30 min. The reaction mixture was heated to 75° C. to 80° C. for 20 h. The progress of the reaction was monitored by TLC. After completion of the reaction, toluene (200 ml) was added to the reaction mixture and extracted with dimineralised water. Organic extracts were concentrated to yield the crude compound. The crude compound was purified by column chromatography using 3% ethyl acetate in pet. ether to yield the title compound (10.3 g, 98.13%)
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])([C:36]([O:38]CC2C=CC=CC=2)=[O:37])[CH2:18][CH2:19][C@H:20]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[C:24]([O:23][C:21](=[O:22])[C@@H:20]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:19][CH2:18][C:17]([C:46]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:47])([CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1)[C:36]([OH:38])=[O:37])([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(CCc1ccc(OCc2ccccc2)cc1)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCC(CCc1ccc(O)cc1)(C(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.8 %

Procedure:
To a solution of 125 mg of 4-benzyl 1,4-di-tert-butyl (1S)-6-[4-(benzyloxy)phenyl]-1-[(tert-butoxycarbonyl)amino]hexane-1,4,4-tricarboxylate (0.18 mmol) in methanol (5 mL) was added 10% palladium on charcoal (15 mg) and the mixture was stirred under an atmosphere of hydrogen for 16 h at room temperature. The catalyst was removed by filtration, and the filtrate was evaporated to give the target compound (84 mg, 89% yield) which was used without further purification.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][NH:7][C:8]#[N:9].Br[CH2:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC>[C:13]([C:12]1[O:17][C:8](=[NH:9])[N:7]([CH2:6][C@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[CH:11]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: N#CNC[C@H]1CCCO1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(C)(C)c1cn(C[C@H]2CCCO2)c(=N)o1

Procedure:
A mixture of Example 32A (2.35 g, 18.63 mmol), 1-bromo-3,3-dimethylbutan-2-one (2.52 mL, 18.63 mmol) and potassium carbonate (2.57 g, 18.63 mmol) in 2-butanone (75 mL) was heated to 80° C. overnight. The mixture was poured into water, and extracted with ethyl acetate (2×). The combined organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure to afford the title compound. MS (ESI) m/z 225 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:35]([CH3:36])=[C:34]([CH:37]=O)[NH:33][C:32]=2[CH3:39])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C.N1CCCCC1>[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:35]([CH3:36])=[C:34]([CH:37]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=4)[NH:13][C:12]3=[O:18])[NH:33][C:32]=2[CH3:39])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)c(C)c1C(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2,4-dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (69.2 mg, 53%).
Reaction SMILES: [Br:1]C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.[CH2:23]([C:25]1[C:26]([NH:33][C@@H:34]2[C:39]3[CH:40]=[CH:41][S:42][C:38]=3[CH2:37][CH2:36][C@H:35]2[CH2:43][CH2:44][CH3:45])=[N:27][C:28]([CH2:31][CH3:32])=[CH:29][N:30]=1)[CH3:24]>>[Br:1][C:29]1[N:30]=[C:25]([CH2:23][CH3:24])[C:26]([NH:33][C@@H:34]2[C:39]3[CH:40]=[CH:41][S:42][C:38]=3[CH2:37][CH2:36][C@H:35]2[CH2:43][CH2:44][CH3:45])=[N:27][C:28]=1[CH2:31][CH3:32]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCC[C@@H]1CCc2sccc2[C@H]1Nc1nc(CC)cnc1CC
Product: CCC[C@@H]1CCc2sccc2[C@H]1Nc1nc(CC)c(Br)nc1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-[Trans-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ 7.07, 6.82, 5.12, 4.41, 2.82, 2.56, 2.15–1.71, 1.68–1.40, 1.28, 0.92; HRMS (FAB) calcd for C19H26BrN3S+H 408.1109, found 408.1123.
Reaction SMILES: C([C:5]1([CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH3:22])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[C:11]=2[CH3:14])[C:6]1=O)CCC>C(O)(=O)C.Cl.CCOC(C)=O>[CH2:13]([CH:18]1[CH:5]2[C:6]([C:7]3[C:12]([CH2:13]2)=[C:11]([CH3:14])[C:10]([O:15][CH3:16])=[CH:9][CH:8]=3)=[C:21]([CH3:22])[C:20](=[O:23])[CH2:19]1)[CH2:5][CH2:6][CH3:7]
Reactant: CCCCC1(CCC(=O)CC)Cc2c(ccc(OC)c2C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCC1CC(=O)C(C)=C2c3ccc(OC)c(C)c3CC21
Temperature: 100 °C

Procedure:
A solution of the crude diketone from step 1 in acetic acid (1 mL) and 6N HCl (1 mL) was stirred and heated in an oil bath at 100° C. for 5 hours. After cooling, the reaction mixture was diluted with EtOAc (20 mL), washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered, and the solvent evaporated under vacuum. The residue was purified by preparative layer chromatography on two 0.1×20×20 cm silica gel GF plates, using 5% EtOAc in CH2Cl2 as developing solvent, to afford 9a butyl-4,8-dimethyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (84 mg) as a gum.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: OB(O)c1ccc(F)c(F)c1
Product: Cc1c2n(c3c(-c4ccc(F)c(F)c4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light grey solid (71 mg, 86%), MS (ISP) m/z=331.4 [(M+H)+], mp 229.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][Si:2]([CH2:5][Mg]Cl)([CH3:4])[CH3:3].[CH:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+]>C(OCC)C>[CH3:1][Si:2]([CH3:3])([CH3:4])[CH2:5][CH:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: C[Si](C)(C)C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C[Si](C)(C)CC(O)c1ccccc1

Procedure:
A 1.0M solution (75 ml) of trimethylsilylmethyl magnesium chloride in diethyl ether was diluted with dry diethyl ether (50 ml). After the interior of an reaction vessel was replaced by nitrogen, a solution (50 ml) of benzaldehyde (5.3 g) in dry diethyl ether was slowly added dropwise to the solution in the reaction vessel while stirring. The reaction mixture was stirred at 40° C. for 2 hours under nitrogen atmosphere and cooled in an ice bath. A 25% aqueous solution (100 ml) of ammonium chloride was added dropwise thereto, the mixture was extracted with diethyl ether, washed with water and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 1-trimethylsilyl-2-hydroxy-2-phenylethane (13.1 g) as pale yellow oily material.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[C:17]([CH:18]=[C:19]4[C:24]=2[CH:23]=[CH:22][CH:21]=[CH:20]4)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:25]Br.C(Cl)(Cl)(Cl)Cl>O>[Br:25][C:18]1[C:19]2[C:24]([C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: BrBr
Reactant: CC(C)(C)c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc(-c2c3ccccc3c(Br)c3ccccc23)cc1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A mixed solution of 13.3 g of the above-mentioned 9-(4-tert-butylphenyl)anthracene, 7.52 g of bromine and 300 ml of carbon tetrachloride was heated to reflux under nitrogen atmosphere for 1 hour. After cooling the mixed solution to room temperature, 200 ml of water was injected thereto to extract 200 ml of dichloromethane therefrom. The organic layer was washed twice in 200 ml of water, dried by magnesium sulfate and thereafter concentrated by evaporation. The organic layer was washed twice in 100 ml of hexane and vacuum dried to thereafter obtain 16.09 g of 9-bromo-10-(4-tert-butylphenyl)anthracene.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[NH2:13]OS(O)(=O)=O.[O-]S([O-])(=O)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>O>[Cl:1][C:2]1[C:3]2[O:12][N:13]=[CH:5][C:4]=2[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: NOS(=O)(=O)O
Reactant: COc1ccc(C=O)c(O)c1Cl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2cnoc2c1Cl

Procedure:
3-chloro-2-hydroxy-4-methoxybenzaldehyde (1.48 g) is suspended in 15 ml of H2O and hydroxylamine-O-sulfonic acid (1.08 g) is added, along with 0.1 g of Na2SO4. After three hours an additional 15 ml of H2O is added. After a total of four hours the reaction mixture is treated with 8% NaHCO3 solution and then extracted into ether. Evaporation and trituration with hexane gives a solid product. Recrystallization from toluene/hexane gives 7-chloro-6-methoxy-1,2-benzisoxazole, mp 115°-118° C.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[C:1]1([C:7]#[C:8][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: O=C(O)c1cc(Br)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1cc(C#Cc2ccccc2)ccn1
Temperature: 80 °C
Yield: 92.2 %

Procedure:
0.728 mL (6.5 mmol) of phenyl acetylene was added to a mixture of 10.1 g (5 mmol) of 4-bromopicolinic acid, 91 mg (0.13 mmol) of dichlorobis(triphenylphosphine)-palladium(II), 29 mg (0.15 mmol) of copper(I) iodide, 10 mL of triethylamine and 2 mL of DMF and heated at 80° C. overnight. The reaction mixture was filtered. The filtrate was concentrated and partitioned between 5 mL of 2 N Na2CO3 solution, 25 mL of water and 30 mL of ether. The aqueous layer was separated and washed again with ether (30 mL). 10% aq. HCl was added to adjust the pH to 5. The aqueous layer was extracted with dichloromethane (2×50 mL), and the combined organic layers were dried over sodium sulfate. Evaporation of the solvents in vacuo gave 1.028 g (4.61 mmol, 92%) of 4-phenylethynyl-pyridine-2-carboxylic acid. LCMS: 224 (M+1)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25]#[N:26].C([O-])(=O)C.[Na+].Cl.[NH2:33][OH:34]>COCCO>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:4][N:3]1[C:25](=[N:33][OH:34])[NH2:26]
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C#N)OCO3
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCO
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=NO)OCO3
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
A mixture of 2.80 g (8.0 mmol) of compound XXIII, 30 ml of 2-methoxyethanol, 0.84 g (10 mmol) of sodium acetate and 0.60 g (8.8 mmol) of hydroxylamine hydrochloride was stirred for 0.5 h, then concentrated in vacuum. The residue was treated with water, the precipitated crystals were filtered off and washed with water to yield 3.05 g (100%) of the title compound, Mp.: 138-145° C.
Reaction SMILES: C(Cl)CCl.[C:5]([OH:13])(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[Cl-].[CH3:15][O:16][NH2+:17][CH3:18]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:15][O:16][N:17]([CH3:18])[C:5](=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCCCC(=O)O
Reactant: C[NH2+]OC
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClCCCl
Product: C=CCCCCC(=O)N(C)OC
Reaction time: 14 h
Yield: 97 %

Procedure:
EDC (1.1 eq.) was added in small portions over 1.5 h to a stirred mixture of hept-6-enoic acid, methoxy(methyl)ammonium chloride (1.1 eq.) and DMAP (1.1 eq.) in CH2Cl2 (0.2 M). After 14 h, the mixture was diluted with CH2Cl2, then washed sequentially with hydrochloric acid (1 M), NaOH (1M), brine and dried (Na2SO4). Evaporation of the solvent afforded the title compound (97%) as a colorless oil. 1H NMR (400 MHz, CDCl3, 300 K) δ 5.87-5.75 (m, 1H), 5.01 (d, J 17.1, 1H), 4.95 (d, J 10.1, 1H), 3.68 (s, 3H), 3.18 (s, 3H), 2.48-2.36 (m, 2H), 2.13-2.04 (m, 2H), 1.71-1.60 (m, 2H), 1.50-1.40 (m, 2H).
Reaction SMILES: [OH:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[N:13]=[CH:12][C:11](=[O:15])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[C:22](OC(=O)C)(=[O:24])[CH3:23].OO>C(O)(=O)C>[C:22]([O:1][C:2]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:14]2[N:13]=[CH:12][C:11](=[O:15])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1cnc2c([nH]1)-c1ccccc1C2(O)c1ccccc1
Agent: OO
Solvent: CC(=O)O
Product: CC(=O)OC1(c2ccccc2)c2ccccc2-c2[nH]c(=O)cnc21

Procedure:
9-Hydroxy-9-phenyl-9H-indeno[1,2-b]pyrazin-3(4H)-one (0.24 g) was stirred with a mixture of acetic acid (3 ml), acetic anhydride (3 ml) and hydrogen peroxide (0.42 ml) at room temperature for 3 weeks. The resulting very complex mixture was evaporated and treated with water resulting in precipitation of 200 mg of a crystalline mixture. Purification on silica gel column using methylene chloride/methanol: (9/1) as eluent resulted in 70 mg of a compound which was recrystallized from ethanol. Yield 40 mg of the title compound. M.p. 220°-223° C. MS showed the molecular ion 318 and a degradation pattern in accordance with the title compound. 1H-NMR (CDCl3 /CD3OD: 9/1, δ): 2.4-2.5 (3H, s), 7.3-7.6 (9H, m), 7.9-8.0 (1H, m), 8.2 (1H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:35]=[CH:34][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:20])=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1>>[CH3:14][C:15]1[C:35]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:12]=[C:11]([CH3:13])[O:10][N:9]=3)=[CH:4][CH:3]=2)=[CH:34][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:20])=[CH:17][CH:16]=1
Reactant: Cc1nc(-c2ccc(Br)cc2)no1
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1nc(-c2ccc(-c3cc(C(=O)Nc4cccc(N5CCOCC5)c4)ccc3C)cc2)no1

Procedure:
Example 3 was prepared using 3-(4-bromophenyl)-5-methyl-1,2,4oxadiazole and 4-methyl-N-[3-(4-morpholinyl)phenyl]-3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)benzamide (Intermediate 5).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:8])[CH3:7])=[CH:2]1.CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[CH3:11][N:12]([CH3:14])/[CH:13]=[CH:7]/[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:8]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccsc1
Product: CN(C)/C=C/C(=O)c1ccsc1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
Stir 1-thien-3-ylethanone (1.26 g, 10 mmol) with N,N-dimethylformamide dimethyl acetal (2.66 mL, 20 mmol) at reflux for 4 h. Cool to RT, concentrate and dry in a vacuum oven to give the title compound as a brown solid (1.27 g, 70%).
Reaction SMILES: C(O)(=O)/C=C\C(O)=[O:5].C(O)(=O)/C=C\C(O)=O.[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][C:18]=1[S:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]([NH:38][C:39]2[C:40]([S:48][CH3:49])=[N:41][C:42]([CH3:47])=[CH:43][C:44]=2[S:45][CH3:46])=[O:37])[CH2:31][CH2:30]1.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl.CO>[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][C:18]=1[S:26][CH2:27][CH2:28][N:29]1[CH2:30][CH2:31][N:32]([CH2:35][C:36]([NH:38][C:39]2[C:40]([S:48]([CH3:49])=[O:5])=[N:41][C:42]([CH3:47])=[CH:43][C:44]=2[S:45][CH3:46])=[O:37])[CH2:33][CH2:34]1
Reactant: O=C(O)/C=C\C(=O)O
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CSc1cc(C)nc(S(C)=O)c1NC(=O)CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 26 h
Yield: 40.1 %

Procedure:
To a mixed solution of this amide (500 mg, 0.664 mmol) in chloroform (10 ml) and methanol (2 ml) was added m-chloroperbenzoic acid (213 mg, 1.23 mmol) with ice-cooling, and stirred at room temperature for 26 hours. The reaction solution was diluted with chloroform. The organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel preparative thin layer chromatography (developing solvent; chloroform:sat. ammonia methanol=10:1) to provide 138 mg (yield 40%) of the desired compound as colorless amorphous. IR (neat) cm−1: 3424, 3155, 1695, 1571, 1481. 1H-NMR (d6-DMSO, 120° C.) δ: 2.51 (3H, s), 2.56 (3H, s), 2.73,(3H, s), 2.59-2.68 (6H, m), 2.77 (2H, t, J=7.1 Hz), 2.81-2.92 (2H, br s), 3.11 (1H, d, J=15.8 Hz), 3.17 (1H, d, J=15.8 Hz), 3.41 (2H, t, J=7.1 Hz), 7.07-7.13 (2H, m), 7.30 (1H, S), 7.38-7.44 (2H, m), 9.26 (1H, br s).