Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@:11]([NH:15][C:16](=[O:19])[CH2:17]Cl)(C)[CH2:12][OH:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[CH3:20]C([O-])(C)C.[K+].O>C(O)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]2[NH:15][C:16](=[O:19])[CH2:17][O:13][C@@H:12]2[CH3:20])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: C[C@@](CO)(NC(=O)CCl)c1cc(Br)cc([N+](=O)[O-])c1
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: C[C@H]1OCC(=O)NC1c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
N—[(R)-1-(3-Bromo-5-nitro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide (4.45 g, 10.76 mmol) and KOtBu (2.414 g, 21.52 g) were suspended in 55 ml tert-butanol under N2 and heated 100° C. for 30 min. After completion water was added to the reaction and tert-butanol was removed under reduced pressure. The product was extracted with ethyl acetate from the remaining aqueous phase. The organic phases were washed with water and brine, combined and dried over Na2SO4. Volatiles were removed under reduced pressure. The crude product was purified by automated column chromatography (cyclohexane/ethyl acetate) yielding the title compound as tan solid. 1H-NMR (360 MHz, DMSO-d6): 8.88 (1H, NH), 8.35 (s, 1H), 8.28 (s, 1H), 8.14 (s, 1H), 4.16 (m, 1H), 4.06 (s, 2H), 3.74 (m, 1H), 1.50 (s, 3H); MS: 316 [(M+H)+].
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7]=2[CH:16]=1)=[O:2].S(=O)(=O)([OH:19])N.Cl([O-])=O.[Na+]>C1COCC1.CC(O)(C)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7]=2[CH:16]=1)([OH:19])=[O:2]
Reactant: CCOC(=O)c1cc2cc(C=O)ccc2o1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cc2cc(C(=O)O)ccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 5-formylbenzofuran-2-carboxylate (3.8 g, 17.4 mmol) was dissolved in a mixture of THF (80 mL) and t-BuOH (20 mL). A solution of sulfamic acid (4.0 g, 41.2 mmol) and sodium chlorite (3.4 g, 37.6 mmol) in water (70 mL) was added dropwise at RT. After 3 h an additional portion of sulfamic acid (1.2 g) and sodium chlorite (1.4 g) in water was added in one portion. The reaction mixture was stirred overnight at RT, then extracted twice with EtOAc, dried over sodium sulfate and concentrated under vacuum to give the crude product, 4.87 g which was suitable for use without purification. 1H NMR (DMSO-d6) 8.42 (m, 1H), 8.07 (m, 1H), 7.49-7.81 (m, 2H), 4.37 (q, 2H, OCH2), 1.34 (t, 3H, OCH2CH3); m/z 234.94 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[C:10]([CH3:22])([CH3:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37]1[C:42]([CH3:43])=[CH:41][C:40]([CH3:44])=[CH:39][N:38]=1>O>[CH3:43][C:42]1[C:37]([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:9](=[O:23])[C:10]([CH3:21])([CH3:22])[O:11][C:12]=3[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:6][CH:7]=2)=[N:38][CH:39]=[C:40]([CH3:44])[CH:41]=1
Reactant: Cc1cnc(CCl)c(C)c1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(c3ccc(OCc4ncc(C)cc4C)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 80 °C
Yield: 77.6 %

Procedure:
4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (3.0 g, 9.6 mmol) was added to a mixture of cesium carbonate (12.6 g, 38.6 mmol) and DMF (1000 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min upon which 2-(chloromethyl)-3,5-dimethylpyridine (2.25 g, 14.5 mmol) was added. The reaction mixture was heated for 4 h at 80° C. (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 15% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (3.2 g, 65.3%,) as an off-white solid. 1H NMR: 500 MHz, DMSO-d6: δ 8.2 (s, 1H), 7.65 (d, 2H), 7.45 (s, 1H), 7.15 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.2 (s, 2H), 3.8 (s, 3H), 2.35 (s, 3H), 2.3 (s, 3H), 1.45 (s, 6H). MS: [M+H]+: m/z=430.4. HPLC (96.3%, Condition-A).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([OH:12])[CH2:10][NH2:11])=[CH:4][C:3]=1[Cl:13].[CH2:14]([C:18]1[CH:31]=[CH:30][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:29])=[CH:20][CH:19]=1)[C:15]([CH3:17])=O>>[NH2:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([CH:9]([OH:12])[CH2:10][NH:11][CH:15]([CH3:17])[CH2:14][C:18]2[CH:19]=[CH:20][C:21]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:30][CH:31]=2)=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)Cc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: NCC(O)c1cc(Cl)c(N)c(Cl)c1
Product: CC(Cc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)c1cc(Cl)c(N)c(Cl)c1

Procedure:
5-[4-[2-[(4-Amino-3,5-dichloro-β-hydroxyphenethyl)amino]propyl]benzyl]thiazolidine-2,4-dione was prepared as a 46:54 mixture of diastereoisomers, mp. 195°-201° C., from 2-(4-amino-3,5-dichlorophenyl)-2-hydroxy ethylamine and 5-(4-acetonylbenzyl)thiazolidine-2,4-dione in an analogous manner to that described in Example 5
Reaction SMILES: Cl.COC(OC)CNC.[CH3:10][O:11][C:12]1[C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=[CH:16][C:13]=1[CH:14]=[O:15].C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)C>[CH3:10][O:11][C:12]1[C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=[CH:16][C:13]=1[CH2:14][OH:15]
Reactant: COc1c(C=O)ccc2c1OCO2
Agent: CNCC(OC)OC
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCO
Product: COc1c(CO)ccc2c1OCO2
Temperature: 25 °C
Yield: 4.5 %

Procedure:
To 100 ml of ethanol, were charged 1.83 ml of ethanol containing 22.2 g of hydrochloric acid dissolved therein, 3.96 g of N-methylaminoacetaldehyde dimethylacetal, 1.0 g of 2-methoxy-3,4-methylenedioxybenzaldehyde, 0.35 g of sodium cyanoborohydride and 10 ml of ethanol, and they were stirred in an oil bath under a nitrogen stream at 70° C. for 2 hours. After the reaction was over, the reaction mixture was cooled to room temperature, made alkaline (pH 11) with 2N NaOH solution and extracted with ethyl acetate. The liquid extract was analyzed by GC and LC to show, as a product, 1.50 g of 2-methoxy-3,4-methylenedioxy-N-methylbenzylamino dimethylacetal (yield 95%) and 0.046 g of 2-methoxy-3,4-methylenedioxy benzylalcohol (yield 4.9%), while 2-methoxy-3,4-methylenedioxy benzaldehyde of the starting material not being recognized (conversion rate:100%). The selectivity to the desired 2-methoxy-3,4-methylenedioxy-N-methylbenzylamino dimethylacetal was 95%.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][Mg+].[Br-]>C1COCC1.CCOCC>[CH3:14][C:10]1([OH:13])[CH2:11][CH2:12][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9]1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(O)CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 45.9 %

Procedure:
To a solution of commercially available 1-(phenylmethyl)-3-pyrrolidinone (1.0 g, 5.71 mmol) in THF (30 mL) and ether (30 mL) at 0° C. was added MeMgBr (1.4 M solution in toluene:THF (3:1)) (6.1 mL, 8.65 mmol). The reaction was stirred at 0° C. for 1.5 hours, then quenched with water and extracted. Removed organic solvent in vacuo and extracted again with ether, dried organics (Na2SO4) and removed solvent in vacuo. Purified by RP-HPLC to provide racemic 3-methyl-1-(phenylmethyl)-3-pyrrolidinol as a yellow oil (0.501 g, 46%). LCMS: (M+H)+=192.3.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)(=[O:4])=[O:3].[NH2:15][CH2:16][CH:17]([OH:20])[CH2:18][OH:19]>CS(C)=O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:15][CH2:16][CH:17]([OH:20])[CH2:18][OH:19])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)(=[O:4])=[O:3]
Reactant: NCC(O)CO
Reactant: CS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(NCC(O)CO)c([N+](=O)[O-])c1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
A mixture of 4-chloro-3-nitrophenyl methyl sulfone (5 g, 21 mmole) and 3-amino-1,2-propanediol (4.25 g, 47 mmole) in DMSO (15 ml) was stirred at 23° C. for 30 min. and poured into crushed ice. The resulting yellow crystal was collected by filtration and washed with ice-cold water to give the compound (21) (5.2 g, 95%) (m.p. 133° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5](=[CH:9][CH:10]=[C:11]([F:13])[CH:12]=1)[C:6]([NH2:8])=[O:7].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5](=[CH:9][CH:10]=[C:11]([F:13])[CH:12]=1)[C:6](/[N:8]=[CH:17]/[N:18]([CH3:20])[CH3:19])=[O:7]
Reactant: COC(=O)c1cc(F)ccc1C(N)=O
Reactant: COC(OC)N(C)C
Product: COC(=O)c1cc(F)ccc1C(=O)/N=C/N(C)C
Temperature: 25 °C

Procedure:
A solution of 5-fluoro-phthalamic acid methyl ester plus regioisomer (2.24 g, 11.36 mmol) in N,N-dimethylformamide dimethyl acetal (10 mL) is heated at 110° C. for 3 hours. The reaction mixture is allowed to cool to room temperature and is concentrated under reduced pressure to afford crude N-[1-dimethylamino-meth-(E)-ylidene]-5-fluoro-phthalamic acid methyl ester plus regioisomer (2.9 g).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1.[CH:21]1([NH:24][C:25]([C:27]2[C:35]3[CH:34]=[C:33]([C:36]4[C:41]([Cl:42])=[CH:40][N:39]=[C:38](Cl)[N:37]=4)[S:32][C:31]=3[C:30]([O:44][CH3:45])=[CH:29][CH:28]=2)=[O:26])[CH2:23][CH2:22]1>O1CCOCC1>[CH:21]1([NH:24][C:25]([C:27]2[C:35]3[CH:34]=[C:33]([C:36]4[C:41]([Cl:42])=[CH:40][N:39]=[C:38]([NH:10][CH2:11][CH2:12][CH2:13][N:14]5[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]5)[N:37]=4)[S:32][C:31]=3[C:30]([O:44][CH3:45])=[CH:29][CH:28]=2)=[O:26])[CH2:22][CH2:23]1
Reactant: COc1ccc(C(=O)NC2CC2)c2cc(-c3nc(Cl)ncc3Cl)sc12
Reactant: CN1CCN(CCCN)CC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)NC2CC2)c2cc(-c3nc(NCCCN4CCN(C)CC4)ncc3Cl)sc12
Yield: 40.3 %

Procedure:
Diisopropylethylamine (1.10 mL, 5.78 mmol) and 1-(3-aminopropyl)-4-methylpiperazine (545 mg, 3.47 mmol) are added to a stirred suspension of 2-(2,5-dichloropyrimidin-4-yl)-7-methoxybenzo[b]thiophene-4-carboxylic acid cyclopropylamide (1.14 g, 2.89 mmol) in dry 1,4-dioxane (25 mL) at room temperature. The resultant mixture is heated in an oil bath at 97° C. for 2 days. At room temperature the mixture is filtered off and the solid is washed with MeOH to give the title compound as a solid (600 mg, 33% yield). The filtrate is concentrated and the residue is purified by HLB cartridge eluting with NH4HCO3 (pH=8) in CH3CN 1:0 to 0:1, and then by Stratta® column, eluting with dichloromethane in MeOH 12:1 to 4:1, to give an additional 339 mg of the title compound as a yellow solid. ES+(m/z) 515 (35Cl) and 517 (37Cl) [M+H].
Reaction SMILES: C(OC(N1C2C(=CC3OC(F)(F)OC=3C=2)[C@H](O)CCC1)=O)(C)(C)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1.[C:53]([O:57][C:58]([N:60]1[C:73]2[C:65](=[CH:66][C:67]3[O:68][C:69]([F:75])([F:74])[O:70][C:71]=3[CH:72]=2)[C@@H:64]([N:76]=[N+]=[N-])[CH2:63][CH2:62][CH2:61]1)=[O:59])([CH3:56])([CH3:55])[CH3:54]>C1(C)C=CC=CC=1.CO.[Pd]>[C:53]([O:57][C:58]([N:60]1[C:73]2[C:65](=[CH:66][C:67]3[O:68][C:69]([F:75])([F:74])[O:70][C:71]=3[CH:72]=2)[C@@H:64]([NH2:76])[CH2:63][CH2:62][CH2:61]1)=[O:59])([CH3:56])([CH3:54])[CH3:55]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N=[N+]=[N-])c2cc3c(cc21)OC(F)(F)O3
Agent: [Pd]
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](O)c2cc3c(cc21)OC(F)(F)O3
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H](N)c2cc3c(cc21)OC(F)(F)O3
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-2,2-Difluoro-9-hydroxy-6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (1.9 mmol) in Toluene, add DPPA (2.5 mmol) and DBU (2.5 mmol). After heating the mixture at 65° C. for 14 h, remove solvent under vacuum and chromatograph the intermediate using ethyl acetate/hexane (5-20%) to elute. This provides (S)-9-Azido-2,2-difluoro-6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester as a colorless oil. To a solution of (S)-9-Azido-2,2-difluoro-6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (1.8 mmol) in methanol (20 mL) add a catalytic amount of Pd/C after purging the solution with nitrogen. Place a balloon of hydrogen on the reaction and purge the solution several times. After stirring for 1 h, purge the solution with nitrogen then filter through celite. Collect the filtrate and remove solvent under vacuum to provide the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[O:20][N:19]=[C:18]([CH3:21])[C:17]=1[CH3:22]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[C:17]=2[CH3:22])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1noc(N)c1C
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1noc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.3 %

Procedure:
4-Tert-butylbenzenesulfonyl chloride (498 mg, 2.14 mmol) and 4-(dimethyl)aminopyridine (5 mg) were added to a solution of 5-amino-3,4-dimethylisoxazole (200 mg, 1.78 mmol) in dry pyridine (2.0 ml). The reaction mixture was stirred at room temperature for 4 h. Pyridine was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with 1N HCl (2×25 ml), brine (25 ml) and dried over anhydrous magnesium sulfate. Evaporation of the solvents left an oily residue which, after purification by column chromatography over silica gel (1% methanol in chloroform as eluent), yielded 320 mg (58%) of an off-white solid. Further purification was achieved by recrystallization from ethyl acetate/hexanes, to yield the pure product as a white solid, m.p. 151°-154° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]3[CH:20]=[N:21][CH:22]=[N:23][CH:24]=3)=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:59][C:60]1[S:61][CH:62]=[CH:63][N:64]=1>C(Cl)Cl.O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[C:18][C:19]3[CH:20]=[N:21][CH:22]=[N:23][CH:24]=3)=[CH:15][CH:16]=2)[C:8]([NH:59][C:60]2[S:61][CH:62]=[CH:63][N:64]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(C#Cc2cncnc2)cc1
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(C#Cc2cncnc2)cc1
Yield: 47.8 %

Procedure:
A solution of 3-cyclopentyl-2-(4-pyrimidin-5-ylethynyl-phenyl)-propionic acid (150 mg, 0.53 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (376 mg, 0.85 mmol), triethylamine (0.22 mL, 1.59 mmol) and 2-aminothiazole (85 mg, 0.85 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 18 h. At this time, the reaction was diluted with water (10 mL). The organic phase was separated and washed with a 1N aqueous sodium hydroxide solution, and a saturated aqueous sodium chloride solution. The aqueous layers were each back-extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-pyrimidin-5-ylethynyl-phenyl)-N-thiazol-2-yl-propionamide (102 mg, 54%) as a white solid: mp 149-151 ° C.; EI-HRMS m/e calcd for C23H22N4OS (M+) 402.1514, found 402.1516.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[N:10]([CH3:14])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=2[N:6]=[C:5]1Cl)[CH:2]=[CH2:3].[CH3:18][C@H:19]1[CH2:24][NH:23][CH2:22][C@@H:21]([CH3:25])[NH:20]1.N12CCCN=C1CCCCC2>CN1CCCC1=O.C(OCC)(=O)C.O>[CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[N:10]([CH3:14])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=2[N:6]=[C:5]1[N:23]1[CH2:22][CH:21]([CH3:25])[NH:20][CH:19]([CH3:18])[CH2:24]1)[CH:2]=[CH2:3]
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(C)c(=O)n2C
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN1CCCC1=O
Product: C=CCn1c(N2CC(C)NC(C)C2)nc2c1c(=O)n(C)c(=O)n2C
Temperature: 150 °C
Reaction time: 0.83 h
Yield: 42.5 %

Procedure:
A suspension of 7-allyl-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (200 mg), cis-2,6-dimethylpiperazine (107 mg), and 1,8-diazabicyclo[5.4.0]undec-7-ene (128 μl) in 1-methyl-2-pyrrolidone (2 ml) was stirred at 150° C. for 50 minutes. The reaction mixture was diluted with ethyl acetate and water, and extracted with ethyl acetate. The aqueous layer was extracted with chloroform, and the combined organic layer was washed with water and dried over magnesium sulfate. The solvent was removed by distillation at reduced pressure to give brown oil. The oil was purified by silica gel column chromatography, and 111 mg of the title compound was obtained from a fraction eluted with methanol-ethyl acetate (1:10).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([C@H:16]4[CH2:20][CH2:19][O:18][CH2:17]4)[N:14]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.[CH3:21][O:22][C:23]1[C:28]([CH3:29])=[C:27](B(O)O)[C:26]([CH3:33])=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)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.O>[CH3:21][O:22][C:23]1[C:28]([CH3:29])=[C:27]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:15]([C@H:16]5[CH2:20][CH2:19][O:18][CH2:17]5)[N:14]=[CH:13][C:7]=4[C:8](=[O:12])[NH:9][C:10]=3[CH:11]=2)[C:26]([CH3:33])=[CH:25][N:24]=1
Reactant: O=c1[nH]c2cc(Br)ccc2c2c1cnn2[C@H]1CCOC1
Reactant: COc1ncc(C)c(B(O)O)c1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc(C)c(-c2ccc3c(c2)[nH]c(=O)c2cnn([C@H]4CCOC4)c23)c1C
Temperature: 100 °C
Reaction time: 4.5 h

Procedure:
(S)-7-bromo-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (100 mg), (2-methoxy-3,5-dimethyl-pyridin-4-yl)boronic acid (65 mg) obtained in Preparation Example 29 (4) and cesium carbonate (293 mg) were added to a mixed solution of DMF (5 mL) and water (1 mL) at room temperature. PdCl2(PPh3)2 (10.5 mg) was added to the mixture in a nitrogen gas stream. The mixture was stirred at 80° C. for one hour and at 100° C. for 4.5 hours. After cooling the reaction mixture to room temperature, water (5 mL) was added, and the mixture was extracted with isopropyl acetate. The organic layer was washed with water and brine and then concentrated under reduced pressure. A crude purified product (64.7 mg) was obtained as the title compound. The instrumental data of this compound were identical to those of the (−)-form of Example 25.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]#[CH:25])[CH:21]=[CH:22][CH:23]=1>CCOCC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:25]#[C:24][C:20]2[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=2)[NH2:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(Br)cc1F
Reactant: C#Cc1cccc(N)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Nc1cccc(C#Cc2ccc(F)c(F)c2)c1
Temperature: 65 °C
Yield: 38.5 %

Procedure:
A multinecked flask as described in Example 1 was charged with 5.0 g (0.026 mol) of 3,4-difluorobromobenzene, 50 ml of dried, degassed triethylamine, 3.0 g (0.026 mol) of 3-aminophenylacetylene, 0.07 g (0.1 mmol) of bis(triphenylphosphine) palladium II chloride, 0.1 g (0.38 mmol) of triphenylphosphine, and 0.02 g (0.1 mmol) of cuprous iodide. The reaction mixture was heated at 65° C. for 36 hours at which point gas chromatography showed the reaction to be complete. The product mixture was cooled to room temperature and diluted with 50 ml of ether. Filtration of the insoluble triethylamine hydrobromide salt by-product followed by concentration of the filtrate gave the crude product (4.2 g, 78% yield) as a off-white solid. Short path distillation of the crude product under reduced pressure gave 2.38 g (0.01 mol, 38% yield) of the purified product as a colorless liquid which crystallized on standing.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][C:14]=2[C:25]([F:28])([F:27])[F:26])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4].COC([C@@H]1C[C@@H](S(C2C=CC(F)=CC=2C(F)(F)F)(=O)=O)CN1)=O.[C:52](OC(C)(C)C)(=[O:57])[CH2:53][C:54]([CH3:56])=[O:55].COC([C@@H]1C[C@@H](S(C2C=CC(F)=CC=2C(F)(F)F)(=O)=O)CN1C(=O)CC(=O)C)=O>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:22])([F:23])[F:24])=[CH:15][C:14]=2[C:25]([F:26])([F:28])[F:27])(=[O:12])=[O:11])[CH2:7][N:6]1[C:52](=[O:57])[CH2:53][C:54](=[O:55])[CH3:56])=[O:4]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(OCC(F)(F)F)cc2C(F)(F)F)CN1
Agent: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1
Agent: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=O)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(OCC(F)(F)F)cc2C(F)(F)F)CN1C(=O)CC(C)=O

Procedure:
In analogy to the procedure described in example 192f, (2S,4R)-4-[4-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid methyl ester containing (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with tert-butyl acetoacetate to give a mixture of the title compound and (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(3-oxo-butyryl)-pyrrolidine-2-carboxylic acid methyl ester as colorless oil. MS (ESI): m/z=520.2 [M+H]+.
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[Cl-].[Hf+4:5].[C:6]1([CH:12]([CH3:14])C)[CH:11]=[CH:10]C=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[Al]>[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2]>[CH2:12]1[C-:14]=[CH:10][CH:11]=[CH:6]1.[CH2:12]1[C-:14]=[CH:10][CH:11]=[CH:6]1.[Cl-:1].[Cl-:1].[Hf+4:5]
Reactant: CC(C)c1ccccc1
Agent: [Fe+2]
Agent: [Hf+4]
Agent: [Al+3]
Product: [C-]1=CC=CC1
Yield: 137.6 %

Procedure:
In accordance with the procedure of Example 5, 4.3 g (0.0134 mol) of hafnium tetrachloride are added at 55° C. under nitrogen over 30 minutes to a stirred mixture of 56 g of cumene, 5 g (0.027 mol) of ferrocene, 4.8 g (0.0358 mol) of aluminium chloride and 0.12 g (0.0045 mol) of aluminium powder. Working up is effected as in Example 4, affording 3.5 g (68.6% of theory) of hafnocene dichloride which melts at 228°-230° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[Br:14][CH:15](O)[CH2:16][CH3:17].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>C1COCC1>[Br:14][CH2:15][CH2:16][CH2:17][O:12][C:9]1[CH:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:13])=[CH:7][CH:8]=1
Reactant: CCC(O)Br
Reactant: COC(=O)C=Cc1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(OCCCBr)cc1
Reaction time: 8 h

Procedure:
To a solution 5 g (28.1 mmol) of 4-Hydroxycinnamic acid methyl ester, 4.9 g (35.1 mmol) of 4 bromopropanol, 9.2 g (35.1 mmol) of triphenylphosphine in 100 mL of THF are added 7.1 g (35.1 mmol) of diisopropylazodicarboxylate under inert atmosphere. The solution is heated up to reflux and allowed to stir overnight. After 20 hours, the reaction mixture is partitioned between EtOAc and water. The organic phase is washed repeatedly with water, dried over sodium sulphate, filtered and concentrated by rotary evaporation to give 7.5 g of (methyl (2E)-3-[4-(3-bromopropoxy)phenyl]prop-2-enoate.