Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[N:6][OH:7])[C:3](=[O:5])[CH3:4].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1>C(O)(=O)C>[CH3:1][C:2]1[N+:6]([O-:7])=[C:13]([C:12]2[CH:15]=[CH:16][C:9]([Br:8])=[CH:10][CH:11]=2)[O:5][C:3]=1[CH3:4]
Reactant: CC(=O)C(C)=NO
Reactant: O=Cc1ccc(Br)cc1
Solvent: CC(=O)O
Product: Cc1oc(-c2ccc(Br)cc2)[n+]([O-])c1C
Yield: 74.1 %

Procedure:
A solution of 2,3-butanedione monooxime (50 g, 0.49 mol) and 4-bromo-benzaldehyde (101 g, 0.54 mol) in acetic acid (500 mL) was cooled to 0° C. and then gaseous HCl was bubbled through the solution for 35 min while the reaction was stirred in an ice bath. Diethyl ether (500 mL) was then added to the reaction to precipitate the product and the resultant slurry stirred 45 min at 0° C. before being filtered. The solids were rinsed with Et2O (50 mL), taken up in water (1 L) and conc. NH4OH (60 mL) added to the slurry. This mixture was extracted with CHCl3, the organic layer was dried (MgSO4), and the solvent removed in vacuo to give 97.4 g (74%) of 4,5-dimethyl-2-(4-bromophenyl)-oxazole oxide as a white solid. The compound should be used directly within 24–48 h: 1H NMR (500 MHz, CDCl3) 8.34 (d, J=9.0 Hz, 2H), 7.61 (d, J=9.0 Hz, 2H), 2.35 (s, 3H), 2.20 (s, 3H); 13C (125 MHz, CDCl3) 142.1, 131.9, 129.5, 126.3, 124.1, 122.2, 11.1, 6.2; IR (KBr) 1685, 1529, 1418, 1377, 1233, 1165 cm−1; UV (EtOH)max 307 nm (24371); HRMS (TOF) m/z calculated for C11H1179BrNO2: 267.997, found 267.9951.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:11]([N:14]1[CH2:16][CH2:15]1)(=[O:13])[CH3:12]>CO>[C:11]([NH:14][CH2:15][CH2:16][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)(=[O:13])[CH3:12]
Reactant: c1ccc2c(c1)CCCN2
Reactant: CC(=O)N1CC1
Solvent: CO
Product: CC(=O)NCCN1CCCc2ccccc21

Procedure:
13.3 g. (0.1 mol) 1,2,3,4-tetrahydroquinoline and 9.4 g. (0.11 mol) acetylaziridine were boiled overnight under reflux in 200 ml. anhydrous methanol. After evaporating in a rotary evaporator, the mixture obtained of unreacted starting material and reaction product (13 g.) was purified by column chromatography on silica gel (elution agent: chloroform/acetone=4/1 v/v; m.p. 102° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(C(C)C)C(C)C)C>C(#N)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1ncc(Br)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(Br)cn2)CC1
Yield: 78 %

Procedure:
To a stirred solution of 5-bromo-2-chloropyrimidine (10.0 g, 51.7 mmol, 1.0 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (10.6 g, 51.7 mmol, 1.0 equiv) in acetonitrile (250 mL) was added at rt drop by drop N-ethyl diisopropylamine (45.2 mL 34.4 g, 266 mmol, 5.1 equiv). Then, the reaction mixture was heated to reflux for 16 h, poured into crashed ice and extracted twice with ethyl acetate. The combined organic layers were washed with brine and water, dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 14.4 g (78%) of the title compound as a colorless solid. MS (ISP): 357.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH2:8][OH:9])=[C:5]([Br:7])[N:6]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C.O>[Br:1][C:2]1[S:3][C:4]([CH2:8][O:9][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:21])[CH3:20])=[C:5]([Br:7])[N:6]=1
Reactant: OCc1sc(Br)nc1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1sc(Br)nc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of (2,4-dibromo-1,3-thiazol-5-yl)methanol (2.64 g, 9.6 mmol) and imidazole (1.6 g, 24 mmol) in DMF (15 mL) was added a solution of tert-butyl(chloro)dimethylsilane (1.7 g, 11.5 mmol) in DMF (15 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured in water (400 mL), and the resultant mixture was extracted with EtOAc (3×50 mL). The organic extracts were combined, extracted with brine (2×150 mL), dried over MgSO4, filtered, evaporated, and dried in vacuo, affording 2,4-dibromo-5-{[(tert-butyldimethylsilyl)oxy]methyl}-1,3-thiazole (3.44 g, 93%). The product was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:25][C:26]([NH2:28])=[O:27]>CN(C=O)C>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[O:16][CH2:25][C:26](=[O:27])[NH2:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: NC(=O)CBr
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1OCC(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
5-Chloro-2-hydroxy-benzyl)-carbamic acid tert-butyl ester 78 (210 mg, 0.8 mmol) was dissolved in DMF (6 mL) and to the stirred solution K2CO3 (13.8 mg, 1 mmol) and 2-bromoacetamide (138 mg, 1 mmol) were added. The mixture was stirred at room temperature overnight. The suspension was concentrated in vacuo, and the residue was partitioned between water (20 mL) and CH2Cl2 (10 mL). The aqueous phase was separated and extracted with CH2Cl2 (20 mL×2). The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate 80/20), to give 79 as a white solid (226 mg, 90%). 1H NMR (CDCl3, 300 MHz) δ7.88 (br s, 1H), 7.27-7.18 (m, 2H), 6.76 (d, J=8.7 Hz, 1H), 5.54 (br s, 1H), 4.78( br s, 1H), 4.47 (s, 1H), 4.36 (d, J=6.3 Hz), 1.43 (s, 9H). MS (m/e) (API-ES) 337.0 (MNa)+. m.p 142-143° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:13]([O:23][CH2:24][CH3:25])(=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH2:24]([O:23][C:13](=[O:22])[CH:14]=[C:15]([C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:25]
Reactant: COc1ccc(Br)c2cc[nH]c12
Reactant: CCOC(=O)C=Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(c1ccccc1)c1ccc(OC)c2[nH]ccc12
Temperature: 25 °C
Yield: 34 %

Procedure:
A stirring mixture of 4-bromo-7-methoxyindole LII (162 mg, 0.717 mmol), ethyl cinnamate (254 mg, 1.43 mmol), tetra-butylammonium bromide (46 mg, 0.143 mmol), TEA (199 μl, 1.43 mmol) and palladium-dichloro-[bis-(tri-ortho-tolyl)phosphine] (28 mg, 0.036 mmol) in DMF (2 ml) was heated in a sealed vial flushed with N2, at 110° C. for 20 hours. The reaction was cooled to room temperature and partitioned between H2O and EtOAc. The organic layer was separated and the aqueous layer was extracted twice with EtOAc. The organics were combined dried over Na2SO4, filtered and evaporated. The crude mixture was purified via flash chromatography (hexane/EtOAc) affording 3-(7-methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LIII (108 mg, 34% yield).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][C:13]2([CH3:28])[C:21]3[S:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:18][C:17]=3[CH2:16][CH2:15][O:14]2)(=O)=O)=CC=1.[Br-:30].[Li+]>CC(C)=O>[Br:30][CH2:11][CH2:12][C:13]1([CH3:28])[C:21]2[S:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][C:17]=2[CH2:16][CH2:15][O:14]1
Reactant: Cc1ccc(S(=O)(=O)OCCC2(C)OCCc3nc(-c4ccccc4)sc32)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: CC1(CCBr)OCCc2nc(-c3ccccc3)sc21

Procedure:
A mixture of 4-[2-(p-toluenesulfonyloxy)ethyl]-6,7-dihydro-4-methyl-2-phenyl-4H-pyrano[4,3-d]thiazole (16 g, 37.2 mmoles, described above), and lithium bromide (16 g) in dry acetone (100 ml) is heated at reflux temperature for two hr. The solvent is removed under reduced pressure, water is added and the aqueous solution is extracted with ether. The ether solution is washed with water, dried over sodium sulfate, treated with charcoal and evaporated under reduced pressure to give 4-(2-bromoethyl)-6,7-dihydro-4-methyl-2-phenyl-4H-pyrano[4,3-d]thiazole, γmaxCHCl3 1545, 1500, 1465 and 1090 cm-1.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:9][CH:10]=1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N+:9]([O-:24])[CH:10]=1
Reactant: COCOc1ccc(CC(C)(C)C)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COCOc1ccc(CC(C)(C)C)[n+]([O-])c1
Reaction time: 4 h
Yield: 99.6 %

Procedure:
5-(Methoxymethoxy)-2-neopentylpyridine (11.0 g, 52.6 mmol) was dissolved in CH2Cl2 (200 mL) to which mCPBA (18.1 g, 105 mmol) was added, and the mixture was stirred under N2 for about 4 h. The mixture was quenched with 1M NaOH (200 mL) and stirring was continued vigorously for 10 min. The mixture was extracted with CH2Cl2 (2×300 ML), the combined organic layers were washed with saturated NaCl, dried (Na2SO4), and evaporated to give 5-(methoxymethoxy)-2-neopentylpyridine-N-oxide (11.8 g, 99.7% yield) as a brown oil which was used without purification in the next step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:2]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][O:13][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:2]1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1c[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCCc1c[nH]c2ccccc12
Temperature: -40 °C

Procedure:
Compound 29 (1.8 g, 5.44 mmol) was transferred to a flame-dried flask filled with argon and dissolved in anhydrous THF then cooled to −40° C. Triethylamine (0.72 g, 7.07 mmol) was added by syringe followed by MeSO2Cl (0.75 g, 6.53 mmol). The temperature of the reaction mixture was allowed to rise to room temperature (10–15 minutes) before it was quickly filtrated and concentrated. The crude oil was dissolved in CH2Cl2 and washed with H2O. The organic phase was dried with MgSO4, filtrated and concentrated in vacuo to a dark, brown oil. The crude product was used immediately in the next step.
Reaction SMILES: [F:1][CH:2]([F:21])[C:3]1[S:7][C:6]([C:8]([O:10]C)=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]2[N:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14][CH:13]=1.[OH-].[Na+].Cl>CO.O>[F:21][CH:2]([F:1])[C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]2[N:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14][CH:13]=1
Reactant: COC(=O)c1cc(-c2cnc3cccnn23)c(C(F)F)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(-c2cnc3cccnn23)c(C(F)F)s1
Temperature: 50 °C

Procedure:
To a stirred solution of methyl 5-(difluoromethyl)-4-(imidazo[1,2-b]pyridazin-3-yl)thiophene-2-carboxylate (57 mg, 0.18 mmol) in methanol (1 mL) and water (0.5 mL) was added NaOH (2 N, 0.28 mL, 0.56 mmol). The mixture was heated to 50° C. for 1 h, cooled to room temperature, and acidified with 1 N HCl. The resultant mixture was concentrated, and used in the next step without further purification. LRMS (APCI) calc'd for (C12H8F2N3O2S) [M+H]+, 296.0. found 296.0.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:21]=[CH:20][C:16]3[O:17][CH2:18][O:19][C:15]=3[CH:14]=2)=[C:11]([NH2:22])[N:10]([CH3:23])[N:9]=1)(=O)C.[CH:24]([C:27]1[CH:28]=[CH:29][C:30]([S:33](Cl)(=[O:35])=[O:34])=[N:31][CH:32]=1)([CH3:26])[CH3:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[O:17]1[C:16]2[CH:20]=[CH:21][C:13]([C:12]3[C:8]([O:7][CH2:6][CH2:5][OH:4])=[N:9][N:10]([CH3:23])[C:11]=3[NH:22][S:33]([C:30]3[CH:29]=[CH:28][C:27]([CH:24]([CH3:26])[CH3:25])=[CH:32][N:31]=3)(=[O:34])=[O:35])=[CH:14][C:15]=2[O:19][CH2:18]1
Reactant: CC(=O)OCCOc1nn(C)c(N)c1-c1ccc2c(c1)OCO2
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)nc1
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: CC(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCO)nn2C)nc1
Reaction time: 8 h
Yield: 2.5 %

Procedure:
To a solution of 2-{[5-amino-4-(1,3-benzodioxol-5-yl)-1-methyl-1H-pyrazol-3-yl]oxy}ethyl acetate (Preparation 33) (500 mg) in anhydrous pyridine (5 ml) at room temperature and under an atmosphere of nitrogen was added 4-dimethylaminopyridine (191 mg) and 5-isopropyl-2-pyridinesulfonyl chloride (1.72 g). After being left to reflux overnight, the reaction mixture was poured onto saturated citric acid solution (50 ml) and extracted with ethyl acetate (2×50 ml). The organic fractions were washed with brine (50 ml), followed by drying over magnesium sulfate, filtering and concentration under reduced pressure. To a solution of the residue in ethanol (50 ml) was added sodium hydroxide solution (5 ml of 2M). The mixture was stirred overnight before being concentrated to approximately 5 ml under reduced pressure and partitioned between ethyl acetate (2×100 ml) and saturated citric acid solution (100 ml). Washing of the organic fractions with brine (100 ml), drying over magnesium sulfate, filtering and concentration under reduced pressure afforded a brown residue. Purification by column chromatography on silica gel (5 g), eluting in an isocratic fashion with ethyl acetate:hexane (2:1) afforded the title compound as a gum (18 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[N+:18]([O-])([O-:20])=[O:19].[Na+]>S(=O)(=O)(O)O>[CH3:17][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][C:6]([N+:18]([O-:20])=[O:19])=[CH:7][CH:8]=2)([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(C)(C)c1cc2ccccc2[nH]1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C(C)(C)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
Ethyl 2-(1H-indol-2-yl)-2-methylpropanoate (1.0 g, 4.3 mmol) was dissolved in concentrated sulfuric acid (6 mL) and cooled to −10° C. (salt/ice-mixture). A solution of sodium nitrate (370 mg, 4.33 mmol) in concentrated sulfuric acid (3 mL) was added dropwise over 30 min. Stirring was continued for another 30 min at −10° C. The mixture was poured into ice and the product was extracted with dichloromethane. The combined organic phases were washed with a small amount of sat. aq. sodium bicarbonate. The product was purified by column chromatography on silica gel (5-30% EtOAc in hexane) to give ethyl 2-methyl-2-(5-nitro-1H-indol-2-yl)propanoate (0.68 g, 57%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].[CH2:14](O)[CH2:15][OH:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:15]1[O:16][C:5]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)([CH2:4][CH2:3][CH2:2][Cl:1])[O:6][CH2:14]1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: Fc1ccc(C2(CCCCl)OCCO2)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of γ-chloro-p-fluorobutyrophenone (50 g. 025 mole, commercially available); ethylene glycol (50 mL); p-toluene sulfonic acid (0.1 g) in 300 mL benzene is refluxed for 18 h with water of reaction being removed by means of a Dean Stark water trap. Upon cooling to room temperature, the reaction mixture is washed with dilute sodium bicarbonate, dried (MgSO4), filtered and the benzene removed by concentration in vacuo. The residual oil was distilled to give 57.7 g (93%) of product, b.p. 106-112/0.01 Torr.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[N:10]=[C:11](Cl)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:8]=2[N:7]=[CH:6][N:5]=1)[CH3:2].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH2:1]([O:3][C:4]1[C:9]2[N:10]=[C:11]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:8]=2[N:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOc1ncnc2c(N3CCOCC3)nc(Cl)nc12
Reactant: C1CNCCN1
Product: CCOc1ncnc2c(N3CCOCC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 2 from 8-ethoxy-2-chloro-4-morpholino-pyrimido-[5,4-d]-pyrimidine m.p.: 153°-155° C.) and piperazine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2([N:20]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[NH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:2].[CH3:32][O:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1[S:42](Cl)(=[O:44])=[O:43]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:42]([C:35]1[CH:36]=[CH:37][C:38]([O:40][CH3:41])=[CH:39][C:34]=1[O:33][CH3:32])(=[O:44])=[O:43])[C:8](=[O:13])[C:7]2([N:20]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[NH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:2]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: CCOC(=O)NN(C(=O)OCC)C1(c2ccccc2)C(=O)Nc2ccc(OCC)cc21
Product: CCOC(=O)NN(C(=O)OCC)C1(c2ccccc2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(OCC)cc21

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 0.500 g of 5-ethoxy-3-(2-ethoxycarbonyl-1-ethoxycarbonylhydrazino)-1,3-dihydro-3-phenylindol-2-one and 0.280 g of 2,4-dimethoxybenzenesulfonyl chloride. The expected product is obtained after crystallization from a DCM/iso ether mixture. m=0.383 g. M.p.=228°-229° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:19][N:20]([CH3:24])[CH2:21][C:22]#[CH:23]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C.[I-]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:23]#[C:22][CH2:21][N:20]([CH3:24])[CH3:19])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C#CCN(C)C
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(CC1CCCC1)c1ccc(C#CCN(C)C)cc1
Temperature: 70 °C
Yield: 91.2 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (716 mg, 2.0 mmol) and triethylamine (2 mL, 0.01 mmol) in N,N-dimethylformamide (2 mL) was treated with 1-dimethylamino-2-propyne (0.54 mL, 5.0 mmol). The resulting reaction mixture was degassed with argon and then treated with cooper iodide (10 mg, 0.05 mmol) and bis(triphenylphosphine)palladium (II) chloride (15 mg, 0.02 mmol). The reaction was then heated at 70° C. for 24 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL) and washed with a half-saturated aqueous sodium chloride solution (1×20 mL). The resulting aqueous layer was back extracted with ethyl acetate (1×120 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 chloroform/methanol) afforded 3-cyclopentyl-2-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-propionic acid methyl ester (572 mg, 91%) as an amber oil: EI-HRMS m/e calcd for C20H27NO3 (M+) 313.2051, found 312.1850.
Reaction SMILES: [F:1][C:2]1([F:27])[C:15]([F:17])([F:16])[C:14]2[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:6][CH:7]=2.[CH2:28]([Mg]Br)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[F:1][C:2]1([F:27])[C:15]([F:17])([F:16])[C:14]2[CH:13]=[C:12]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:6][CH:7]=2
Reactant: CCCCCC[Mg]Br
Reactant: CCCCCCCCc1ccc2c(c1)C(F)(F)C(F)(F)c1cc(Br)ccc1-2
Product: CCCCCCCCc1ccc2c(c1)C(F)(F)C(F)(F)c1cc(CCCCCC)ccc1-2

Procedure:
In analogy to Example 1, from 9,9,10,10-tetrafluoro-2-bromo-7-octyl-9,10-dihydrophenanthrene and hexylmagnesium bromide. The catalyst used is 1,3-bis(diphenylphosphine)propanenickel(l I) chloride. Chromatography gives 9,9,10,10-tetrafluoro-2-hexyl-7-octyl-9,10-dihydrophenanthrene
Reaction SMILES: [Li+].[BH4-].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][C@@H:12]3[N:18]([CH:19]=2)[C:17](=[O:20])[C:16]2[CH:21]=[C:22]([O:66][CH3:67])[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]4[C:63]([O:64][CH3:65])=[CH:62][C:35]5[C:36](=[O:61])[N:37]6[CH:52]=[C:51]([C:53]7[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=7)[CH2:50][C@H:38]6[C:39](=O)[N:40](COCC[Si](C)(C)C)[C:34]=5[CH:33]=4)=[CH:24][C:15]=2[N:14](COCC[Si](C)(C)C)[C:13]3=O)=[CH:6][CH:5]=1.CCO>C1COCC1>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][C@@H:12]3[N:18]([CH:19]=2)[C:17](=[O:20])[C:16]2[CH:21]=[C:22]([O:66][CH3:67])[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]4[C:63]([O:64][CH3:65])=[CH:62][C:35]5[C:36](=[O:61])[N:37]6[CH:52]=[C:51]([C:53]7[CH:54]=[CH:55][C:56]([O:59][CH3:60])=[CH:57][CH:58]=7)[CH2:50][C@H:38]6[CH:39]=[N:40][C:34]=5[CH:33]=4)=[CH:24][C:15]=2[N:14]=[CH:13]3)=[CH:6][CH:5]=1
Reactant: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7ccc(N)cc7)C[C@H]5C(=O)N6COCC[Si](C)(C)C)cc4N(COCC[Si](C)(C)C)C(=O)[C@@H]3C2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7ccc(N)cc7)C[C@H]5C=N6)cc4N=C[C@@H]3C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.6 %

Procedure:
Fresh LiBH4 (66 mg, 3.04 mmol) was added to a stirred solution of the SEM-dilactam 12 (428 mg, 0.42 mmol) in THF (3 mL) and EtOH (3 mL) at 0° C. (ice bath). The ice bath was removed and the reaction mixture was allowed to reach room temperature (vigorous effervescence). After 2 hours LC/MS analysis indicated the complete consumption of starting material. The reaction mixture was poured onto ice (50 mL) and allowed to warm to room temperature with stirring. The aqueous mixture was extracted with DCM (3×50 mL) and the combined organic layers washed with H2O (50 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The resulting residue was treated with DCM (2 mL), EtOH (5 mL), H2O (2.5 mL) and silica gel (3.7 g). The viscous mixture was allowed to stir at room temperature for 3 days. The mixture was filtered through a sinter funnel and the silica residue washed with 90% CHCl3: 10% MeOH (˜250 mL) until UV activity faded completely from the eluent. The organic phase was dried (MgSO4) filtered and evaporated in vacuo to provide the crude material. The crude product was purified by flash chromatography (99.5% CHCl3: 0.5% MeOH to 97.5% CHCl3: 2.5% MeOH in 0.5% increments)) to provide the pure C2/C2′ aryl PBD dimer 13 (59 mg, 52%).
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6](=[O:13])[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[N:9]=2)[CH2:3][CH2:2]1.[ClH:14].Cl[O-].[Na+].S([O-])([O-])=O.[Na+].[Na+].Cl[O-]>O>[Cl:14][C:7]1[C:6](=[O:13])[NH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[N:9][C:8]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1cc(=O)[nH]c(C2CC2)n1
Reactant: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: O=C(O)c1nc(C2CC2)[nH]c(=O)c1Cl
Temperature: 7.5 °C
Yield: 87.5 %

Procedure:
A 2-L Morton flask with overhead stirrer, thermocouple and addition funnel was charged with 2-cyclopropyl-1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acid (161 g, 0.90 mol), hydrochloric acid (37 wt. % in water, 300 g, 250 mL, 3 mol) and water (400 mL). The reaction mixture was stirred at 5-10° C., and sodium hypochlorite (14 wt % aqueous solution, 522 g, 0.99 mol) was added over 2 h. The reaction mixture was maintained at 10-12° C. for 1 h until a KI-starch paper test using sodium sulfite showed no remaining hypochlorite. The resulting mixture was cooled and filtered. The collected solid was washed with cold water (160 mL), and dried to constant weight in a vacuum-oven at 50° C. to give 169 g (88% yield) of the title compound as a solid melting at 189-190° C.