Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]([OH:14])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:32][CH2:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[C:39](=[O:43])[N:38]([CH:44]1[CH2:49][CH2:48][C:47](=[O:50])[NH:46][C:45]1=[O:51])[CH2:37]2.O>CN(C=O)C>[O:51]=[C:45]1[CH:44]([N:38]2[CH2:37][C:36]3[C:40](=[CH:41][CH:42]=[C:34]([CH2:33][NH:32][C:12](=[O:14])[CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[CH:35]=3)[C:39]2=[O:43])[CH2:49][CH2:48][C:47](=[O:50])[NH:46]1
Reactant: O=C(O)Cc1ccc2ncccc2c1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccc2ncccc2c1)NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of quinolin-6-yl-acetic acid (0.19 g, 1.02 mmol) in dry DMF (5 mL) was added CDI (0.16 g, 1.02 mmol). After 1 h of stirring at rt, 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.30 g, 0.81 mmol) was added. After 18 h, water (20 mL) was added. The solids were collected by filtration, washed with water and dried in vacuo for 18 h to give N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(quinolin-6-yl)acetamide as a white solid (355 mg, 99%). HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 10/90, CH3CN/0.1% H3PO4, 4.54 min (95.6%); mp: 205-207° C.; 1H NMR (DMSO-d6) δ 1.89-2.10 (m, 1H), 2.37 (qd, J=4.3, 13.2 Hz, 1H), 2.63 (br. s., 1H), 2.80-3.02 (m, 1H), 3.73 (s, 2H), 4.12-4.30 (m, 1H), 4.30-4.48 (m, 3H), 5.10 (dd, J=5.1, 13.2 Hz, 1H), 7.29-7.47 (m, 2H), 7.52 (dd, J=4.2, 8.3 Hz, 1H), 7.60-7.76 (m, 2H), 7.84 (s, 1H), 7.97 (d, J=8.7 Hz, 1H), 8.32 (d, J=7.7 Hz, 1H), 8.75 (t, J=5.9 Hz, 1H), 8.87 (dd, J=1.7, 4.2 Hz, 1H), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.48, 31.18, 42.16, 42.31, 47.03, 51.55, 121.53, 122.02, 122.91, 127.07, 127.52, 127.72, 128.72, 130.36, 131.21, 134.66, 135.61, 142.32, 143.73, 146.73, 150.07, 167.87, 169.99, 170.98, 172.86. LCMS: MH=443; Anal Calcd for C25H22N4O4+1.6H2O: C, 63.71%; H, 5.39%; N, 11.89%. Found: C, 63.71%; H, 5.25%; N, 11.99%.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[NH:7][C:8]([O:10][C:4]2=[CH:3][CH:2]=1)=[O:9].[CH3:11][NH:12][CH2:13][CH2:14][OH:15].CO>C(OCC)C>[OH:10][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[NH:7][C:8]([N:12]([CH3:11])[CH2:13][CH2:14][OH:15])=[O:9]
Reactant: O=c1[nH]c2ccccc2o1
Reactant: CNCCO
Solvent: CO
Solvent: CCOCC
Product: CN(CCO)C(=O)Nc1ccccc1O
Temperature: 75 °C

Procedure:
Benzoxalinone (202 g) and N-methylethanolamine (133 g) were stirred and heated at 75° C. for 3 hours, then cooled to 65° C. and methanol (50 ml) was added. The mixture was cooled to ambient temperature and diethyl ether (750 ml) was added. The precipitate was filtered off and recrystallised from methanol to give the desired urea which had a m.pt. of 128° C. (decomp.).
Reaction SMILES: C(O[C:6](=[O:21])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:22]([O:24][C:25](=[O:37])[CH:26](C(OCC)=O)[C:27](OCC)=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25]([C:26]1[C:6](=[O:21])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]2[C:27]=1[OH:28])=[O:37])[CH3:23]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(Cl)c1)n1cccc1
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2cccc(Cl)c2)c1=O

Procedure:
Prepared according to the thermal cyclization condition used in Example 1 step c) from (3-chloro-benzyl)-pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.0 eq.). ESI (m/z): 347 (M+H)+.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:24]1[S:28][C:27]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:38][CH:37]=3)[N:30]=2)=[CH:26][CH:25]=1.CN(C)C=O.[C:51]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=1)#[CH:52]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[N:54]1[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=1[C:51]#[C:52][C:24]1[S:28][C:27]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:38][CH:37]=3)[N:30]=2)=[CH:26][CH:25]=1
Reactant: NS(=O)(=O)c1ccc(Nc2nccc(-c3ccc(Br)s3)n2)cc1
Reactant: C#Cc1ccccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(Nc2nccc(-c3ccc(C#Cc4ccccn4)s3)n2)cc1
Temperature: 180 °C
Yield: 11.5 %

Procedure:
A 10 mL glass microwave reaction vessel with stir bar contained palladium acetate (5 mg, 22 μmol), tri-o-tolylphosphine (13 mg, 44 μmol), and 4-[4-(5-bromo-thiophen-2-yl)-pyrimidin-2-ylamino]-benzenesulfonamide (80 mg, 200 μmol). Anhydrous dimethylformamide (DMF) (3.5 mL), 2-ethynylpyridine (46 mg, 450 μmol), and triethylamine (50 μL) is added to the reaction vessel. The reaction vessel is sealed and heated to 180° C. for 660 seconds in a microwave reactor (Emrys Microwave Reactor, personal Chemistry AB, Uppsala, Sweden). The reaction is filtered through celite, concentrated, redissolved in dimethylsulfoxide (DMSO), and purified by reverse phase (RP) HPLC to obtain 10 mg of the title compound. LC/MS data (Condition A; molecular ion and retention time): m/z 434 (M+H); 2.52 min.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.OC[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([CH2:16][OH:17])[CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:5][CH2:1][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([CH2:16][OH:17])[CH:9]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(CO)cc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(CO)cc(CBr)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 38.2 %

Procedure:
Carbon tetrabromide (3.47 g) was added to a stirred solution of 1,3-dihydroxymethyl-5-methoxy-benzene (800 mg) in anhydrous dichloromethane (16 mL) under argon. After cooling the resulting solution at 0° C., a solution of triphenylphosphine (2.68 g) in anhydrous dichloromethane (16 mL) was added dropwise. The reaction mixture was stirred at room temperature for 20 h and then concentrated in vacuo to a residue. The residue was purified by silica gel chromatography (Merck SuperVarioPrep 90 g column, Si60 15-40 μm, eluted with methanol/dichloromethane, 4:96) to give 1-bromomethyl-3-hydroxymethyl-5-methoxy-benzene (420 mg):
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:14][CH3:15])=[C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:8]=1)[NH2:2].[CH:16]([O-])=[O:17].[Na+].C(O)=O>C(O)C>[CH:16]([NH:2][NH:1][C:3]1[CH:4]=[CH:5][C:6]([O:14][CH3:15])=[C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:8]=1)=[O:17]
Reactant: COc1ccc(NN)cc1CCC(=O)O
Reactant: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CCO
Product: COc1ccc(NNC=O)cc1CCC(=O)O

Procedure:
3-(5-Amino-2-methoxyphenyl)propionic acid (4 g, 0.02 mole), concentrated hydrochloric acid (30 ml) and water (45 ml) were stirred together at 0°. The mixture was treated with sodium nitrite (1.38 g, 0.02 mole) in water (10 ml) at 0°. The solution was then stirred for a further one-half hour. The excess of nitrous acid was destroyed with urea. The above reaction mixture was added to a solution of stannous chloride (7.6 g) in concentrated hydrochloric acid (10 ml). The precipitate (5 g) was collected by filtration. Free hydrazine was obtained from a concentrated aqueous solution of the crude hydrochloride by addition of saturated aqueous solution of sodium acetate. A mixture of 3-(5-hydrazino-2-methoxyphenyl)propionic acid (8.8 g, 0.025 mole), sodium formate (2.8 g, 0.04 mole), formic acid (18 ml) and ethanol (60 ml) was heated under reflux for one hour. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate (1 liter). The organic layer was then washed with water and dilute aqueous hydrochloric acid (1 percent). The organic layer was dried with sodium sulphate, the solvent was removed under reduced pressure and the residue crystallized from water (5 g).
Reaction SMILES: Br[C:2]1[N:3]([C:13]2[N:14]=[C:15]([I:21])[N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6].[CH2:22]([NH2:26])[CH2:23][CH2:24][CH3:25].O.CO>C(Cl)Cl>[I:21][C:15]1[N:16]=[C:17]([NH2:20])[C:18]2[N:19]=[C:2]([NH:26][CH2:22][CH2:23][CH2:24][CH3:25])[N:3]([C:13]=2[N:14]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6]
Reactant: Nc1nc(I)nc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CCCCN
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CCCCNc1nc2c(N)nc(I)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
The reaction was performed with 2-iodo-8-bromoadenosine (5, 1.15 g, 2.44 mmol) and n-butylamine (25 ml). Some drops of water were added to dissolve everything. Yield 0.92 g (1.98 mmol, 81%), mp 142–144÷C, Rƒ 0.23 (10% MeOH in CH2Cl2); 1H NMR (DMSO-d6) δ 6.94–6.86 (m, 3H, NH, NH2), 5.79 (d, 1H, J=7.56 Hz, H-1′), 5.67–5.62 (m, 1H, OH-2′), 5.30–5.16 (m, 2H, OH-3′,5′), 4.54–4.49 (m, 1H, H-2′), 4.07–4.04 (m, 1H, H-3′), 3.95–3.92 (m, 1H, H-4′), 3.64–3.57 (m, 2H, H-5′), 2.49–2.42 (m, 2H, NHCH2), 1.55–1.26 (m, 4H, CH2CH2CH3), 0.88 (t, 3H, J=7.21 Hz, CH3); MS m/z 464 (M+H)+; Anal. (C14H21IN6O4) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15].[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C(Cl)Cl>[CH3:13][N:14]([CH3:16])[CH:15]=[CH:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:10]
Reactant: CC(=O)c1ccccc1F
Reactant: COC(OC)N(C)C
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: ClCCl
Product: CN(C)C=CC(=O)c1ccccc1F

Procedure:
A mixture of 25.0 g. of o-fluoroacetophenone and 35 ml. of dimethylformamide dimethylacetal is refluxed for 16 hours. Evaporation gives a thick oil which is dissolved in methylene chloride and passed through a short column of hydrous magnesium silicate. Evaporation of the solvent gives 34.2 g. of the desired compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11].C([Li])CCC.CN(C)[CH:20]=[O:21]>O1CCCC1>[Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[C:8]([CH:20]=[O:21])[S:7][C:6]=2[C:10]=1[Cl:11]
Reactant: Oc1cc2ccsc2c(Cl)c1Cl
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc2cc(O)c(Cl)c(Cl)c2s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 8.7 g of 6,7-dichloro-5-hydroxybenzo[b]thiophene in 50 ml of anhydrous tetrahydrofuran is placed in a 250 ml 3-necked flask and cooled to -25°. To the solution under nitrogen, is added dropwise 42 ml of a solution of 2.5M n-butyllithium at a rate such that the temperature did not rise above -10°. After total addition, the mixture is stirred at 0°-5° for 3 hrs. To the mixture is added 14 ml of anhydrous dimethylformamide over a period of 20 mins. The reaction mixture is allowed to warm to room temperature and stirred for 1 hr. Quenching with 400 ml of 2N hydrochloric acid, followed by extraction with ethyl acetate, gives a precipitate. Recrystallization from acetone-hexane affords 6.5 g of 6,7-dichloro-2-formyl-5-hydroxy-benzo[b]thiophene, mp 197°-198°.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]1[C:10]#[N:11].O>C(O)(=O)C>[Br:1][C:7]1[CH:6]=[C:5]([C:10]#[N:11])[N:4]([CH3:3])[C:8]=1[CH3:9]
Reactant: Cc1ccc(C#N)n1C
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(Br)cc(C#N)n1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of bromine (6.58 mL, 0.13 mol) in acetic acid (60 mL) is added dropwise, with the aid of a dropping funnel, to a solution of 1,5-dimethyl-1H-pyrrole-2-carbonitrile (15.0 g, 0.12 mol) in acetic acid (300 mL). The batch is stirred at ambient temperature for 24 hours. The reaction mixture is then poured into a beaker containing 300 mL of water.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.CC([O-])(C)C.[K+].[O:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]1>CS(C)=O>[O:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH2:19][CH2:18]1
Reactant: OCCN1CCOCC1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(OCCN2CCOCC2)nc1
Temperature: 95 °C
Yield: 9.4 %

Procedure:
To a solution of 6-chloronicotinic acid (Aldrich, 1.00 g, 6.35 mmol) and t-BuOK (1.42 g, 12.7 mmol) in DMSO (10.0 mL) was added 2-morpholinoethanol (1.5 mL, 12.7 mmol) at room temperature. The reaction mixture was then heated at 95° C. for 16 h. Additional t-BuOK (1.42 g, 12.7 mmol), 2-morpholinoethanol (1.54 mL, 12.7 mmol) and DMSO (10.0 mL) were added, and the reaction mixture was heated at 95° C. for another 24 h. The reaction mixture was then cooled to room temperature, poured into ice cold 4N aq. HCl solution and extracted with EtOAc (3×). The aqueous layer was concentrated in vacuo to near dryness and purified using preparative HPLC to give the title compound (150 mg, 9%) as a white solid after lyophilization. 1H NMR (DMSO-d6) δ 13.1 (br s, 1H), 8.74 (d, J=1.8 Hz, 1H), 8.21 (dd, J=8.6, 2.2 Hz, 1H), 6.98 (d, J=8.6 Hz, 1H), 4.69 (br s, 4H), 3.96 (br s, 2H), 3.75-3.70 (m, 2H), 3.19 (br s, 4H); MS(ESI+) m/z 253.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([NH:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]3[N:13]=[C:14]([S:16][CH3:17])[O:15][C:11]=3[CH:10]=2)=[C:5]([N+:22]([O-])=O)[CH:4]=1.CC(O)=O.CO>C(Cl)Cl.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:22])[C:6]([NH:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]3[N:13]=[C:14]([S:16][CH3:17])[O:15][C:11]=3[CH:10]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(NCc2ccc3nc(SC)oc3c2)c([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(NCc2ccc3nc(SC)oc3c2)c(N)c1
Reaction time: 2 h
Yield: 79 %

Procedure:
To a stirred solution of 4-methoxy-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitroaniline (1.07 g, 3.11 mmol), HOAc (3.7 mL) and MeOH (3.7 mL) in DCM (40 mL) at 0° C. was added zinc dust (2.02 g, 31.1 mmol) portionwise. After stirring for 2 h, the mixture was filtered. The filtrate was washed with aq NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure to give 4-methoxy-N1-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)benzene-1,2-diamine (775 mg, 79.1%). 1H NMR (300 MHz, DMSO-d6) δ 7.60 (s, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.35 (d, J=9.6 Hz, 1H), 6.26 (d, J=8.1 Hz, 1H), 6.21 (s, 1H), 5.97 (d, J=9.0 Hz, 2H), 4.74 (t, 1H), 4.68 (s, 1H), 4.31 (d, J=5.7 Hz, 1H), 3.55 (s, 3H), 2.74 (s, 3H). LCMS (ESI) m/z 316 (M+H)+.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C([O-])(=O)C.[Na+].Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:23][CH2:22]1.O>CS(C)=O>[O:7]=[C:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:12])[N:2]1[O:1][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:25][CH2:26]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1N1CCN(CCON2C(=O)c3ccccc3C2=O)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 50.6 %

Procedure:
A mixture of 6.73 g of N-hydroxyphthalimide, 3.73 g of sodium acetate and 10 g of 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine in 100 ml of anhydrous dimethylsulfoxide was stirred at 100° C. for 4 hours. The reaction mixture was then cooled to room temperature, poured into water and extracted with ethyl acetate. The collected organic layers were washed with 1N aqueous sodium hydroxide solution, dried on anhydrous sodium sulfate and evaporated to dryness in vacuo to give 7.58 g of the title compound. A sample was crystallized from cyclohexane, m.p. (76) 80°-83° C.
Reaction SMILES: [NH2:1][C:2](=NO)[C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1.C(#[N:30])C>[Pd]>[NH2:30][N:1]=[CH:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCc1ccc(CNC(=O)c2cccc(C(N)=NO)c2)cc1
Reactant: CC#N
Agent: [Pd]
Product: CCOC(=O)CCc1ccc(CNC(=O)c2cccc(C=NN)c2)cc1

Procedure:
The compound of Example 13 (0.49 g, 1.3 mmol) was dissolved in ACOH and hydrogenated with 4% Pd/C (53% wet, 0.050 g) in a Parr Shaker (60 psi, 60C). The catalyst was filtered off and the filtrate concentrated in vacuo to give a white solid. The solid was slurried with acetonitrile and the resulting white solid was collected by vacuum filtration (0.423 g). Analysis Calculated for C20H23N3O3.1.6 AcOH: C, 61.99; H, 6.59; N, 9.35. Found: C, 61.81; H, 6.50; N, 9.42. M+=353.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li].[CH3:15][C:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[C:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.O>O1CCCC1>[CH:17]1([C:16]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH3:15])[CH:21]=[CH:20][CH:19]=[CH:18]1
Reactant: CC(=C1C=CC=C1)c1ccccc1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: CC(c1ccccc1)(C1C=CC=C1)C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A solution of 67.8 mmol of lithium-fluorene in 50 cm3 of tetrahydrofuran was added to a solution of 11.4 g (67.8 mmol) of 6-methyl-6-phenylfulvene in 40 cm3 of tetrahydrofuran at room temperature. After the mixture had been stirred at room temperature for 2 hours, 60 cm3 of water were added. The substance which precipitated out was filtered off with suction, washed with diethyl ether and dried under an oil pump vacuum. 19.2 g (84.2%) of 1-cyclopentadienyl-1-(9-fluorenyl)-ethylbenzene were obtained (correct elemental analyses; 1 H-NMR spectrum). 10.0 g (19.9 mmol) of the compound were dissolved in 60 cm3 of tetrahydrofuran and 26 cm3 (65 mmol) of a 2.5 molar hexane solution of n-butyllithium were added at 0° C. After the mixture had been stirred for 15 minutes, the solvent was stripped off in vacuo. The dark red residue which remained was washed several times with hexane and dried under an oil pump vacuum. 15.6 g of the red dilithium salt were obtained as the tetrahydrofuran adduct which contained about 30% of tetrahydrofuran. A suspension of 4.78 g (14.9 mmol) of HfCl4 in 70 cm3 of CH2CH2 was reacted with 14.9 mmol of the dilithium salt and the reaction product was worked up. Crystallization at -35° C. gave 2.6 g (30%) of the hafnocene dichloride compound as orange crystals. Correct elemental analysis.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][N:10]=[C:4]2[C:3]=1[C:17]#[N:18].O(Cl)[Cl:20].[P+5].C([O-])(O)=O.[Na+].P(Cl)(Cl)(Cl)=O>CCOCC.CCOC(C)=O>[Cl:20][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][N:10]=[C:4]2[C:3]=1[C:17]#[N:18]
Reactant: ClOCl
Reactant: N#Cc1c(O)ccn2c(-c3ccccc3)cnc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [P+5]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1c(Cl)ccn2c(-c3ccccc3)cnc12
Temperature: 120 °C
Yield: 33 %

Procedure:
A mixture of compound D5 (2.3 g, 9.77 mmol) and phosphorus(V) oxychloride (50 ml) was heated at 120° C. for 5 h. After cooling to room temperature the solvents were evaporated in vacuo. The residue thus obtained was carefully poured into a mixture of crushed ice and NaHCO3 (aqueous sat. solution). Then EtOAc was added and the mixture was stirred for 2 h. until complete hydrolysis of the remaining phosphorus oxychloride had occurred. The organic layer was then separated, washed with brine, dried (Na2SO4) and the solvent evaporated in vacuo to give a residue that forms a precipitate upon the addition of Et2O. The solid was filtered off and dried in vacuo to yield compound D6 (0.82 g, 33%) as yellow solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][N:9]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23])[CH2:10][CH2:11][N:12]1[CH:17]=[CH:16][C:15]2[CH:18]=[CH:19][O:20][C:14]=2[C:13]1=[O:21])(=O)=O.[I-:34].[Na+].CC(C)=O>O>[I:34][CH2:6][CH2:7][CH2:8][N:9]([CH2:10][CH2:11][N:12]1[CH:17]=[CH:16][C:15]2[CH:18]=[CH:19][O:20][C:14]=2[C:13]1=[O:21])[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)OCCCN(CCn1ccc2ccoc2c1=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=c1c2occc2ccn1CCN(CCCI)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92.9 %

Procedure:
3-{(2-Nitrobenzenesulfonyl)-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]amino}propyl methanesulfonate (480 mg, 0.96 mmol) and sodium iodide (720 mg, 4.8 mmol) were added to acetone (20 ml), and heated under reflux for 5 hours. The reaction mixture was cooled to room temperature, water was added, and extraction with dichloromethane was performed. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure to thereby obtain 474 mg (yield: 93%) of N-(3-iodopropyl)-2-nitro-N-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]benzenesulfonamide as a yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:20])[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH3:21][NH:22][C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>O.O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([Cl:20])[C:5]2[C:10]([C:28]3[CH:29]=[CH:30][C:25]([C:23]([NH:22][CH3:21])=[O:24])=[CH:26][CH:27]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(Cl)c23)cc1
Temperature: 90 °C
Yield: 68 %

Procedure:
2,4-Dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), (4-(methylcarbamoyl)phenyl)boronic acid (1.2 equiv), sodium carbonate (3 equiv) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (0.1 equiv) were combined in a 5:1 mixture of 1,4-dioxane and water (0.27 M). The mixture was heated to 90° C. for 3 h. The crude product was purified on silica gel (0-100% ethyl acetate in hexane) to give the title compound (68% yield) an orange solid. MS (ESI) m/z 451.2 [M]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:19])[S:9][C:10]=1[C:11](=[O:16])N(OC)C.[CH:26]1([Mg]Br)[CH2:28][CH2:27]1.[Cl-].[NH4+]>C1COCC1>[CH:26]1([C:11]([C:10]2[S:9][C:8]([NH:17][C:18]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[O:19])=[N:7][C:6]=2[C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:16])[CH2:28][CH2:27]1
Reactant: Br[Mg]C1CC1
Reactant: CON(C)C(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CC2)s1)c1ccncc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78 %

Procedure:
Compound 98 (127 mg, 0.355 mmol) was suspended in THF (2.5 mL), and a 0.5 mol/L solution of cyclopropylmagnesium bromide in THF (4.00 mL, 2.00 mmol) was added thereto under ice-cooling, followed by stirring at room temperature for 2.5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with a mixed solvent (4:1) of chloroform and 2-propanol. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried, over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate) to afford the entitled Compound 417 (94.1 mg, 78%) as a pale yellow solid.