Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:28]1([C:34]2[CH:47]=[C:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:45]3[C:36](=[C:37]4[C:42](=[CH:43][CH:44]=3)[C:41]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:40][CH:39]=[N:38]4)[N:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>C1COCC1>[C:28]1([C:34]2[CH:47]=[C:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:45]3[C:36](=[C:37]4[C:42](=[CH:43][CH:44]=3)[C:41]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)=[CH:40][C:39]([C:2]3[CH:7]=[CH:6][C:5]([C:8]5[N:12]([C:13]6[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=6)[C:11]6[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=6[N:9]=5)=[CH:4][CH:3]=3)=[N:38]4)[N:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: c1ccc(-c2cc(-c3ccccc3)c3ccc4c(-c5ccccc5)ccnc4c3n2)cc1
Reactant: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(-c2cc(-c3ccccc3)c3ccc4c(-c5ccccc5)cc(-c5ccc(-c6nc7ccccc7n6-c6ccccc6)cc5)nc4c3n2)cc1
Temperature: -78 °C
Yield: 47 %

Procedure:
To a three-necked flask of 250 ml, 3.84 g (11 mmol) of 2-(4-bromophenyl)-1-phenyl-1H-benzo[d]imidazole and 70 ml of THF were charged, then 6.9 ml (11 mmol) n-butyllithium (1.6M in Hexane solution) was dropped under stirring at −78° C. in a nitrogen atmosphere. The mixture was stirred for one hour at −78° C., and a solution of 2.29 g (5.6 mmol) 2,4,7-triphenyl-1,10-phenanthroline in 30 ml THF was dropped. Then the mixture was stirred at room temperature for overnight and was added with water. The organic layer was extracted with Dichloromethane and dried with anhydrous magnesium sulfate, the solvent was removed by rotary evaporation. The product was purified by column chromatography on alumina using Dichloromethane/Hexane as eluent and dried in vacuo, obtaining white powder compound 1.78 g (yield of 47.12%). MS (m/z, FAB+) 676.8(100%).
Reaction SMILES: [NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].OC1C2N=NNC=2C=CC=1.[NH2:35][CH2:36][C:37]([NH:39][CH2:40][C:41]([NH2:43])=[O:42])=[O:38].Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:12]([NH:35][CH2:36][C:37]([NH:39][CH2:40][C:41]([NH2:43])=[O:42])=[O:38])=[O:14])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: NCC(=O)NCC(N)=O
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)NCC(N)=O
Reaction time: 0.17 h
Yield: 86.2 %

Procedure:
40 mL of Dimethyl formamide was added to 2.52 g (7.47 mmol) of Z-Glu(OtBu)-OH, 1.3 g (8.49 mmol) of hydroxybenzotriazole, 1.3 g (7.76 mmol) of H-Gly-GlyNH2, and 1.52 g (7.93 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride. 2.5 mL (14.3 mmol) of diisopropyl ethyl amine was added and the reaction was stirred over night. The reaction mixture was purified in three equal portions by direct injection on a preparative 5 cm×25 cm C18 HPLC column. The column was run at 100 mL/min with deionized water containing 0.3% formic acid with 5% acetonitrile for 10 min followed by a 15 min linear gradient from 5% acetonitrile to 90% acetonitrile. Product fractions (retention time 18-20 min) were combined and solvent was removed by rotary evaporation under vacuum to give 2.9 g (83%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.79-7.68 (m, 1H), 7.64 (s, 1H), 7.27 (q, J=4.9, 5H), 6.90 (s, 1H), 6.42 (s, 1H), 6.35 (d, J=6.8, 1H), 5.08 (d, J=12.0, 1H), 4.98 (d, J=12.2, 1H), 4.20 (dd, J=12.9, 7.6, 1H), 3.84-3.95 (m, 2H), 3.83 (d, J=5.0, 2H), 2.42-2.19 (m, 2H), 2.07 (d, J=6.9, 1H), 1.96-1.83 (m, 1H), 1.39 (s, 9H). 13C NMR (101 MHz, DMSO) δ 171.79, 171.65, 170.82, 168.87, 163.04, 156.08, 136.86, 128.31, 127.74, 79.64, 65.58, 53.96, 42.17, 41.81, 31.25, 27.73, 27.01.
Reaction SMILES: [C:1]([C:3]1[N:4]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=2[O:37][CH3:38])[C:5](=[O:27])[N:6]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19](C)[CH:18]=2)[C:7]=1[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)#[N:2].[CH3:39][S:40]([O:43][CH2:44][CH2:45][CH2:46]OS(C)(=O)=O)(=[O:42])=[O:41].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:39][S:40]([O:43][CH2:44][CH2:45][CH2:46][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:7]2[N:6]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[C:5](=[O:27])[N:4]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=3[O:37][CH3:38])[C:3]=2[C:1]#[N:2])=[CH:9]1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)OCCCOS(C)(=O)=O
Reactant: COc1ccc(Cn2c(C#N)c(-c3c[nH]c4ccccc34)n(-c3cn(C)c4ccccc34)c2=O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(C#N)c(-c3cn(CCCOS(C)(=O)=O)c4ccccc34)n(-c3c[nH]c4ccccc34)c2=O)c(OC)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution 0.15 g (0.298 mmol) of the product from step b) in 2 ml of DMF was 0.40 g (1.72 mmol) of 1,3-propandiol bismethansulfonate and 0.50 g (3.62 mmol) of K2CO3. The mixture was stirred at 70° C. overnight and partitioned between EtOAc and water. The organic phase was washed with water and brine and finally evaporated. The residue was purified by chromatography on silica furnishing 0.11 g (59%) of the sub-title compound.
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1[CH:25]=[C:24]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH:23]=[CH:22][C:8]=1[O:9][C:10]1[CH:11]=[C:12]([CH2:18][C:19]([OH:21])=[O:20])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])([CH3:4])([CH3:3])[CH3:2].[CH2:33]([O:40][C:41]([C@H:43]1[C@H:48]([OH:49])[C@@H:47]([OH:50])[C@H:46]([OH:51])[C@H:45](O)[O:44]1)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CC#N>[CH2:33]([O:40][C:41]([C@H:43]1[C@H:48]([OH:49])[C@@H:47]([OH:50])[C@H:46]([OH:51])[C@H:45]([O:20][C:19](=[O:21])[CH2:18][C:12]2[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:10]([O:9][C:8]3[CH:22]=[CH:23][C:24]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:25][C:7]=3[CH2:6][S:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=2)[O:44]1)=[O:42])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1O[C@@H](O)[C@@H](O)[C@H](O)[C@H]1O
Reactant: COc1ccc(CC(=O)O)cc1Oc1ccc(NC(=O)C(C)(C)C)cc1CSC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COc1ccc(CC(=O)O[C@@H]2O[C@@H](C(=O)OCc3ccccc3)[C@H](O)[C@@H](O)[C@@H]2O)cc1Oc1ccc(NC(=O)C(C)(C)C)cc1CSC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid (0.200 g, 0.44 mmol), (2R,3R,4R,5S,6R)-3,4,5,6-tetrahydroxy-tetrahydro-pyran-2-carboxylic acid benzyl ester (0.200 g, 0.7 mmol; prepared according to the procedure described in Tetrahedron 2007, 63, 7596), HATU (0.266 g, 0.7 mmol), and N-methylmorpholine (0.1 mL, 0.7 mmol) were combined in MeCN, and the reaction was stirred overnight at room temperature. The mixture was concentrated, and the residue was purified by preparative HPLC to give (2R,3R,4R,5S,6S)-6-(2-{3-[2-tert-butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetoxy)-3,4,5-trihydroxy-tetrahydro-pyran-2-carboxylic acid benzyl ester, which was subsequently treated with palladium hydroxide on carbon and stirred under an atmosphere of H2 overnight. The crude material was purified by preparative HPLC to give (2R,3R,4R,5S,6S)-6-(2-{3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetoxy)-3,4,5-trihydroxy-tetrahydro-pyran-2-carboxylic acid.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](Cl)[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([NH:14][C@H:12]([C:10]2[N:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]3[CH:21]=[C:4]([F:3])[CH:5]=[CH:6][C:7]=3[N:11]=2)[CH3:13])[N:26]=[CH:25][N:24]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Reactant: N#Cc1c(N)ncnc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 90 °C
Yield: 64.3 %

Procedure:
(S)-1-(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (328 mg, 1.00 mmol) was placed in a sealed tube with 4-amino-6-chloropyrimidine-5-carbonitrile (154.5 mg, 1.00 mol), DIPEA (0.7 mL, 4.00 mol) and IPA (1 mL). The tube was flushed with argon, sealed and the contents heated at 90° C. for 16 h. The cooled mixture was evaporated then diluted with EtOAc and water. The organic layer was washed with brine, dried (MgSO4) and evaporated. The crude residue was purified by chromatography on silica (Si—PCC, 1-80% EtOAc in DCM). The product containing fractions were pooled and evaporated almost to dryness. The residue was triturated in ether to afford 246 as a cream solid (240 mg, 65%). 1H NMR (CDCl3, 400 MHz): δ 8.01 (1H, s), 7.69 (1H, dd, J=8.8, 4.7 Hz), 7.59-7.49 (3H, m), 7.43-7.36 (2H, m), 7.02 (1H, td, J=9.2, 1.1 Hz), 6.77 (1H, dd, J=8.6, 2.4 Hz), 6.18 (1H, d, J=7.5 Hz), 5.52 (1H, quin, J=7.2 Hz), 5.30 (2H, br s), 1.54 (3H, d, J=6.9 Hz). LCMS (Method K): RT 3.80 min [M+H]+ 374
Reaction SMILES: BrC1C=CC([C:8]2[CH:21]=[CH:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11][C:10]=3[CH:9]=2)=CC=1.C1C2C=CC3C(=CC=CC=3)C=2C=C(B(O)O)C=1.[Br:39][C:40]1[CH:41]=[C:42](I)[CH:43]=[CH:44][CH:45]=1>>[Br:39][C:40]1[CH:45]=[C:44]([C:10]2[CH:11]=[CH:12][C:21]3[CH:20]=[CH:19][C:18]4[C:17]([C:8]=3[CH:9]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:43]=[CH:42][CH:41]=1
Reactant: Brc1ccc(-c2ccc3c(ccc4ccccc43)c2)cc1
Reactant: Brc1cccc(I)c1
Agent: OB(O)c1ccc2ccc3ccccc3c2c1
Product: Brc1cccc(-c2ccc3ccc4ccccc4c3c2)c1

Procedure:
Synthesis was performed in the same manner as in the synthesis of 2-(4-bromophenyl)phenanthrene except that: phenanthrene-3-boronic acid was used instead of phenanthrene-2-boronic acid; and 3-bromoiodobenzene was used instead of 4-bromoiodobenzene.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[N:25][OH:26])=[CH:19][CH:18]=1.C(N(CC)CC)C>O1CCCC1>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[CH:2]=[C:1]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=3)[O:26][N:25]=2)=[CH:19][CH:18]=1
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccn2)cc1
Reactant: C#Cc1cccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: c1ccc(COc2ccc(Cc3cc(-c4cccnc4)on3)cc2)nc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 42.6 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynylpyridine (50 mg, 0.485 mmol) and (4-(pyridin-2-ylmethoxy)-phenyl)-acetohydroximoyl chloride (215 mg, 0.776 mmol) described in Manufacturing Example 203-1-4 was added triethylamine (270 μL, 1.94 mmol), which was stirred for 2.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4 to 1:2, then 1:1) to obtain the title compound (71 mg, 43%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([OH:9])[CH2:8][CH2:7][O:6][CH2:5]1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][C:17](=O)[O:18]C1C=CC=CN=1>C1COCC1.CCOC(C)=O>[C:17](=[O:18])([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=1)[O:9][C:4]1([CH3:3])[CH2:8][CH2:7][O:6][CH2:5]1
Reactant: CC1(O)CCOC1
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(OC(=O)Oc2ccccn2)CCOC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
To a suspension of sodium hydride, 60% in mineral oil (185 mg, 4.63 mmol) in THF (20 mL) was added 3-methyltetrahydrofuran-3-ol (394 mg, 3.86 mmol) at 0° C. After stirring 30 min, the solution was transferred to a solution of di(pyridin-2-yl)carbonate (834 mg, 3.86 mmol) in THF (20 mL) through a cannula. The formed slurry was stirred at 0° C. for 30 min. The slurry was warmed to rt and stirred for 2 h. The reaction was diluted with EtOAc, washed with brine, dried over MgSO4, filtered, concentrated to give a residue that was purified by Biotage (5-40% EtOAc:Hex) to afford the desired product 3-methyltetrahydrofuran-3-yl pyridin-2-yl carbonate (334 mg, 38.8% yield) as an oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.48-8.29 (m, 1H), 7.91-7.73 (m, 1H), 7.29-7.25 (m, 1H), 7.16-7.12 (m, 1H), 4.23 (d, J=10.3 Hz, 1H), 4.02 (td, J=8.5, 7.2 Hz, 1H), 3.95 (td, J=8.4, 4.5 Hz, 1H), 3.76 (d, J=10.3 Hz, 1H), 2.58-2.47 (m, 1H), 2.11-2.02 (m, 1H), 1.76 (s, 3H).
Reaction SMILES: [C:1]([C:3]1([C:13](OC)=[O:14])[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2)#[N:2].CO.[BH4-].[Li+]>O1CCCC1>[OH:14][CH2:13][C:3]1([C:1]#[N:2])[CH:4]2[CH2:12][CH:8]3[CH2:7][CH:6]([CH2:11][CH:10]1[CH2:9]3)[CH2:5]2
Reactant: COC(=O)C1(C#N)C2CC3CC(C2)CC1C3
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: N#CC1(CO)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Yield: 91.3 %

Procedure:
To a solution of methyl 2-cyanoadamantane-2-carboxylate (1.33 g, 6.07 mmol) in anhydrous tetrahydrofuran (50 mL) was added anhydrous methanol (0.49 mL, 12 mmol) and lithium borohydride (4.0 M solution in tetrahydrofuran, 3.0 mL, 12 mmol). The mixture was heated to reflux under a nitrogen atmosphere for 7 hours, cooled to ambient temperature and quenched with careful addition of saturated aqueous ammonium chloride (10 mL). The mixture was diluted with ethyl acetate (200 mL), washed with a 3:1 mixture of saturated aqueous ammonium chloride and water (2×200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound (1.06 g, 91%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 3.92 (s, 2H), 2.24-2.20 (m, 2H), 2.10-1.97 (m, 4H), 1.86-1.84 (m, 5H), 1.73-1.64 (m, 4H); MS (ES−) m/z 192.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].Br[CH:13]([CH3:17])[C:14](=O)[CH3:15]>C1(=O)CCCCC1>[NH2:1][C:2]1[C:3]2[N:4]([C:13]([CH3:17])=[C:14]([CH3:15])[N:11]=2)[CH:5]=[C:6]([C:7]([NH2:9])=[O:8])[CH:10]=1
Reactant: CC(=O)C(C)Br
Reactant: NC(=O)c1cnc(N)c(N)c1
Solvent: O=C1CCCCC1
Product: Cc1nc2c(N)cc(C(N)=O)cn2c1C
Temperature: 20 °C
Reaction time: 2 h
Yield: 129.5 %

Procedure:
5,6-Diamino-nicotinamide (30.0 g; 0.183 mol; 1.0 equiv) was suspended in cyclohexanone (280 mL). 3-Bromo-2-butanone (24 mL; 0.22 mol; 1.2 equiv) was added and the mixture was heated for 4 h to 100° C. The reaction mixture was cooled to 20° C. and allowed to stir for another 2 h. The solid was filtered off, washed with TBME (200 mL) and dried to yield 48.4 g of the title compound. Yield: 78%.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)([O-:5])=[O:4].[CH3:15][NH:16][C:17](=O)[O:18]C1C=CC=CC=1>CN(C)C=O>[CH3:15][NH:16][C:17]([N:11]1[C:12]2[C:8](=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)=[O:18]
Reactant: CNC(=O)Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Yield: 52.7 %

Procedure:
Sodium hydride (60% in oil, 228 mg, 5.7 mmol) was gradually added to a N,N-dimethylformamide (0.5 ml) solution of 5-nitroindole (0.841 g, 5.19 mmol) while stirring at room temperature; phenyl N-methylcarbamate (1.02 g, 6.74 mmol) was added thereto; and the reaction mixture was stirred overnight. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was washed with water and brine, dried over anhydrous sodium sulfate. This was concentrated under reduced pressure; and the residue was purified by silica gel column chromatography (hexane-ethyl acetate, sequentially ethyl acetate) to yield the title compound (600 mg).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:13]>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: N#Cc1ccc(C=O)cc1
Product: N#Cc1ccc(C=CC(=O)c2ccc(F)cc2)cc1

Procedure:
3-(4cyanophenyl)-1-(4-fluorophenyl)prop-2-en-1-one is prepared according to the procedure described in Example 4a using 4-cyanobenzaldehyde and 4-fluoroacetophenone as starting materials.
Reaction SMILES: C1([C@H]2[C@H](C3C4C(=CC=CC=4)NC=3)C(=O)NC2=O)C2=C3C(=CC=C2)CCCN3C=1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30]1.[Br:38][C:39]1[C:40](=[O:52])[N:41]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:42](=[O:45])[C:43]=1Br.C[Mg]Br>>[Br:38][C:39]1[C:40](=[O:52])[N:41]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:42](=[O:45])[C:43]=1[C:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH:29][CH:30]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1C(Br)=C(Br)C(=O)N1c1ccccc1
Agent: C[Mg]Br
Agent: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1c[nH]c2ccccc12
Product: O=C1C(Br)=C(c2c[nH]c3ccccc23)C(=O)N1c1ccccc1

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione may be prepared by reacting 1H-indole and 3,4-dibromo-1-phenyl-pyrrole-2,5-dione in the presence of methyl magnesium bromide to yield 3-bromo-4-(1H-indol-3-yl)-1-phenyl-pyrrole-2,5-dione. The 3-bromo-4-(1H-indol-3-yl)-1-phenyl-pyrrole-2,5-dione is subsequently reacted with 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline and LiHMDS (lithium hexamethyldisilane) in toluene or (5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-boranediol and Pd(PPh3)-4-(tetrakis(triphenylphosphine)palladium) to yield 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1-phenyl-pyrrole-2,5-dione, which is reduced and deprotected by treatment with Mg in methanol, as in Example 2 procedure C, followed by catalytic hydrogenation over palladium on carbon to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl) pyrrolidine-2,5-dione. Bnz is benzyl.
Reaction SMILES: C1C(=O)N(Br)C(=O)C1.[CH:9]1[C:13]2=[C:14]([NH2:18])[N:15]=[CH:16][N:17]=[C:12]2[N:11]([C@@H:19]2[O:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[CH2:20]2)[CH:10]=1.C[C:28]([O-:30])=[O:29].[Na+]>CN(C=O)C>[NH2:18][C:14]1[C:13]2[C:9]([C:28]([OH:30])=[O:29])=[CH:10][N:11]([C@@H:19]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[CH2:20]3)[C:12]=2[N:17]=[CH:16][N:15]=1
Reactant: CC(=O)[O-]
Reactant: Nc1ncnc2c1ccn2[C@H]1C[C@H](O)[C@@H](CO)O1
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(C(=O)O)cn2[C@H]1C[C@H](O)[C@@H](CO)O1
Reaction time: 0.17 h

Procedure:
NBS (1.42 g, 8.0 mmol, dissolved in 4 ml of dried DMF) is added, at room temperature, to a solution of 2′-deoxytubercidin (1.0 g, 4.0 mmol) and NaOAc (0.78 g, 8.0 mmol) in dried DMF (10 ml). The red solution is stirred for 10 minutes and then evaporated. Title compound (38) is obtained as colorless crystals (400 mg, 25%) following flash chromatography (column: 20×5 cm, CH2Cl2/MeOH, 9:1), evaporation of the more rapidly migrating zone and subsequent recrystallization from isopropanol. Isolation of the more slowly migrating zone yields 5-bromo-2′-deoxytubercidin (130 mg, 10%). Method B: a solution of NBS (1.42 g, 8.0 mmol, dissolved in 4 ml of dried DMF) is added to a solution of 5-bromo-2′-deoxytubercidin (1.3 g, 4.0 mmol) and NaOAc (0.785 g, 8.0 mmol) in dried DMF (10 ml). Purification, see method A. Yield: 490 mg, 30% of 21. Melting point: 181° C. TLC (silica gel, CH2Cl2/MeOH, 9:1): Rf 0.40. 1H-NMR (D6-DMSO): δ=2.12 (m, Hα-2′); 2.50 (m, Hβ-2′); 3.51 (m, 2H, H-5′); 3.84 (m, 1H, H-4′); 4.44 (m, 1H, H-3′); 5.20, (br, 2H, 5′-OH, 3′-OH); 6.42 (“t”, J=6.2 Hz, 1H, H-1′); 6.93 (br, 2H, NH2); 8.10 (s, 1H, H-2).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].[CH3:6][N:7]1[C:11]([CH:12]=O)=[CH:10][N:9]=[C:8]1[N+:14]([O-:16])=[O:15]>CO>[OH:1][CH2:2][CH2:3][NH:4][N:5]=[CH:12][C:11]1[N:7]([CH3:6])[C:8]([N+:14]([O-:16])=[O:15])=[N:9][CH:10]=1
Reactant: NNCCO
Reactant: Cn1c(C=O)cnc1[N+](=O)[O-]
Solvent: CO
Product: Cn1c(C=NNCCO)cnc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
A solution of 0.300 g. of 2-hydroxyethylhydrazine and 0.4 g. of 1-methyl-2-nitro-5-imidazolecarboxaldehyde in 20 ml. of methanol is allowed to stand for two days. The solid which precipitates is recovered on the filter and washed with water. Yield: 0.245 g., m.p. 138°-140° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].[S:22]1(=[O:28])(=[O:27])[CH:26]=[CH:25][CH2:24][CH2:23]1.CO>C1COCC1>[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:17][CH2:18][N:19]([CH:24]4[CH2:25][CH2:26][S:22](=[O:28])(=[O:27])[CH2:23]4)[CH2:20][CH2:21]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(OC2CCNCC2)c2ncccc2c1
Reactant: O=S1(=O)C=CCC1
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1cc(OC2CCN(C3CCS(=O)(=O)C3)CC2)c2ncccc2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
To a solution of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, as prepared for Intermediate 4) (0.15 g, 0.53 mmol) in THF (5 ml) was added 2,3-dihydrothiophene 1,1-dioxide (commercially available, for example, from AKOS) (0.150 g, 1.27 mmol). The solution was heated to 80° C. for 2.5 h. To the solution at ambient temperature was added a further amount of 2,3-dihydrothiophene 1,1-dioxide (0.150 g, 1.27 mmol) and the solution stirred overnight at ambient temperature. The solution was heated to reflux for 2 h and then at ambient temperature for 7 days. The reaction was applied to an SCX-2 cartridge (20 g), preconditioned with methanol, and the cartridge washed with methanol (2 column volumes). The cartridge was eluted with 10% 0.880 s.g. ammonia in methanol (2 column volumes) and the basic fractions concentrated in vacuo. The residue was purified by MDAP and the appropriate fractions combined and evaporated. The combined fractions were applied to an SCX-2 cartridge (20 g), preconditioned with methanol, and the cartridge washed with methanol. The cartridge was eluted with 10% 0.88 s.g. ammonia in methanol (2 column volumes) and the basic fractions concentrated in vacuo to give the title compound (17 mg, 8%). LCMS RT=2.59 min, ES+ve m/z 403 (M+H)+.