Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.OC(C(F)(F)F)=O.[CH:20]1([C:26]2[C:27]3[CH:28]=[CH:29][C:30]([C:57](OC(C)(C)C)=[O:58])=[CH:31][C:32]=3[N:33]3[CH2:39][C:38]([C:40]([N:42]4[CH:47]5[CH2:48][CH2:49][CH:43]4[CH2:44][N:45]([CH3:50])[CH2:46]5)=[O:41])=[CH:37][C:36]4[CH:51]=[C:52]([O:55][CH3:56])[CH:53]=[CH:54][C:35]=4[C:34]=23)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[CH2:64]([C:66]1([S:69]([NH2:72])(=[O:71])=[O:70])[CH2:68][CH2:67]1)[CH3:65].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:20]1([C:26]2[C:27]3[CH:28]=[CH:29][C:30]([C:57]([NH:72][S:69]([C:66]4([CH2:64][CH3:65])[CH2:68][CH2:67]4)(=[O:71])=[O:70])=[O:58])=[CH:31][C:32]=3[N:33]3[CH2:39][C:38]([C:40]([N:42]4[CH:43]5[CH2:49][CH2:48][CH:47]4[CH2:46][N:45]([CH3:50])[CH2:44]5)=[O:41])=[CH:37][C:36]4[CH:51]=[C:52]([O:55][CH3:56])[CH:53]=[CH:54][C:35]=4[C:34]=23)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COc1ccc2c(c1)C=C(C(=O)N1C3CCC1CN(C)C3)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Reactant: CCC1(S(N)(=O)=O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Product: CCC1(S(=O)(=O)NC(=O)c2ccc3c(C4CCCCC4)c4n(c3c2)CC(C(=O)N2C3CCC2CN(C)C3)=Cc2cc(OC)ccc2-4)CC1
Temperature: 60 °C
Yield: 17 %

Procedure:
CDI (80 mg, 0.49 mmol) was added to a solution of tert-butyl 13-cyclohexyl-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate TFA (200 mg, 0.30 mmol) in THF (1.5 mL) and the reaction mixture was heated at 60° C. for 2 h. The reaction was cooled to rt and then ⅓ (˜0.55 mL) of the reaction solution was added to a stirring solution of 1-ethylcyclopropane-1-sulfonamide (40 mg, 0.27 mmol) in DBU (0.20 mL, 1.3 mmol) and THF (0.20 mL). The reaction was stirred at rt ON (˜75% conversion by LCMS), concentrated to an oil, quenched with 1N HCl (˜1 mL) (prec. formed) and extracted with EtOAc (2×1 mL) and DCM (2×1 mL). The combined organics were concentrated to dryness, dissolved into MeOH (1.5 mL) and purified by preparative HPLC (CH3CN/H2O with 10 mM NH4OAc) to yield 13-cyclohexyl-N-((1-ethylcyclopropyl)sulfonyl)-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (30.9 mg, 0.046 mmol, 45% yield) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ ppm 0.97-2.35 (m, 29H), 2.56-2.73 (m, 1H), 2.80-2.94 (m, 1H), 3.38-3.58 (m, 1H), 3.94 (s, 3H), 4.29-4.64 (m, 2H), 5.14-5.31 (m, 1H), 7.05 (s, 1H), 7.09-7.20 (m, 2H), 7.57 (d, J=8.4 Hz, 1H), 7.65 (dd, J=8.4, 1.5 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 8.16 (br s, 1H). LC-MS retention time: 2.91 min; m/z 669 (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[C:27]1[O:28][CH2:29][CH:30]([C:32]2[CH:37]=[CH:36][C:35](I)=[CH:34][CH:33]=2)[N:31]=1>C1COCC1.[Cl-].[Cl-].[Zn+2].C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[F:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[C:21]=1[C:27]1[O:28][CH2:29][CH:30]([C:32]2[CH:33]=[CH:34][C:35]([C:2]3[CH:7]=[CH:6][C:5]([S:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=3)=[CH:36][CH:37]=2)[N:31]=1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(I)cc2)CO1
Reactant: CC(C)[Si](Sc1ccc(Br)cc1)(C(C)C)C(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: C1CCOC1
Product: CC(C)[Si](Sc1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.8 %

Procedure:
The title compound of Step A (4.3 g) was dissolved in 15 mL of THF under a nitrogen atmosphere and the reaction mixture was cooled below -65° C. and then 4.7 mL of 2.5 M n-BuLi/hexanes solution was added dropwise. After 15 minutes, 26 mL of 0.5 M ZnCl2 /THF solution was added dropwise. In a separate reaction flask, 67 mg of Pd(OAc)2 was added to a solution of 201 mg of tri(o-tolyl)phosphine in 5 mL of THF, and this mixture was stirred for 5 minutes before its addition, via cannula, to the main reaction mixture. A solution of 3.85 g of 2-(2,6-difluorophenyl)-4,5-dihydro-4-(4-iodophenyl)oxazole (prepared as described in WO 95/04726) in 10 mL of THF was added, and the reaction mixture was allowed to warm to room temperature and stir for 2 to 3 hours. The reaction mixture was poured into ice-cold aqueous NH4Cl and extracted with ethyl acetate. The organic phase was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated under vacuum. The oily residue was adsorbed onto silica gel, applied to a column of silica gel and eluted with hexane/ethyl acetate (6:1 v:v) to obtain 3.6 g of the title compound of Step B as a viscous oil. 1H NMR (CDCl3, 300 MHz) δ 1.1 (m, 18H), 1.3 (m, 3H), 4.3 (m, 1H), 4.8 (m, 1H), 5.5 (m, 1H), 7.0 (m, 2H), 7.3-7.5 (m, 5H), 7.5-7.6 (m, 4H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36].CN(C)CCN.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[O:36]=[C:32]1[CH2:33][CH2:34][CH2:35][N:31]1[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(I)cc4)CC3)c2cc1OC
Reactant: O=C1CCCN1
Agent: [Cu]I
Agent: CN(C)CCN
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(N5CCCC5=O)cc4)CC3)c2cc1OC
Temperature: 105 °C
Yield: 16.4 %

Procedure:
To a mixture of 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-iodo-phenyl)-amide (57.9 mg, 0.11 mmol), as prepared in Example 2b, and pyrrolidin-2-one (13.3 mg, 0.16 mmol) in toluene (3 mL) was added CuI (1.5 mg), followed by N,N-dimethylethylenediamine (1.4 mg) and K3PO4 (56.7 mg). The reaction mixture was heated at 105° C. overnight. It was concentrated under reduced pressure and the crude residue was purified by flash column chromatography on silica gel (10% MeOH/EtOAc as eluent) to afford the desired product (8.6 mg, 16.4% yield). 1H NMR (300 MHz, CD3OD) δ 8.95 (s, 1H), 7.58 (s, 1H), 7.50 (d, J=9.26 Hz, 2H), 7.41 (d, J=9.27 Hz, 2H), 7.32 (s, 1H), 4.36 (m, 2H), 4.06 (s, 3H), 4.04 (s, 3H), 3.91 (t, J=6.93 Hz, 2H), 3.39 (m, 1H), 3.19 (m, 2H), 2.59 (t, J=8.46 Hz, 2H), 1.94-2.30 (m, 6H). LC-MS (ESI) calcd mass 475.2, found 476.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:29][CH2:30][NH:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.C(N)C(C)C>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:29][CH2:30][NH:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2cn(CCNCC3CC3)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F
Solvent: CC(C)CN
Product: Cc1cc(-c2cn(CCNCC(C)C)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using isobutylamine instead of cyclopropylmethylamine. LC-MS: (M+1=477, obsd.=477).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:9][C:10]1[CH:15]=[C:14](Cl)[N:13]=[CH:12][N:11]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:9][C:10]1[CH:15]=[C:14]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:13]=[CH:12][N:11]=1
Reactant: OC1CCCC1
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1cc(OC2CCCC2)ncn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of cyclopentanol (2.25 g, 26.1 mmol) in tetrahydrofuran (12 ml) was added dropwise to a suspension of sodium hydride (1.31 g, 32.6 mmol) in tetrahydrofuran (48 ml) at 0° C. The mixture was stirred at 0° C. for 30 min and a solution of 4,6-dichloropyrimidine (3.6 g, 24.16 mmol) in tetrahydrofuran (12 ml) was added at 0° C. The reaction mixture was stirred at ambient temperature for 3 h and poured into sat. aqueous ammonium chloride and extracted with ethyl acetate. The organic layers were washed with water, dried over magnesium sulfate and concentrated in vacuo. The orange residue was purified by column chromatography (10-40% ethyl acetate/hexanes). To afford 4-chloro-6-(cyclopentyloxy)pyrimidine as a pale yellow oil. This material was used directly for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:28][C:29]([F:32])([F:31])[F:30])[C:13](=[O:27])[C@H:14]([NH:16]C(=O)OCC3C=CC=CC=3)[CH2:15][C:4]=2[CH:3]=1.C1(OC)C=CC=CC=1.CS(O)(=O)=O.C(OCC)C>ClCCl>[NH2:16][C@H:14]1[C:13](=[O:27])[N:12]([CH2:28][C:29]([F:30])([F:32])[F:31])[CH2:11][C:5]2[C:6]3[CH:7]=[N:8][NH:9][C:10]=3[C:2]([Cl:1])=[CH:3][C:4]=2[CH2:15]1
Reactant: O=C(N[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O)OCc1ccccc1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CCOCC
Solvent: COc1ccccc1
Product: N[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
(R)-Benzyl 4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-ylcarbamate (450 mg, 964 μmol) was dissolved in dichloromethane (20 ml). Anisole (250 μl, 2300 μmol) was added to the mixture followed by methanesulfonic acid (5.0 ml, 77051 μmol). Reaction stirred at room temperature for 1.5 hours. 100 mL of diethyl ether was added to the mixture. Reaction stirred at room temperature for 45 minutes. Liquids were decanted off. Remaining solid was washed with diethyl ether and the liquids decanted. Solids were dissolved in water. Mixture was made basic with aqueous sodium bicarbonate. Mixture was extracted twice with ethyl acetate and the aqueous phase was discarded. Material was washed successively with aqueous sodium bicarbonate, water and brine and the aqueous phases were discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as light yellow solid in 78% yield. MS (M+H)+=321.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][N:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[N:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2cnccc21
Product: CC1c2ccncc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-methyl-1,2,3,4-tetrahydro-[2,6]naphthyridine to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:37]=[CH:36][C:20]([C:21]([N:23]([CH3:35])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33]O)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:58].CO>ClCCl.C(OCC)(=O)C.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:37]=[CH:36][C:20]([C:21]([N:23]([CH3:35])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][Br:58])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCO)cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCBr)cc2)cc1
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(3-hydroxypropoxy)phenyl]benzamide (520 mg) in dichloromethane (20 ml) was added triphenylphosphine (827 mg) and carbon tetrabromide (1.39 g) at ambient temperature. The mixture was stirred for 2 hours and diluted with ethyl acetate and washed successively with saturated sodium hydrogen carbonate and brine, and dried over magnesium sulfate. The solid was removed and the solvent was removed by evaporation to give crude product. The crude material was subjected to a silica gel column chromatography (SiO2; 50 g, 0.5% methanol in chloroform) to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(3-bromopropoxy)phenyl]benzamide (540 mg) as white amorphous.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([O:22][CH3:23])=[O:21])=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:23][O:22][C:20]([C:19]1[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=1[O:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:28])=[O:5])=[CH:10][CH:11]=1)=[O:21]
Reactant: COC(=O)c1ccccc1OCCc1ccc(OCC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccccc1OCCc1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
Methyl 2-{2-[4-(2-tert-butoxy-2-oxoethoxy)phenyl]ethoxy}benzoate (0.400 g, 1.0351 mmol) was dissolved in DCM and trifluoracetic acid (0.8 ml, 8.281 mmol) was added. The mixture was stirred at room temperature for 3 h. The solvent was evaporated to give 325 mg of a white powder.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C:24](=[O:28])[CH2:23][CH2:22]4)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[CH:24]([OH:28])[CH2:23][CH2:22]4)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc4c(c3)CCC4=O)cc3ccccc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCN1CCN(c2nc(-c3ccc4c(c3)CCC4O)cc3ccccc23)CC1
Yield: 59.7 %

Procedure:
1-(4-Ethylpiperazin-1-yl)-3-(1-indanon-5-yl)isoquinoline (0.20 g) obtained in the previous Example was dissolved in methanol (20 ml), followed by the addition of sodium borohydride (0.10 g) at room temperature, and the mixture was reacted for 15 min. The reaction solution was concentrated, and the resulting residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give the title compound (0.12 g) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:25][Mn](=O)(=O)=O.[K+].C(=O)C1C=CC=CC=1>CC(C)=O.O>[CH2:1]([O:8][C:9]1[C:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]([OH:25])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1OCc1ccccc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: O=Cc1ccccc1
Product: O=C(O)c1cccc(OCc2ccccc2)c1OCc1ccccc1
Temperature: 40 °C
Yield: 212.7 %

Procedure:
19.8 g of 2,3-dibenzyloxybenzaldehyde are dissolved in 100 ml of acetone. While stirring vigorously and heating at 40° C., a solution of 4.0 g of KMnO4 in 90 ml of H2O is added within 45 min, the precipitated benzaldehyde being redissolved by the addition of a total of 150 ml of acetone. Once addition of the KMnO4 solution is complete, the mixture is boiled under reflux for one hour. The hot solution is then filtered, and the precipitate is washed with hot water. The carboxylic acid crystallizes out in fine white needles on acidification of the cold aqueous solution with dilute HCl. 18.0 g of the desired compound are obtained (92% yield). MS: 334 (M+); M.p.: 185°-187° C.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.B(O)(O)[C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+].C1COCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.B(O)(O)C1C=CC(C)=CC=1.O>[C:20]1([CH3:23])[CH:21]=[CH:22][C:17]([C:2]2[C:3]3[C:8]([CH:9]=[C:10]4[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:18][CH:19]=1
Reactant: Brc1c2ccccc2cc2ccccc12
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2c3ccccc3cc3ccccc23)cc1
Temperature: 85 °C
Yield: 107.5 %

Procedure:
5 g (1 eq, 15.6 mmol) of 9-bromo anthracene, 3.61 g of p-tolylboronic acid (1.7 eq, 26.5 mmol), 2.15 g (1.3 eq, 20.3 mmol) of Na2CO3, and 0.54 g (0.03 eq, 0.47 mmol) of tetrakis(triphenylphosphine)palladium were put into a 500-ml round-bottomed flask in Ar gas condition. 5 ml of THF and 2.2 ml of water, based on 1 mmol of p-tolylboronic acid, were added into the flask and refluxed at 85° C. for 16 hours. After the color of the solution changed to dark brown, water was added to the solution, and the organic phase was extracted using ethyl acetate. The extracted organic phase was dried using anhydrous magnesium sulfate and filtered to remove the solvent. The dried organic phase was dissolved in a small amount of toluene and separated using column chromatography (silica and hexane). A resulting solid was recrystallized using toluene and methanol to obtain 4.5 g (86%) of a white solid.
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[O:18][CH:17]2[C@:13]([CH3:21])([O:14][C:15]([CH3:20])(C)[O:16]2)[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]([O:25]C(C)=O)=[O:24].N1C=CC=CC=1.[CH2-]C(C)=O>C(O)(=O)C.C(OCC)(=O)C.CN(C1C=CN=CC=1)C>[C:1]([O:9][CH2:10][C@@H:11]1[CH2:12][C@:13]([O:25][C:23](=[O:24])[CH3:22])([CH3:21])[CH:17]([O:16][C:15](=[O:14])[CH3:20])[O:18]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC2O[C@H](COC(=O)c3ccccc3)C[C@@]2(C)O1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: [CH2-]C(C)=O
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)C[C@@]1(C)OC(C)=O
Temperature: 70 °C
Yield: 75.5 %

Procedure:
A mixture of 3.8 g of ((5S,6aR)-2,2,6a-trimethyl-dihydro-5H-furo[3,2-d][1,3]dioxol-5-yl)methyl benzoate (from step 9) in 25 mL of 70% acetic acid was heated to 70° C. for 48 h. The reaction mixture was diluted with ethyl acetate and washed with water and saturated NaHCO3. The organic layers were dried over anhydrous Na2SO4, filtered and concentrated. Crude diol obtained was aceylated using Ac2O (0.03373 mol, 3.18 mL) and 20 mL of anhydrous pyridine with catalytic amount of DMAP (5 mol %). The progress of the reaction was monitored by TLC. Pyridine was removed under vacuum and the residue was diluted with ethyl acetate and was washed with 1N HCl and saturated NaHCO3. The organic layers were dried over anhydrous Na2SO4, filtered and concentrated. Purified by column chromatography to give 3.3 g of the title compound (88% yield) and 0.55 g of starting material acetonide was recovered.
Reaction SMILES: [N+:1]([CH2:4][CH:5]1[O:9][B:8]([OH:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]1=2)([O-:3])=[O:2].[N+:15]([O-])([OH:17])=[O:16]>>[N+:15]([C:12]1[CH:13]=[CH:14][C:6]2[CH:5]([CH2:4][N+:1]([O-:3])=[O:2])[O:9][B:8]([OH:10])[C:7]=2[CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])CC1OB(O)c2ccccc21
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])CC1OB(O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C

Procedure:
3-Nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (20.0 g, 104 mmol) was added in small portions with stirring over 2 h to fuming HNO3 (200 mL) at −45° C. (bath temp). The cold reaction mixture was then poured into crushed ice and allowed to warm to rt. The aqueous phase was extracted with EtOAc. The EtOAc phase was concentrated in vacuo and the residue was poured into crushed ice. The precipitate was filtered and washed with H2O. The solid was dissolved in EtOAc, dried (Na2SO4), and concentrated in vacuo to yield the title compound: yield (14.3 g, 58%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]([N:16]2C(=O)C3=CC=CC=C3C2=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][CH:3]=1.O.NN>CO>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1C(Cc1ccccn1)c1cccc(Cl)n1
Agent: NN
Solvent: CO
Solvent: O
Product: NC(Cc1ccccn1)c1cccc(Cl)n1
Yield: 45.2 %

Procedure:
1 l of methanol was mixed with 77 g of the crude N-{1-(6-chloropyridin-2-yl)-2-(pyridin-2-yl)ethyl}-phthalimide prepared in the Preparative Example 23 and 16.5 g of hydrazine monohydrate. The obtained mixture was heated under reflux for 2 hours to conduct a reaction. After the reaction mixture was allowed to stand at room temperature, the precipitated crystals were filtered out and the filtrate was concentrated. Water and ethyl acetate were added to the concentrate to conduct extraction. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (with a methanol/dichloromethane (5:95 mixture) to give 22.38 g of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:6][CH:5]1[N:7]1[CH:14]=[CH:13][C:11](=O)[NH:10][C:8]1=[O:9].C[Si](C)(C)[NH:17][Si](C)(C)C.C(N)=O>CO>[OH:1][CH2:2][CH2:3][CH:4]1[CH2:6][CH:5]1[N:7]1[CH:14]=[CH:13][C:11]([NH2:17])=[N:10][C:8]1=[O:9]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=c1ccn(C2CC2CCO)c(=O)[nH]1
Solvent: CO
Solvent: NC=O
Product: Nc1ccn(C2CC2CCO)c(=O)n1
Temperature: 140 °C
Reaction time: 85 h

Procedure:
To 79 mg (0.42 mmol) of 1-(2'-(2"-hydroxyethyl)cyclopropyl) uracil, the product of Step B of Example 8, is added 0.44 mL (2.1 mmol) of hexamethyldisilazane and 0.034 mL (0.82 mmol) of formamide and the resultant mixture is heated with stirring in a sealed tube at 140° C. After 85 h, 10 mL of methanol is added to the cooled reaction mixture, the tube resealed and heated to 65° C. After 3 h at 65° C., the cooled reaction mixture is concentrated under reduced pressure. The residue is dissolved in 10 mL of water and the resultant aqueous solution treated with 50 mg of Darco G-60 charcoal, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel eluted with a gradient of methanol in methylene chloride from 100% methylene chloride to 30% methanol affords the title compound.