Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]2[CH:13]=[C:12]([CH3:14])[C:11](=[O:15])[N:10]([CH3:16])[C:9]=2[N:17]([C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])C(=O)OC(C)(C)C)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:32][C:26]1[CH:27]=[C:28]([I:31])[CH:29]=[CH:30][C:25]=1[NH:17][C:9]1[N:10]([CH3:16])[C:11](=[O:15])[C:12]([CH3:14])=[CH:13][C:8]=1[NH:7][S:4]([CH:1]1[CH2:2][CH2:3]1)(=[O:6])=[O:5]
Reactant: Cc1cc(NS(=O)(=O)C2CC2)c(N(C(=O)OC(C)(C)C)c2ccc(I)cc2F)n(C)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(NS(=O)(=O)C2CC2)c(Nc2ccc(I)cc2F)n(C)c1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 49.9 %

Procedure:
A 100 mL round bottom flask was charged with tert-butyl 3-(cyclopropanesulfonamido)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-2-yl(2-fluoro-4-iodophenyl)carbamate (120 mg, 0.21 mmol) in 20% mixture of TFA in DCM (10 mL). The reaction mixture was stirred at room temperature for 14 hours and the solvents were removed under reduced pressure. The crude material was purified by flash chromatography (Biotage system) using a gradient of EtOAc (0-50%) in hexane to afford the title product as a white solid (50 mg, 50%).
Reaction SMILES: C1(C2N=C([C:9]([NH2:11])=[NH:10])SC=2)CC1.Br[C:13]1[S:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1.BrCC(C1CC1)=O>>[F:19][C:18]([F:21])([F:20])[C:16]1[N:17]=[C:13]([C:9]([NH2:11])=[NH:10])[S:14][CH:15]=1
Reactant: FC(F)(F)c1csc(Br)n1
Reactant: N=C(N)c1nc(C2CC2)cs1
Agent: O=C(CBr)C1CC1
Product: N=C(N)c1nc(C(F)(F)F)cs1

Procedure:
4-Trifluoromethyl-thiazole-2-carboxamidine (Compound U) was prepared in analogy to Compound M with procedure shown in Example 10 by using 2-bromo-4-trifluoromethyl-thiazole (CAS: 41731-39-9) instead of 2-bromo-4-cyclopropyl-thiazole which is made from 2-bromo-1-cyclopropyl-ethanone in Example 10. MS: calc'd (MH+) 196, measured (MH+) 196.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][C:16]([C:18]2[N:19]([CH3:27])[N:20]=[C:21]3[C:26]=2[CH:25]=[CH:24][CH:23]=[CH:22]3)=[O:17])=[CH:4][C:5]([F:14])=[C:6]([CH2:8][C:9]([O:11]CC)=[O:10])[CH:7]=1.C1COCC1.[OH-].[Na+]>Cl>[Cl:1][C:2]1[C:3]([NH:15][C:16]([C:18]2[N:19]([CH3:27])[N:20]=[C:21]3[C:26]=2[CH:25]=[CH:24][CH:23]=[CH:22]3)=[O:17])=[CH:4][C:5]([F:14])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2c3ccccc3nn2C)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1nc2ccccc2c1C(=O)Nc1cc(F)c(CC(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 340 %

Procedure:
To ethyl (5-chloro-2-fluoro-4-((2-methyl-3-indazolylcarbonyl)amino)phenyl)acetate (390 mg, 1.00 mmol) were added THF (10 ml) and 0.25N NaOH (6.00 ml, 1.50 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured in 1N HCl (1.5 ml). The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (5-chloro-2-fluoro-4-((2-methyl-3-indazolylcarbonyl)amino)phenyl)acetic acid (1.23 g, 95%) as a brown solid.
Reaction SMILES: [N:1]1[N:5]2[C:6]([N:10]3[CH2:14][CH2:13][CH2:12][C@@H:11]3[CH2:15][OH:16])=[CH:7][CH:8]=[N:9][C:4]2=[N:3][CH:2]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>ClCCl>[CH3:24][S:25]([O:16][CH2:15][C@H:11]1[CH2:12][CH2:13][CH2:14][N:10]1[C:6]1[N:5]2[N:1]=[CH:2][N:3]=[C:4]2[N:9]=[CH:8][CH:7]=1)(=[O:27])=[O:26]
Reactant: OC[C@H]1CCCN1c1ccnc2ncnn12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CCCN1c1ccnc2ncnn12
Temperature: 0 °C

Procedure:
1.5 g of ((R)-1-[1,2,4]triazolo[1,5-a]pyrimidin-7-ylpyrrolidin-2-yl)methanol are dissolved in 15 ml of dichloromethane with stirring, and 1.9 ml of triethylamine are added. This solution is cooled to 0° C., and a solution of 0.8 ml of methanesulfonyl chloride in 5 ml of dichloromethane is added dropwise. When the addition is complete, the mixture is allowed to warm to RT for 12 h. For workup, the solution is poured into equal proportions by volume of water, the organic phase is extracted to exhaustion with ethyl acetate, the combined organic phases are dried over sodium sulfate, filtered off with suction, evaporated and chromatographed on silica gel, giving 1.1 g of ((R)-1-[1,2,4]triazolo-[1,5-a]pyrimidin-7-ylpyrrolidin-2-yl)methyl methanesulfonate as colourless oil;
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][OH:5].O[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][O:5][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: OCCC(F)(F)F
Reactant: COC(=O)CCCCCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCCCCCOCCC(F)(F)F
Reaction time: 0.25 h

Procedure:
3,3,3-Trifluoropropanol (10 ml, 110 mmol), methyl 7-hydroxyheptanoate (133 mmol, 1.2 eq), triphenylphosphine (35 g, 133 mmol, 1.2 eq) are initially introduced in 37 ml of THF in a round-bottomed flask and introduced into an ultrasound bath for a few minutes in order to mix the substances. During the exposure to ultrasound, DIAD (26.5 ml, 133 mmol, 1.2 eq) is very slowly added dropwise (temperature rises), and the reaction mixture is left under ultrasound for 15 min. A TLC sample is taken and subsequently left in the ultrasound bath for a further 2 hours.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[C:12]([NH:14][CH:15]2[CH2:17][CH2:16]2)[N:11]=[C:10]([CH2:18][CH2:19][CH3:20])[N:9]=1>O1CCOCC1>[CH:15]1([NH:14][C:12]2[N:13]=[C:8]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:9]=[C:10]([CH2:18][CH2:19][CH3:20])[N:11]=2)[CH2:17][CH2:16]1
Reactant: CCCc1nc(Cl)nc(NC2CC2)n1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: CCCc1nc(NC2CC2)nc(N2CCOCC2)n1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
45 ml (0.45 mole) of morpholine dissolved in 200 ml of dioxane are added to a solution containing 43 g (0.163 mole) of 2-chloro-4-cyclopropylamino-6-n-propyl-1,3,5-triazine in 300 ml of dioxane, while maintaining the mixture at room temperature. After the addition, the mixture is heated under reflux for one to two hours. The reaction mixture is then allowed to return to room temperature and the precipitate is filtered off. The filtrate is concentrated and the residue is redissolved in dichloromethane. The solution is washed with water. The organic phase is separated off and dried over sodium sulfate. The solvent is evaporated under reduced pressure. The residue is purified by chromatography on silica (eluent: 98.5:1.5 (v/v) dichloromethane-ethanol) and the product is finally recrystallized from diethyl ether. 36.2 g of 2-cyclopropylamino-4-morpholino-6-n-propyl-1,3,5-triazine are obtained. Yield: 85%. M.P.: 104° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[OH:20])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[C:35]([O:42][CH3:43])[CH:34]=1)=[O:32])[CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.O.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>[C:13]([O:12][C:11]([N:10]([CH2:18][C@@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[OH:20])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:36]2[CH:37]=[CH:38][C:33]([C:31]([O:30][CH2:28][CH3:29])=[O:32])=[CH:34][C:35]=2[O:42][CH3:43])=[CH:3][CH:4]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1ccc(B(O)O)c(OC)c1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Br)cc1)C[C@H](O)c1cccc(Cl)c1
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: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)c(OC)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 49.9 %

Procedure:
To a solution of tert-butyl [2-(4-bromophenyl)ethyl]-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate (365 mg) in 1,2-dimethoxyethane (6 ml) was added [4-(ethoxycarbonyl)-2-methoxyphenyl]boronic acid (216 mg), tetrakis(triphenylphosphine)palladium (46 mg) and aqueous solution of sodium carbonate (2M, 0.85 ml), and the mixture was stirred at 80° C. for 4 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give ethyl 4′-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-amino]ethyl]-2-methoxy-1,1′-biphenyl-4-carboxylate (222 mg).
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH2:40])=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>C(OCC)(=O)C>[C:41]1([CH:39]([C:28]2[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=2)[CH3:40])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: C=C(c1ccccc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: CCOC(C)=O
Product: CC(c1ccccc1)c1cc(O)c(=O)[nH]n1

Procedure:
Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-(1-phenylethenyl)pyridazine (Intermediate 25) except that upon completion of the reaction the resulting mixture was filtered through Celite washing with ethanol and then concentrated in vacuo to afford an orange solid. This was purified initially by eluting on a reverse phase C18 chromatography column (0-60% methanol in water with an acidic modifier) and upon combining and concentrating the appropriate fractions the crude product was recrystallised from a mixture of ethyl acetate and heptanes to afford a white solid and the final compound was recrystallised from a mixture of ethyl acetate and heptanes (32% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:15][OH:16])[CH:6]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:8]=1.CC#N>C1(C)C=CC=CC=1.O=[Mn]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:8]=1)[CH:15]=[O:16]
Reactant: COCCCOc1cc(CO)cc(OC)c1
Agent: O=[Mn]=O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: COCCCOc1cc(C=O)cc(OC)c1

Procedure:
The title compound is synthesized by MnO2 oxidation of [3-Methoxy-5-(3-methoxy-propoxy)-phenyl]-methanol (4.20 g, 18.6 mmol) in toluene at RT for 12 h. Yellow oil; MS: 225 [M+H]+; tR (HPLC, CombiScreen ODS-AM 50×4.6 mm; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 2 min, flow 2.0 ml/min): 3.59 min.
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[C:6]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=[CH:10][C:9]([C:12]2[C:21]([Cl:22])=[CH:20][C:15]3[NH:16][C:17](=[S:19])[NH:18][C:14]=3[CH:13]=2)=[CH:8][CH:7]=1.[OH-].[K+].Cl>CCO.O>[C:6]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=[CH:10][C:9]([C:12]2[C:21]([Cl:22])=[CH:20][C:15]3[NH:16][C:17]([S:19][CH2:2][C:3]([OH:5])=[O:4])=[N:18][C:14]=3[CH:13]=2)=[CH:8][CH:7]=1
Reactant: S=c1[nH]c2cc(Cl)c(-c3ccc(-c4ccccc4)cc3)cc2[nH]1
Reactant: O=C(O)CBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CSc1nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of bromoacetic acid (43.4 mg, 0.312 mmol) in EtOH (1 mL) was added dropwise to a 20 mL scintillation vial equipped with a stirring bar and a septum cap containing a solution of compound 2-3 (52.6 mg, 0.156 mmol) in EtOH (0.5 mL). To this solution, 1M KOH (1.5 mL) was added dropwise, and the resulting mixture was stirred at rt for 1 h. The reaction mixture was then diluted with water (4 mL) and acidified with 10% aqueous HCl. The solution was extracted with EtOAc (3 mL, then three times 1 mL). Extracts were combined and evaporated to dryness in vacuo. The resulting oily residue was dissolved in DMSO (1 mL), filtered and purified by reverse-phase HPLC with to give the title compound as white solid. 1H NMR (DMSO-d6, 400 MHz) δ 7.70-7.76 (4H, m), 7.64 (1H, s), 7.46-7.55 (4H, m), 7.45 (1H, s), 7.36-7.40 (1H, m), 4.12 (2H, s); LRMS (API-ES): calculated for C21H15ClN2O2S 394.1, observed m/e 395.0 (M+H)+ (Rt 3.14 min).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>O1CCCC1>[C:21]([N:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)(=[O:23])[CH3:22]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCN(Cc2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
A solution of 1-benzylpiperazine (1 g) and triethylamine (1.19 mL) in tetrahydrofuran (20 mL) was stirred at room temperature under argon. Acetyl chloride (0.424 mL) was added and the mixture was stirred for 10 minutes. The reaction was filtered and the white solid washed with ether. The filtrate was concentrated at reduced pressure to give the title compound as a colourless oil (1.2 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([C@H:22]([CH2:34][CH:35]=O)[CH2:23][N:24]([CH3:33])[C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:18]=[CH:19][C:20]=1[Cl:21].ClCCl.CO>O>[ClH:14].[Cl:14][C:15]1[CH:16]=[C:17]([C@H:22]([CH2:34][CH2:35][N:11]2[CH2:10][CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[CH2:13][CH2:12]2)[CH2:23][N:24]([CH3:33])[C:25](=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: Oc1ccc(C2CCNCC2)cc1
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CN(C[C@@H](CCN1CCC(c2ccc(O)cc2)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Product: Cl

Procedure:
Using a procedure similar to that described in Example 1 (alternative preparation), except using 4-(4-hydroxyphenyl)piperidine and (S)-N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide, the title compound was prepared. Chromatography with dichloromethane:methanol followed by conversion to the hydrochloride salt gave a white solid; mp 144°-160° C.; MS: 511; NMR (CD3OD): 1.8-2.2 (m, 6), 27 (s, 3), 2.8-3.3 (m, 5), 3.4-3.9 (m, 3), 6.7 (d, J=8, 2), 7.0-7.2 (m, 5), 7.3-7.6 (m, 5); [α]D =-36.8°, c=1.06 (methanol). Analysis for C29H32Cl2N2O2 ·1.0 HCl·0.5 H2O: Calculated: C, 62.54; H, 6.15; N, 5.03; Found: C, 62.16; H, 6.20; N, 4.74.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:10]([CH3:23])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[Li]C1C=CC=CC=1.Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C1COCC1.CCCCCC>[CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:10]([CH2:23][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1cc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Reactant: BrCCCCCCCCCOCc1ccccc1
Agent: [Li]c1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(-n2c(C)ccc2C)nc(CCCCCCCCCCOCc2ccccc2)c1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution at −78° C. containing 1.42 g (4.63 mmol) of 2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-benzyloxy-4,6-dimethylpyridine (16) in 20 mL of anhydrous THF were added 5.15 mL (9.27 mmol) of a 1.8 M solution of PhLi in hexane followed by 1.45 g (4.63 mmol) of 9-bromo-1-(benzyloxy)nonane (1). The reaction mixture was stirred under argon atmosphere at −78° C. for 30 min. then the reaction mixture was warmed to room temperature slowly, and the reaction mixture was stirred 30 min. The reaction was quenched with saturated aqueous NaHCO3 and the poured into 150 mL of water. The mixture was then extracted with two portions of 150 mL of ethyl acetate. The combined organic solution was then washed with a portion of 100 mL of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with hexanes-ethyl acetate 4:1 gave the expected product as light yellow oil: yield 1.22 g (49%) 1H-NMR (CDCl3) δ 7.54-7.37 (m, 10H), 6.93, (s, 1H), 5.94 (s, 2H), 4.95 (s, 2H), 4.55 (s, 2H), 3.52 (t, 2H, J=6.4), 2.91 (t, 2H, J=8.0) 2.39 (s, 3H), 2.51 (s, 6H), 1.82 (m, 2H), 1.65 (m, 2H), 1.33 (m, 12H); 13C-NMR (CDCl3) δ 155.94, 150.86, 146.89, 142.59, 138.80, 136.92, 128.69, 128.49, 128.38, 127.81, 127.65, 127.49, 121.75, 106.55, 75.30, 72.89, 70.55, 32.21, 29.85, 29.68, 29.63, 29.60, 29.59, 29.57, 29.53, 28.99, 26.27, 16.42, 13.30.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](F)[CH:7]=[C:6]([NH2:11])[C:5]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[O:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[Na].C(O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:1]([O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:23][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=[C:6]([NH2:11])[C:5]=1[N+:12]([O-:14])=[O:13])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: [Na]OCc1ccccc1
Reactant: OCc1ccccc1
Reactant: COC(=O)c1cc(F)cc(N)c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Product: Nc1cc(OCc2ccccc2)cc(C(=O)OCc2ccccc2)c1[N+](=O)[O-]

Procedure:
3.0 g (14.0 mmol) of 3-amino-5-fluoro-2-nitro-benzoic acid methyl ester in 1.6 g (15.4 mmol) of triethylamine and 2.1 g (15.4 mmol) of NaOBn/BnOH was heated at 60° C. for 0.5 h to produce 3-amino-5-benzyloxy-2-nitro-benzoic acid benzyl ester. LCMS: 380 (M+1)+.
Reaction SMILES: [N:1]#[N:2].[C:3]([NH:6][C:7]1[NH:8][C:9](=[O:37])[C:10]2[N:11]=[CH:12][N:13]([CH2:16][O:17][CH:18]([CH2:28][O:29]CC3C=CC=CC=3)[CH2:19][O:20]CC3C=CC=CC=3)[C:14]=2[N:15]=1)(=[O:5])[CH3:4].[H][H]>CO.O.[OH-].[OH-].[Pd+2]>[N:1]#[N:2].[C:3]([NH:6][C:7]1[NH:8][C:9](=[O:37])[C:10]2[N:11]=[CH:12][N:13]([CH2:16][O:17][CH:18]([CH2:19][OH:20])[CH2:28][OH:29])[C:14]=2[N:15]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1nc2c(ncn2COC(COCc2ccccc2)COCc2ccccc2)c(=O)[nH]1
Reactant: [H][H]
Agent: [Pd+2]
Agent: N#N
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)Nc1nc2c(ncn2COC(CO)CO)c(=O)[nH]1
Yield: 44.5 %

Procedure:
To a solution of N2 -acetyl-9-(1,3-dibenzyloxy-2-propoxymethyl)guanine (4.62 g, 9.67 mmol) in 150 ml of methanol plus 40 ml of water was added 20% palladium hydroxide on carbon as a slurry in 10 ml of water. The mixture was hydrogenated on a Parr hydrogenator at 60 psi of hydrogen for 38 hours then filtered through celite and concentrated to a white solid. Recrystallization from methanol/ethyl acetate gave 1.4 g of N2 -acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine, mp 205°-208° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:10]=1[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1([CH2:32]Br)[CH2:31][CH2:30]1>>[CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:10]=1[CH2:11][N:12]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][N:14]=1)[CH2:32][CH:29]1[CH2:31][CH2:30]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)nc1
Reactant: BrCC1CC1
Product: CCOC(=O)c1ccc(N(Cc2cc(Br)ccc2OCc2ccccc2)CC2CC2)nc1

Procedure:
Ethyl 2-[N-(2-benzyloxy-5-bromobenzyl)-N-(cyclopropyl-methyl)amino]pyridine-5-carboxylate was prepared from ethyl 2-[N-(2-benzyloxy-5-bromobenzyl)amino]pyridine-5-carboxylate and cyclopropylmethyl bromide by a similar method to that described in Reference example 5, purifying the product by MPLC and eluting with 80% dichloromethane in hexane.
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[N:19]([CH2:37][CH2:38][C:39]([O:41]C)=[O:40])[C:20]2[C:25]([C:26]=1[CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[CH:24][CH:23]=[C:22]([C:33]([O:35][CH3:36])=[O:34])[CH:21]=2)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C1COCC1.O>[C:4]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[N:19]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])[C:20]2[C:25]([C:26]=1[CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)=[CH:24][CH:23]=[C:22]([C:33]([O:35][CH3:36])=[O:34])[CH:21]=2)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: COC(=O)CCn1c(-c2ccccc2NC(=O)OC(C)(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3NC(=O)OC(C)(C)C)n(CCC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
1.1 eq of lithium hydroxide monohydrate was added to a solution of methyl 2-{2-[(tert-butoxycarbonyl) amino]phenyl}-3-cyclohexyl-1-(3-methoxy-3-oxopropyl)-1H-indole-6-carboxylate in a mixture THF:H2O (4:1; 0.1 M). The mixture was stirred at RT for 1.5 h. The reaction was quenched with 1 N HCl and the solvent evaporated in vacuo. The residue was washed with the minimum amount of Et2O and the resultant precipitate filtered to obtain the title compound as a white solid (81%); MS (ES+) m/z 521 (M+H)+.
Reaction SMILES: [Br-].[Li+].[C:3]([Li])([CH3:6])([CH3:5])[CH3:4].[Cl:8][C:9]1[CH:22]=[CH:21][C:20]2[CH:19]3[CH2:23][C:12]([CH2:24][N:25]4[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]4)([C:13]4[C:18]3=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:11]=2[CH:10]=1>O1CCCC1>[Cl:8][C:9]1[CH:22]=[CH:21][C:20]2[CH:19]3[CH2:23][C:12]([CH2:24][N:25]4[CH2:26][CH2:27][C:28]([C:3]([CH3:6])([CH3:5])[CH3:4])([OH:31])[CH2:29][CH2:30]4)([C:13]4[C:18]3=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:11]=2[CH:10]=1
Reactant: [Li]C(C)(C)C
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)C1(O)CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Temperature: 25 °C
Yield: 52 %

Procedure:
To a cooled solution (-78° C.) of lithium bromide (770 mg, 8.87 mmol, 1.5 eq) in tetrahydrofuran (60 mL) under nitrogen was added recently titrated t-butyllithium (1.7M in pentane, 4.20 mL, 7.10 mmol, 1.2 eq). The resulting strong yellow color was quenched on the addition of a 1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 1m) (2.00 g, 5.92 mmol) solution in tetrahydrofuran (15 mL). The reaction was warmed to room temperature over 10 min and quenched with water (50 mL). The aqueous phase was extracted with ethyl acetate (3×60 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The reaction mixture was purified by flash chromatography over silica gel (150 mL, eluent: 15% ethyl acetate in hexane) to obtain 1.22 g (52%) of the title compound as a white solid. TLC analysis (Rf 0.23, 20% ethyl acetate in hexane). 1H NMR (CDCl3, 300 MHz) 7.24 (m, 1H), 7.14 (m, 2H), 6.95 (m, 3H), 6.87 (m, 1H), 4.24 (br s, 1H), 3.56 (s, 2H), 2.82 (m, 2H), 2.59 (d, J=1.4 Hz, 2H), 2.50 (m, 2H), 1.74 (m, 2H), 1.50 (m, 2H), 0.91 (br s, 9H) MS (CI, CH4) m/z 396 (M+1,100), 398 (35), 424 (M+29,17), 378 (45), 360 (6). The free base was dissolved in diethyl ether containing a small amount of methylene chloride and acidified with ethereal HCl. The hydrochloride salt was filtered, washed with fresh ether and dried in vacuo (60° C., 13 pascal, 18 h) to yield a white solid, mp 294°-296° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[Br:10]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:10][C:7]1[C:2]([NH2:1])=[N:3][C:4]([Cl:9])=[N:5][C:6]=1[Cl:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(Cl)nc(Cl)c1Br
Temperature: 25 °C

Procedure:
2 g (12.2 mmol) of 4-amino-2,6-dichloropyrimidine were dissolved in 10 ml of DMF. To this solution were added 2.6 g (14.6 mmol) of N-bromosuccinimide. The reaction mixture was stirred at room temperature over night. The solution was poured onto 200 ml of cool water. The formed precipitate was filtered and washed with water. The product was obtained 2.7 g (91.9%) as a white powder.