Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][NH2:9])[CH2:2][CH2:3][CH3:4].Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][N:19]=2)[N:14]=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22].C(N(CC)CC)C.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][NH:9][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][N:19]=2)[N:14]=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Reactant: CCCCOCCCN
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCCOCCCNc1c([N+](=O)[O-])cnc2cccnc12
Temperature: 25 °C
Yield: 79.2 %

Procedure:
Under a nitrogen atmosphere, 3-butoxypropylamine (4.0 mL, 26 mmol) was added dropwise over a period of 10 minutes to a solution of 4-chloro-3-nitro[1,5]naphthyridine (4.6 g, 22 mmol) and triethylamine (4.6 mL, 33 mmol) in dichloromethane (150 mL). The reaction mixture was maintained at ambient temperature overnight. Water (100 mL) was added and the phases were separated. The aqueous phase was extracted with dichloromethane (100 mL). The organic fractions were combined, dried over magnesium sulfate, filtered and then concentrated under vacuum to provide a yellow oil. The oil was purified by flash chromatography (silica gel eluting with 1:1 ethyl acetate:hexanes) to provide 5.3 g of N4-(3-butoxypropyl)-3-nitro[1,5]naphthyridin-4-amine as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 10.08 (broad s, 1H), 9.38 (broad s, 1H), 8.78 (m, 1H), 8.22 (dd, J=8.4, 1.6 Hz, 1H), 7.64 (dd, J=8.4, 4.1 Hz, 1H), 4.57 (broad s, 2H), 3.63 (t, J=5.8 Hz, 2H), 3.46 (t, J=6.7 Hz, 2H), 2.10-2.03 (m, 2H), 1.65-1.55 (m, 2H), 1.44-1.32 (m, 2H), 0.92 (t, J=7.3 Hz, 3H); MS (EI): m/e 304.1535 (304.1535 calc'd for C15H20N4O3).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[C@@H:12]([C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])[CH2:11]1)[CH3:9].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1.CO>ClCCl>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([N:28]2[CH2:27][CH2:26][N:25]([C:23]([C@H:12]3[CH2:11][N:10]([CH2:8][CH3:9])[CH2:15][CH2:14][NH:13]3)=[O:24])[CH2:30][CH2:29]2)=[O:40])=[CH:34][CH:33]=1
Reactant: CCN1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)N2CCNCC2)C1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCN1CCN[C@@H](C(=O)N2CCN(C(=O)Nc3ccc(Cl)cc3)CC2)C1
Reaction time: 18 h
Yield: 115.8 %

Procedure:
Triethylamine (29 uL) was added to a solution of tert-butyl (2R)-4-ethyl-2-(piperazin-1-ylcarbonyl)piperazine-1-carboxylate (67.5 mg) in dry dichloromethane (5 ml) followed by 4-chloro phenylisocyanate (35 mg) and the reaction was stirred for 18 h under argon. Methanol (1 ml) was added, the solvent was evaporated and the product purified by chromatography (3-15% MeOH-DCM) to afford the homologated product (91 mg) as a foam. The foam was then dissolved in TFA/DCM (1:1, 6 ml) and stirred for 1 h. The solvent was removed under reduced pressure then taken up in 1M. aqueous sodium hydroxide (30 ml) and extracted with dichloromethane (2×30 ml). The combined organic layers were dried (MgSO4), filtered and evaporated to form the title compound (70 mg) as a white foam.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH:8]1[C:16]2[C:15]3[CH:17]=[C:18]4[C:23](=[CH:24][C:14]=3[CH:13]=[CH:12][C:11]=2[NH:10][C:9]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19]4>CCOC(C)=O.CCCCCC>[CH3:5][N:10]1[C:11]2[CH:12]=[CH:13][C:14]3[CH:24]=[C:23]4[C:18](=[CH:17][C:15]=3[C:16]=2[CH:8]=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:19]=[CH:20][CH:21]=[CH:22]4
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1cc2c(ccc3cc4ccccc4cc32)[nH]1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c3cc4ccccc4cc3ccc2n1C
Yield: 97 %

Procedure:
Using the procedure described in Example 34A except that dimethyl sulfate was used as the alkylating agent, ethyl 3H-naphth[2,3-e]indole-2-carboxylate (H.G. Pars Pharmaceutical Laboratories, Inc.) gave a 97% yield of ethyl 3-methyl-3H-naphth[2,3-e]indole-2-carboxylate, mp 141°-144°, (EtOAc/hexane), (C,H,N).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.[Cl:12]Cl>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([Cl:12])[S:8][C:7]=2[CH:11]=1
Reactant: COc1ccc2ccsc2c1
Reactant: ClCl
Product: COc1ccc2cc(Cl)sc2c1

Procedure:
The same operations as in Preparation example 1 were carried out using 495 mg of 6-methoxybenzo[b]thiophene, and chlorine gas in place of cyclohexanone, and then purification was carried out by TLC (developing solvent, chloroform:n-hexane=4:1) to obtain 172 mg of 6-methoxy-2-chlorobenzo[b]thiophene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:9]([O:10][CH2:15][CH2:16][CH2:17][Cl:18])=[C:6]([O:7][CH3:8])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCl)c(OC)c1
Yield: 97 %

Procedure:
A mixture of 100 g (0.549 mole) of methylvanillate, 172.8 g (1.1 mole) of 1-bromo-3-chloropropane and 228 g (1.65 mole) of anhydrous potassium carbonate in 1 L of acetone was heated at reflux for 20 hr. The mixture was cooled, filtered, and the filtrate concentrated to give a white solid as residue. The solid was triturated with petroleum ether, collected by filtration, and dried to yield 137.8 g (97%) of title compound as a white powder, mp 104°-105° C. (2-propanol).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[C:8]([C:15]([F:18])([F:17])[F:16])[C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[F:19].C([O-])=[O:21].[Na+].C(O)C>O>[F:19][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=2[C:15]([F:18])([F:17])[F:16])[C:3]=1[CH2:2][OH:21]
Reactant: O=C[O-]
Reactant: COc1ccc2c(CBr)c(F)ccc2c1C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(CO)c(F)ccc2c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of 1-bromomethyl-2-fluoro-6-methoxy-5-(trifluoromethyl)naphthalene (11.16 g, 35 mmol), sodium formate (5.85 g, 86 mmol), ethanol (134 mL) and water (34 mL) was heated to reflux with stirring. Dissolution occurred within 20 minutes. After 1.5 hours the heating source was removed, 2.5N NaOH (14 mL) was added, and the reaction mixture was cooled to room temperature. The ethanol was removed, water (100 mL) was added and the solid was filtered. The white solid was washed with water and dried in vacuo to give the product in quantitative yield. A small portion was recrystallized from petroleum ether:ethyl acetate, m.p. 113°-114° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1I.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:11][C:12]1[C:17]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1
Reactant: Oc1ccc(Cl)c(I)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccc(Cl)c(-c2ccc(F)cc2)c1
Temperature: 75 °C
Yield: 70.3 %

Procedure:
A solution of 4-fluorophenylboronic acid (500 mg, 3.57 mmol), 4-chloro-3-iodophenol (455 mg, 1.79 mmol) and caesium carbonate (1.75 g) in dioxane (10 mL) and water (5 mL) was degassed 1 hour with nitrogen. Tetrakis(triphenylphosphine)palladium (0) (104 mg, 0.09 mmol) was added and the reaction mixture was heated for 18 hours at 75° C. The cooled reaction mixture was concentrated in vacuo and the residual aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layer were dried over MgSO4, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 20% ethyl acetate in heptane to afford the title compound (280 mg, 70%) as a yellow oil.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Li+].CC([N-]C(C)C)C.[CH3:27][O:28][C:29]([C@@H:31]1[C@@H:35]([OH:36])[CH2:34][CH2:33][N:32]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:30].IC>C1COCC1>[CH3:27][O:28][C:29]([C@@:31]1([CH3:1])[C@@H:35]([OH:36])[CH2:34][CH2:33][N:32]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:30]
Reactant: COC(=O)[C@@H]1[C@@H](O)CCN1C(=O)OC(C)(C)C
Reactant: CC(C)NC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCC
Product: COC(=O)[C@@]1(C)[C@@H](O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 20.4 %

Procedure:
To diisopropylamine (4.88 mL, 34.8 mmol) in THF (33 mL) at −78° C. was added a 1.37 M solution of n-butyllithium in hexane (24.6 mL, 33.7 mmol). After stirring at the same temperature for 40 min, the LDA solution was transferred via cannula over 30 min to a solution of compound 1B (2.75 g, 11.2 mmol) in THF (112 mL) at −78° C. The reaction was stirred for 1.5 h when iodomethane (10.5 mL, 168 mmol) was added and the reaction was stirred at −78° C. for 2 h then was stored at −40° C. overnight. After warming to rt and stirring overnight, the reaction was quenched with saturated aqueous ammonium chloride. Ethyl acetate was added and the layers were separated. The organic layer was washed with brine, and the aqueous layer was back-extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified using preparative HPLC (Luna C-18, 30×250 mm, eluting with 40-100% solvent B (A=90% H2O-10% MeOH and B=10% H2O- 90% MeOH) over 30 min; Flow rate at 10 mL/min. UV detection at 220 nm) to provide compound 3A as a yellow oil (591 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:18][CH:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16](Br)[C:15](=[O:27])[C:8]=2[S:9][C:10]=1[NH:11][C:12](=[O:14])[CH3:13])=[O:5])[CH3:2].[Li+].[Br-].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:18]=[C:17]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:16]=[C:15]([OH:27])[C:8]=2[S:9][C:10]=1[NH:11][C:12](=[O:14])[CH3:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(NC(C)=O)sc2c1CC(Cc1ccccc1)C(Br)C2=O
Agent: [Br-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(NC(C)=O)sc2c(O)cc(Cc3ccccc3)cc12
Temperature: 25 °C
Yield: 77 %

Procedure:
A flame dried three-necked flask was purged with N2 and charged with bromide 01-5 (3.35 g, 7.4 mmol), LiBr (707 mg, 8.2 mmol, 1.1 equiv.), Li2CO3 (601 mg, 8.2 mmol, 1.1 equiv.) and DMF (85 mL). The resulting suspension was refluxed overnight under N2-atmosphere. The reaction mixture was cooled to RT and poured into saturated aqueous NH4Cl (500 mL). The aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with H2O (3×200 mL), brine (200 mL) and dried over Na2SO4. The solvent was removed in vacuo to give the crude product as a brownish solid. The solid was washed with Et2O (25 mL) to give 01-6 (2.1 g, 5.7 mmol, 77%) as a slightly brown solid.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][O:10][C:11](=[O:19])[C:12](=[O:18])[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.[Cl-].[NH4+]>C(OCC)C.C1COCC1>[CH3:9][O:10][C:11](=[O:19])[C:12]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([OH:18])[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cl[Mg]C1CCCCC1
Reactant: COC(=O)C(=O)c1cccs1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C(O)(c1cccs1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
98.6 ml (0.197 mol) of a 2M solution of Cyclohexylmagnesium chloride in diethyl ether, were added to a solution of 27.97 g (0.164 mol) of 2-oxo-2-thien-2-ylacetic acid methyl ester dissolved in 370 ml of THF, at −78° C. under a N2 atmosphere. The mixture was stirred at this temperature for 10 minutes, and then warmed to room temperature. After 1 h, the reaction mixture was treated with a saturated solution of ammonium chloride and extracted three times with ethyl acetate. The organic phases were combined, washed with water, and dried over MgSO4. After removal of the solvent, the oil obtained was purified by column chromatography (silica gel) using hexane/AcOEt 90:10 as eluent. The yield was 16.2 g (39.5%) of a pure product, whose structure was confirmed by 1H-NMR.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][CH:9]([CH2:13][CH3:14])[CH2:10][Mg]Br.Cl.[Cl-].[Na+]>[Ni].CCOCC>[CH3:8][CH:9]([CH2:13][CH3:14])[CH2:10][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: CCC(C)C[Mg]Br
Agent: [Ni]
Agent: Cl
Agent: [Cl-]
Solvent: CCOCC
Product: CCC(C)Cc1ccccc1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
To a mixture of the nickel catalyst prepared in step (a) (208 gm, 0.39 mmol), chlorobenzene (135 mmol) and ether (50 ml) was added (+)-2-methylbutyl magnesium bromide (60 mmol), prepared in step (b), in 50 ml ether. The mixture was kept at 0° C., with stirring, over 10 minutes. The resulting mixture was heated to reflux for 20 hr. The reactants were cooled to 20° C. and 10% hydrochloric acid was added to hydrolyze the mixture. Sodium chloride is added to saturate the aqueous layer and the water phase was extracted with 3-50 ml portions of ether. The combined extracts are washed with water, dried over calcium chloride, and concentrated in vacuo. The residue was distilled under reduced pressure and the product, which boiled at 91° C. (25 mm Hg), was collected. The structure of the product was confirmed by NMR.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[C:28]([O:32][C:33]([NH:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:39]3[CH:38]=[CH:37][C:36]([NH:35][C:33](=[O:34])[O:32][C:28]([CH3:30])([CH3:29])[CH3:31])=[CH:41][CH:40]=3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(-c2ccc(NC(=O)OC(C)(C)C)cc2)nc(N2CCOCC2)n1
Temperature: 25 °C
Yield: 71 %

Procedure:
A mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2), 4-[(tert-butoxycarbonyl)amino]phenylboronic acid (90 mg, 0.380 mmol), PdCl2(dppf) (10.3 mg, 0.0126 mmol) and aq. K2CO3 (2M, 2 mL) in 1,4-dioxane (10 mL) was refluxed under nitrogen for 1 hr. The mixture was cooled to room temperature and diluted with H2O, and the aqueous phase was extracted with CH2Cl2 (3×). The combined organic extracts were dried (Na2SO4) and the solvent was removed under vacuum. Chromatography on alumina, eluting with CH2Cl2, followed by recrystallization from CH2Cl2/MeOH/hexanes gave tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenylcarbamate (99 mg, 71%): mp (CH2Cl2/MeOH/hexanes) 188-190° C.; 1H NMR (CDCl3) δ 8.41 (d, J=8.8 Hz, 2H), 8.08 (dd, J=8.4, 0.6 Hz, 1H), 7.62 (t, JHF=53.4 Hz, 1H), 7.52 (d, J=8.8 Hz, 2H), 7.41 (t, J=8.2 Hz, 1H), 6.86 (d, J=7.7 Hz, 1H), 6.69 (s, 1H), 4.12 (m, 2H), 4.07 (s, 3H), 3.99 (m, 2H), 3.85 (m, 4H), 1.55 (s, 9H); Anal. Calcd. for C27H29F2N7O4: C, 58.6; H, 5.3; N, 17.2. Found: C, 58.5; H, 5.0; N, 17.7%.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:8])=[O:7]>>[N+:6]([C:9]1[CH:10]=[C:11]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7]
Reactant: O=S(=O)(O)Cl
Reactant: O=[N+]([O-])c1ccccc1
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Temperature: 82.5 °C
Reaction time: 3 h

Procedure:
Chlorosulfonic acid (4.16 mmol, 0.475 grams) was taken in 1 L three neck round bottom flask equipped with a guard tube and liquid addition funnel. Chlorosulfonic acid was cooled in ice bath to 5-10° C. and nitrobenzene (0.83 mmol, 0.102 grams) was added to the acid slowly, at such a rate that the temperature maintained below 10° C. Reaction mixture was then brought to 25° C. and then slowly heated in an oil bath to 80-85° C. The above reaction mixture was stirred further at 80-85° C. for a period of 3 hours. After completion of the reaction, the reaction mixture was cooled to 10° C. and poured on to the ice-water mixture under stirring, while maintaining the temperature below 10° C. The resulting slurry was then filtered on buchner funnel. The solid cake was dried on phosphorous pentoxide in a desiccator to obtain the title compound as off white solid. Yield: 0.144 grams.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:21]1[O:33][C@H:32]([CH2:34][O:35]C(=O)C)[C@@H:27]([O:28]C(=O)C)[C@H:22]1[O:23]C(=O)C.[NH3:39]>C(O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][O:11][C:9]2[N:10]=[C:2]([NH2:39])[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=2)[C@@H:21]2[O:33][C@H:32]([CH2:34][OH:35])[C@@H:27]([OH:28])[C@H:22]2[OH:23])=[CH:15][CH:16]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(OCCc4ccc(Cl)cc4)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N
Solvent: CCO
Product: Nc1nc(OCCc2ccc(Cl)cc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: -50 °C

Procedure:
A 2 liter stainless steel autoclave is charged with 6-chloro-2-[2-(4-chlorophenyl)-ethoxy]-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (22.4 g, 39.4 mmoles) and anhydrous ethanol (800 mL) and chilled to −50° C. Liquid ammonia (200 mL) is condensed, added to the autoclave, the autoclave sealed, and the mixture heated to 105±5° C. for 24 hours. The autoclave is then cooled in an ice bath and vented when the pressure drops below 100 psi. After evaporating to approximately 250 mL, activated charcoal (2 g) is added, the mixture heated to reflux for 30 minutes, filtered through Celite®, and evaporated to dryness. The residue is extracted with boiling ethyl acetate (3×250 mL), then partitioned between ethyl acetate (200 mL) and water (250 mL). The final ethyl acetate extraction is washed once with water (100 mL), dried (Na2SO4), filtered, and added to the original ethyl acetate extracts. The combined organic extracts are evaporated to dryness and the solid recrystallized from ethanol (100 mL). The crystalline product is collected by filtration, washed with cold ethanol, and dried at 75° C./2 Torr for 24 hours. A second crop is obtained by concentrating the mother liquor and a third crop may be collected by chromatography of the mother liquor.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH:12]([CH3:16])[N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:34]=[C:35]([C:37]1[CH:38]=[CH:39][C:40]([CH3:43])=[N:41][CH:42]=1)[CH3:36]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:34]=[C:35](/[C:37]3[CH:42]=[N:41][C:40]([CH3:43])=[CH:39][CH:38]=3)\[CH3:36])[C:6]3[CH2:11][CH:12]([CH3:16])[N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(=CBr)c1ccc(C)nc1
Reactant: CC1Cc2[nH]c3ccc(Cl)cc3c2CN1C
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)C(C)C2)c1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8-Chloro-2,3-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (117 mg, 0.5 mmol) was dissolved in DMF. Copper (I) iodide (9.5 mg, 0.05 mmol), L-proline (11.5 mg, 0.1 mmol) and potassium phosphate (212 mg, 1 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 5-(2-Bromo-1-methyl-vinyl)-2-methyl-pyridine (107.83 mg, 0.55 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-30% EtOAc-Hexane. The product was further purified by HPLC. 1H NMR (CDCl3, TFA salt) δ (ppm): 9.0 (s, 1H), 8.10 (d, 1H), 7.50 (d, 1H), 7.40 (s, 1H), 7.22 (m, 1H), 7.08 (d, 1H), 7.0 (s, 1H), 4.70 (m, 1H), 4.18 (m, 1H), 4.05 (m, 1H), 3.30 (m, 1H), 2.90 (s, 3H), 2.80 (s, 3H), 2.70 (m, 1H), 2.0 (s, 3H), 1.50 (d, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[CH:4]=1)#[N:2].[Li+].CC([N-]C(C)C)C.[B:19](OC)([O:22]C)[O:20]C.O>C1COCC1.CC(O)=O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[C:4]=1[B:19]([OH:22])[OH:20])#[N:2]
Reactant: COB(OC)OC
Reactant: N#Cc1cccc(C#N)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1cccc(C#N)c1B(O)O
Temperature: -96 °C
Reaction time: 0.5 h

Procedure:
1,3-Dicyanobenzene (1.00 g) was dissolved in freshly distilled THF (70 mL). This solution was cooled to −96° C. and LDA (4.2 mL of a 2M solution) was added dropwise to the cold solution under N2. The mixture was stirred for 30 min at −96° C. and (MeO)3B (1.3 mL) was added. The resulting mixture was allowed to warm to room temperature and stirred overnight. Water was added and the resulting mixture was stirred for 0.5 h, then acidified with HOAc and extracted with EtOAc. The organic layer was further washed with water and brine, dried (MgSO4), filtered and evaporated. The residue was taken up in CH2Cl2, filtered and evaporated to yield 2,6-dicyanobenzeneboronic acid(0.56 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[NH:23]1[CH2:27][C@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]1.Cl>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:23]1[CH2:27][C@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(F)c(Br)c1
Reactant: O[C@H]1CNC[C@@H]1O
Agent: Cl
Solvent: CS(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A solution of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.2, 500 mg, 1.322 mmol), (3S,4S)-pyrrolidine-3,4-diol (205 mg, 1.984 mmol) and TEA (553 μL, 3.97 mmol) in DMSO (994 μL) was stirred at 90° C. for 24 h. Additional (3S,4S)-pyrrolidine-3,4-diol, (68.2 mg, 0.661 mmol) and TEA (183 μL, 1.322 mmol) were added and mixture was stirred at 100° C. for 16 h. The cooled treated with 0.5 M HCl (20 mL) and extracted with TBME/EtOAc (1:1). The combined extracts were washed with 0.5 M HCl (20 mL) and brine, dried over MgSO4 and the solvent was evaporated off under reduced pressure to give a residue which was crystallized from cyclohexane/EtOAc to afford the title compound as an off-white solid. UPLC-MS (Condition 1) tR=2.41 min, m/z=460.9/462.9 [M+H]+, m/z=459.0/461.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.24 (d, J=10.76 Hz, 2H) 3.88 (dd, J=10.51, 3.67 Hz, 2H) 4.02 (br. s, 2H) 5.15 (d, J=3.18 Hz, 2H) 6.89 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.84 (dd, J=8.68, 2.08 Hz, 1H) 7.85-7.89 (m, 2H) 8.13 (d, J=2.20 Hz, 1H) 10.17 (s, 1H).