Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([N:9]1[CH2:15][CH2:14][CH2:13][C@H:10]1[CH2:11][OH:12])=[O:8].[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1>C(#N)C.C1(C)C(S(O)(=O)=O)=CC=CC=1.N1C=CC=CC=1>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([N:9]1[CH2:15][CH2:14][CH2:13][C@H:10]1[CH2:11][O:12][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][O:16]1)=[O:8]
Reactant: C1=COCCC1
Reactant: O=C1CC[C@@H](C(=O)N2CCC[C@H]2CO)N1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C1CC[C@@H](C(=O)N2CCC[C@H]2COC2CCCCO2)N1
Temperature: 25 °C
Reaction time: 48 h
Yield: 109.9 %

Procedure:
The thus obtained L-pyroglutamyl-L-prolinol (110 g, 0.519 mol) and dihydropyran (220 g, 2.62 mol) are dissolved in acetonitrile (2.75 l), and pyridine toluenesulfonate (11 g) is added under water-cooling. The mixture is stirred at room temperature for two days, and the reaction liquid is concentrated under reduced pressure, dissolved again in methylene chloride (1.5 l) and washed successively with 5% potassium carbonate (1 l) and water (1 l). The methylene chloride layer is dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated to dryness under reduced pressure to give N-pyroglutamyl-O-tetrahydropyranyl-L-prolinol (169 g, 110%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.N1C=CC=CC=1.[C:30](=[O:37])(Cl)[S:31][CH2:32][CH2:33][CH2:34][CH3:35]>ClCCl>[CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH:23][C:30](=[O:37])[S:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][N:4]=[N:3]1
Reactant: CCCCSC(=O)Cl
Reactant: Cn1nnnc1C(=NOCc1cccc(N)n1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCSC(=O)Nc1cccc(CON=C(c2ccccc2)c2nnnn2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a stirred solution of 6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine (150.0 mg, 0.485 mmol) in dichloromethane (5 mL), under argon atmosphere, were added pyridine (0.078 mL, 0.97 mmol) and S-butyl carbonochloridothioate (133 mg, 0.87 mmol) at room temperature. After stirring at room temperature overnight, the reaction mixture was diluted with dichloromethane (50 mL), filtered through “Chem Elut” cartridge, washed with dichloromethane (50 mL) and the filtrate was concentrated in vacuo yielding to S-butyl {6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamothioate as a honey [82 mg, yield 38%; HPLC/MS m/z=426 (M+H); logP(HCOOH)=4.25].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].[CH3:31][Sn](C)(C)C>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:31])=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(C)sc1C(=O)OCC

Procedure:
A solution of 2-Bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethyl ester (4 g, 8 mmol, example 81(b), tetramethyl tin (3.3 mL, 24 mmol), dichlorobis(triphenylphosphine)palladium II (460 mg, 0.66 mmol) in 50 mL anhydrous DMF was heated to 130° C. for 1 h. The reaction mixture was cooled, diluted with ethyl acetate, and washed successively with water, saturated sodium bicarbonate, and brine. The organic fraction was dried over anhydrous sodium sulfate, concentrated to a crude residue and purified by column chromatography (eluting from silica gel with a gradient of 15-60% ethyl acetate in hexanes) to give 3.13 mg of the title compound. MS (ESI+): m/z 436.8 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:13]=3[CH:28]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].N[C:30]([CH3:34])([CH3:33])[CH2:31][OH:32]>C1(Cl)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH3:33][C:30]1([CH3:34])[CH2:31][O:32][C:1]([C:3]2[CH:4]=[C:5]([C:9]3[CH:10]=[CH:11][C:12]4[O:16][C:15]([C:17]5[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=5)=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:13]=4[CH:28]=3)[CH:6]=[CH:7][CH:8]=2)=[N:2]1
Reactant: CC(C)(N)CO
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C#N)c3)cc12
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C4=NC(C)(C)CO4)c3)cc12
Temperature: 200 °C
Reaction time: 168 h
Yield: 14.6 %

Procedure:
Zinc chloride (1 mg) was added to a stirring solution of 5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (40 mg, 0.108 mmol) and 2-amino-2-methylpropan-1-ol (10 mg, 0.108 mmol) in PhCl (3 mL) at 130° C. It was allowed to stir for 7 days. ˜20% conversion was observed. Additional amounts of ZnCl (8 mg) and 2-amino-2-methylpropan-1-ol (50 mg) were added and the reaction was heated in the microwave for 1 hr at 200° C. The reaction had progressed-50%. The mixture was concentrated and purified on silica gel (BIOTAGE®, EtOAc/hexanes gradient, Rf˜0.2 in 50% EtOAc/hexanes; fraction collection at λ=254 nm) followed by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (7 mg, 14%). 1H NMR (500 MHz, CD3OD) δ ppm 8.24 (1H, s), 7.97 (2H, dd, J=8.09, 5.65 Hz), 7.93 (1H, s), 7.88 (2H, dd, J=11.44, 8.39 Hz), 7.68 (2H, s), 7.57 (1H, t, J=7.78 Hz), 7.27 (2H, t, J=8.55 Hz), 4.25 (2H, s), 2.99 (3H, s), 1.42 (6H, s). LC-MS retention time 1.60 min; m/z (MH+): 443. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u 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 2 min, a hold time of 1 min, and an analysis time of 3 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. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=12.24 min, purity=95%; Column: Waters XBridge phenyl column 4.6×150 mm, 3.5 μm, Rt=10.02 min, purity=95%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[N:6][CH:7]=1.[Br-].[CH:19]1([Zn+])[CH2:21][CH2:20]1>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>[CH:19]1([C:2]2[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])=[N:6][CH:7]=2)[CH2:21][CH2:20]1
Reactant: O=C(OCc1ccccc1)c1ccc(Br)cn1
Reactant: [Zn+]C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1ccc(C2CC2)cn1
Temperature: 80 °C

Procedure:
To a solution of benzyl 5-bromopicolinate (876 mg, 3.0 mmol) in THF (10 mL) was added Pd(PPh3)4 (173 mg, 0.15 mmol) under N2. After addition of a solution of cyclopropylzinc bromide in THF (0.5 M, 10 mL), the mixture was heated at 80° C. for 3 hours and then cooled to room temperature. The reaction mixture was quenched with sat. H4Cl (aq) and extracted with EtOAc (5×). The organic layer was washed with sat. NaHCO3(aq.), brine, and dried (MgSO4). The product benzyl 5-cyclopropylpicolinate (510 mg) was obtained by silica gel chromatography (elution with 0-15% EtOAc/Hex, then 15% EtOAc/Hex).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:19]1([CH2:22]Br)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CC#N.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:22][CH:19]2[CH2:21][CH2:20]2)[CH2:15][CH2:16][O:17][CH3:18])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCC1CC1
Reactant: COCCNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: COCCN(CC1CC1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A mixture of 4-(2-methoxy-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester (525 mg), cyclopropylmethyl bromide (218 μL) and potassium carbonate (340 mg) was heated to reflux in MeCN for 16 h. After cooling the reaction mixture was diluted with chloroform, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-[cyclopropylmethyl-(2-methoxy-ethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (475 mg). Removal of the BOC group with HCl yielded the desired compound, which was isolated as the hydrochloride salt.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([N:15]3[CH:23]([OH:24])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]3=[O:25])=[N:12]2)=[CH:7][CH:6]=1.Cl[C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)=[O:28].CN(P(N(C)C)(N(C)C)=O)C>CN(C)C=O>[CH3:3][O:4][C:5]1[N:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([N:15]3[CH:23]([O:24][C:27]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[O:28])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]3=[O:25])=[N:12]2)=[CH:7][CH:6]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OC(=O)N3CCN(C)CC3)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
Sodium hydride (50% dispersion in mineral oil) (0.8 g.) is added to a suspension of 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-1-one (4.63 g.) in anhydrous dimethylformamide (45 cc.), whilst keeping the temperature between 18°-20° C. The reaction mixture is stirred for a further 4 hours 30 minutes. A solution of 1-chlorocarbonyl-4-methylpiperazine (2.7 g.) in anhydrous dimethylformamide (25 cc.) is then added over the course of 15 minutes and at a temperature of 20° C. The suspension is stirred for 17 hours at a temperature of about 20° C., and then anhydrous hexamethylphosphotriamide (7 cc.) is added. After 15 minutes, the reaction mixture is poured into ice-water (500 g.). The precipitate is filtered off and washed with water (45 cc.). A product (6.1 g.) is obtained and is recrystallised from diisopropyl ether (1,500 cc.). 2-(7-Methoxy-1,8 -naphthyridin-2-yl)-3-(4-methylpiperazin-1-yl)carbonyloxy-isoindolin-1-one (3 g.), melting at 191° C., is thus obtained.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[O:27])=[CH:22][CH:21]=4)=[CH:15][C:14]=3[Cl:34])[C:8]2=[O:35])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:37][CH2:38][F:39]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:14]([Cl:34])=[CH:15][C:16]([C:20]4[CH:21]=[CH:22][C:23]([C:26]([N:28]5[CH2:29][CH2:30][N:31]([CH2:37][CH2:38][F:39])[CH2:32][CH2:33]5)=[O:27])=[CH:24][CH:25]=4)=[CH:17][C:18]=3[Cl:19])[C:8]2=[O:35])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1)N1CCNCC1
Reactant: FCCBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1)N1CCN(CCF)CC1
Temperature: 55 °C
Yield: 64.5 %

Procedure:
Treat a solution of 1-cyclohexyl-3-[3,5-dichloro-4′-(piperazine-1-carbonyl)-biphenyl-4-ylmethyl]-pyrrolidin-2-one (0.67 g, 1.30 mmol) in dimethylformamide (7 mL) with 1-bromo-2-fluoroethane (0.99 g, 7.80 mmol) and heat to 55° C. for 16 hours under a nitrogen atmosphere. Cool the reaction, dilute with ethyl acetate and wash with saturated aqueous sodium bicarbonate then water. Dry the organic layer with sodium sulfate and purify the crude product by silica gel chromatography using a gradient of 0 to 10% methanol in dichloromethane to afford 0.47 g (64%) of the title compound in its racemic form. Separate into the enantiomers by chiral HPLC (Chiralpak AD 8×33 cm column, isocratic 90:10 3 A ethanol:acetonitrile with 0.2% dimethylethylamine, 400 mL/min, 300 nM UV) to afford 286 mg of Isomer 1 (>99% ee) and 283 mg of Isomer 2 (98.9% ee): MS (m/z): 560. Check the purity of each isomer using chiral HPLC (Chiralpak AD-H 4.6×150 mm column, isocratic 90:10 3A ethanol:acetonitrile with 0.2% dimethylethylamine, 0.6 mL/min, 270 nM).
Reaction SMILES: [OH:1][CH:2]([CH3:7])[C:3]([NH:5][OH:6])=[NH:4].[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=O>N1C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]([C:12]2[O:6][N:5]=[C:3]([CH:2]([OH:1])[CH3:7])[N:4]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CC(O)C(=N)NO
Solvent: c1ccncc1
Product: CC(O)c1noc(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 59.9 %

Procedure:
To a solution of 3.19 g (30.6 mmol) 2,N-dihydroxy-propionamidine in 25 ml pyridine was added 4.3 ml (33.7 mmol) 3-chloro-benzoyl chloride at 0° C. Cooling was removed and the mixture was stirred at room temperature for 25 min and at reflux for 25 min. After cooling the mixture was poured into water and extracted twice with CH2Cl2. The organic phase was dried and concentrated. Recrystallization from heptane/EtOAc afforded 4.12 g (60%) of a white solid. 1H NMR (CDCl3), d (ppm): 1.68 (d, 3 H) 2.67 (m, 1 H) 5.09 (m, 1 H) 7.46 (t, 1 H) 7.56 (d, 1 H) 8.01 (d, 1 H) 8.13 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3]#[C:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1CN.CCC[CH2:21][N+:22](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:2]([C:3]1[N:22]([CH3:21])[C:6]2[C:5]([CH:4]=1)=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][CH:7]=2)([CH3:1])([CH3:16])[CH3:17]
Reactant: CC(C)(C)C#Cc1cc([N+](=O)[O-])ccc1CN
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1c(C(C)(C)C)cc2cc([N+](=O)[O-])ccc21
Yield: 94 %

Procedure:
A solution of [2-(3,3-dimethyl-but-1-ynyl)-4-nitro-phenyl]methyl-amine (5.0 g, 22.9 mmol) and TBAF (23.9 g, 91.6 mmol) in THF (50 mL) was heated at reflux overnight. The solvent was removed by evaporation under vacuum and the residue was dissolved in brine (100 mL) and EtOAc (100 mL). The organic phase was separated, dried over Na2SO4 and evaporated under vacuum to give 2-tert-butyl-1-methyl-5-nitro-1H-indole (5.0 g, 99%), which was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 8.47 (d, J=2.4 Hz, 1H), 8.07 (dd, J=2.4, 9.2 Hz, 1H), 7.26-7.28 (m, 1H), 6.47 (s, 1H), 3.94 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[O:14]1CCC[CH2:15]1.C([Li])CCC.CN(C)C=O>O>[C:8]1([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[CH:15]=[O:14])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C1CCOC1
Reactant: Brc1cccc(-c2ccccc2)c1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
To a mixture of 3-bromobiphenyl (0.50 mL, 3.0 mmol) and tetrahydrofuran (8 mL) was added n-butyl lithium (2.6 mL, 1.5 M n-hexane solution, 3.9 mmol) under nitrogen atmosphere at −78° C., which was stirred for 20 minutes at that temperature. N,N-dimethylformamide (0.35 mL, 4.5 mmol) was added to the reaction mixture at the same temperature, and the temperature was gradually raised to 0° C. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=6:1) to obtain the title compound (430 mg, 79%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH2:3]1.C(Cl)(Cl)Cl.[BrH:13]>C(OCC)(=O)C>[Br:13][CH:3]1[CH:2]([CH3:1])[CH2:7][CH2:6][CH2:5][C:4]1=[O:8]
Reactant: CC1CCCC(=O)C1
Reactant: Br
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC1CCCC(=O)C1Br

Procedure:
3-Methylcyclohexanone, 22.4 grams, contained in 250 ml. of chloroform and 50 ml. of ethyl acetate, is heated to boiling. A mixture of 98.3 grams of cupric bromide and 50 ml. of ethyl acetate is added and heated to maintain elimination of hydrogen bromide. When all of the hydrogen bromide is evolved, the mixture is heated to its reflux temperature for 15 minutes, filtered and the filtrate evaporated to a small volume. The residue is placed upon an alumina column and eluted with methylene chloride. Evaporation of the eluate yields 35.5 grams of crude 2-bromo-3-methylcyclohexanone suitable for condensation with the triazoles of Examples 1 or 2.
Reaction SMILES: CS([O:5][CH2:6][CH:7]1[CH2:11][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9](=[O:20])[CH2:8]1)(=O)=O.O[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([N:10]2[CH2:11][CH:7]([CH2:6][O:5][C:22]3[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=3)[CH2:8][C:9]2=[O:20])=[CH:13][CH:14]=1
Reactant: COc1ccc(N2CC(COS(C)(=O)=O)CC2=O)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CC(COc3ccc(C=O)cc3)CC2=O)cc1
Yield: 82.2 %

Procedure:
Then, 3.20 g of {1-(4-methoxyphenyl)-2-pyrrolidon-4-yl}methyl methanesulfonate and 1.4 g of 4-hydroxybenzaldehyde were dissolved in 32 ml of anhydrous N,N-dimethylformamide, to which 1.92 g of anhydrous potassium carbonate were added. The resultant mixture was stirred at 70° C. for 15 hours. The reaction mixture was filtered and the filtrate was concentrated. The thus-obtained residue was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column and then purified using gradient elution with hexane-ethyl acetate, whereby 2.86 g of the title compound were obtained (yield: 74%).
Reaction SMILES: CO[N:3](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:4]1[NH:5][C:6](=[O:20])[C:7]2[N:8]=[CH:9][N:10]([CH2:13][CH2:14][CH:15]([CH2:18][OH:19])[CH2:16][OH:17])[C:11]=2[N:12]=1.[C:40](Cl)(=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42]>N1C=CC=CC=1>[C:40]([O:19][CH2:18][CH:15]([CH2:16][O:17][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:14][CH2:13][N:10]1[CH:9]=[N:8][C:7]2[C:6](=[O:20])[NH:5][C:4]([NH2:3])=[N:12][C:11]1=2)(=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CON(c1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCC(CCn1cnc2c(=O)[nH]c(N)nc21)COC(=O)C(C)(C)C
Reaction time: 0.75 h
Yield: 58 %

Procedure:
To a solution of N2-monomethoxytrityl-9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (0.47 g, 0.9 mmol) in pyridine (4.5 ml) was added pivalyl chloride (0.55 ml, 4.5 mmol) and the solution was stirred for 45 minutes. The mixture was precipitated in water (45 ml) and the resulting precipitate was stirred in 80% acetic acid (10 ml) at 80° for 20 minutes. The solvent was removed and the residue was purified by column chromatography on silica gel eluting with chloroform-methanol (10:1) to afford 9-(4-pivalyloxy-3-pivalyloxymethylbut-1-yl)guanine (0.22 g, 58%), m.p. 225-237° C.; νmax (KBr) 3430, 2980, 1730, 1690, and 1620 cm−1; δH [(CD3)2SO] 1.11 (18H, s, 2×C(CH3)3), 1.81 (2H, q, J 6.8 Hz, 2′-H), 1.93 (1H, m, 3′-H), 4.0-4.1 (6H, m, 1′-H and 2×4′-H), 6.38 (2H, s, 2-NH2), 7.69 (1H, s, 8-H), and 10.58 (1H, br.s, 1-H); (Found: C, 56.58; H, 7.26; N, 16.14%; C20H31N5O5 requires: C, 56.99; H, 7.41; N, 16.62%).
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][CH:37]=[N:38][CH:39]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CO.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>[OH:25][CH2:24][CH2:23][O:22][C:3]1[C:2]([C:34]2[CH:35]=[N:36][CH:37]=[N:38][CH:39]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: CC1(C)OB(c2cncnc2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(OCCO)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(OCCO)c(-c2cncnc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 5-bromo-6-(2-hydroxyethoxy)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 52.1, 50 mg, 0.119 mmol), Pd(Ph3P)4 (14 mg, 0.012 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (37 mg, 0.178 mmol) in toluene (0.5 mL) was stirred for 15 min. at RT. K3PO4 (76 mg, 0.356 mmol) was added and the RM was stirred at 110° C. for 6 h. The RM was diluted with MeOH, filtered through a cartridge of PL-Thiol MP-Resin, and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by preparative SFC (Column DEAP, from 12% to 17% in 6 min.) to afford the title compound as an off-white powder. UPLC-MS (Condition 2) tR=0.93 min, m/z=419.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 3.74 (q, J=4.83 Hz, 2H) 4.48 (t, J=4.71 Hz, 2H) 4.90 (t, J=5.27 Hz, 1H) 7.39 (d, J=8.66 Hz, 2H) 7.87 (d, J=8.85 Hz, 2H) 8.50 (d, J=1.51 Hz, 1H) 8.81 (s, 1H) 9.19 (s, 2H) 9.21 (s, 1H) 10.46 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([F:14])=[C:5]([O:12][CH3:13])[CH:6]=[C:7]([O:10][CH3:11])[C:8]=1[F:9])#[CH:2].Br[C:16]1[N:17]=[C:18]2[CH:24]=[CH:23][N:22]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:19]2=[N:20][CH:21]=1.C(N(CC)CC)C>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:14][C:4]1[C:5]([O:12][CH3:13])=[CH:6][C:7]([O:10][CH3:11])=[C:8]([F:9])[C:3]=1[C:1]#[C:2][C:16]1[N:17]=[C:18]2[CH:24]=[CH:23][N:22]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:19]2=[N:20][CH:21]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2nc(Br)cnc21
Reactant: C#Cc1c(F)c(OC)cc(OC)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(OC)c(F)c(C#Cc2cnc3c(ccn3S(=O)(=O)c3ccccc3)n2)c1F
Reaction time: 14 h
Yield: 62.6 %

Procedure:
To a stirred solution of 3-ethynyl-2,4-difluoro-1,5-dimethoxybenzene (340 mg, 1.72 mmol) and 2-bromo-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (696 mg, 2.06 mmol, from Example 1, Step 1) in N,N-dimethylformamide (4 mL), copper(I) iodide (26 mg, 0.14 mmol), bis(triphenylphosphine)palladium(II) chloride (60.0 mg, 0.0885 mmol) and triethylamine (0.36 mL, 2.6 mmol) were added sequentially at room temperature. After 14 hours, the reaction was quenched with saturated aq. NH4Cl, then extracted with methylene chloride. The combined organic layers were dried over MgSO4, then concentrated. The residue was purified on silica gel (eluting with 0 to 50% ethyl acetate (EtOAc) in hexanes) to give the desired product (490 mg, 63%). LCMS calculated for C22H15F2N3O4S (M+H)+: m/z=456.1. Found: 456.1.