Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([C:7]([O:9]C)=[O:8])=O)=O.Cl.Cl.[CH2:13]([NH:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C>[CH3:1][C:2]1[N:20]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:21]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=1
Reactant: NNCc1ccccc1
Reactant: COC(=O)C(=O)CC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(C(=O)O)nn1Cc1ccccc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of methyl acetopyruvate (1.0 g, 6.94 mmol) and benzylhydrazine dihydrochloride (1.49 g, 7.63 mmol) in acetic acid (7 mL) was stirred for 4 h at 90° C. After removal of the solvent (rotavapor), the residue was subjected to MPLC (silica, cyclohexane/ethyl acetate 10:1→2:1, followed by dichloromethane/methanol 10:1). The eluate obtained with dichloromethane/methanol contained the title compound as a crude product. After evaporation of the solvent, this fraction was further purified by preparative HPLC to afford the title compound (260 mg, 17%): 1H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 7.37-7.27 (m, 3H), 7.12 (d, 2H), 6.53 (s, 1H), 5.36 (s, 2H), 2.22 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[F:21])[CH2:33][CH2:32]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Reactant: Fc1ccccc1N1CCNCC1
Product: COc1ccc2nc(NC(=O)N3CCN(c4ccccc4F)CC3)c(OC)nc2c1
Yield: 95 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 95%). 1H NMR (300 MHz, CDCl3): δ 3.18 (s, 4H), 3.66 (s, 4H), 3.78 (s, 3H), 4.15 (s, 3H), 6.94-7.27 (m, 7H), 7.73-7.87 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:13][C:14]1([F:29])[CH2:19][CH2:18][C:17]([CH2:27][NH2:28])([C:20]2[CH:21]=[N:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[F:29][C:14]1([F:13])[CH2:15][CH2:16][C:17]([CH2:27][NH:28][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:2]=2[F:1])([C:20]2[CH:21]=[N:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:18][CH2:19]1
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Reactant: COc1cccc(C(=O)O)c1F
Product: COc1cccc(C(=O)NCC2(c3ccc(F)nc3)CCC(F)(F)CC2)c1F

Procedure:
From 2-fluoro-3-methoxybenzoic acid and C-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=397.2, tR (minutes, Method D)=0.69
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>C(O)C>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]2[CH2:16][CH2:15][C:14](=[N:19][OH:20])[CH2:13][CH2:12]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCN(c2cccc3c2OCCC3)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1CCN(c2cccc3c2OCCC3)CC1
Yield: 84.6 %

Procedure:
A mixture composed of 1 g (4.32 mmol) of the product obtained in Step 1, 1.26 g of hydroxylamine hydrochloride, 1.26 g of sodium acetate and 20 ml of ethanol are heated at reflux for 1 hour. After removal of the solvent by evaporation, the residue is taken up in 100 ml of methylene chloride, washed with water, dried and evaporated to yield 0.9 g of the expected product.
Reaction SMILES: C(OC([NH:8][C:9]([NH:31]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:22]([O:23][Si](C(C)(C)C)(C)C)=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=1)=O)(C)(C)C.[ClH:39]>ClCCl.O1CCOCC1>[ClH:39].[ClH:39].[OH:23][C:22]1[C:17]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:31])=[NH:8])[CH:16]=[CH:15][CH:14]=2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC(=Nc1cccc(-c2ncccc2O[Si](C)(C)C(C)(C)C)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N=C(N)Nc1cccc(-c2ncccc2O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-tert-butyldimethylsilyloxypyridine-2-yl)phenyl)guanidine (300 mg) in dichloromethane (3 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 6 ml), and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the precipitate was collected by filtration and dried under reduced pressure to give 3-(3-hydroxypyridin-2-yl)phenylguanidine dihydrochloride (145 mg).
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1N.[Na+].[Br-:11].Br.N([O-])=O.[Na+]>O>[Br:11][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:2]=1[Cl:1]
Reactant: [Br-]
Reactant: Nc1cccc(Cl)c1Cl
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1cccc(Br)c1Cl
Temperature: 37.5 °C
Reaction time: 0.25 h
Yield: 97.4 %

Procedure:
32.7 g 2,3-Dichloroaniline (0.20 mole) is added to a mixture of 21.4 g of NaBr (0.20 mole, 1.0 equivalent), 110.0 g of 48% aqueous HBr (0.66 mole, 3.3 equivalents) and 70 ml water at 30-45° C. The mixture is stirred for 15 minutes at 30-45° C. and then heated to 60° C. Then 2.9 g Cu(I)Br (0.02 mole, 0.10 equivalent) is added and the mixture is stirred for 15 minutes at 60° C. After this, an aqueous solution of NaNO2 (40% solution in water, 37.6 g, 0.22 mole, 1.1 equivalents) is added via subsurface feeding over a period of 2 hours at 60-65° C. The reaction mixture is stirred for 30 minutes at 60-65° C. The organic phase containing the reaction product is separated from the aqueous phase and is cooled to ambient temperature, leading to solidification of the reaction product. The remaining liquid is discarded and the crude product is washed two times with 10 ml water and dried under vacuum. 44.0 g (89% of theory) of 1-bromo-2,3-dichlorobenzene is obtained in the form of a light brown solid (purity: 91%). For further characterisation, the crude product was purified by vacuum distillation (130° C./20 mmHg). 38.0 g (84% of theory) of pure 1-bromo-2,3-dichlorobenzene is obtained in the form of white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[NH:9][C:10](=[O:14])[CH:11]([CH3:13])[O:12][C:7]=2[CH:6]=1)=[O:4].[H-].[Na+].[CH2:19](I)[CH3:20].O>CN(C)C=O.C(OCC)(=O)C>[CH2:19]([N:9]1[C:8]2[CH:15]=[CH:16][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=2[O:12][CH:11]([CH3:13])[C:10]1=[O:14])[CH3:20]
Reactant: COC(=O)c1ccc2c(c1)OC(C)C(=O)N2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)Oc2cc(C(=O)OC)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of 7-methoxycarbonyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (prepared in Preparation 1) (1.00 g) in dimethylformamide (5 ml) were added 60% sodium hydride (in oil) (0.22 g) and ethyl iodide (0.78 g) and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure to give 4-ethyl-7-methoxycarbonyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (0.89 g).
Reaction SMILES: [H-].C[O:3][C:4](=O)[CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11]>C1(C)C=CC=CC=1>[O:11]=[C:7]1[CH2:8][CH2:9][CH2:10][N:6]1[CH2:5][CH:4]=[O:3]
Reactant: COC(=O)CN1CCCC1=O
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=CCN1CCCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.7 %

Procedure:
A 1.02M solution of diisobutylalminium hydride in toluene (16 ml) was added dropwise to a solution of methyl(2-oxopyrrolidin-1-yl)acetate (1.01 g) in toluene (10 ml) at −78° C., and the mixture was stirred for 1 hour. The reaction solution was quenched with methanol at −78° C., then diluted with a 1N aqueous solution of hydrochloric acid, and allowed to warm to room temperature with stirring. The reaction solution was filtered through celite and then the filtrate was dried up. The residue was purified by silica gel column chromatography (chloroform:methanol=95:5→90:10) to yield 2-oxopyrrolidin-1-yl-acetaldehyde (120 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]([C:14]3[CH:20]=[C:19]([C:21]#[C:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:18]=[CH:17][C:15]=3[NH2:16])=[O:13])=[CH:8][CH:7]=2)[NH:5][NH:4]1>C(OCC)C.[O-2].[Mn+4].[O-2]>[F:28][C:2]([F:1])([F:27])[C:3]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]([C:14]3[CH:20]=[C:19]([C:21]#[C:22][Si:23]([CH3:25])([CH3:24])[CH3:26])[CH:18]=[CH:17][C:15]=3[NH2:16])=[O:13])=[CH:8][CH:7]=2)[N:5]=[N:4]1
Reactant: C[Si](C)(C)C#Cc1ccc(N)c(C(=O)c2ccc(C3(C(F)(F)F)NN3)cc2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Product: C[Si](C)(C)C#Cc1ccc(N)c(C(=O)c2ccc(C3(C(F)(F)F)N=N3)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
2-({4-[3-(trifluoromethyl)diaziridin-3-yl]phenyl}carbonyl)-4-[2-(trimethylsilyl)ethynyl]aniline (66 mg, 0.16 mmol, 1 eq.) was dissolved in diethyl ether (10 mL) and manganese(IV) oxide (300 mg, 3.4 mmol, 21 eq.) was added to the solution. The reaction was stirred at room temperature for 30 minutes and then filtered through Celite with DCM to remove the manganese(IV) oxide. The solvent was evaporated, and the residue was purified on silica column (hexanes/ethyl acetate, 9:1→2:1), resulting in 64 mg (97%) of the title compound as a yellow-orange solid. 1H NMR (500 MHz, CDCl3) δ 7.63 (d, J=8.4, 2H, Ar—H), 7.46 (d, J=1.7, 1H, Ar—H), 7.37 (dd, J=1.8, 8.6, 1H, Ar—H), 7.28 (d, J=8.2, 2H, Ar—H), 6.64 (d, J=8.6, 1H, Ar—H), 6.30 (s, 2H, NH2), 0.18 (s, 9H, Si(CH3)3). 13C NMR (126 MHz, CDCl3) δ 197.20 (CO), 151.24 (C—Ar), 140.72 (C—Ar), 138.19 (C—Ar), 137.94 (C—Ar), 132.27 (C—Ar), 129.59 (C—Ar), 126.48 (q, C—Ar, J=1.19), 122.13 (q, J=274.80, CF3), 117.35 (C—Ar), 117.10 (C—Ar), 110.28 (C—Ar), 104.86 (CSi(CH3)3), 92.21 (CCSi(CH3)3), 28.62 (q, J=40.69, CN2), 0.22 (Si(CH3)3). Exact Mass, 401.12. 399.7011 [M−H]−, 401.7108 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([SH:11])[CH2:8][CH2:9][SH:10].Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH2:20][OH:21])[C:15]=1[CH3:22]>O>[SH:10][CH2:9][CH2:8][CH2:7][S:11][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH2:20][OH:21])[C:15]=1[CH3:22]
Reactant: SCCCS
Reactant: Cc1c(Cl)ccnc1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1c(SCCCS)ccnc1CO
Temperature: 80 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
A solution of potassium carbonate (691 g, 5 mol) in 1.5 l of water is treated with 1,3-propanedithiol (432.8 g, 4 mol) under a nitrogen atmosphere and heated to 80° C. A solution of (4-chloro-3-methylpyridin-2-yl)methanol hydrochloride (194.1 g, 1 mol) in 400 ml of water is then added dropwise at this temperature with vigorous stirring during the course of about 2 h. The mixture is additionally stirred at 80 to 85° C. for 18 h and then cooled to room temperature. After separating off the aqueous phase, the organic phase is treated with toluene (1.5 l) and washed with water (2×1 l). The organic phase is then extracted with 2M hydrochloric acid (2 l). The hydrochloric acid phase is concentrated and the residue is recrystallized from isopropanol. 159 g (60%) of the title compound are isolated. The crude product is employed without further purification for the synthesis of the compound of Example 1.
Reaction SMILES: [OH:1][CH:2]1[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:3]1[NH:12]C(C)=O.[ClH:16]>>[OH:1][CH:2]1[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:3]1[NH2:12].[ClH:16]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Product: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
GlcNAc hydrolysis proceeds quantitatively in 0.1 N HCl at 100° C. for 2 hr. Spray drying or concentrating the solution removes excess HCl and the acetic acid, giving GlcN.HCl.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.N1CCNCC1.[CH:17](=[O:26])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C1(C)C=CC=CC=1>[OH:8][CH2:7][CH2:6][C:5]1[CH:4]=[C:3]2[C:2](=[CH:10][CH:9]=1)[O:1][CH:17]([OH:26])[CH2:18][CH:19]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCc1ccc(O)cc1
Reactant: O=CC=Cc1ccccc1
Agent: C1CNCCN1
Agent: Cl
Solvent: Cc1ccccc1
Product: OCCc1ccc2c(c1)C(c1ccccc1)CC(O)O2
Temperature: 80 °C

Procedure:
To a solution of 4-hydroxyphenethyl alcohol (Tyrosol) (5.0 g, 36 mmol, 1 equiv), piperazine (1.87 g, 22 mmol, 0.6 equiv) and toluene (50 ml) at reflux under N2 and Dean & Stark conditions was added cinnamaldehyde (6.4 ml, 51 mmol, 1.4 equiv) and the reaction mixture maintained at heat for 17 h. The reaction was cooled to 80° C. and quenched with aqueous HCl (0.7 molar, 1.3 equiv) then stirred at heat for 18 h. The biphasic mixture was allowed to cool to ambient temperature, separated, the organic phase washed with aqueous HCl and water and the organic phase concentrated to a black residue under reduced pressure. Flash chromatography eluting with 20% EtOAc/Heptane afforded the title compound as the main constituent of an approximately 80% pure yellow oil, Rf=0.37 (50% EtOAc/Heptane) and structure confirmed by 1H NMR and LC-MS (M+1=271).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH:15]2[CH:10]([CH2:11][CH:12]([CH2:18][O:19][S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:13][C:14]2=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:14]1([OH:17])[CH2:13][CH:12]([CH2:18][O:19][S:20]([C:23]2[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=2)(=[O:22])=[O:21])[CH2:11][CH:10]2[CH:15]1[CH2:16][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2
Reactant: Cc1ccc(S(=O)(=O)OCC2CC(=O)C3CN(C(=O)OC(C)(C)C)CC3C2)cc1
Reactant: COc1ccccc1[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1C1(O)CC(COS(=O)(=O)c2ccc(C)cc2)CC2CN(C(=O)OC(C)(C)C)CC21
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 12.07 g .of (3aRS,6SR,7aSR)-2-tert-butyloxycarbonyl-6-tosyloxymethylperhydroisoindol-4-one in 50 cm3 of anhydrous tetrahydrofuran is run over a period of 15 minutes into a suspension, cooled to +5° C., of 2-methoxyphenylmagnesiumbromide (prepared from 6.4 cm3 of 2-bromoanisole and 1.24 g of magnesium) in 200 cm3 of anhydrous tetrahydrofuran. The reaction mixture is stirred at 20° C. for one hour, cooled to +5° C., treated with 250 cm3 of saturated aqueous ammonium chloride solution and extracted with 200 cm3 of ethyl acetate. The organic phase is washed with 300 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The oily residue is recrystallized from a mixture of ethyl acetate and diisopropyl ether, and the crystals are filtered, washed with diisopropyl ether, subjected to suction and then dried under reduced pressure (2.7 kPa). 11.38 g of (3aRS,4RS,6SR,7aSR)-4-(2-methoxyphenyl)-2-tert-butyloxycarbonyl-6-tosyloxymethylperhydroisoindol-4-ol are obtained in the form of white crystals. M.p.K =153° C.
Reaction SMILES: [Cl-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:21]([O:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([CH:31]=O)[CH2:27][CH2:26]1)[CH2:22][CH3:23].C[CH2:34][O:35][CH2:36]C>>[CH3:34][O:35][CH:36]=[CH:31][C@H:28]1[CH2:27][CH2:26][C@H:25]([O:24][CH2:21][CH2:22][CH3:23])[CH2:30][CH2:29]1
Reactant: CCCO[C@H]1CC[C@H](C=O)CC1
Reactant: CCOCC
Agent: [Cl-]
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Product: CCCO[C@H]1CC[C@H](C=COC)CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A suspension of 94.6 g. of (methoxymethyl)(triphenylphosphonium chloride in 1000 ml. of dry ether is treated with 33.0 g. of potassium tert.butylate. After stirring for 45 minutes, a solution of 31.4 g. of trans-4-n-propyloxycyclohexane carboxaldehyde in 200 ml. of ether is added dropwise. The mixture is stirred for a further 2.5 hours and then poured into 1.2 liters of ice-water. The organic phase is separated, washed neutral with water, dried over sodium sulfate and evaporated. The crude trans-2-(4-n-propyloxycyclohexyl)vinyl methyl ether obtained is distilled at 82°-85° C./0.6 mmHg in order to separate the residual triphenylphosphine.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[C:14]3=[N:15][C:16]([Sn](C)(C)C)=[CH:17][N:18]=[C:13]3[NH:12][CH2:11][C:10]2=[O:23])[CH2:3][CH2:2]1.Br[C:25]1[CH:30]=[CH:29][N:28]=[C:27]2[N:31](C(O)=O)[CH:32]=[CH:33][C:26]=12.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1.[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[NH:31]1[C:27]2=[N:28][CH:29]=[CH:30][C:25]([C:16]3[N:15]=[C:14]4[N:9]([CH2:8][CH2:7][CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[C:10](=[O:23])[CH2:11][NH:12][C:13]4=[N:18][CH:17]=3)=[C:26]2[CH:33]=[CH:32]1
Reactant: O=C(O)n1ccc2c(Br)ccnc21
Reactant: C[Sn](C)(C)c1cnc2c(n1)N(CCC1CCOCC1)C(=O)CN2
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1CNc2ncc(-c3ccnc4[nH]ccc34)nc2N1CCC1CCOCC1
Temperature: 95 °C
Reaction time: 3.5 h
Yield: 35 %

Procedure:
A mixture of 1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (See Example 15.C) (1 equiv), 4-bromo-pyrrolo[2,3-b]pyridine-1-carboxylic acid tent-butyl ester (1 equiv), tris(dibenzylideneacetone) palladium (0.13 equiv), tri-o-tolylphosphine (0.25 equiv) and triethylamine (2.8 equiv) in anhydrous dioxane was purged, degassed for 2 min and stirred at 95° C. under nitrogen for 3-4 h. Upon completion of the reaction as indicated by TLC, the volatiles were removed under reduced pressure and the residue was purified by column chromatography to give the desired product in 35% yield. MS (ESI) m/z 479.7 [M+1]+. Tert-Butyl 4-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was stirred in methanolic hydrochloride solution at room temperature. Upon completion of the reaction as indicated by TLC, the solvent was removed under reduced pressure and the residue was purified on silica gel to give the title compound in 63% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 11.72 (s, 1H), 8.38 (s, 1H), 8.25 (d, J=4.8 Hz, 1H), 7.79 (s, 1H), 7.53-7.51 (m, 2H), 6.97 (q, J=1.6 Hz, 1H), 4.23 (s, 2H), 4.14 (t, J=7.6 Hz, 2H), 3.81 (dd, J1=2.4 Hz, J2=11.2 Hz, 2H), 3.25 (d, J=10.8 Hz, 2H), 1.67 (d, J=13.2 Hz, 2H), 1.61 (m, 3H), 1.22 (m, 2H); MS (ESI): m/z 379.2 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([CH2:8][CH2:9][C@@:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][O:14]C2CCCCO2)=[O:12])[CH:7]=1)#[N:2].Cl>CCO>[C:1]([C:3]1[CH:4]=[N:5][N:6]([CH2:8][CH2:9][C@@:10]([CH3:25])([S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([NH:13][OH:14])=[O:12])[CH:7]=1)#[N:2]
Reactant: C[C@@](CCn1cc(C#N)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CCO
Product: C[C@@](CCn1cc(C#N)cn1)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.5 %

Procedure:
To a solution of (2R)-4-(4-cyano-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (0.165 g, 0.445 mmol) in EtOH (20 mL) was added HCl (1 M solution, 5 mL). The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was concentrated and was purified via reverse-phase chromatography system, using 5%-95% acetonitrile/water with 0.1% formic acid modifier as the gradient elution solvent. Target fractions were combined and evaporated to yield (2R)-4-(4-cyano-1H-pyrazol-1-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (21 mg, 16% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.47 (s, 3H), 2.16-2.33 (m, 1H), 2.59-2.80 (m, 1H), 3.04 (s, 3H), 3.96-4.17 (m, 1H), 4.18-4.39 (m, 1H), 8.05 (s, 1H) 8.57 (s, 1H), 9.24 (br. s., 1H) 10.97 (br. s., 1H). LC-MS M−H 285.3.
Reaction SMILES: [F:1][CH:2]([F:14])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]2[N:10]=[C:11]([NH2:13])[CH:12]=[C:6]2[CH2:5]1.Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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].O1CCOCC1>[Br:22][C:20]1[CH:21]=[C:16]([NH:13][C:11]2[CH:12]=[C:6]3[CH2:5][N:4]([CH2:3][CH:2]([F:1])[F:14])[CH2:9][CH2:8][N:7]3[N:10]=2)[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=1
Reactant: Nc1cc2n(n1)CCN(CC(F)F)C2
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2cc3n(n2)CCN(CC(F)F)C3)c1=O
Temperature: 25 °C
Yield: 72.1 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 135b (290 mg, 1.43 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (383 mg, 1.43 mmol), cesium carbonate (932 mg, 2.86 mmol), and 1,4-dioxane (20 mL). After bubbling nitrogen through the suspension for 10 minutes, xantphos (82 mg, 0.143 mmol) and Pd2(dba)3 (65 mg, 0.072 mmol) were added. The system was subjected to three cycles of vacuum/argon flush and heated at reflux for 5 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (30 mL). The combined organic filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80/1 to 30/1) to afford 135c (400 mg, 72%) as a yellow solid. MS-ESI: [M+H]+ 387.8
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][C:12]([NH2:15])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:15][C:12]2[N:11]=[CH:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[CH:14][N:13]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(-c2cnc(N)nc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(-c2cnc(NS(=O)(=O)c3ccc(C)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 27.6 %

Procedure:
To a solution of 5-(4-methoxyphenyl)pyrimidin-2-amine (302 mg, 1.5 mmol) in 10 mL of dry pyridine was added 4-methylbenzenesulfonyl chloride (320 mg, 1.68 mmol). The solution was stirred at room temperature under Argon. After 21 h, the pyridine was removed in vacuo and flashed off with toluene. The residue was partitioned between CH2Cl2 and 1M NaOH. The organic phase was washed with 1M NaOH until no turbidity was observed on rectification of a small sample. The alkaline phase was made acidic (˜pH 3) with 1M HCl and extracted with EtOAc. The crude solid product weighed 180 mg. The crude product was taken up in hot HOAc (4 mL) and diluted with 2 mL of water to initiate crystallization. The product was collected by filtration, washed with water and EtOH and dried in vacuo to give white needles (147 mg) with mp 220-223° C.