Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[C-:15]#[N:16].[K+].C(=O)([O-])O.[Na+]>CN(C)P(=O)(N(C)C)N(C)C>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:6]2[O:5][CH2:4][CH:3]([CH2:2][C:15]#[N:16])[O:8][C:7]=2[CH:9]=1
Reactant: COc1ccc2c(c1)OC(CI)CO2
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1ccc2c(c1)OC(CC#N)CO2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1.35 g (4.43 mmol) of the iodinated compound obtained in Step C and 1.37 g (26.6 mmol) of potassium cyanide are dissolved in 15 ml of anhydrous hexamethylphosphoric triamide; the reaction mixture is then stirred for 2 days under argon and at ambient temperature. The solution is then hydrolysed with a solution of sodium hydrogen carbonate; the aqueous phase is then extracted with dichloromethane. The organic phase, dried over magnesium sulphate acid then filtered, is concentrated under reduced pressure. The title nitrile is obtained pure in the form of a clear oil after chromatography on silica gel (eluant:PE then AcOEt/PE:15/85).
Reaction SMILES: [N:1]([O-])=O.[Na+].[F:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1.[ClH:16]>O>[ClH:16].[F:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][NH2:1])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium nitrite (3.6 g) in water (18 ml) was added dropwise to an ice-salt cooled solution of 4-fluoro-2-nitroaniline 7 g) in conc. hydrochloric acid (45 ml) over a 30 minutes interval. The mixture was stirred at 0° C. for 30 minutes. Then to the mixture was added dropwise a solution of stannous chloride dihydrate (28.6 g) in conc. hydrochloric acid (24 ml) below 5° C. over an hour interval. The precipitates were collected by filtration and washed with ether to give crystals of 4-fluoro-2-nitrophenylhydrazine hydrochloride 4.4 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[CH3:8].ClC1C=C(C=CC=1)C(OO)=[O:16]>ClCCl>[Br:1][C:2]1[C:3]([CH3:10])=[N+:4]([O-:16])[CH:5]=[C:6]([F:9])[C:7]=1[CH3:8]
Reactant: Cc1ncc(F)c(C)c1Br
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1c(F)c[n+]([O-])c(C)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
A mixture of 3-bromo-5-fluoro-2,4-dimethyl-pyridine (220 mg, 1.08 mmol) and 3-chloroperoxybenzoic acid (399 mg, 1.62 mmol) in dichloromethane (3 mL) was stirred overnight at room temperature. The reaction mixture was diluted with DCM (50 mL) and washed with saturated aqueous sodium thiosulfite (10 mL) followed by saturated aqueous sodium bicarbonate (10 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by flash chromatography (4 g, Silica, 0-10% methanol in DCM). Desired fractions were combined and evaporated in vacuo to afford the title compound as a white solid (220 mg, 93%), which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1C
Reactant: NCc1ccc(F)cc1
Product: Cc1sc2nc(-c3ccno3)nc(NCc3ccc(F)cc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(4-fluorobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:28][NH:29][CH3:30]>>[CH3:28][N:29]([CH3:30])[CH2:20][CH2:19][CH2:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:27])([F:26])[F:1])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: CS(=O)(=O)OCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: CNC
Product: CN(C)CCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 17.1; Methanesulfonic acid 3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propyl ester and Dimethylamine were converted to yield Dimethyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propyl}-amine as light brown oil, MS: 365 (MH+).
Reaction SMILES: [CH:1]1([CH:4]([OH:16])[C:5]2[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=2[OH:15])[C:8]([O:10][CH3:11])=[O:9])[CH2:3][CH2:2]1>[O-2].[Mn+4].[O-2].O1CCOCC1>[CH:1]1([C:4]([C:5]2[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=2[OH:15])[C:8]([O:10][CH3:11])=[O:9])=[O:16])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(O)c(C(O)C2CC2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(O)c(C(=O)C2CC2)c1
Yield: 828.1 %

Procedure:
To a flask with methyl 3-(cyclopropyl(hydroxy)methyl)-4-hydroxybenzoate (66.38B) (845 mg, 0.38 mmol) was added manganese (IV) oxide (1.65 g, 1.9 mmol). Then dioxane 3.5 mL was added and the reaction was heated at reflux for 4 hours. The reaction was filtered and concentrated and silica gel chromatography afforded 693 mg of 66.38C (83%).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10](O)[C:9]2[C:4](=[C:5]([Br:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:25])=O>C1C=CC=CC=1>[CH3:1][C:2]1[N:11]=[C:10]([Cl:25])[C:9]2[C:4](=[C:5]([Br:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(O)c2cccc(Br)c2n1
Solvent: c1ccccc1
Solvent: CN(C)c1ccccc1
Product: Cc1nc(Cl)c2cccc(Br)c2n1
Temperature: 80 °C
Yield: 80.3 %

Procedure:
Part C: To a suspension of 14.2 g (59.5 mmol) of 2-methyl-4-hydroxy-8-bromo-quinazoline in 300 ml of benzene, 16 ml (120 mmol) of dimethylaniline and 6 ml (64 mmol) of phosphorus oxychloride were added under nitrogen. The light yellow solution resulting after heating to 80° C. while stirring was further heated at 80° C. for 3 hours. After cooling to room temperature 500 ml of benzene were added. The solution was extracted three times with 300 ml of 20% NaOH/water and 200 ml of water. The organic layer was dried over magnesium sulphate and concentrated in vacuo. The product was purified by column chromatography over silicagel using ether/petroleum-ether 1:9 as the eluent. A total of 12.3 g of 2-methyl-4-chloro-8-bromo-quinazoline was obtained as a white solid (80% yield).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([N+:21]([O-])=O)[CH:15]=2)=[O:12])[N:7]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:21][C:16]1[CH:15]=[C:14]([NH:13][C:11]([NH:10][C:8]2[N:7]([C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=2)=[O:12])[CH:19]=[CH:18][C:17]=1[CH3:20]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(C)c([N+](=O)[O-])c2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(C)c(N)c2)cc1
Yield: 85.9 %

Procedure:
1-[3-tert-Butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-3-(4-methyl-3-nitrophenyl)urea (93 mg) was hydrogenated over 10% Pd/C (50% wet, 10 mg) at atmospheric pressure of hydrogen in MeOH (2 mL) for 4 hr. The catalyst was removed by filtration through Celite® pad and the filtrate was evaporated in vacuo. The residue was triturated with IPE and the precipitates produced were collected by filtration to give 1-(3-amino-4-methylphenyl)-3-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea (74 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]([F:10])[CH3:9])[N:5]=[C:4]([C:11]([O:13]C)=[O:12])[C:3]=1[O:15][CH3:16].[OH-].[Na+].Cl>C1COCC1.CO>[NH2:1][C:2]1[CH:7]=[C:6]([CH:8]([F:10])[CH3:9])[N:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[O:15][CH3:16]
Reactant: COC(=O)c1nc(C(C)F)cc(N)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(N)cc(C(C)F)nc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.6 %

Procedure:
To a solution of methyl 4-amino-6-(1-fluoroethyl)-3-methoxypicolinate (0.125 g, 0.548 mmol) in THF (2.74 ml) and MeOH (2.74 ml) was added a 2 N solution of sodium hydroxide (0.822 ml, 1.643 mmol). The reaction mixture was stirred at room temperature (LC monitoring). After 4 h, the reaction mixture was acidified with a 2 N solution of HCl (1 mL) and then concentrated (rotavap). The resulting white solid was dissolved into DMF+a few drops of water and was purified by preparative HPLC (reverse phase, C18 column) to afford 4-amino-6-(1-fluoroethyl)-3-methoxypicolinic acid (98 mg, 0.458 mmol, 84% yield) as an orange solid. ESIMS m/z 213 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 9.06 (s, 1H), 6.82 (s, 1H), 6.47 (s, 2H), 5.49 (dq, J=47.7, 6.3 Hz, 1H), 3.69 (s, 3H), 2.51 (d, J=24.0 Hz, 1H), 1.52 (dd, J=24.5, 6.4 Hz, 3H); 19F NMR (376 MHz, DMSO) δ −171.64.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([O:29][C:30]([C@@:32]1([CH2:47]CO)[CH:36]([F:37])[C:35](=[O:38])[N:34]([C@@H:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH3:40])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>ClCCl>[C:25]([O:29][C:30]([C@@:32]1([CH2:47][CH2:1][Br:5])[CH:36]([F:37])[C:35](=[O:38])[N:34]([C@@H:39]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH3:40])[CH2:33]1)=[O:31])([CH3:26])([CH3:27])[CH3:28]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CCO)(C(=O)OC(C)(C)C)C(F)C1=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1C[C@@](CCBr)(C(=O)OC(C)(C)C)C(F)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.5 %

Procedure:
Carbon tetrabromide (1.88 g, 5.68 mmol) and triphenylphosphine (1.49 g, 5.68 mmol) were sequentially added to a solution of (3S)-4-fluoro-3-(2-hydroxyethyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (1.66 g, 4.74 mmol) in dichloromethane (20 mL) in a nitrogen atmosphere at 0° C. After heating to room temperature, the reaction solution was stirred for one hour and concentrated to about 5 mL. The residue was purified by silica gel column chromatography (dichloromethane→hexane:ethyl acetate=2:1) to give 2.17 g (91%) of the title compound as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]([F:16])([F:15])[F:14].[S:17]([O-:20])([O-:19])=[O:18].[Na+].[Na+].C(O)C>O>[F:14][C:13]([F:16])([F:15])[O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:17]([OH:20])(=[O:19])=[O:18]
Reactant: O=S([O-])[O-]
Reactant: FC(F)(F)OCCCCCCCCCCBr
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)(O)CCCCCCCCCCOC(F)(F)F

Procedure:
6.8 g of bromide from Example 5b (22.35 mmol) and 3.7 g (29 mmol; 1.3 eq) of sodium sulfite are dissolved in 40 ml of deionised water and 40 ml of ethanol in a 250 ml one-necked flask, and the mixture is heated at 100° C. for 20 h. The cooled reaction mixture is extracted with methyl t-butyl ether/heptane (1:1). The aqueous phase is acidified (pH=0) and extracted with methyl t-butyl ether. The combined organic phases are dried over sodium sulfate and evaporated.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[S:20][C:21]([C:24](O)=[O:25])=[CH:22][N:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[N:3]=1.[CH3:34][NH:35][CH3:36]>O1CCCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[S:20][C:21]([C:24]([N:35]([CH3:36])[CH3:34])=[O:25])=[CH:22][N:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)[N:3]=1
Reactant: CNC
Reactant: CC1Cc2ccc(-c3ncc(C(=O)O)s3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Solvent: C1CCOC1
Product: CC1Cc2ccc(-c3ncc(C(=O)N(C)C)s3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 133 starting from 2-{2-[2-amino-6-(4-methylpiperazin-l-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1,3-thiazole-5-carboxylic acid and 2.0 M of dimethylamine in tetrahydrofuran solution. LCMS (M+H)+: m/z=493.2.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]1[CH2:52][CH2:51][C:46]2([O:50][CH2:49][CH2:48][O:47]2)[CH2:45][CH2:44]1)=O>>[O:50]1[C:46]2([CH2:45][CH2:44][N:43]([CH2:41][CH2:40][O:1][C:2]3[CH:38]=[CH:37][C:5]([CH2:6][CH2:8][CH2:9][CH2:10][NH:11][C:12]4[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=4[CH:20]4[CH2:29][CH2:28][C:27]5[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=5[CH2:21]4)=[CH:4][CH:3]=3)[CH2:52][CH2:51]2)[O:47][CH2:48][CH2:49]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Reactant: O=C(CCl)N1CCC2(CC1)OCCO2
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCCc2ccc(OCCN3CCC4(CC3)OCCO4)cc2)c1
Yield: 38.1 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-1-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethanone (18 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.1 mg) was obtained.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[C:21]([CH3:22])=[C:20]([CH3:23])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]3[O:11][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[C:21]([CH3:22])=[C:20]([CH3:23])[S:19][C:17]=2[N:18]=1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1C
Reactant: NCc1ccc2c(c1)OCO2
Product: Cc1sc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1C

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxybenzylamine with 2,4-dichloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidine gives 2-chloro-5,6-dimethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([N:15](CC1C=CC(OC)=CC=1OC)[C:16]1[S:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([NH:15][C:16]1[S:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cccc3c2)c(OC)c1
Reactant: COc1ccccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1-c1cccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
A vial was charged with 5-bromo-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (INTERMEDIATE D) (73.69 mg, 0.142 mmol), 2-methoxyphenylboronic acid (43.0 mg, 0.283 mmol), Pd(AmPhos)2Cl2 (5.01 mg, 7.08 μmol), potassium phosphate (90 mg, 0.425 mmol), 1,4-dioxane (708 μl), and water (236 μl). The vial was sealed and heated in a microwave reactor for 30 min at 100° C. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were concentrated. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL). After 2 h, the mixture was diluted with MeOH and filtered through diatomaceous earth with the aid of DCM. The filtrate was concentrated. The residue was purified twice by chromatography on silica gel (12-g columns, first with 0 to 5% MeOH/DCM, then with 2.5% MeOH/DCM), and the resulting material was dissolved in DCM and loaded onto a 1-g PE-AX ion exchange column (Biotage AB, Uppsala, Sweden). The column was flushed with 1:1 MeOH/DCM, then eluted with 10% HCl/MeOH (made by dissolving 1 mL on conc. HCl in 9 mL of MeOH). The acidic fraction was concentrated to give 5-(2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (41.62 mg, 0.105 mmol, 74.0% yield) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=8.59-8.44 (m, 2H), 8.20 (d, J=8.2 Hz, 1H), 7.77-7.66 (m, 2H), 7.58 (d, J=8.9 Hz, 1H), 7.54-7.45 (m, 2H), 7.26-7.16 (m, 2H), 7.13-7.05 (m, 1H), 3.63 (s, 3H); m/z (ESI) 398.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[Br-].[CH2:23]([Zn+])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1COCC1.Cl>>[CH2:23]([C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Clc1nccnc1Oc1ccc(Nc2ccccn2)cc1
Reactant: [Zn+]Cc1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: c1ccc(Cc2nccnc2Oc2ccc(Nc3ccccn3)cc2)cc1
Temperature: 70 °C

Procedure:
A suspension of N-(4-(3-chloropyrazin-2-yloxy)phenyl)pyridin-2-amine (200 mg, 0.670 mmol), benzylzinc bromide, 0.5M in THF (6.7 mL, 3.35 mmol), and bis(di-t-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (80 mg, 0.11 mmol) was sparged with argon for 5 minutes then heated to 70° C. for 2 h. The reaction was then partitioned between EtOAc (30 mL) and sat NH4Cl (10 mL). The separated organic layer was dried over MgSO4, concentrated under reduced pressure, then purified on silica (40 g) eluting with 1.5-2.0% MeOH/DCM. The resulting residue was then dissolved in MeOH (5 mL) and 0.105 mL of HCl (5 M; 0.105 mL, 0.525 mmol) added. The resulting solid was isolated by filtration to give the title compound. MS (ESI positive ion) m/z: 355.1 (M+1). IC50 (uM) 0.250.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:35][CH2:36]SC)[C:13]([NH:15][C@H:16]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][C@H:17]1[CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+]>IC.CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:35][CH2:36][N:15]([C@H:16]2[CH2:21][CH2:20][C@@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:18][C@H:17]2[CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:13]1=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)C[C@H]1CS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 38 %

Procedure:
Tert-butyl (1R,3R,4S)-4-((S)-2-benzyloxycarbonylamino-4-(methylthio)butanamido)-3-(methylsulfonylmethyl)cyclohexylcarbamate (6.9 g) was dissolved in iodomethane (100 mL), and the resulting solution was stirred at rt for 72 h before being concentrated in vacuo. The residue was dissolved in methylene chloride, and the resulting solution was concentrated; this was repeated to afford the salt. MS found: (M+H)+=586.5. This material was dissolved in DMF (20 mL) and the solution was charged with Cs2CO3 (12.0 g). After 12 h, the reaction was partitioned between EtOAc and brine. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford tert-butyl (1R,3R,4S)-4-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-3-(methylsulfonylmethyl)cyclohexylcarbamate (2.4 g). MS found: (M+H)+=524.3.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[C:34]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)(=[O:37])[CH2:35][CH3:36]
Reactant: CCC(=O)Cl
Reactant: O=C(N[C@@H]1CCCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: CCC(=O)N1CCC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-piperidin-3-ylamide hydrochloride (example A149) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].[H-].[Na+].Cl[C:11]1[C:16]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:15][N:14]=[C:13]([NH:26]C=O)[N:12]=1>O1CCCC1>[NH2:26][C:13]1[N:14]=[C:15]([O:7][CH2:1][CH2:2][O:3][CH2:4][CH2:5][OH:6])[C:16]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:11][N:12]=1
Reactant: O=CNc1ncc(C#Cc2ccc(Cl)cc2)c(Cl)n1
Reactant: OCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ncc(C#Cc2ccc(Cl)cc2)c(OCCOCCO)n1
Temperature: 25 °C
Reaction time: 40 h
Yield: 50.5 %

Procedure:
11 g of Diethylene glycol and 0.78 g of a 60% suspension of sodium hydride in mineral oil were stirred in 200 ml of tetrahydrofuran (dried over sieves) for 15 minutes then 1.3 g of 4-chloro-5-(4-chlorophenylethynyl)-2-formamido-pyrimidine was added and the mixture was stirred at 25° C. in a dry atmosphere (drying tube) for 40 hours. The reaction mixture was then evaporated under reduced pressure at 55° C. The resulting syrup was stirred with 250 ml of ethyl acetate, 125 ml of saturated aqueous sodium bicarbonate and 125 ml of water for 15 minutes. The organic phase was washed with 250 ml of water and then 100 ml of brine. After drying over sodium sulfate, the filtered solution was combined with 16 g of Silica gel 60 (230–400 mesh) and evaporated under reduced pressure. The solids were applied to column of silica gel 60 (2.5×9.5 cm). The final height of the column was 16 cm. After eluting the column with increasing concentrations of ethyl acetate in dichloromethane, the product-rich fractions were combined and the solvent evaporated under reduced pressure. The product was recrystallized twice from ethyl acetate to give 0.75 g of the desired product, m.p. 142–143° C.
Reaction SMILES: [CH:1](=[C:8]1[C:13](=[O:14])[O:12][C:11]([CH3:16])([CH3:15])[O:10][C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:18]#[N:19].[K+]>>[CH3:16][C:11]1([CH3:15])[O:10][C:9](=[O:17])[CH:8]([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:18]#[N:19])[C:13](=[O:14])[O:12]1
Reactant: CC1(C)OC(=O)C(=Cc2ccccc2)C(=O)O1
Reactant: [C-]#N
Agent: [K+]
Product: CC1(C)OC(=O)C(C(C#N)c2ccccc2)C(=O)O1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 120, Step 2 starting from 5-benzylidene-2,2-dimethyl-1,3-dioxane-4,6-dione and potassium cyanide.