Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH:6]([C:11]1[C:16](Br)=[CH:15][C:14]([F:18])=[C:13]([N:19]=[N:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:12]=1[F:26])[CH2:7][N+:8]([O-])=O)[CH3:2]>CCN(CC)CC.C(O)C.[Ni]>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH:6]([C:11]1[CH:16]=[CH:15][C:14]([F:18])=[C:13]([N:19]=[N:20][N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:12]=1[F:26])[CH2:7][NH2:8])[CH3:2]
Reactant: CCOC(=O)CC(C[N+](=O)[O-])c1c(Br)cc(F)c(N=NN2CCCC2)c1F
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CC(CN)c1ccc(F)c(N=NN2CCCC2)c1F
Temperature: 0 °C
Yield: 75.5 %

Procedure:
In a 500 ml pressure jar, under inert atmosphere, 6.29 g (14 mmol) of 3-[6-bromo-2,4-difluoro-3-(pyrrolidin-1-ylazo)-phenyl]-4-nitro-butyric acid ethyl ester all and Et3N (5.9 ml) are dissolved in 120 ml of ethanol. A suspension of 6 g of predried (3 times, ethanol) Raney nickel is added and the mixture hydrogenated on a Parr hydrogenator at a maximum of 20 psi H2 pressure (strongly exothermically reaction, ice/water cooling required). The mixture is degassed, filtered on a Celite/Norite pad, and the filtrate concentrated in vacuo, to give 6.2 g of crude. It is again hydrogenated as described above to remove the bromide using 0.59 g of Pd/C instead of Raney nickel during 0.75 h on a Parr hydrogenator at a maximum of 40 psi H2 pressure. The crude amino-ester is purified by chromatography on silicagel (CH2Cl2/EtOH/NH4OH: 94.5/5/0.5 (v/v/v)) to give 3.6 g of 4-amino-3-[2,4-difluoro-3-(pyrrolidin-1-ylazo)-phenyl]-butyric acid ethyl ester a12 (76% yield) used as such in the next step.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][CH:29]=[C:30]([C:32]3[CH:37]=[CH:36][C:35](Br)=[CH:34][CH:33]=3)[N:31]=2)=[CH:23][CH:22]=1.[CH3:39][N:40]([CH3:44])[CH2:41][C:42]#[CH:43]>C(NCC)C.C(#N)C.Cl[Pd]Cl.[Cu]I>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][CH:29]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([CH2:43][C:42]#[C:41][N:40]([CH3:44])[CH3:39])=[CH:34][CH:33]=3)[N:31]=2)=[CH:23][CH:22]=1
Reactant: C#CCN(C)C
Reactant: Fc1ccc(-c2nc(-c3ccc(Br)cc3)cs2)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CC#N
Product: CN(C)C#CCc1ccc(-c2csc(-c3ccc(F)cc3)n2)cc1
Reaction time: 0.25 h

Procedure:
In a 100 ml flask is placed triphenylphosphine (80 mg, 10%), PdCl2 (40 mg, 5%) and 2-(4′-fluorophenyl)-4-(4′-bromophenyl)thiazole (0.98 g, 2.9 mmol) in 20 mL of diethylamine. After stirring for 15 min under N2 atmosphere, CuI (30 mg, 5%) and 1-dimethylamino-2-propyne (0.27 g, 3.18 mmol) in 20 ml of acetonitrile are added to the mixture. After 18 h of heating, the solvent is evaporated under reduced pressure and the residue is filtered through silica gel pad (50 g) using CHCl3 (400 mL) and 2% MeOH in CHCl3(400 mL). A large portion of unreacted 2-(4′-fluorophenyl)-4-(4′-bromophenyl)thiazole is recovered after removal of chloroform filtrate (0.55 g, 56%). The second part of the filtrate (2% MeOH in CHCl3) is concentrated and the residual solid is then purified over silca gel column eluting with 2% MeOH in CHCl3. 2-(4′-fluorophenyl)-4-[4′-(3-dimethylamino-2-propyn-1-yl)phenyl]thiazole is obtained after concentration and trituration with hexane (0.25 g, 27% yield), mp. 98-9° C. 1H NMR (CDCl3): δ 2.39 (s, 6H), 3.50 (s, 2H), 7.16 (t, 2H), 7.48 (s, 1H), 7.51 (d, 2H), 7.93 (d, 2H), 8.03 (m, 2H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[N:14]([CH2:19][CH:20]([OH:22])[CH3:21])[S:15]([CH3:18])(=[O:17])=[O:16].C(N(CC)CC)C>ClCCCl>[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[N:14]([CH2:19][CH:20]([O:22][S:2]([CH3:1])(=[O:4])=[O:3])[CH3:21])[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(C)c1N(CC(C)O)S(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cccc(C)c1N(CC(C)OS(C)(=O)=O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.5 %

Procedure:
31.4 ml (46.6 g, 0.4 moles) of methanesulfonyl chloride are added dropwise, within one hour, to a solution of 94.5 g (0.368 moles) of 1-[N-(2,6-dimethylphenyl)-methane-sulfonamido]-2-propanol and 55.3 ml (40.5 g, 0.4 moles) of trietyl amine in 600 ml of 1,2-dichloroethane. During the addition the mixture is cooled with ice to maintain its temperature at 10°-12° C. The mixture is stirred at room temperature for additional 4 hours and then washed thrice with 100 ml of water, each. The dichloroethane solution is dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, and the thick, oily residue is triturated with 120 ml of isopropanol. The resulting crystals are filtered off, washed with ice-cold isopropanol and dried. 93.2 g (75.8%) of 1-[N-(2,6-dimethylphenyl)-methane-sulfonamido]-2-methanesulfonyloxy-propane are obtained as a white, crystalline substance melting at 111°-114° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[C:43]([C:50]([F:53])([F:52])[F:51])[CH:42]=1>>[NH2:30][C:29]1[S:28][C:27]([C:44]2[CH:45]=[CH:46][C:41]([O:40][CH3:39])=[CH:42][C:43]=2[C:50]([F:51])([F:52])[F:53])=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1)=[O:24]
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Reactant: COc1ccc(B(O)O)c(C(F)(F)F)c1
Product: COc1ccc(-c2nc(C(=O)Nc3cnn(C)c3N3CCC(CN)CC3)c(N)s2)c(C(F)(F)F)c1
Yield: 54 %

Procedure:
Following the procedure for Example 337 starting with tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 4-methoxy-2-(trifluoromethyl)benzeneboronic acid gave 280 as a brown solid (56 mg, 54%). 1H NMR (400 MHz, d4-MeOD) δ 7.65 (d, J=8.6 Hz, 1H), 7.58 (s, 1H), 7.37 (d, J=2.6 Hz, 1H), 7.27 (dd, J=8.6, 2.6 Hz, 1H), 3.94 (s, 3H), 3.72 (s, 3H), 3.19-3.06 (m, 4H), 2.62 (d, J=6.5 Hz, 2H), 1.84 (d, J=12.5 Hz, 2H), 1.57-1.46 (m, 1H), 1.37 (qd, J=11.7, 4.9 Hz, 2H). LCMS (ES+) m/z 510 (M+1).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][C:12](=[O:21])[CH:13]([P:15]([O:19][CH3:20])([O:17][CH3:18])=[O:16])[NH2:14].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.[Br:56][C:57]1[CH:65]=[C:64]([C:66]([NH:68][CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([OH:76])[CH:71]=2)=[O:67])[CH:63]=[CH:62][C:58]=1[C:59](O)=[O:60]>CN(C)C=O>[CH3:10][O:11][C:12](=[O:21])[CH:13]([P:15]([O:17][CH3:18])([O:19][CH3:20])=[O:16])[NH:14][C:59](=[O:60])[C:58]1[CH:62]=[CH:63][C:64]([C:66]([NH:68][CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([OH:76])[CH:71]=2)=[O:67])=[CH:65][C:57]=1[Br:56]
Reactant: COC(=O)C(N)P(=O)(OC)OC
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)O)c(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br)P(=O)(OC)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
Diisopropylethylamine (1.81 g, 14 mmol) was added to a solution of rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125) freshly prepared from rac.-N-benzyloxycarbonyl)-2-(dimethoxyphosphinyl)glycine methyl ester (5.00 g, 15.1 mmol), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (5.20 g, 13.7 mmol), 1-hydroxybenzotriazole (1.85 g, 13.7 mmol) and 2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoic acid (Example 79; 4.80 g, 13.7 mmol) in N,N-dimethylformamide (50 mL). After the reaction was stirred for 4 h at 25° C., the volatiles were removed in vacuo. A solution of the residue in ethyl acetate (200 mL) was washed with 1N hydrochloric acid solution (100 mL), saturated aqueous sodium bicarbonate solution (100 mL), water (100 mL) and brine (100 mL). The organic layer was dried over MgSO4, filtered, concentrated and the resulting residue was flash chromatographed over silica gel (ethyl acetate-3% methanol in ethyl acetate) to give rac.-N-[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (5.50 g, 76% yield) as a colorless foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=[O:21])[C@H:11]([CH3:22])[CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.[BH4-].[Na+].Cl.O>C(O)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[C@H:11]([CH3:22])[CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@H](C)C[C@@H]12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@H](C)C[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
16.0 g of 3-methoxy-16α-methyl-1,3,5(10)-estratrien-17-one is dissolved in 200 ml of ethanol and, under ice cooling, combined dropwise with a solution of 2.1 g of sodium borohydride in 100 ml of 80% aqueous ethanol. The mixture is stirred for 16 hours at room temperature, then 1 N hydrochloric acid is gently added to the reaction solution, the latter is poured into water and extracted with ethyl acetate. Crystallization from acetonitrile yields 13.4 g of 3-methoxy-16α-methyl-1,3,5(10)-estratrien-17β-ol, m.p. 100°-102° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:12]([N:3]1[C:2]([CH3:1])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1c[nH]nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnn(Cc2ccccc2)c1C
Temperature: 20 °C
Yield: 43.4 %

Procedure:
To a solution of methyl 3-methyl-1H-pyrazole-4-carboxylate (280 mg, 2 mmol) in N, N-dimethylformamide (30 mL) was added (bromomethyl)benzene (0.34 g, 2 mmol) and potassium carbonate (0.55 g, 4 mmol). The mixture was stirred at 20° C. and stirred for 12 hours. The solvent was evaporated in vacuo and the residue was purified by CXTH (Column: Dsisol, 10 μM, C18, 250 mm*50 mm; Mobile: acetonitrile (0.1% formic acid)-water (0.1% formic acid), acetonitrile from 30% to 70% in 80 minutes; oven: 20° C.; flow rate: 50 mL/minute, wavelength: 214 nm) to give crude methyl 1-benzyl-5-methyl-1H-pyrazole-4-carboxylate (200 mg, 42%). LRMS (M+H+) m/z: calcd. 230.11. found 230.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].Cl>O1CCOCC1.[OH-].[Na+]>[CH2:5]([O:4][C:2]([NH:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCCC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5.16 g (0.103 mmol) of benzyl chloroformate in 100 ml of dry dioxan is added dropwise over a period of 30 minutes to a solution of 10.60 g (0.1 mmol) of 4-aminobutyric acid in 300 ml of 1N sodium hydroxide solution in an ice bath. The reaction mixture is stirred for 30 minutes at room temperature, acidified with 2N hydrochloric acid and extracted with methylene chloride. The organic phase is dried with sodium sulphate and concentrated in vacuo. The 4-benzyloxycarbonylaminobutyric acid obtained is recrystallised from ethyl acetate, methylene chloride and hexane; melting point 61°-62°.
Reaction SMILES: [CH:1]1([CH:7]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:11](=[O:22])[CH2:10][O:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[C:28]([Si:32]([O:35][CH2:36][CH2:37][CH2:38]I)([CH3:34])[CH3:33])([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[C:28]([Si:32]([CH3:34])([CH3:33])[O:35][CH2:36][CH2:37][CH2:38][CH:10]1[O:9][CH2:8][CH:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:11]1=[O:22])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)OCCCI
Reactant: COc1ccc(CN2C(=O)COCC2C2CCCCC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C(CCCO[Si](C)(C)C(C)(C)C)OCC2C2CCCCC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
To a solution of 5-cyclohexyl-4-(4-methoxy-benzyl)-morpholin-3-one (700 mg, 2.3 mmol, 1.0 equiv) in THF (10.0 mL) at −78° C. was added n-BuLi (1.58 mL, 1.6 M in heptane, 2.54 mmol, 1.1 equiv). The resulting solution was stirred at −78° C. for 30 minutes, after which it was added a solution of tert-Butyl-(3-iodo-propoxy)-dimethyl-silane (693 mg, 2.3 mmol, 1.0 equiv) in THF (1.0 mL). The solution was stirred at −78° C. for 30 minutes and 2 hours at room temperature after which it was quenched by addition of sat. aq. NH4Cl solution. The mixture was extracted with EtOAc. The organic layer was combined, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography, EtOAc/heptane 30% to give product 480 mg (yield 44%).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1)[NH2:2].[Si:10]([O:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[C:25]([CH:28]=O)[CH:24]=[CH:23]2)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>CCO>[Si:10]([O:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[C:25](/[CH:28]=[N:2]/[NH:1][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1)[CH:24]=[CH:23]2)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(C=O)nc12
Reactant: Cc1ccnc(NN)c1
Solvent: CCO
Product: Cc1ccnc(N/N=C/c2ccc3cccc(O[Si](C)(C)C(C)(C)C)c3n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
2-Hydrazinyl-4-methylpyridine (0.280 g, 2.27 mmol) and 8-(tert-butyldimethylsilyloxy)quinoline-2-carbaldehyde (0.653 g, 2.27 mmol) were suspended in EtOH (6 mL) and stirred overnight at ambient temperature. The resulting suspension was filtered and the solid was washed with cold EtOH and dried in vacuo to provide the title compound (0.720 g; 81%).
Reaction SMILES: [OH-].[Na+].[CH:3]12[CH2:12][CH:9]([CH2:10][CH2:11]1)[CH:8]1[C:4]2([C:13]([OH:15])=[O:14])[CH2:5][CH2:6][CH2:7]1.S(OC)(O[CH3:20])(=O)=O>>[CH:3]12[CH2:12][CH:9]([CH2:10][CH2:11]1)[CH:8]1[C:4]2([C:13]([O:15][CH3:20])=[O:14])[CH2:5][CH2:6][CH2:7]1
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)C12CCCC1C1CCC2C1
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C12CCCC1C1CCC2C1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
55.0 g (0.275 mole) of a 20% aqueous sodium hydroxide solution was added dropwise to a mixture of 90.0 g (0.5 mole) of tricyclo[5.2.1.02,6 ]decane-2-carboxylic acid (mixture of endo- and exo-compounds) and 69.3 g (0.55 mole) of dimethyl sulfate over one hour under stirring at 50° C. After completion of the addition, stirring was continued at that temperature for 30 minutes. After completion of the stirring, the mixture was allowed to stand at room temperature for a while to form layers. The lower aqueous layer was taken out. The temperature was elevated again to 50° C. 55.0 g (0.275 mole) of sodium hydroxide in a 20% aqueous solution was added dropwise to the remainder over one hour under stirring at 50° C. After completion of the addition, the mixture was stirred at that temperature for 30 minutes. Then, 16.5 g (0.0825 mole) of a 20% aqueous sodium hydroxide solution was added thereto and the whole mixture was stirred at 100° C. for 45 minutes in order to decompose unreacted dimethyl sulfate. The mixture was allowed to cool and divided into layers. After the distillation, 88.3 g (yield 91.0%) of pure methyl tricyclo[5.2.1.02,6 ]decane-2-carboxylate was obtained.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1.Br[CH2:22][C:23]1[C:24]([CH3:35])=[N:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:27][CH:28]=1>C(COC)OC>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:22][C:23]3[C:24]([CH3:35])=[N:25][C:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[N:27][CH:28]=3)[CH2:17][CH2:16]2)=[CH:13][CH:14]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: Cc1nc(-c2ccccc2)ncc1CBr
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Cc1nc(-c2ccccc2)ncc1CN1CCN(c2ccc(O)cc2)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
A solution of 1.05 g of triethylamine in 20 ml of absolute dimethoxyethane was added dropwise over 30 minutes with stirring to a mixture of 1.78 g (10 mmol) of 1-(4-hydroxyphenyl)piperazine, 3.05 g of 95% strength 5-bromomethyl-4-methyl-2-phenylpyrimidine (=11 mmol) and 80 ml of absolute 1,2-dimethoxyethane at 45° C. The mixture was stirred for a further 1 hour at 45° C. and 3 hours at 80° C., the solvent was evaporated in vacuo, the residue was taken up in CH2Cl2 water and neutralized to pH 6-7, the phases were separated, and the aqueous phase was extracted three times with CH2Cl2. The combined CH2Cl2 extracts were dried, filtered and evaporated in vacuo. The crystalline residue (3.7 g) was recrystallized from methanol. 2.35 g (65% of theory) of pure 4-(4-hydroxyphenyl)-1-(4 -methyl-2-phenylpyrimidin-5-ylmethyl)piperazine, melting point 201°-202° C., were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]#[C:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N+:19]([O-])([OH:21])=[O:20].O>C(O)(=O)C>[Cl:1][C:2]1[C:3]([C:13]#[C:14][Si:15]([CH3:16])([CH3:18])[CH3:17])=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)cc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)c([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
A solution of methyl 5-chloro-2-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate (540 g, 1.9 mol) in acetic acid (3.7 L) was heated at 55-59° C. The heating was discontinued and the reaction mixture was flushed with nitrogen and treated with a solution of nitric acid (120 mL, 2.9 mol) in acetic acid (200 mL, 3.6 mol) over 30 minutes. The reaction temperature reached 98.9° C. The resulting solution was stirred for 30 minutes at which time the temperature went from 98.9 to 87.5° C. The reaction was cooled to room temperature and treated with crushed ice (3.5 kg) in one portion. The reaction mixture temperature dropped to −12° C. The reaction mixture was treated with water (3.5 kg) and and stirred at room temperature for 1 hour. The product was filtered, rinsed with water (2 L), and dried on the filter under vacuum overnight to give the desired product (450 g, 72%) as a yellow solid. HPLC 92.9% pure @ 220 nm. LCMS for C13H15ClNO5Si (M+H)+: m/z=328.0; Found: 327.9; 1H NMR (300 MHz, DMSO-d6): δ 11.2 (br s, 1 H), 8.00 (s, 1 H), 3.89 (s, 3 H), 0.23 (s, 9 H).
Reaction SMILES: C([O:4][NH:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][N:9]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:7])C=C.C([O-])=O.C([NH+](CC)CC)C.C(#N)C>O>[OH:4][NH:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][N:9]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:7]
Reactant: C=CCONC(=O)C1CCC(OC)CN1S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: CC[NH+](CC)CC
Agent: O=C[O-]
Solvent: CC#N
Solvent: O
Product: COC1CCC(C(=O)NO)N(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)C1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 29.7 %

Procedure:
To a solution of 1-(4-benzyloxy-benzenesulfonyl)-5-methoxy-piperidine-2-carboxylic acid allyloxy-amide (0.090 g, 0.20 mmol), triethylammonium formate (0.28 mL of a 3M solution in water, 0.83 mmol) and acetonitrile (1.1 mL) was added tetrakistriphenylphosphine palladium. After stirring for 15 min at 80° C., the mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with ether and extracted 2× into 1 M NaOH. The combined aqueous layers were washed 2× with ether, acidified with 1M HCl and extracted 3× with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated. Purification of the residue by silica gel chromatography eluting with ethyl acetate afforded 0.025 g of 1-(4-benzyloxy-benzenesulfonyl)-5-methoxy-piperidine-2-carboxylic acid hydroxyamide as a yellow solid after trituration from CH2Cl2-hexane:
Reaction SMILES: Cl[C:2]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([Cl:26])=[CH:19][C:3]=1[C:4]([NH:6][C@H:7]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)[CH3:8])=[O:5].[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH2:32]>C1COCC1>[Cl:26][C:20]1[CH:21]=[C:22]([N+:23]([O-:25])=[O:24])[C:2]([NH:32][CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([Cl:27])[CH:29]=2)=[C:3]([CH:19]=1)[C:4]([NH:6][C@H:7]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)[CH3:8])=[O:5]
Reactant: NCc1cccc(Cl)c1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cc([N+](=O)[O-])c2Cl)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cc([N+](=O)[O-])c2NCc2cccc(Cl)c2)cc1

Procedure:
Methyl 4-{(1S)-1-[(2,5-dichloro-3-nitrobenzoyl)amino]ethyl}benzoate (500 mg, 1.26 mil) and 3-chlorobenzyl amine (1089 mg, 7.69 mmol) were dissolved in 50 ml THF. The mixture was refluxed overnight then cooled. The solvent was removed and the crude mixture purified by flash chromatography on silica gel. 1H NMR (400 MHz, DMSO): δ 9.25 (d, 1H), 8.20 (t, 1H), 8.15 (s, 1H), 7.95 (d, 2H), 7.70 (s, 1H), 7.60 (d, 2H), 7.30 (m, 2H), 7.15 (s, 1H), 7.05 (d, 1H), 5.10 (m, 2H), 4.10 (m, 2H), 4.85 (s, 3H), 1.45 (d, 3H).
Reaction SMILES: [CH3:1][C:2]([OH:30])([CH3:29])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[O:13][C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=1.Br[C:32]1[C:36]2=[N:37][CH:38]=[CH:39][CH:40]=[C:35]2[N:34]([CH:41]([CH3:43])[CH3:42])[N:33]=1.C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>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.O>[CH3:29][C:2]([OH:30])([CH3:1])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:32]2[C:36]3=[N:37][CH:38]=[CH:39][CH:40]=[C:35]3[N:34]([CH:41]([CH3:43])[CH3:42])[N:33]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(O)Cn1c(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc2ccccc21
Reactant: CC(C)n1nc(Br)c2ncccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CC(C)n1nc(-c2ccc(Oc3nc4ccccc4n3CC(C)(C)O)cc2)c2ncccc21
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
A mixture of 2-methyl-1-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol (237 mg), 3-bromo-1-(1-methylethyl)-1H-pyrazolo[4,3-b]pyridine (139 mg), Cs2CO3 (378 mg), Pd(PPh3)4 (20.1 mg), DME (5 mL), and water (1 mL) was stirred at 140° C. for 30 min under microwave irradiation. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) and recrystallized from AcOEt/hexane to give the title compound (175 mg).