Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:21]=[C:5]2[C:6]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:22]1([CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:20][S:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:36][C:33]3[CH:34]=[CH:35][C:30]([O:29][CH2:28][CH2:27][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:31][CH:32]=3)[N:21]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:19])=[O:18]
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: CS(=O)(=O)c1ccccc1Nc1cccn2nc(Cl)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccccc1Nc1cccn2nc(Nc3ccc(OCCN4CCCC4)cc3)nc12

Procedure:
N(8)-(2-Methanesulfonyl-phenyl)-N(2)-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-phenyl)-amine (75.0 mg, 0.232 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (58.0 mg, 0.281 mmol)(prepared as described in J. Med. Chem., 2006, 49, 4451-4454) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.064 g, 56%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.46 (s, 1H), 8.11 (d, J=6.7 Hz, 1H), 7.98 (dd, J=7.9, 1.1 Hz, 1H), 7.57-7.50 (m, 2H), 7.48 (d, J=9.0 Hz, 2H), 7.28-7.24 (m, 1H), 7.14-7.09 (m, 1H), 6.93 (d, J=9.0 Hz, 2H), 6.79 (t, J=6.4 Hz, 1H), 6.68 (s, 1H), 4.10 (t, J=6.1 Hz, 2H), 3.14 (s, 3H), 2.90 (t, J=5.9 Hz, 2H), 2.68-2.58 (m, 4H), 1.86-1.76 (m, 4H). MS=493 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[CH2:25]([O:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[NH2:1][C:2]1[C:7]2=[C:8]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([O:32][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:34]=3)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Br)c3c(N)ncnn23)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnn23)CC1
Yield: 88 %

Procedure:
In a manner similar to the procedure described for step 7 of Example 330 and using tert-butyl 4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate and (3-benzyloxyphenyl)boronic acid as starting material, 300 mg (88%) of the desired product was isolated. LC-MS m/z [M+H]+500.2, RT 3.47 min.
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:19][C:18]([NH2:20])=[N:17][N:16]=3)=[CH:11][CH:10]=2)[CH:3]=1.[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>N1C=CC=CC=1.CO>[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:20][C:18]2[O:19][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][C:4]4[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=4)=[CH:14][CH:13]=3)=[N:16][N:17]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1
Agent: Br
Solvent: CO
Solvent: c1ccncc1
Product: O=C(Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1)c1ccc(Br)cc1
Reaction time: 3 h
Yield: 21.3 %

Procedure:
5-[4-(Pyridin-3-yloxy)phenyl]-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. 4-Bromobenzoyl chloride (164.6 mg, 0.75 mmol) was added to the solution. The reaction mixture formed an orange-red solution with a small amount of white precipitate. It was left to stir for 3 hours. Then it was diluted with ca. 1 mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (46.5 mg). Yield 21.2%.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:4].CCN=C=NCCCN(C)C.C(N(CC)CC)C.[F:38][CH2:39][CH2:40][NH2:41]>ClCCl>[CH3:19][N:2]([CH3:1])[C:3]([CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH:41][CH2:40][CH2:39][F:38])=[O:15])=[O:4]
Reactant: CN(C)C(=O)CCCC#Cc1cccc(C(=O)O)c1
Reactant: NCCF
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)CCCC#Cc1cccc(C(=O)NCCF)c1
Temperature: 25 °C
Yield: 89.5 %

Procedure:
To a solution of 3-(5-dimethylcarbamoyl-pent-1-ynyl)-benzoic acid (0.100 g, 0.38 mmol) in dry dichloromethane (1.5 mL) under a nitrogen atmosphere at room temperature, EDCI (0.0728 g, 0.38 mmol) was added followed by triethylamine (0.162 mL, 1.14 mmol), the resulting mixture was stirred at room temperature for further minutes. 2-Fluoro ethylamine (0.189 g, 1.9 mmol) was then added and the mixture stirred at room temperature for 16 hrs. The reaction mixture was washed with a mixture of saturated brine and saturated sodium bicarbonate (1:1; 2×150 mL) followed by saturated brine solution (100 mL). The organic layer was separated and dried over magnesium sulfate and the solvent evaporated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM:MeOH, 95% to 5% methanol gradient) to afford 3-(5-dimethylcarbamoyl-pent-1-ynyl)-N-(2-fluoro-ethyl)benzamide (26) (0.103 g, 0.34 mmol, 91% yield).
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[Br:18]C1(Br)C(=O)NC(=O)NC1=O>C(OCC)C>[Br:18][CH:3]([CH:2]=[O:1])[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: O=C1NC(=O)C(Br)(Br)C(=O)N1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC=O)CC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(CC(Br)C=O)CC1
Yield: 167 %

Procedure:
To a solution of tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate (Wityak J., et al., J. Med. Chem., 40, p. 50 (1997): 27.6 g) in diethyl ether was added dibromobarbituric acid (17.0 g), and the mixture was mixed for 12 hours. The insolubles were filtered off, and the filtrate was diluted with diethyl ether, sequentially washed with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (31.8 g) as a pale yellow viscous oily matter.
Reaction SMILES: [NH2:1][C:2](=[C:10]([C:15](=O)[CH:16]([CH3:18])[CH3:17])[C:11]([O:13][CH3:14])=[O:12])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[N:20]#[C:21][NH2:22].C(OCC)(=O)C>O>[NH2:22][C:21]1[N:1]=[C:2]([C:3]2[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=2)[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:15]([CH:16]([CH3:18])[CH3:17])[N:20]=1
Reactant: COC(=O)C(C(=O)C(C)C)=C(N)c1ccc(F)cc1
Reactant: N#CN
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N)nc1C(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 8.4 %

Procedure:
A suspension of 1.33 g of methyl 2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate (5.00 mmol) in 4.20 g of 50% strength aqueous cyanamide solution (50.0 mmol) was heated to reflux. After 17 h, it was cooled to room temperature and treated with ethyl acetate (5 ml) and water (5 ml). The undissolved solid was filtered off. The organic phase was separated off and the aqueous phase was extracted with ethyl acetate (2×5 ml). The combined organic phases were dried over magnesium sulphate and concentrated in vacuo. The crude product (0.97 g) was purified by flash chromatography on silica gel (eluent: methylene chloride). 121.6 mg of methyl 2-amino-4-(4-fluorophenyl)-6-isopropylpyrimidine-5-carboxylate were obtained in the form of a colourless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH2:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:4][CH:3]=1.O.N>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][C:8]3=[N:16][CH:15]=[CH:14][CH:13]=[C:9]3[C:10](=[O:12])[C:17]=2[CH:18]=1
Reactant: Cc1ccc(CCc2ncccc2C(=O)O)cc1
Agent: N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc2c(c1)C(=O)c1cccnc1CC2
Temperature: 140 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
A mixture consisting of 7.23 g of 2 -(p-methylphenethyl)nicotinic acid and 94.00 g of polyphosphoric acid was stirred for 1 hour at 140° C. The reaction mixture was poured into 94 ml of concentrated ammonia water with ice-cooling. To the resulting mixture was added carbon tetrachloride, and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 5.95 g of brown oily 7-methyl-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=3)[C:13]=2[CH2:17]Cl)[N:8]([CH2:30][C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])[CH:7]=1)=[O:5])[CH3:2].[CH3:39][NH:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=3)[C:13]=2[CH2:17][N:40]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH3:39])[N:8]([CH2:30][C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CNCc1ccccc1
Reactant: CCOC(=O)c1cn(Cc2c(F)cccc2F)c2ccc(Oc3ccc(NC(C)=O)cc3)c(CCl)c2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn(Cc2c(F)cccc2F)c2ccc(Oc3ccc(NC(C)=O)cc3)c(CN(C)Cc3ccccc3)c2c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
78 mg of 6-(4-acetamidophenoxy)-5-(chloromethyl)-1-(2′,6′-difluorobenzyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid-ethyl ester, dissolved in 3 ml of dimethylformamide, was mixed with 84 μl of N-methylbenzylamine and 84 μl of N,N-diisopropyl-ethylamine at 0° C. and stirred at room temperature for 20 hours. After 20 ml of aqueous sodium bicarbonate solution was added, the precipitate was suctioned off, washed with water and then with n-hexane, and dried at room temperature in a vacuum. 70 mg of the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:14][C:15]#[CH:16])[C:8](=[O:13])[CH:9]([S:11][CH3:12])[CH3:10])=[CH:5][N:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.[OH:23]O>>[Cl:1][C:2]1[C:6]([N:7]([CH2:14][C:15]#[CH:16])[C:8](=[O:13])[CH:9]([S:11]([CH3:12])=[O:23])[CH3:10])=[CH:5][N:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1
Reactant: OO
Reactant: C#CCN(C(=O)C(C)SC)c1cn(-c2cccnc2)nc1Cl
Product: C#CCN(C(=O)C(C)S(C)=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-(methylthio)-N-(prop-2-yn-1-yl)propanamide (0.1 g, 0.30 mmol) in hexafluoroisoproanol (2.0 ml) was added hydrogen peroxide (35 wt %, 0.08 ml, 0.90 mmol) and the reaction mixture was stirred vigorously at ambient temperature. The reaction was complete after 1 h. The reaction was quenched with saturated sodium sulfite solution and the organic layer was extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified using silica gel chromatography (0-20% methanol (MeOH)/DCM) to afford the title compound as an off-white foam (82 mg, 0.21 mmol, 78%): 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.65 (d, J=4.6 Hz, 1H), 8.23 (s, 1H), 8.11-7.97 (m, 1H), 7.51-7.41 (m, 1H), 4.88 (br s, 1H), 4.14 (br s, 1H), 2.64 (s, 1.2H), 2.55 (s, 1.8H), 2.33-2.27 (m, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.42 (br s, 1H); 13C NMR (101 MHz, CDCl3) δ 168.11, 148.95, 148.78, 140.45, 140.33, 140.20, 135.56, 126.54, 124.10, 121.68, 121.58, 121.48, 77.69, 73.49, 38.60; ESIMS m/z 351 ([M+H]+).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(CC)CC)C.C(O[CH:22]=[CH:23][C:24](=O)[C:25]([F:28])([F:27])[F:26])C.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:22]=[CH:23][C:24]([C:25]([F:28])([F:27])[F:26])=[C:3]([S:2][CH3:1])[C:4]=1[OH:11])[CH3:10]
Reactant: CCOC(=O)CC(=O)CSC
Reactant: CCOC=CC(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(C(F)(F)F)c(SC)c1O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
100 g of ethyl 4-(methylsulphanyl)-3-oxobutanoate and 27.8 g of triethylamine were initially charged in 260 ml of toluene and cooled to 0° C. under nitrogen. Then 102.8 g of 4-ethoxy-1,1,1-trifluorobut-3-en-2-one were added dropwise at 0-7° C. within 30 minutes and the mixture was stirred for a further 5 h. After 16 hours, the reaction was warmed up to 18° C. The reaction mixture was concentrated, admixed with 150 ml of acetonitrile and concentrated at 5 mbar. The crude product was admixed with 2 equivalents of 10% sodium hydroxide solution while stirring and cooling with ice-water and stirred for 1 h, and the solids were filtered off with suction, washed three times with 50 ml of 3.5% sodium hydroxide solution and dried by suction. The solids were then admixed with 150 ml of water and 150 ml of toluene, and adjusted to pH 1 with about 150 ml of 10% HCl, and further HCl was metered in with continued stirring until the pH remains below 3. Then the filtered phases were separated and the water phase was extracted once more with toluene. The combined toluene phases were dried and concentrated: Yield 122.3 g (78% of theory). 1H NMR (CDCl3, 400 MHz): δ=11.77 ppm (1H, s), 7.93 ppm (1H, d), 7.23 ppm (1H, d), 4.47 ppm (2H, q), 2.44 ppm (3H, s), 1.45 ppm (3H, t).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]=[C:6]([CH3:12])[CH2:7][CH2:8][C:9](Cl)=[O:10].Cl.[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([C:9](=[O:10])[CH2:8][CH2:7][C:6](=[O:5])[CH3:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccccc1
Reactant: CC(=O)CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)CCC(=O)c1ccccc1
Reaction time: 0.54 h
Yield: 24.07 %

Procedure:
To a well stirred suspension of anhydrous aluminium chloride (27.0 g, 205.9 mmol) in 126 ml of benzene was added 4-oxopentanoylchloride (23.0 g, 171.6 mmol) drop-wise, over a period of 30-35 minutes at room temperature (25-30° C.). The reaction mixture was stirred at the same temperature for 1 hour. After decomposition of the reaction mixture by the addition of solid ice and hydrochloric acid (10 ml) the precipitated solid was filtered and the filtrate evaporated on a rotary evaporator to remove all the solvents. The residue was dissolved in ethyl acetate (400 ml), washed with water (2×100 ml), brine (100 ml) and dried over anhydrous sodium sulfate and the solvent evaporated off. The crude product so obtained was chromatographed over silica gel (100-200 mesh) using chloroform as eluent to give 8.6 g (24.07%) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[CH:24]([OH:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:29](Cl)(=[O:31])[CH3:30].[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35]>CN(C)C=O.C(C(C)=O)C>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[C:29]([O:26][CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24](=[O:25])[N:16]1[CH2:15][CH2:14][CH2:13][N:10]1[CH2:9][CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)(=[O:31])[CH3:30]
Reactant: O=C1c2ccccc2C(O)N1CCCN1CC=C(c2ccccc2)CC1
Reactant: CC(=O)Cl
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OC1c2ccccc2C(=O)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 20 h
Yield: 25.9 %

Procedure:
A solution of 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-3-hydroxy-1-isoindolinone (6 g) in anhydrous dimethylformamide (70 cc) is added to a suspension of sodium hydride (as a 50% suspension in oil) (0.8 g) in anhydrous dimethylformamide (20 cc) at a temperature close to 20° C. in the course of 10 minutes and agitation is continued for 1 and a half hours. Then, 1.4 g of acetyl chloride is added in the course of 10 minutes, and agitation is continued for a further 20 hours. The suspension obtained is poured into distilled water (70 cc) and extracted with methylene chloride (4×50 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in methyl ethyl ketone (55 cc). A solution of oxalic acid (1.3 g) in methyl ethyl ketone (20 cc) is added and agitation continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration. 1.8 g of 3-acetoxy-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate are thus obtained, melting at 166° C.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23]C(OC(C)(C)C)=O)[CH:17]=1)[CH2:5][P:6]([CH:11]([NH2:15])[CH:12]([CH3:14])[CH3:13])([O:8]CC)=[O:7].CCN(C(C)C)C(C)C.[C:41]1([S:47](Cl)(=[O:49])=[O:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C[Si](Br)(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH2:23][CH2:22][C:18]1[CH:17]=[C:16]([CH:4]([CH2:5][P:6]([CH:11]([NH:15][S:47]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:49])=[O:48])[CH:12]([CH3:13])[CH3:14])([OH:8])=[O:7])[C:3]([OH:2])=[O:31])[CH:21]=[CH:20][CH:19]=1
Reactant: CCOP(=O)(CC(C(=O)OC)c1cccc(CNC(=O)OC(C)(C)C)c1)C(N)C(C)C
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: C[Si](C)(C)Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C(NS(=O)(=O)c1ccccc1)P(=O)(O)CC(C(=O)O)c1cccc(CN)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a solution of 2-(3-(t-butoxycarbonylamino)methylphenyl)-3-((1-amino-2-methylpropyl)(ethoxy)phosphinoyl)propanoic acid methyl ester (344 mg, 0.75 mmol) in methylene chloride (10 mL) was added DIEA (394 μL, 2.25 mmol) followed by DMAP (3.4 mg (cat.)). The reaction mixture was cooled to 0° C. and a solution of benzenesulfonyichloride (200 mg, 1.13 mmol) in methylene chloride was added dropwise over 15 minutes. The reaction mixture was stirred at 0° C. for 30 minutes and allowed to warm to ambient temperature overnight. The reaction was diluted with methylene chloride and washed with 2 N aq NaHSO4, water, brine and dried over sodium sulfate. Evaporation gave a crude residue (425 mg) that was dissolved in 2.5 mL of methylene chloride and cooled to 0° C. under N2. TMSBr (1 mL) was added dropwise and the reaction was stirred at ambient temperature overnight, quenched with MeOH and evaporated. The resulting residue was dissolved in 5 mL of MeOH/H2O (1:1), neutralized with 0.25 M aq LiOH and 300 mg of LiOH and 10 mL of H2O. The reaction mixture was stirred at ambient temperature overnight. The solvents were evaporated and purification by preparative HPLC yielded 150 mg of 2-(3-(amino)methylphenyl)-3-((1-(phenylsulfonyl)amino-2-methylpropyl)(hydroxy)-phosphinoyl)propanoic acid, NMR (DMSO-d6) 0.5-0.8 (m, 6), 1.8 (m, 1), 1.92 (m, 1), 2.35 (m, 1) 3.25 (m, 1), 3.82 (m, 1), 4.0 (s, 2), 7.2 (dd, 1), 7.25-7.4 (m, 3), 7.4-7.6 (m, 3), 7.8 (m, 3), 8.18 (s, 3) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH:13]O.[OH-].[Na+].O>CO>[Br:1][C:2]1[CH:10]=[C:9]([C:11]([NH2:12])=[O:13])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: N#Cc1cc(Br)c2cc[nH]c2c1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=O)c1cc(Br)c2cc[nH]c2c1
Yield: 97.6 %

Procedure:
A solution of 4-bromo-1H-indole-6-carbonitrile (1 g, 4.50 mmol) in methanol (10 mL) was treated with 30% aqueous hydrogen peroxide (2.7 mL, 4.95 mmol) and a 1 M aqueous sodium hydroxide solution (5 mL) then heated at 40° C. for 1 h. The reaction mixture was cooled, treated with water and cooled in an ice-bath. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to obtain 4-bromo-1H-indole-6-carboxylic acid amide (1.05 g, 97%), which was transformed into the title boronic ester by the general method (Scheme 1) (0.80 g, 67%).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([C:19]2[CH:40]=[CH:39][C:22]([CH2:23][N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[C:26]([CH3:38])([CH3:37])[CH2:25]3)=[CH:21][CH:20]=2)[CH3:18])[N:11]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(Cl)Cl>[CH3:38][C:26]1([CH3:37])[NH:27][CH2:28][CH2:29][N:24]([CH2:23][C:22]2[CH:39]=[CH:40][C:19]([C@@H:17]([NH:16][C:12]3[N:11]=[C:10]([N:5]4[C@@H:4]([CH:1]([CH3:2])[CH3:3])[CH2:8][O:7][C:6]4=[O:9])[CH:15]=[CH:14][N:13]=3)[CH3:18])=[CH:20][CH:21]=2)[CH2:25]1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(CN3CCN(C(=O)OC(C)(C)C)C(C)(C)C3)cc2)n1
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(CN3CCNC(C)(C)C3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.3 %

Procedure:
To a solution of tert-butyl 4-(4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzyl)-2,2-dimethylpiperazine-1-carboxylate (78 mg, 0.14 mmol) in DCM (1 mL) was added TFA (1 mL, 12 mmol) slowly at −78° C. The reaction was stirred at room temperature for 1 h then was concentrated and diluted with DCM (10 mL). The solution was stirred with 3 eq. of MP-carbonate resin (3.28 mmol/g, Biotage) for 1 h at room temperature. The resin was removed by filtration and washed (2×5 mL) with DCM. The filtrate was concentrated and purified through HPLC to give (S)-3-(2-(((S)-1-(4-((3,3-dimethylpiperazin-1-yl)methyl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one as a white solid (23 mg, 36% yield).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23](O)=[O:24])[CH:18]=2)[CH2:13][CH2:12]1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[C:35]([OH:37])=[O:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:12][CH2:13][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:28][CH:27]3[C:35]([OH:37])=[O:36])=[O:24])[CH:18]=2)[CH2:15][CH2:16]1
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Reactant: O=C(O)C1Cc2ccccc2N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)C1Cc2ccccc2N1C(=O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1

Procedure:
107 mg (0.31 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 65.0 mg (0.40 mmol) 2,3-dihydro-1H-indole-2-carboxylic acid, 107.0 mg (0.33 mmol) TBTU and 100 μL (0.71 mmol) triethylamine in 10 mL DMF were stirred overnight at RT. The mixture was evaporated down i. vac. and the residue was dissolved in 5 mL DMF. The purification was carried out by preparative HPLC. The product fractions were combined and lyophilised.