Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-].[Na+].[Na].[C:5]([C:9]1[O:13][N:12]=[C:11]([NH:14][C:15](=[O:18])[O:16][CH3:17])[CH:10]=1)([CH3:8])([CH3:7])[CH3:6]>CO>[CH3:1][N:14]([C:11]1[CH:10]=[C:9]([C:5]([CH3:8])([CH3:6])[CH3:7])[O:13][N:12]=1)[C:15](=[O:18])[O:16][CH3:17]
Reactant: C[O-]
Reactant: COC(=O)Nc1cc(C(C)(C)C)on1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)N(C)c1cc(C(C)(C)C)on1
Reaction time: 1 h

Procedure:
To the sodium methoxide obtained by mixing sodium (1.57 g) with anhydrous methanol (45 ml), methyl N-(5-t-butyl-3-isoxazolyl)carbamate (12.88 g) is added. The resultant mixture is stirred at room temperature for 10 minutes, and the methanol is evaporated under reduced pressure. The residue is mixed with anhydrous benzene (100 ml) and dimethyl sulfate (8.61 g). The resultant mixture is stirred for 1 hour and refluxed for 1 hour. After cooling, the precipitate is filtered off. The organic layer is washed with an aqueous saturated solution of sodium bicarbonate and water in order, dried over anhydrous sodium sulfate, and the solvent is evaporated. The residue is distilled to give methyl N-methyl-N-(5-t-butyl-3-isoxazolyl)carbamate (11.45 g) as a distillate boiling at 84.0° to 87.0° C/0.55 mm Hg.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([NH:11][C:12](=[O:14])[CH3:13])=[CH2:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1>CO>[F:1][C:2]1[C:3]([C@@H:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C=C(NC(C)=O)c1ncc(F)cc1F
Solvent: CO
Product: CC(=O)N[C@@H](C)c1ncc(F)cc1F
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of N-(1-(3,5-difluoropyridin-2-yl)vinyl)acetamide (Method 53, 2.2 g, 11.1 mmol) in MeOH (20 ml) under N2 was added (+)-1,2-bis((2S,5S)-2,5-dimethyl phospholano)benzene (cyclooctadiene)rhodium(I)trifluoromethanesulfonate (0.074 g, 0.111 mmol). The solution was transferred to a high-pressure bomb and charged 150 psi H2. The reaction stirred at room temperature and maintained inside pressure between 120-150 psi for 24 hours. The solvent was removed and the resulted residue was purified by column chromatography (EtOAc) to give the title compound as a white solid (2.0 g, 90%). 1H NMR (400 MHz) δ 8.47 (d, J=2.4 Hz, 1H), 8.34 (d, J=7.2 Hz, 1H), 7.89 (m, 1H), 5.21 (m, 1H), 1.81 (s, 3H), 1.34 (d, J=6.8 Hz, 3H). MS: Calcd.: 200. Found: [M+H]+ 201.
Reaction SMILES: [NH+]12CC[NH+](CC1)CC2.[F:9][B-:10]([F:13])([F:12])[F:11].F[B-](F)(F)F.[CH2:19]([C:21]1([CH2:34][CH3:35])[CH2:26][N+:25]2(P(O)(O)=O)[CH2:27][CH2:28][N+:22]1(F)[CH2:23][CH2:24]2)[CH3:20].[P:36](Cl)([O:41]CC)([O:38]CC)=[O:37].F[B-](F)(F)F.[Na+]>C1COCC1.C(#N)C>[F:9][B-:10]([F:13])([F:12])[F:11].[CH2:34]([C:21]1([CH2:19][CH3:20])[CH2:26][N:25]2[CH2:27][CH2:28][N+:22]1([P:36]([OH:38])([OH:41])=[O:37])[CH2:23][CH2:24]2)[CH3:35]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCC1(CC)C[N+]2(P(=O)(O)O)CC[N+]1(F)CC2
Agent: C1C[NH+]2CC[NH+]1CC2
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CCC1(CC)CN2CC[N+]1(P(=O)(O)O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl 1-Fluoro-4-phosphono-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) 1,4-Diazoniabicyclo[2.2.2]octane (11 g, 10 mmol) in THF (100 mL) is reacted with diethyl chlorophosphate (17.3 g, 10 mmol) until the reaction is complete by TLC. The reaction is evaporated, diluted with acetonitrile (100 mL) and sodium tetrafluoroborate (40 g, 20 mmol) added. The solution is stirred overnight at room temperature and then filtered to remove all undissolved salts. The filtrate is evaporated to afford diethyl- 1-phosphono-4-aza-1-azoniabicyclo[2.2.2]octane tetrafluoroborate.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=O)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:50][CH2:51][C:52]([C:54]1[CH:59]=[CH:58][C:57]([Br:60])=[CH:56][CH:55]=1)=[O:53]>CN(C=O)C>[Br:60][C:57]1[CH:56]=[CH:55][C:54]([C:52](=[O:53])[CH2:51][NH:50][C:19]([C@@H:18]2[CH2:22][CH2:23][CH2:24][N:17]2[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:21])=[CH:59][CH:58]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NCC(=O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)c1ccc(Br)cc1
Yield: 95.9 %

Procedure:
N,N-Diisopropylethylamine (18 mL, 103.3 mmol) was added dropwise, over 15 minutes, to a heterogeneous mixture of N-Boc-L-proline (7.139 g, 33.17 mmol), HATU (13.324 g, 35.04 mmol), the HCl salt of 2-amino-1-(4-bromo-phenyl)ethanone (8.127 g, 32.44 mmol), in DMF (105 mL) and stirred at ambient condition for 55 minutes. DMF was removed in vacuo, and the resulting residue was partitioned between ethyl acetate (300 mL) and water (200 mL). The organic layer was washed with water (200 mL) and brine, dried (MgSO4), filtered, and concentrated. A silica gel mesh was prepared from the residue and submitted to flash chromatography (silica gel; 50-60% ethyl acetate/hexanes) to provide Example 14, (S)-tert-butyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)pyrrolidine-1-carboxylate as a white solid (12.8 g). 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): δ 8.25-8.14 (m, 1H), 7.92 (br d, J=8.0, 2H), 7.75 (br d, J=8.6, 2H), 4.61 (dd, J=18.3, 5.7, 1H), 4.53 (dd, J=18.1, 5.6, 1H), 4.22-4.12 (m, 1H), 3.43-3.35 (m, 1H), 3.30-3.23 (m, 1H), 2.18-2.20 (m, 1H), 1.90-1.70 (m, 3H), 1.40/1.34 (two app br s, 9H). RT=1.70 min (condition 1); LCMS: Anal. Calcd. for C18H23BrN2NaO4: 433.07. found 433.09 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16](I)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1.[NH:31]1[CH2:36][CH2:35][S:34](=[O:38])(=[O:37])[CH2:33][CH2:32]1>CN1CCCC1=O>[O:37]=[S:34]1(=[O:38])[CH2:35][CH2:36][N:31]([C:16]2[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=[C:14]([C:7]3[C:8]4[C:9](=[N:10][CH:11]=[CH:12][CH:13]=4)[N:5]([CH2:4][C:3]4[CH:27]=[CH:28][CH:29]=[CH:30][C:2]=4[F:1])[N:6]=3)[N:15]=2)[CH2:32][CH2:33]1
Reactant: O=S1(=O)CCNCC1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N3CCS(=O)(=O)CC3)c21
Temperature: 200 °C

Procedure:
Under argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was suspended in 4 ml of absolute 1-methyl-2-pyrrolidone and 652 mg (4.82 mmol) of thiomorpholine-1,1-dioxide was added. The mixture was heated in the microwave for 3 h at 150° C. and 1 h at 200° C. After cooling, the reaction mixture was purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→100:0). 72 mg (57% of theor.) of the target compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]([Cl:16])=[CH:14][C:13]2[C:8](=[C:9]([O:17]C)[CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].B(Cl)(Cl)Cl.O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:15]([Cl:16])=[CH:14][C:13]2[C:8](=[C:9]([OH:17])[CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(OC)cccc2cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc2c(O)cccc2cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Tetrabutylammonium iodide (3.74 g, 10.12 mmol, 1.3 equiv) was added to a solution of 3-chloro-8-methoxy-naphthalene-2-carboxylic acid ethyl ester (2.06 g, 7.79 mmol) in anhydrous CH2Cl2 (39 ml). After cooling to −78° C., BCl3 (1M solution in CH2Cl2, 19.46 ml, 19.46 mmol, 2.5 equiv) was added dropwise. The reaction mixture was stirred at −78° C. for 30 minutes and then let warm to room temperature. After 2 hours at room temperature, cold water (4° C., 40 ml) was added slowly, and the resulting mixture was vigorously stirred for 30 minutes before it was extracted with EtOAc (800 ml total). The combined organic layers were washed with concentrated aqueous NaHCO3 solution (100 ml) and concentrated aqueous NH4Cl solution (100 ml), dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (gradient of hexane/EtOAc 100:0 to 6:4) afforded the title compound (1.84 g, 95%, inseparable 1:1.3 mixture of regioisomers A:B) as a slightly yellow solid. 1H NMR (400 MHz, d6-DMSO): δ=10.69 (br s, 1H isomer B), 10.55 (br s, 1H isomer A), 8.60 (s, 1H isomer B), 8.35 (s, 1H isomer A), 8.16 (s, 1H isomer A), 8.06 (s, 1H isomer B), 7.55-7.36 (m, 2H isomer A+2H isomer B), 7.01 (d, J=7.6 Hz, 1H isomer A), 6.95 (d, J=7.5 Hz, 1H isomer B), 4.36 (q, J=7.1 Hz, 2H isomer A+2H isomer B), 1.37-1.33 (m, 3H isomer A+3H isomer B). MS (ES+): 251 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([N:9]([CH2:19][CH2:20][Cl:21])[C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].[OH:28][C:29]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(O)CCC>C(Cl)(Cl)Cl>[ClH:21].[CH2:2]([N:9]([CH2:19][CH2:20][N:32]1[CH2:33][CH2:34][C:29]([OH:28])([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:30][CH2:31]1)[C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NC(=O)c1ccccc1N(CCCl)Cc1ccccc1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCCCO
Product: NC(=O)c1ccccc1N(CCN1CCC(O)(c2ccccc2)CC1)Cc1ccccc1
Yield: 53.8 %

Procedure:
A mixture of 19.5 g 2-[Benzyl(2-chloroethyl)amino]benzamide hydrochloride, 15.75 g powdered anhydrous Na2CO3, 10.6 g 4-hydroxy-4-phenylpiperidine and 250 ml butanol was refluxed 20 hours, cooled and an equal volume of chloroform added. The mixture was filtered and the filtrate concentrated on the rotovap to dryness. The residue was dissolved in 500 ml ether, a little dry ice added, the mixture filtered and concentrated to dryness. The residue in 300 ml ether was treated with dry HC1 and filtered to give 15 g product.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17](Cl)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH:19]1([CH:24]([N:28]2[CH:32]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:30]=[N:29]2)[CH2:25][C:26]#[N:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.COCCOC.O.C(=O)([O-])[O-].[K+].[K+]>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>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:31]3[CH:30]=[N:29][N:28]([CH:24]([CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:25][C:26]#[N:27])[CH:32]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(Cl)ncnc21
Reactant: CC1(C)OB(c2cnn(C(CC#N)C3CCCC3)c2)OC1(C)C
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: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(C(CC#N)C4CCCC4)c3)ncnc21
Temperature: 82 °C
Reaction time: 6 h
Yield: 88.4 %

Procedure:
Method B. Into a 50 ml round bottom flask equipped with a stir bar, condenser and 3-way valve connected to nitrogen and vacuum was charged (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (3f, 700 mg, 2.61 mmol), 3-cyclopentyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile (23, 935 mg, 2.97 mmol, 1.13 equiv), 1,2-dimethoxyethane (DME, 10 mL, 96 mmol), water (5 mL, 0.28 mol) and potassium carbonate (K2CO3, 1.82 g, 7.84 mmol, 3.0 equiv) at room temperature. The resulting reaction mixture was degassed three times back filling with nitrogen each time before being charged tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.026 mmol, 0.010 equiv). The resulting reaction mixture was degassed four times back filling with nitrogen each time and then warmed to 82° C. The reaction mixture was stirred at 82° C. for 6 hours. When the reaction was deemed complete, the reaction mixture was cooled to room temperature before being diluted with ethyl acetate (45 mL) and water (10 mL). The resulting mixture was stirred until the majority of solids had gone into solution. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×25 mL). The combined organic fractions were washed with aqueous brine (2×25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0-50% ethyl acetate/hexane gradient elution) to afford racemic 4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 0.97 g, 1.1 g theoretical, 88.6% yield) as colorless oil, which solidified upon standing at room temperature in vacuo. For 20: 1H NMR (CDCl3, 300 MHz) δ 8.85 (s, 1H), 8.29 (s, 1H), 8.27 (s, 1H), 7.45 (d, 1H, J=3.8 Hz), 6.73 (d, 1H, J=3.8 Hz), 6.22 (s, 2H), 4.23 (ddd, 1H, J=10.0, 8.6, 4.0 Hz), 3.10 (dd, 1H, J=17.0, 8.6 Hz), 2.92 (dd, 1H, J=17.0, 4.0 Hz), 2.56 (m, 1H), 2.0-1.25 (m, 8H), 1.12 (s, 9H); C23H28N6O2 (MW, 420.51), LCMS (EI) m/e 421 (M++H).
Reaction SMILES: [O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:8][O:9][C:10](=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[C:13]([N+:18]([O-])=O)[CH:12]=1>CCO>[CH3:8][O:9][C:10](=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[C:13]([NH2:18])[CH:12]=1
Reactant: COC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc(Br)c(N)c1

Procedure:
Add Na2SO4(8.5 mmol) to a solution of 4-Bromo-3-nitro-benzoic acid methyl ester (1.2 mmol) in EtOH (40 mL). Heat the reaction at 70° C. for 30 min and then at room temperature overnight. Add a saturated solution of NaHCO3(pH=11-12) and extract with EtOAc (2×50 mL). Dry over NaSO4, filter and evaporate to dryness to provide 4-Bromo-3-amino-benzoic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:8]([CH:20]([NH:22][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][N:27]3C1CCCCO1)[CH3:21])=[CH:7]2.C([O-])(O)=O.[Na+]>CO>[N:31]1[C:23]([NH:22][CH:20]([C:8]2[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[C:10](=[O:12])[C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])[CH3:21])=[C:24]2[C:28]([NH:27][CH:26]=[N:25]2)=[N:29][CH:30]=1
Reactant: Cc1ccccc1-n1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc2cccc(C)c2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1ccccc1-n1c(C(C)Nc2ncnc3[nH]cnc23)cc2cccc(C)c2c1=O
Reaction time: 2 h
Yield: 54.1 %

Procedure:
8-Methyl-3-(1-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)-2-o-tolylisoquinolin-1(2H)-one 4105 (180 mg, 0.36 mmol) was dissolved in MeOH (HCl) (50 mL) and stirred for 2 h. Aqueous NaHCO3 solution was added to the reaction mixture and the pH value was adjusted to 9. The mixture was then filtered and the filtrate was concentrated in vacuo to afford the desired product, 3-(1-(9H-purin-6-ylamino)ethyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (4106, compound 191 in Table 4) (80 mg, 54% yield) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[N:10]=1.Br[C:36]1[CH:37]=[C:38]([CH:42]([C:44]2[C:49]([C:50]([F:53])([F:52])[F:51])=[CH:48][CH:47]=[CH:46][N:45]=2)[OH:43])[CH:39]=[CH:40][CH:41]=1.C(#N)C.C(=O)(O)[O-].[Na+]>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].ClCCl.C1(C)C=CC=CC=1>[OH:43][CH:42]([C:44]1[C:49]([C:50]([F:53])([F:51])[F:52])=[CH:48][CH:47]=[CH:46][N:45]=1)[C:38]1[CH:37]=[C:36]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][N:11]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])[C:12]3=[N:13][CH:14]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: COc1ccccc1-c1nn(COC(=O)C(C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: OC(c1cccc(Br)c1)c1ncccc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])O
Solvent: CC#N
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1nn(COC(=O)C(C)(C)C)c2ncc(-c3cccc(C(O)c4ncccc4C(F)(F)F)c3)cc12
Temperature: 65 °C
Yield: 66 %

Procedure:
465 mg (1.00 mmol) of 2,2-dimethyl-propionic acid 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester, 50 mg (61 μmol) of dichloro[1,1′-bis(diphenyl-phoshino)ferrocene]palladium(II) dichloromethane adduct and 340 mg (1.02 mmol) of (3-bromo-phenyl)-(3-trifluoromethyl-pyridin-2-yl)-methanol were place in a microwave vial. 8 mL of acetonitrile, 3 mL of toluene and 8 mL of a saturated aqueous solution of sodium bicarbonate were added. The vial was sealed and the resulting mixture heated in an oil bath to 65° C. for 22 h. The resulting mixture was distributed between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulfate and evaporated. The resulting residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford 388 mg (0.66 mmol, 66%) of 2,2-dimethyl-propionic acid 5-{3-[hydroxy-(3-trifluoromethyl-pyridin-2-yl)-methyl]-phenyl}-3-(2-methoxy-phenyl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester as a beige solid. 1H NMR (500 MHz, DMSO-d6) α 8.90 (d, 1H), 8.86 (d, 1H), 8.34 (d, 1H), 8.20 (d(d), 1H), 7.81 (s, 1H), 7.67-7.64 (m, 2H), 7.56-7.50 (m, 2H), 7.45 (t, 1H), 7.39 (d, 1H), 7.27 (d, 1H), 7.13 (t, 1H), 6.51 (s, 2H), 6.26 (d, 1H), 6.11 (d, 1H), 3.86 (s, 3H), 1.12 (s, 9H); MS: m/z 591.1 (M+H+), 613.1 (M+Na+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8](=[O:13])[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH:6]=[CH:5]2.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([S:36]C2C=C3C(=CC=2Cl)C=NC=C3)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].ClC1C=C2C(C=CNC2=O)=CC=1SC1CCNCC1>>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([S:36][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[Cl:12])[C:8](=[O:13])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:6]=[CH:5]3)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2cc3ccncc3cc2Cl)CC1
Reactant: COc1ccc(Cn2ccc3cc(Br)c(Cl)cc3c2=O)cc1
Agent: O=c1[nH]ccc2cc(SC3CCNCC3)c(Cl)cc12
Product: COc1ccc(Cn2ccc3cc(SC4CCN(C(=O)OC(C)(C)C)CC4)c(Cl)cc3c2=O)cc1

Procedure:
Starting from 7-Chloro-6-fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (264) 4-[7-Chloro-2-(4-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinolin-6-ylsulfanyl]-piperidine-1-carboxylic acid tert-butyl ester could be obtained as described for compound (274). 7-Chloro-6-(piperidin-4-ylsulfanyl)-2H-isoquinolin-1-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl.Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: ClCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCCN2CCOCC2)cc1F
Reaction time: 16 h
Yield: 93 %

Procedure:
A mixture of 3-fluoro-4-nitrophenol (1.6 g, 10 mmol), 4-(2-chloroethyl)morpholine hydrochloride (1.9 g, 10 mmol), and potassium carbonate (5.5 g, 52 mmol) in acetone (50 mL) was heated to reflux with stirring for 16 hours. The mixture was cooled and evaporated under vacuum. The residue was partitioned between water (100 mL) and ethyl acetate (100 mL), and the organic phase was washed with water (100 mL) and brine (100 mL), was dried (MgSO4), and evaporated, providing 2.6 g, in 93% yield; 1H NMR (DMSO-d6) δ 2.47 (t, 4H, J=4.6), 2.71 (t, J=5.6 Hz, 2H), 3.57 (t, J=4.6, 4H), 4.25 (t, J=5.6 Hz, 2H), 6.99 (dd, J=9.3 Hz, J=2.7 Hz, 1H), 7.19-7.24 (m, 1H), 8.14 (t, J=9.3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@@H:4]([OH:14])[C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])[OH:6].[CH2:16](OC(OCC)C)[CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:1][O:2][C:3]([C@@H:4]1[C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[O:6][CH:16]([CH3:17])[O:14]1)=[O:15]
Reactant: CCOC(C)OCC
Reactant: COC(=O)[C@@H](O)[C@H](O)c1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: COC(=O)[C@H]1OC(C)O[C@@H]1c1ccccc1Cl
Temperature: 25 °C
Yield: 70 %

Procedure:
Dichloromethane (MC) was added to (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate at room temperature. 1,1-Diethoxyethane (8 ml) and p-toluenesulfonic acid (0.27 g) was added and stirred at room temperature. The reaction mixture was quenched with H2O, extracted with MC, washed with H2O, dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated. The crude compound was purified by a silica gel column to produce the title compound (3.6 g, 70˜95%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[C:5]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N:14]1[C:18]([CH2:19][N:20]([CH3:22])[CH3:21])=[N:17][C:16]([C:23]([OH:25])=[O:24])=[N:15]1)=[O:6].[CH3:30]O>>[CH3:30][O:24][C:23]([C:16]1[N:17]=[C:18]([CH2:19][N:20]([CH3:22])[CH3:21])[N:14]([C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[C:5](=[O:6])[C:4]2[CH:26]=[CH:27][CH:28]=[CH:29][C:3]=2[Cl:2])[N:15]=1)=[O:25]
Reactant: CN(C)Cc1nc(C(=O)O)nn1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: CO
Agent: Cl
Product: COC(=O)c1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1

Procedure:
For conversion into the methyl ester already mentioned, 10 ml of a 6 N solution of hydrogen chloride in methanol is added to a solution of 2.08 g (0.005 mole) of crude 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(dimethylaminomethyl)-1H-1,2,4-triazole-3-carboxylic acid in 30 ml of methanol, and the whole is refluxed for 16 hours. The reaction mixture is thereupon concentrated in vacuo. Water is added to the residue, and extraction is performed twice with methylene chloride. The organic phase is washed twice with ice-cold 1N sodium bicarbonate solution and twice with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo. The residue crystallises out on trituration with ether. After filtration with suction and drying in vacuo, there is obtained pure 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(dimethylamino-methyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester, m.p. 133°-135°.