Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:2]2=[O:1])[CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCNC1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCCN(c2cccc(Cl)c2)C1=O
Temperature: 25 °C
Reaction time: 36 h
Yield: 10.1 %

Procedure:
To a stirred solution of (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (400 mg, 1.75 mmol) in DCM (7.5 mL) was added TEA (0.488 mL, 3.50 mmol) followed by copper (II) acetate (477 mg, 2.63 mmol) and 3-chlorophenylboronic acid (548 mg, 3.50 mmol) at rt under argon. Then, activated molecular sieves (˜1 gm) were added. The reaction mixture was stirred at rt for 36 hr. The reaction mixture was filtered through CELITE®. The filtrate was concentrated. The residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give (S)-tert-butyl 1-(3-chlorophenyl)-2-oxoazepan-3-ylcarbamate (60.0 mg, 0.177 mmol, 10.1% yield) as white solid. Anal. Calcd. for C17H23ClN2O3 m/z 338.8. found: 339.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([OH:23])[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)[NH:7]C(OC(C)(C)C)=O.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.[C:35]([O-])([O-])=O.[K+].[K+]>CCO.O>[CH2:1]([O:2][C:3](=[O:24])[C@H:4]([OH:23])[CH2:5][N:6]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:25])[CH:31]=2)=[CH:20][CH:21]=1)[NH2:7])[CH3:35]
Reactant: COC(=O)[C@H](O)CN(Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@H](O)CN(N)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
(R)-3-[N-(4-Bromobenzyl)-N′-t-butoxycarbonylhydrazino]-2-hydroxypropionic acid methyl ester (600 mg, 1 mmol), 3-chlorophenylboronic acid (419 mg, 2.7 mmol), and K2CO3 (617 mg, 4.5 mmol) were combined in EtOH (5 mL) and water (1 mL), followed by the addition of SilicaCat®Pd(0) (0.09 mmol/g loading, 1160 mg, 104 μmol). The mixture was heated in a microwave reactor at 120° C. until the reaction was complete (˜30 minutes). The mixture was filtered and concentrated. The residue was dissolved into MeCN/AcOH and purified by reverse phase chromatography (55 g column; gradient 30-95% MeCN in water with 0.1% TFA). The clean fractions were collected, concentrated and then dissolved in 4M HCl in dioxane (6 mL) and EtOH (6 mL). The mixture was stirred at room temperature overnight, then concentrated to yield the title compound (250 mg), which was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.I[C:7]1[CH:8]=[C:9]([CH:19]=[CH:20][CH:21]=1)[CH2:10][C:11]1([CH3:18])[NH:16][C:15](=[O:17])[CH2:14][O:13][CH2:12]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[CH3:18][C:11]1([CH2:10][C:9]2[CH:19]=[CH:20][CH:21]=[C:7]([N:2]3[N:3]=[CH:4][CH:5]=[N:1]3)[CH:8]=2)[NH:16][C:15](=[O:17])[CH2:14][O:13][CH2:12]1
Reactant: c1c[nH]nn1
Reactant: CC1(Cc2cccc(I)c2)COCC(=O)N1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(Cc2cccc(-n3nccn3)c2)COCC(=O)N1
Temperature: 25 °C

Procedure:
DMCDA (85 μL, 0.538 mmol) followed by 1H-1,2,3-triazole (0.31 mL, 5.38 mmol) were added to a mixture of rac-5-(3-iodo-benzyl)-5-methyl-morpholin-3-one H-8 (890 mg, 2.69 mmol), Cs2CO3 (1.75 g, 5.38 mmol) and CuI (77 mg, 0.40 mmol) in DMF (5 mL) under argon and the resulting blue suspension was heated to 120° C. for 18 h. The reaction mixture was cooled to RT before being quenched with water and filtered over celite rinsing with water and DCM. The layers were separated and the aqueous phase was re-extracted with DCM (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The crude product was purified by flash chromatography (eluting with a gradient of 75% to 100% EtOAc in hexane) to give the title compound as a pale brown solid. LC-MS A: tR=0.69 min; [M+H]+=273.21.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[C:5](=[C:6]3[C:11](=[CH:12][N:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]3)[CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:25])C=1.CSC.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[N+:13]([O-:25])=[CH:12][C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc2ncc3c(c2c1)CCCC3
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CSC
Product: COc1ccc2c(c1)c1c(c[n+]2[O-])CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a solution of Compound 273 (91.80 g, 430 mmol) in dichloromethane (500 mL) cooled at zero degrees C. was added a solution of mCPBA (55 percent, 161.7 g, 516 mmol) in dichloromethane (900 mL), and the resulting mixture was stirred at 25° C. for 1 hour. Dimethyl sulfide (6.95 mL, 94.6 mmol) was added and stirring was continued for 15 minutes followed by addition of saturated aqueous sodium bicarbonate solution (1000 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (500 mL). The combined organic layers were dried (MgSO4), filtered through a 3 cm×3 cm plug of silica, and evaporated in vacuo. The residue was purified by recrystallization from benzene-cyclohexane to give a total of 88.34 g (90 percent) of the N-oxide Compound 280a: off-white crystalline solid; mp 167°-169° C.; Rf =0.31 (silica, 20 percent methanol in ethyl acetate); IR (CHCl3) νmax 2943, 1617, 1512, 1459, 1428, 1379, 1108 cm-1 ; 1H NMR (500 MHz, CDCl3) δ 8.65 (d, J=9.5 Hz, 1 H, H4), 8.18 (s, 1 H, H 6), 7.30 (dd, J=9.5, 2.6 Hz, 1 H, H3), 7.10 (d, J=2.6 Hz, 1 H, H1), 2.95 (t, J=6.2 Hz, 2 H, H10), 2.77 (t, J=6.2 Hz, 2 H, H7), 1.99-1.94 and 1.89-1.85 (m, 2 H each, H8 and H9); 13C NMR (125 MHz, CDCl3 ) δ 159.1, 134.8, 134.3, 131.4, 130.8, 121.7, 120.3, 101.8, 55.5, 27.0, 24.7, 22.1, 21.8; MS (FAB+) m/e (rel intensity) 230 (M+H, 100), 213 (10); HRMS for C 14 H16NO2 (M+H), calcd 230.1181, found 230.1194.
Reaction SMILES: [CH3:1][C:2]1[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[N:12]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(C(F)(F)F)nc1C
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(C(F)(F)F)nc1CBr
Temperature: 15 °C
Reaction time: 3 h

Procedure:
434.4 g (1.866 mol) of ethyl 2-methyl-6-trifluoromethylnicotinate (preparation similar to Heterocycles 129, 46, 1997) and 398.5 g (2.239 mol) of N-bromosuccinimide in 3500 ml of carbon tetrachloride in the presence of 30.6 g (0.1866 mol) of α,α-azaisobutyronitrile are heated at 75° C., with irradiation from a 150 Watt lamp. After 3 hours, the reaction is terminated, the mixture is cooled to 15° C. and precipitated succinimide is removed by filtration. After evaporation of the solvent, the residue is distilled under reduced pressure. This gives ethyl 2-bromomethyl-6-trifluoromethylnicotinate as an oily product (260.2 g, 44.7% of theory, b. p. 74° C./0.04 mmHg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[CH3:44][N:45]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[O:53][CH:54]=[C:55]([Sn](CCCC)(CCCC)CCCC)[CH:56]=2)[CH2:47][CH2:46]1.BrC1C=C(CN2CCN(C)CC2)OC=1[Sn](CCCC)(CCCC)CCCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[C:11]3[C:10]([C:55]3[CH:56]=[C:52]([CH2:51][N:48]4[CH2:47][CH2:46][N:45]([CH3:44])[CH2:50][CH2:49]4)[O:53][CH:54]=3)=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1coc(CN2CCN(C)CC2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](CCCC)(CCCC)c1oc(CN2CCN(C)CC2)cc1Br
Solvent: C1COCCO1
Product: COc1ccc(Cn2nc(-c3coc(CN4CCN(C)CC4)c3)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)cc1
Temperature: 90 °C

Procedure:
A stirred mixture of N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (35 mg, 0.0503 mmol) and a 14:86 mixture of 1-methyl-4-((4-(tributylstannyl)furan-2-yl)methyl)piperazine and 1-((4-bromo-5-(tributylstannyl)furan-2-yl)methyl)-4-methylpiperazine (26.0 mg, 0.0554 mmol, prepared in Example 66, Step B) in dioxane (0.5 mL) was sparged with N2 for 2 minutes. PdCl2(PPh3)2 (2 mg, 0.003 mmol) was added, and the reaction was heated to 90° C. for 18 hours in a sealed vessel. After cooling to ambient temperature, the crude reaction mixture was loaded directly on to a preparative TLC plate (0.5 mm thickness, Rf=0.60) eluting with 90:10 CHCl3/MeOH (containing 7N NH3). Isolated product as an off-white solid (27 mg, 83:17 mixture of N-(4-(1-(4-methoxybenzyl)-3-(3-bromo-5-((4-methylpiperazin-1-yl)methyl)furan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and N-(4-(1-(4-methoxybenzyl)-3-(5-((4-methylpiperazin-1-yl)methyl)furan-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide by 1H-NMR). The mixture of products were carried forward without further purification.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([NH2:12])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1[CH2:19][CH2:18][O:17]CC1.[C:20](Cl)(=[O:22])[CH3:21]>C(Cl)Cl.O>[C:20]([N:10]1[C:9]([NH:12][C:18](=[O:17])[CH3:19])=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:11]1)(=[O:22])[CH3:21]
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Reactant: CN1CCOCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1cc(-c2ccccc2)nn1C(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
To a solution of 5-phenyl-1H-pyrazol-3-amine (18.6 g, 0.117 mol) and N-methylmorpholine (30.8 mL, 0.281 mol) in CH2Cl2 (250 mL) was added acetyl chloride (20 mL, 0.281 mol) dropwise at 0° C. under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with CH2Cl2 and water. The layers were separated and the organic layer was washed with water and brine, dried (phase separator cartridge) and concentrated in vacuo. Diethyl ether was added to the residue and the solid was collected by filtration, yielding the title compound as a solid (25.1 g).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([N:15]([CH3:31])[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[CH2:8]([N:15]([CH3:31])[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(CCC1CCN(C(=O)OC(C)(C)C)CC1)Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCC1CCNCC1)Cc1ccccc1
Reaction time: 1 h

Procedure:
TFA (2.78 ml) was added dropwise at 0° C. to a solution of tert-butyl 4-(2-(benzyl(methyl)-amino)ethyl)piperidine-1-carboxylate (600 mg, 1.8 mmol, 1 eq) in dichloromethane (30 ml), and stirring was carried out for 1 h at RT. After monitoring by thin-layer chromatography, the reaction mixture was concentrated to dryness. The residue was dissolved in MeOH (50 ml), Amberlyst A-21 ion-exchanger resin (2 g) was added, and stirring was carried out for 30 min. The reaction mixture was filtered and the filtrate was concentrated to dryness under reduced pressure and used in the next stage without being purified further.
Reaction SMILES: Br.[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([OH:13])=[CH:8][CH:9]=2)[CH2:4]1.[Cl:14][C:15]1[CH:25]=[CH:24][C:18]([CH:19]([OH:23])[C:20](O)=[O:21])=[CH:17][CH:16]=1.C(N(CC)CC)C.[Cl-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[OH:13][C:7]1[CH:6]=[C:5]2[C:10]([CH2:11][CH2:12][CH:3]([NH:2][C:20](=[O:21])[CH:19]([C:18]3[CH:24]=[CH:25][C:15]([Cl:14])=[CH:16][CH:17]=3)[OH:23])[CH2:4]2)=[CH:9][CH:8]=1
Reactant: NC1CCc2ccc(O)cc2C1
Reactant: O=C(O)C(O)c1ccc(Cl)cc1
Agent: Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCc2ccc(O)cc2C1)C(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
To a mixture of 3.2 g of 2-amino-7-hydroxytetralin hydrobromide (PREPARATION Ic), 2.4 g of 4-chloromandelic acid and 5.2 g of benzotriazolyl-N-oxytris-(dimethylamino) phosphonium hexafluorophosphate in 50 ml of methylene chloride, there is added 3.6 ml of triethylamine. The solution obtained is left under stirring at room temperature for 3 hours, then a saturated sodium chloride solution is added and the mixture is stirred for 30 minutes. The organic phase that separates is evaporated to dryness and an oil is obtained that is dissolved in 200 ml of ethyl acetate. The solution thus obtained is washed twice with 40 ml of a 2N hydrochloric acid, twice with a saturated sodium bicarbonate solution and, then, with a saturated sodium chloride solution. The solution is dried over sodium sulfate, filtered and evaporated to dryness. The oil so obtained is chromatographed (elution with a 1/1 mixture of ethyl acetate/cyclohexane) and all of the fractions are collected. An amount of 2.7 g (63%) of N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-4-chloromandelamide is obtained as a diastereoisomeric mixture; m.p. about 170° C. (large interval of melting), pure enough for a further reaction. In this mixture, the (RS,SR) and (RR,SS) diastereoisomers are well detectable by chromatography; they are easily separable and obtainable in pure form.
Reaction SMILES: [OH:1][CH2:2][C@@:3]([C:6]1[CH:24]=[CH:23][C:9]([C:10]([NH:12][C:13]2[N:18]=[CH:17][C:16]3[CH:19]=[CH:20][N:21]([CH3:22])[C:15]=3[CH:14]=2)=[O:11])=[CH:8][CH:7]=1)([OH:5])[CH3:4].C1C(=O)N([Cl:32])C(=O)C1>CN(C=O)C>[Cl:32][C:19]1[C:16]2[CH:17]=[N:18][C:13]([NH:12][C:10](=[O:11])[C:9]3[CH:23]=[CH:24][C:6]([C@:3]([OH:5])([CH3:4])[CH2:2][OH:1])=[CH:7][CH:8]=3)=[CH:14][C:15]=2[N:21]([CH3:22])[CH:20]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1ccc2cnc(NC(=O)c3ccc([C@@](C)(O)CO)cc3)cc21
Solvent: CN(C)C=O
Product: Cn1cc(Cl)c2cnc(NC(=O)c3ccc([C@@](C)(O)CO)cc3)cc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 21.3 %

Procedure:
(R)-4-(1,2-dihydroxypropan-2-yl)-N-(1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)benzamide (750 mg, 2.3 mmol) was dissolved in DMF (20 ml) and NCS (310 mg, 2.3 mmol) was added to it. Stirring continued at 50° C. for 3 hours. The mixture was poured into 50 ml ice water and was extracted into ethyl acetate (3×100 ml). Combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by preparatory HPLC (TFA mode, 15-50% ACN in water). Fractions containing the desired mono chlorinated product were combined, concentrated, washed with saturated NaHCO3 and brine, and then extracted into ethyl acetate (2×100 ml). Combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the title compound (R)—N-(3-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide (18 mg, 0.49 mmol, 21%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (s, 3H) 3.45 (dd, J=5.81, 2.53 Hz, 2H) 3.78 (s, 2H) 4.74 (t, J=5.81 Hz, 1H) 5.03 (s, 1H) 7.46-7.69 (m, 2H) 8.01 (d, J=8.59 Hz, 2H) 8.34 (d, J=0.76 Hz, 1H) 8.59 (d, J=0.76 Hz, 1H) 10.64 (s, 1H); ESI-MS: m/z 360 (M+H)+; m.p. 210-212° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][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][CH2:2]1.Cl[C:35]([C@@H:37]([O:39]C(=O)C)[CH3:38])=[O:36]>>[OH:39][C@@H:37]([CH3:38])[C:35]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][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])[CH2:5][CH2:6]1)=[O:36]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: O=C(NCC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: C[C@H](O)C(=O)N1CCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (piperidin-4-ylmethyl)-amide (example A144) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1([S:7][CH2:8][C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]3[CH3:21])[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH3:32])=[O:30])=[CH:24][CH:23]=3)[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:41])C=1.[Mn]([O-])(=O)(=O)=O.[Na+].[OH2:50]>O1CCOCC1>[CH:1]1([S:7]([CH2:8][C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]3[CH3:21])[N:12]=[C:11]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:31][CH3:32])=[O:30])=[CH:26][CH:27]=3)[N:10]=2)(=[O:41])=[O:50])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O
Reactant: CNC(=O)Nc1ccc(-c2nc(CSC3CCCCC3)cc(N3CCOC[C@@H]3C)n2)cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CNC(=O)Nc1ccc(-c2nc(CS(=O)(=O)C3CCCCC3)cc(N3CCOC[C@@H]3C)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[4-[4-(Cyclohexylsulfanylmethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-methyl-urea (0.35 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). 3-chloroperbenzoic acid (75%) (121 mg) was added to the solution followed immediately by sodium permanganate (140 mg) and the reactions stirred at RT for 1 hour. Further 3-chloroperbenzoic acid (75%) (121 mg) and sodium permanganate (140 mg) were added and the reactions allowed to stir at RT for 1 hour. Further 3-chloroperbenzoic acid (75%) (121 mg) and sodium permanganate (140 mg) were added and the reactions allowed to stir at RT for another 1 hour then loaded onto a SCX-3 column. The column was washed with methanol and the desired material removed with 7N ammonia in methanol. The crude material was purified by prep-HPLC (basic) to give the desired material (74 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH3:38])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:19]=[C:18]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[CH:17]=[C:16]([O:25][CH2:26][CH2:27]SC)[CH:15]=3)[N:12]=2)[N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:6]=1)=[O:4].[S:40](=[O:43])(O)[O-:41].[Na+].[CH2:45](Cl)Cl>O.CC(C)=O.O=[Os](=O)(=O)=O>[CH3:45][S:40]([CH2:27][CH2:26][O:25][C:16]1[CH:15]=[C:14]([C:11]2[N:12]=[C:13]3[C:5]([C:3](=[O:4])[C:2]([CH3:1])([CH3:39])[CH3:38])=[CH:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:35])[CH3:36])[C:8]3=[N:9][CH:10]=2)[CH:19]=[C:18]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:17]=1)(=[O:43])=[O:41]
Reactant: CSCCOc1cc(-c2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)cc(N2CCCC2)c1
Reactant: ClCCl
Reactant: O=S([O-])O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cc(OCCS(C)(=O)=O)cc(N4CCCC4)c3)nc12

Procedure:
To a solution of 2,2-dimethyl-1-[2-[3-(2-methylsulfanyl-ethoxy)-5-pyrrolidin-1-yl-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one (82 mg, 0.14 mmol) in 20% water/acetone (3 ml) was added 4-methylmorpholine n-oxide (50 mg, 0.43 mmol) followed by addition of aqueous OsO4 solution (0.01 ml, catalytic). After 8 hours stirring a solution of 5% aqueous sodium bisulfite (25 ml) was added followed by CH2Cl2 (25 ml). The material was partitioned and the organic phase collected and then washed with brine (25 ml). The aqueous phases were back-extracted with methylene chloride (2×25 ml), the organic phases combined, dried (MgSO4), filtered and stripped to provide a crude remainder. The material was loaded onto 1 preparative TLC plate, eluting with 40% ethyl acetate in hexanes. The product band was collected to afford 75 mg of 1-[2-[3-(2-methanesulfonyl-ethoxy)-5-pyrrolidin-1-yl-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a yellow viscous oil.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:23])[CH:16]=2)[C@H:10]1[CH2:24][CH3:25])(C(C)(C)C)(C)C.CO.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:23][C:17]1[CH:16]=[C:15]([N:11]2[C:12](=[O:14])[CH2:13][C@@H:9]([OH:8])[C@@H:10]2[CH2:24][CH3:25])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: CC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@H]1[C@H](O)CC(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.5 %

Procedure:
To a solution of 4-[(2S,3R)-3-(tert-butyldimethylsilyloxy)-2-ethyl-5-oxopyrrolidin-1-yl]-2-chlorobenzonitrile (366 mg) in tetrahydrofuran (5 mL)-methanol (5 mL) was added 6 mol/L hydrochloric acid (5 mL), and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=10/1→1/3) to give the title compound as a colorless solid (yield: 221.2 mg, 87%).
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=O)[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[F:22])[N:18]=[C:17]([CH3:23])[CH:16]=[CH:15]2.C(OC(=O)C)(=O)C>C1(C)C(C)=CC=CC=1>[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[F:22])[N:18]=[C:17]([CH:23]=[CH:5][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[CH:1]=[O:10])[CH:16]=[CH:15]2
Reactant: Cc1ccc2cc(F)c(F)cc2n1
Reactant: O=Cc1cccc(C=O)c1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1C
Product: O=Cc1cccc(C=Cc2ccc3cc(F)c(F)cc3n2)c1
Yield: 59429.1 %

Procedure:
A solution of isophthalaldehyde (312.4 g, 2.33 mmol), 6,7-difluoro-2-methylquinoline (278.4 g, 1.55 mmol) and acetic anhydride (416 mL) in 2 L of xylene was heated to reflux overnight. The solvent was evaporated and the product was swished in 2.5 L of EtOAc to yield the title compound (272 g, 56%). 1H NMR (CD3COCD3): δ 10.12 (1H, s), 8.4 (1H, d), 8.29 (1H, s), 8.1-7.85 (6H, m), 7.7-7.55 (2H, m).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C-:16]#[N:17].[K+]>>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:16]#[N:17])[CH2:12][CH2:11]1
Reactant: O=Cc1ccccn1
Reactant: CN1CCNCC1
Reactant: [C-]#N
Agent: [K+]
Product: CN1CCN(C(C#N)c2ccccn2)CC1

Procedure:
By the procedure of Example 23, 2-pyridinecarboxaldehyde is reacted with N-methylpiperazine and potassium cyanide to give 2-(4-methylpiperazino)-2-(2-pyridyl)acetonitrile.