Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-])=O)=[C:7]([CH:10]=1)[CH:8]=[O:9].CC([O-])=O.[Na+].CCN(C(C)C)C(C)C.[C:28]([O:31][CH2:32][C:33](Cl)=[O:34])(=[O:30])[CH3:29]>CCOC(C)=O.O=[Pt]=O>[C:28]([O:31][CH2:32][C:33]([NH:11][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:10][C:7]=1[CH:8]=[O:9])=[O:34])(=[O:30])[CH3:29]
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: O=[Pt]=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)COC(C)=O)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.8 %

Procedure:
To the solution of 5-methoxy-2-nitrobenzaldehyde (6 g, 0.33 mol) in EtOAc (100 mL) was added 20% PtO2/C (1.2 g, 20%) and NaOAc (1.2 g, 20%). The reaction was stirred under hydrogen at room temperature for 0.5 h. The mixture was filtered through a Celite pad, and the filtrate was dried over anhydrous Na2SO4. After filtration, the solution was cooled to −78° C., and to which was added DIPEA (6.4 g, 0.5 mol, 1.5 eq) and 2-chloro-2-oxoethyl acetate (4.5 g, 0.33 mol, 1.0 eq). The resulting mixture was gradually warmed up to room temperature and stirred overnight. The reaction mixture was washed with water twice, dried over Na2SO4 and evaporated most of the solvent in vacuum. Then the solid separating out was collected by filtration to give 2-(2-formyl-4-methoxyphenylamino)-2-oxoethyl acetate (5.6 g, yield: 71%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[CH2:3].S(Cl)([Cl:11])=O.O>C(Cl)Cl>[Cl:11][C:2]([CH3:1])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: C=C(C)CC(C)(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)CC(C)(C)Cl
Temperature: -30 °C
Yield: 85 %

Procedure:
15 ml of 2,4,4-trimethyl-pentene-1 are dissolved in 150 ml of CH2Cl2, cooled to -30° C. and mixed dropwise with a mixture of 10.3 ml of thionyl chloride and 5.4 ml of H2O. The mixture is then heated to 0° C. and washed after 2.5 hours with cold 1% aqueous K2CO3 solution, then with ice-cold water. The product is dried over MgSO4 and distilled off. Yield 85%; nD20 =1.4308; Bpt.10 mm 38° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][NH:6][C:7]([CH:9]1[CH2:12][N:11]([C:13]2[S:14][CH2:15][C:16](=[O:18])[N:17]=2)[CH2:10]1)=[O:8].[F:20][C:21]([F:45])([F:44])[C:22]1[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][C:23]=1[CH2:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([CH:34]=O)=[CH:31][CH:32]=2)[CH:27]=[N:26]1>>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][NH:6][C:7]([CH:9]1[CH2:10][N:11]([C:13]2[S:14][C:15](=[CH:34][C:30]3[CH:29]=[C:28]4[C:33](=[CH:32][CH:31]=3)[N:25]([CH2:24][C:23]3[CH:36]=[CH:37][C:38]([C:40]([F:43])([F:42])[F:41])=[CH:39][C:22]=3[C:21]([F:45])([F:20])[F:44])[N:26]=[CH:27]4)[C:16](=[O:18])[N:17]=2)[CH2:12]1)=[O:8]
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Reactant: COC(=O)CCNC(=O)C1CN(C2=NC(=O)CS2)C1
Product: COC(=O)CCNC(=O)C1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C1

Procedure:
3-[(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carbonyl)-amino]-propionic acid methyl ester was prepared from 3-{[1-(4-oxo-4,5-dihydro-thiazol-2-yl)-azetidine-3-carbonyl]-amino}-propionic acid methyl ester and 1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde following General Procedure D.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:9](=[O:16])[NH:10][C:11](SC)=[N:12][CH:13]=2)[CH:2]=1.[CH3:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH2:23][S:24][CH2:25][CH2:26][CH2:27][NH2:28]>>[CH3:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH2:23][S:24][CH2:25][CH2:26][CH2:27][NH:28][C:11]1[NH:10][C:9](=[O:16])[C:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:13][N:12]=1
Reactant: CSc1ncc(Cc2cccnc2)c(=O)[nH]1
Reactant: Cc1[nH]cnc1CSCCCN
Product: Cc1[nH]cnc1CSCCCNc1ncc(Cc2cccnc2)c(=O)[nH]1

Procedure:
An intimate mixture of 5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone and 3-(5-methyl-4-imidazolylmethylthio)propylamine is heated at 130°-135° for 7 hours. The cool mixture is triturated with hot water and treated with dilute ethanolic HCl to give the trihydrochloride of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[NH:29]1[CH2:33][CH2:32][C@H:31]([CH2:34][OH:35])[CH2:30]1>>[CH3:28][N:4]1[C:3]([CH2:2][N:29]2[CH2:33][CH2:32][C@H:31]([CH2:34][OH:35])[CH2:30]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: OC[C@H]1CCNC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC[C@H](CO)C3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with (S)-pyrrolidin-3-ylmethanol via General Procedure E to give 18.8 mg of 305 following reverse phase purification. MS (Q1) 463.2 (M)+
Reaction SMILES: C([NH+]([CH2:6][CH3:7])CC)C.[C:8]12(C(Cl)=O)C[CH:12]3[CH2:13][CH:14](C[CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2>C(#N)C.N1C=CC=CC=1>[CH3:14][CH2:15][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:6][CH3:7]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CC[NH+](CC)CC
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCCCCCCC

Procedure:
The dimethoxytrityl group of the derivatized CPG from Example 9 is removed by a treatment with 2% dichloroacetic acid followed by washing with dry acetonitrile. The CPG is washed with acetonitrile-pyridine (1:1) followed by a simultaneous treatment of the CPG with 10 to 30 equivalents of the 10-O-(dimethoxytrityl)decyl-phosphonic acid as the triethylammonium salt, 20-30 equivalents of adamantane carbonyl chloride in acetonitrile-pyridine. The CPG is then washed with acetonitrile-pyridine and then treated with diisopropyl phosphite adamantane carbonyl chloride (0.2M) to cap all unreacted hydroxyl groups. Finally, the CPG is washed with acetonitrile/pyridine 1:1 and then acetonitrile. An estimate of coupling efficiency is derived from the treatment of the CPG with dichloracetic acid in acetonitrile followed by a measurement of the absorbance of an aliquot at 498 nm. Repeating the above procedure n times will yield an oligomer with n+1 decane units and n H-phosphonate linkages. The oligomer is tethered to a LCAA CPG by a succinate group as described above.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:9]2)=[CH:6][N:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(-c2nc(C3CCCNC3)cnc2N)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc(C3CCCN(S(C)(=O)=O)C3)cnc2N)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of crude methyl 4-(3-amino-6-(piperidin-3-yl)pyrazin-2-yl)-2-fluorobenzoate (38 mg, 0.114 mmol) in DCM (2 mL) in an ice bath was added DIEA (79 μL, 0.454 mmol) followed by methanesulfonyl chloride (9.73 μL, 0.125 mmol). The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was partitioned between DCM and water. The DCM layer was separated and washed with brine. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude product (50% purity) was proceeded to next step. LCMS (m/z): 409.1 (MH+), 0.721 min.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][C:9]1[C@H:10]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:12]([O:15][CH2:16][CH3:17])[CH2:13][N:14]=1)[CH3:7].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>O1CCCC1.C(OCC)C>[CH2:6]([O:8][C:9]1[C@H:10]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:12]([O:15][CH2:16][CH3:17])[C@@H:13]([CH2:25][CH2:24][CH2:23][CH2:22][Br:21])[N:14]=1)[CH3:7]
Reactant: CCOC1=N[C@@H](C(C)C)C(OCC)=NC1
Reactant: BrCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC1=N[C@H](CCCCBr)C(OCC)=N[C@H]1C(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 52.5 %

Procedure:
n-butyllithium (13.3 mL of a 1.6 M solution in hexanes,21.3 mmol) was added to a solution of (2S)-2,5-dihydro-3,6-diethoxy-2-isopropyl pyrazine (Schöllkopf reagent)(4.30 g, 20.3 mmol) in tetrahydrofuran (THF) over the course of five minutes. The solution was maintained at −78° C. for 15 minutes after which 1,4-dibromobutane (9.75 mL, 81.2 mmol) was added in a single portion. After 2.5 hours at −78° C. the reaction was allowed to warm to room temperature and diluted with diethyl ether (100 mL). The organic phase was washed with water (100 mL), brine (100 mL) and then dried with magnesium sulfate (MgSO4). Following filtration and concentration most of the residual 1,4-dibromobutane was removed under high vacuum. The remaining oil was purified by silica gel chromatography (2% ethyl acetate in hexanes) to provide 5 (3.7 g, 57%) as a colorless liquid;[α]25D−1.13° (c=4.5, CHCl3); IR (thin film) 2957, 1689, 1456, 1364, 1304, 1230, 1144, 1038 cm−1; 1H NMR(300 MHz, CDCl3) δ4.04-4.18 (m, 4H) 3.94-4.02 (m, 1H) 3.90 (t, J=3.9, 1H) 3.39 (t, J=6.9, 2H) 2.21-2.32 (m, 1H) 1.68-1.92 (m, 4H) 1.33-1.47 (m, 2H) 1.274 (t, J=7.2, 3H) 1.268 (t, J=7.2, 3H) 1.03 (d, J=6.9, 3H) 0.70 (d, J=6.9, 3H); 13C NMR (100.6 MHz, CDCl3) d 163.12, 163.05, 60.72, 60.48, 55.09, 33.60, 33.11, 32.66, 31.80, 23.22, 19.03, 16.6, 14.34, 14.31; Mass Spectrum (FAB+) 347.1 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH:11]=[C:10]([CH2:13][C:14]([NH2:16])=[O:15])[C:9]=2[CH:17]=1)[CH3:3].C[O:19][C:20](=O)[C:21]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=O.CC([O-])(C)C.[K+]>C1COCC1>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH:11]=[C:10]([C:13]3[C:14](=[O:15])[NH:16][C:20](=[O:19])[C:21]=3[C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][CH:24]=3)[C:9]=2[CH:17]=1)[CH3:3]
Reactant: COC(=O)C(=O)c1c[nH]c2ccccc12
Reactant: CN(C)Cc1ccc2occ(CC(N)=O)c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)Cc1ccc2occ(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
To a solution of 2-(5-dimethylaminomethyl-benzofuran-3-yl)-acetamide (91 mg, 0.39 mmol) and (1H-indol-3-yl)-oxo-acetic acid methyl ester (119 mg, 0.59 mmol) in anhydrous THF (5.0 mL) is added dropwise a 1 M solution of t-BuOK in THF (1.6 mL) under an argon atmosphere at 0° C. The resulting deep red reaction mixture is stirred for 5 min. at 0° C. and 30 min. at room temperature followed by partitioning between brine and EtOAc. The layers are separated and the aqueous layer is extracted twice with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated at reduced pressure to afford an orange solid. Purification by flash column chromatography (silica gel, EtOAc/acetic acid/water 7:1:1) affords the title compound as an orange solid (91.4 mg, 0.237 mmol, 63%). 1H NMR (400 MHz, DMSO-d6, 298 K): δ=11.90 (bs, 1H), 11.06 (bs, 1H), 8.28 (s, 1H), 7.89 (s, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.94 (t, J=8.2 Hz, 1H), 6.82 (d, J=8.1 Hz, 1H), 6.63 (d, J=8.2 Hz, 1H), 6.60 (s,1H), 2.98 (s, 2H), 1.69 (s, 6H). MS (ES+): 386 (M(C23H19N3O3)+H)+.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:19][NH2:20]>C(O)C>[CH:1]1([C:7]2[C:9]3[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11](=[O:12])[NH:20][N:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: O=C(O)c1ccccc1C(=O)C1CCCCC1
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(C2CCCCC2)c2ccccc12
Yield: 63.6 %

Procedure:
12.0 g of o-(cyclohexanoyl) benzoic acid and 3.1 g of hydrazine hydrate were dissolved in 60 ml of ethanol, and the solution was refluxed for 4 hours. Ethanol was distilled off and the remaining solution was crystallized by adding ether, thereby obtaining 7.5 g of 4-cyclohexyl-1-phthalazinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[C:12]([NH2:13])=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1.[CH2:16]=O.C[O-].[Na+].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([NH:13][CH3:16])=[N:11][N:10]=[N:9]2)=[CH:14][CH:15]=1
Reactant: C=O
Reactant: COc1ccc(Cn2nnnc2N)cc1
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNc1nnnn1Cc1ccc(OC)cc1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
Next, to a suspension of 1-(4-methoxy-benzyl)-1H-tetrazol-5-ylamine (600 mg, 2.92 mmol) in MeOH (10 mL) were added paraformaldehyde (132 mg, 4.39 mmol) and sodium methoxide (632 mg, 25 wt % in MeOH). The mixture was refluxed for 30 min until the suspension turned into a clear solution. The mixture was cooled to room temperature and sodium borohydride (332 mg, 8.77 mmol) was added portionwise. The reaction mixture was refluxed again for 15 min. After cooled to room temperature, the reaction was quenched with H2O. The mixture was diluted with EtOAc, partially concentrated, and washed with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 10% MeOH in DCM) to give [1-(4-methoxy-benzyl)-1H-tetrazol-5-yl]-methyl-amine (0.63 g). 1H NMR (400 MHz, CDCl3) δ 3.00 (d, 3H, J=5.3 Hz), 3.61 (bs, 1H), 3.82 (s, 3H), 5.25 (s, 2H), 6.91 (d, 2H, J=8.8 Hz), 7.16 (d, 2H, J=8.8 Hz); MS: m/z (MH+) 220.
Reaction SMILES: [CH2:1]([C@H:4]1[C@@H:8]([OH:9])[CH2:7][O:6][C:5]1=[O:10])[CH:2]=[CH2:3].N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C)C=O>[CH2:1]([C@H:4]1[C@@H:8]([O:9][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:7][O:6][C:5]1=[O:10])[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1C(=O)OC[C@@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CC[C@@H]1C(=O)OC[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
The hydroxy lactone of Example 8 (6.0 g, 42.2 mmol) was dissolved in dry dimethylformamide (10 ml) under nitrogen. Imidazole (4.78 g, 70.2 mmol) and then tert-butyldimethylsilyl chloride (7.05 g, 46.80 mmol) were added. The mixture was stirred at room temperature overnight and then partitioned between water (50 ml) and heptane (2×30 ml). The heptane extracts were dried (MgSO4), filtered and evaporated to give the crude product (10.5 g). This was crystallised from heptane (40 ml) at −15° C. to give the title compound as a white solid (7.60 g, 29.6 mmol, 70%); m.p. 48° C. (onset by DSC); Found: C, 61.1; H, 9.5. C13H24O3Si requires C, 60.9; H, 9.4%; vmax (Nujol) 1763 and 1644 cm−1; [α] +88.0° (c=1.0, CH2Cl2); 1HNMR(400 MHz, CDCl3) δ ppm5.94-5.80 (1 H, m), 5.18-5.06(2 H, m), 4.53 (1 H, t, J 3.5), 4.26 (1 H, dd, J 10,3), 4.17 (1 H, d, J 10), 2.60-2.35 (3 H, m), 0.89 (9 H, s), 0.10 (3 H, s) and 0.08 (3 H, s); m/z (GCMS, EI) 199 (M-tBu, 4%) and 117 (100).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[C:4]([CH2:11][CH2:12][C:13]([OH:15])=O)[C:3]1=2.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[N:35]1([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>ClCCl>[C:44]([O:43][C:41]([N:35]1[CH2:40][CH2:39][N:38]([C:13](=[O:15])[CH2:12][CH2:11][C:4]2[C:3]3[C:2](=[O:1])[CH2:10][CH2:9][CH2:8][C:7]=3[NH:6][CH:5]=2)[CH2:37][CH2:36]1)=[O:42])([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)CCc1c[nH]c2c1C(=O)CCC2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCc2c[nH]c3c2C(=O)CCC3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 118.5 %

Procedure:
3-(4-Oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (2.07 g, 10 mmol), prepared as described in Example 1 above, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-hydrochloide (2.3 g, 12 mmol), anhydrous 1-hydroxybenzotriazole (1.62 g, 12 mmol) and N,N-diisopropylethylamine (1.75 ml, 10 mmol) were mixed together in 50 ml of dichloromethane and stirred for one hour at room temperature. Tert-butyl 1-piperazinecarboxylate (2.24 g, 12 mmol) was added to the mixture and stirred at room temperature overnight. The reaction mixture was concentrated and the syrup was dissolved in dichloromethane then purified by flash chromatography, eluting with dichloromethane followed by (dichloromethane: methanol 50/1, 30/1) to give 4-[3-(4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionyl]-piperazine-1-carboxylic acid tert-butyl ester (4.45 g, 86% pure).
Reaction SMILES: [Cl:1][C:2]1[C:7](=O)[NH:6][CH:5]=[C:4]([C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:3]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[N:6][C:7]=1[Cl:19]
Reactant: COC(=O)CCC(=O)c1c[nH]c(=O)c(Cl)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)CCC(=O)c1cnc(Cl)c(Cl)c1
Temperature: 75 °C

Procedure:
A suspension of 37 g (152 mmol) of methyl 4-(5-chloro-1,6-dihydro-6-oxopyridin-3-yl)-4-oxobutyrate in 230 ml of phosphorus oxychloride was heated at 75° C. for 25 hours. The phosphorus oxychloride was subsequently distilled off in vacuo. The pale red residue was taken up in 200 ml of dichloromethane, 100 ml of water was added, and the pH of the aqueous phase was brought to 8.5 using 30 percent sodium hydroxide solution. After phase separation, the aqueous phase was extracted using 100 ml of dichloromethane. The combined organic phases were treated with active charcoal and evaporated. The residue was recrystallized from 300 ml of diisopropyl ether and filtered at 2° C. The yield was 32.83 g of pale pink crystals. A further 1.76 g of product was obtained from the mother liquor in the form of crystals. The total product yield was 87 percent. The melting point of the product was 85.2° to 86° C. Other data concerning the product was:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.B(O)(O)[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.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>[Cl:8][C:7]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: Cc1ccc(B(O)O)cc1
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: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2ncccc2Cl)cc1
Yield: 87 %

Procedure:
{circle around (2)} 100 g (0.676 mol) of 2,3-dichloropyridine was dissolved in 500 mL of ethanol, and 91.87 g (0.676 mol) of p-tolylboronic acid and 78 g (0.0676 mol) of Pd(PPh3)4 were sequentially added. A solution of 86 g (0.811 mol) of sodium carbonate in 500 mL of distilled water was placed in the reactor, and the mixture was heated to reflux for 4˜6 hours so as to allow it to react. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove ethanol, and then extracted with ethyl acetate. The extract was treated with magnesium sulfate, filtered, and concentrated under reduced pressure, yielding 3-chloro-2-para-tolylpyridine as represented below in a 87% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Br:12]N1C(=O)CCC1=O>C(#N)C>[Br:12][C:9]1[CH:10]=[C:2]([F:1])[CH:3]=[C:4]2[C:8]=1[NH:7][C:6](=[O:11])[CH2:5]2
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: O=C1Cc2cc(F)cc(Br)c2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A suspension of 5-fluoro-1,3-dihydro-indol-2-one (1.5 g, 10 mmol) in 15 ml of acetonitrile and N-bromosuccinimide (1.8 g, 10 mmol) was stirred at room temperature overnight until the precipitate was formed. The solid was filtered, washed with ethanol (5 ml) and dried in vacuo to give 7-bromo-5-fluoro-1,3-dihydro-indol-2-one (1.6 g, 69.6%) as a white solid.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][N:21]=1>C(OCC)(=O)C>[Br:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[N:21]=1
Reactant: C1=COCCC1
Reactant: Brc1n[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1nn(C2CCCCO2)c2ccccc12
Yield: 98.1 %

Procedure:
3,4-Dihydro-2H-pyran (0.232 mL, 2.54 mmol) and p-toluenesulfonic acid monohydrate (0.024 g, 0.127 mmol) were added to a solution of 3-bromo-1H-indazole (0.250 g, 1.269 mmol) in ethyl acetate (12.0 ml), and the mixture was heated at reflux for 48 h. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column. gradient elution with 0-25% ethyl acetate-hexane) to afford 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.350 g, 98%) as a colorless oil. MS (ESI, pos. ion) m/z 281, 283 [M+H]+.
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1)=[O:5].[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>ClCCl>[N:13]1([CH2:3][C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=2)=[O:5])[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: c1c[nH]cn1
Reactant: O=C(CBr)c1ccc(Cl)cn1
Agent: Br
Solvent: ClCCl
Product: O=C(Cn1ccnc1)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
15 g of 2-bromoacetyl-5-chloropyridine hydrobromide are dissolved in 50 ml of dry dichloromethane, 9.7 g of imidazole are added and the mixture is stirred for 24 hours at room temperature. Evaporation of the solvent in vacuo and subsequent chromatography of the residue over silicagel (dichloromethane/methanol/heptane=7/1/4) yield the compound as a cream coloured solid; m.p.: 122°-129°.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[F:41][C:42]1[CH:43]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:48]([C:44]2[CH:45]=[CH:46][CH:47]=[C:42]([F:41])[CH:43]=2)(=[O:50])=[O:49])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2cccc(F)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.6 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) was added a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (323 mg) in tetrahydrofuran (5 mL) at 0° C., 15-crown-5 (330 mg) and 3-fluorobenzenesulfonyl chloride (292 mg) were added at the same temperature. The mixture was stirred at room temperature for 30 min, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous is sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:1→3:1) to give the title compound as a colorless oil (yield 527 mg, quantitative).