Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[N:12]=[N:11][C:10]([C:13]2([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([CH2:25][NH:26][C:27]([N:29]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[C:31]5([CH2:41][CH2:40][CH2:39][CH2:38]5)[C:30]4=[O:42])=[O:28])[CH2:21][CH2:20]3)[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[O:42]=[C:30]1[C:31]2([CH2:38][CH2:39][CH2:40][CH2:41]2)[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]1[C:27]([NH:26][CH2:25][CH:22]1[CH2:23][CH2:24][N:19]([CH2:18][C:13]2([C:10]3[N:9]=[N:8][NH:12][N:11]=3)[CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:20][CH2:21]1)=[O:28]
Reactant: O=C(NCC1CCN(CC2(c3nnn(Cc4ccccc4)n3)CCCC2)CC1)N1C(=O)C2(CCCC2)c2ccccc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C(NCC1CCN(CC2(c3nn[nH]n3)CCCC2)CC1)N1C(=O)C2(CCCC2)c2ccccc21
Reaction time: 8 h
Yield: 79.8 %

Procedure:
A mixture of N-[(1-{[1-(2-benzyl-2H-tetrazol-5-yl)cyclopentyl]methyl}piperidin-4-yl)methyl]-2′-oxospiro[cyclopentane-1,3′-indole]-1′(2′H)-carboxamide (120 mg, 0.21 mmol, step 6 of Example 14) and palladium hydroxide (20 mg, 20 wt. % palladium on carbon) in methanol (10 mL) was stirred for 8 h under H2 atmosphere. The mixture was filtered through a pad of Celite, and washed with methanol and the filtrate was concentrated to give a clear colorless oil. The residue was chromatographed on a column of silica gel eluting with CH2Cl2/methanol (16:1) to give 80 mg (80%) of the title compound as a white solid. The solid was triturated with ethyl acetate/hexane and collected by filtration to give 72 mg (72%) of the title compound as a white solid.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:20]([CH3:26])[CH2:21][C:22]([O:24]C)=[O:23])[CH:17]=3)[CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C>[C:1]1([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:20]([CH3:26])[CH2:21][C:22]([OH:24])=[O:23])[CH:17]=3)[CH2:12]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CC(C)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Solvent: CCO
Product: CC(CC(=O)O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Reaction time: 1 h

Procedure:
2.4 g of methyl 3-(2-benzenesulphonamido-indan-5-yl)-butyrate are dissolved in 10 ml of ethanol, 2 ml of 15N sodium hydroxide solution are added, and saponification is carried out by boiling for 1 hour.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:44])=[C:9]([CH2:11][O:12][C:13]2[CH:41]=[CH:40][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[P:26](=[O:33])([O:30]CC)[O:27]CC)=[CH:22][N:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:20]=3)=[CH:15][C:14]=2[O:42][CH3:43])[N:10]=1.C(#N)C.C[Si](Br)(C)C>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:44])=[C:9]([CH2:11][O:12][C:13]2[CH:41]=[CH:40][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[P:26](=[O:27])([OH:33])[OH:30])=[CH:22][N:21]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:20]=3)=[CH:15][C:14]=2[O:42][CH3:43])[N:10]=1
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/P(=O)(O)O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a mixture of diethyl (E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate (0.40 g) and acetonitrile (20 mL) was added trimethylsilyl bromide (0.40 g) at room temperature. After stirring the reaction mixture at room temperature for 1 hr, trimethylsilyl bromide (0.30 g) was added again, and the mixture was further stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give (E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonic acid as pale-yellow crystals (0.28 g, yield 76%). Recrystallization from tetrahydrofuran-hexane gave pale-yellow prism crystals. melting point: 138-140° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Br[C:49]1[CH:61]=[CH:60][C:52]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[C:51]([NH:62][C:63]([C:65]2[CH:66]=[N:67][CH:68]=[C:69]([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)[CH:70]=2)=[O:64])[CH:50]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[NH:7]([C:49]1[CH:61]=[CH:60][C:52]([C:53]([O:55][C:56]([CH3:58])([CH3:57])[CH3:59])=[O:54])=[C:51]([NH:62][C:63]([C:65]2[CH:66]=[N:67][CH:68]=[C:69]([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)[CH:70]=2)=[O:64])[CH:50]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1cncc(-c2ccccc2)c1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(Nc2ccccc2)cc1NC(=O)c1cncc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
Cesium carbonate (0.14 g), aniline (0.030 mL), tris(dibenzylideneacetone)dipalladium(0) (2 mg), palladium(II) acetate (1 mg), and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (5 mg) were added to a toluene (2.5 mL) solution of tert-butyl 4-bromo-2-(5-phenylpyridine-3-carboxamido)benzoate (0.10 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour and 10 minutes. The reaction mixture was cooled to room temperature, and then ethyl acetate and a 10% aqueous solution of citric acid were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 91-80% hexane/ethyl acetate] to obtain tert-butyl 4-anilino-2-(5-phenylpyridine-3-carboxamido)benzoate.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH3:27])[C:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[O:25][CH3:26])=[N+:11]([O-])[CH:12]=1)[CH2:4][CH3:5])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].O=P(Cl)(Cl)[Cl:36]>>[Cl:36][C:12]1[C:7]([O:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:8][C:9]([CH3:27])=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[O:25][CH3:26])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC(CC)Oc1cc(C)c(-c2ccc(OC(F)(F)F)cc2OC)[n+]([O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCC(CC)Oc1cc(C)c(-c2ccc(OC(F)(F)F)cc2OC)nc1Cl
Temperature: 25 °C

Procedure:
A solution of compound 44 (340 mg, 0.88 mmol) in POCl3 (0.4 ml) is stirred at 65° C. for 1 hour, then cooled to room temperature and poured onto ice (10 g). The resulting solution is neutralized with Na2CO3, and extracted with 50% EtOAc in hexane. The combined extracts are washed with water, brine, dried, filtered and evaporated. The crude product is purified by chromatography (eluted with 6% EtOAc in hexane) to give the product as a white crystalline solid. 1H NMR (CDCl3) δ 1.01 (t, J=7.6 Hz, 6H), 1.76 (m, 4H), 2.12 (s, 3H), 3.78 (s, 3H), 4.19 (m, 1H), 6.78 (s, 1H), 6.89 (dd, 1H), 7.05 (s, 1H), 7.26 (s, 1H), 7.27 (d, J=8.4 Hz, 1H). LCMS 404.27 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[C:11]1[C:12]2[NH:16][C:15]([C:17]([C:55]3[C:60]([O:61]C)=[CH:59][CH:58]=[CH:57][C:56]=3[O:63]C)=[C:18]3[N:54]=[C:21]([C:22]([C:44]4[C:49]([O:50]C)=[CH:48][CH:47]=[CH:46][C:45]=4[O:52]C)=[C:23]4[NH:43][C:26](=[C:27]([C:33]5[C:38]([O:39]C)=[CH:37][CH:36]=[CH:35][C:34]=5[O:41]C)[C:28]5[CH:29]=[CH:30][C:31]=1[N:32]=5)[CH:25]=[CH:24]4)[CH:20]=[CH:19]3)=[CH:14][CH:13]=2.B(Br)(Br)Br.C(OCC)(=O)C>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[C:4]=1[C:11]1[C:12]2[NH:16][C:15]([C:17]([C:55]3[C:56]([OH:63])=[CH:57][CH:58]=[CH:59][C:60]=3[OH:61])=[C:18]3[N:54]=[C:21]([C:22]([C:44]4[C:49]([OH:50])=[CH:48][CH:47]=[CH:46][C:45]=4[OH:52])=[C:23]4[NH:43][C:26](=[C:27]([C:33]5[C:34]([OH:41])=[CH:35][CH:36]=[CH:37][C:38]=5[OH:39])[C:28]5[CH:29]=[CH:30][C:31]=1[N:32]=5)[CH:25]=[CH:24]4)[CH:20]=[CH:19]3)=[CH:14][CH:13]=2
Reactant: COc1cccc(OC)c1-c1c2nc(c(-c3c(OC)cccc3OC)c3ccc([nH]3)c(-c3c(OC)cccc3OC)c3nc(c(-c4c(OC)cccc4OC)c4ccc1[nH]4)C=C3)C=C2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Oc1cccc(O)c1-c1c2nc(c(-c3c(O)cccc3O)c3ccc([nH]3)c(-c3c(O)cccc3O)c3nc(c(-c4c(O)cccc4O)c4ccc1[nH]4)C=C3)C=C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.9 %

Procedure:
To a solution of porphyrin 1 (400 mg, 0.47 mmol) in dry dichloromethane (25 mL) at −20° C. was added BBr3 (451 μL, 4.68 mmol). The resulting green solution was stirred for 12 hours at room temperature, then placed in ice water, ethyl acetate was added to the suspension and the mixture was washed with NaHCO3. The organic layer was separated, washed twice with water and then dried over anhydrous Na2SO4. The resulting solution was evaporated. The residue was purified by column chromatography (silica gel, 20:1 ethyl acetate/methanol) to yield porphyrin 2 as a purple powder (300 mg, 87%). 1H NMR (400 MHz, MeOD): δ 8.81 (s, 8H), 7.38 (t, J=8 Hz, 4H), 6.72 (d, J=8 Hz, 8H). HRESI-MS ([M+H]+) calcd for C44H31N4O8 743.2436, found 743.2136.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]([OH:14])=O)=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH2:56][CH2:57][C:58]1[CH:59]=[C:60]([OH:64])[CH:61]=[CH:62][CH:63]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12](=[O:14])[NH:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([OH:64])[CH:59]=2)=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4]
Reactant: CCc1cc(C(=O)O)sc1C(=O)OC
Reactant: NCc1cccc(O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)NCc2cccc(O)c2)sc1C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.5 %

Procedure:
To a solution of 3-Ethyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (250 mg, 1.17 mmol) in anhydrous DMF (10 mL) was added triethylamine (0.50 mL, 3.51 mmol), HBTU (0.67 g, 1.76 mmol), HOBT (190 mg, 1.40 mmol), and 3-Aminomethyl phenol (160 mg, 1.29 mmol). The mixture was stirred at room temperature 2 d, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-50% EtOAc in hexane to afford the desired product (0.140 g, 38% yield).
Reaction SMILES: [OH:1][C:2]1([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][CH2:3]1.[C:18](=O)(OCCCC)[O:19]CCCC.[Na].C(O)CCC>C1C=CC=CC=1>[CH:15]([N:14]1[CH2:13][C:2]2([CH2:8][O:7][C:6]3[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=3[O:4][CH2:3]2)[O:1][C:18]1=[O:19])([CH3:17])[CH3:16]
Reactant: CCCCOC(=O)OCCCC
Reactant: CC(C)NCC1(O)COc2ccccc2OC1
Agent: [Na]
Solvent: c1ccccc1
Solvent: CCCCO
Product: CC(C)N1CC2(COc3ccccc3OC2)OC1=O

Procedure:
A mixture of 3-hydroxy-3-isopropylaminomethyl-3,4-dihydro-2H-1,5-benzodioxepin (11.85 g.; 50 millimoles), prepared as described in Example 1, and dibutyl carbonate (13.1 g.) with a small piece of metallic sodium is heated in an oil bath. The temperature then is slowly raised to 170° C. with removal of butanol. Finally, the mixture is heated between 170°-200° C. with removal of excess dibutyl carbonate. The cooled reaction product is dissolved in benzene, washed with water, dried over sodium sulfate, and the solvent evaporated to give 3'-isopropyl-3,4-dihydro-2H-1,5-benzodioxepin-3-spiro-5'-oxazolidin-2'-one, m.p. 121°-122° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:11]=[CH:10][NH:9][C:5]2=[N:6][C:7]=1[CH3:8].C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:11]=[CH:10][NH:9][C:5]2=[N+:6]([O-:20])[C:7]=1[CH3:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nc2[nH]cnc2cc1Br
Solvent: ClCCl
Product: Cc1c(Br)cc2nc[nH]c2[n+]1[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-bromo-5-methyl-3H-imidazo[4,5-b]pyridine (1.00 equivalent) (Graboyes et al J. Am. Chem. Soc. 1957, 79, 6421-6426) in CH2Cl2 is added m-CPBA (1.50 equivalents). The resulting solution is stirred at room temperature for 16 hours. The precipitate is filtered off, washed with ether, and dried in vacuo to afford the desired product. The product is purified by re-crystallization if further purification is necessary.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:14]2[C:15]([NH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=3)=[N:16][S:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([NH:5][S:6]([C:9]1[C:14]2[C:15]([NH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:24]3[CH:29]=[CH:28][C:27]([C:37]4[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=4)=[CH:26][CH:25]=3)=[O:31])=[N:16][S:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc2snc(NCCCNC(=O)c3ccc(I)cc3)c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2ccc(C(=O)NCCCNc3nsc4cccc(S(=O)(=O)NC(C)(C)C)c34)cc2)cc1
Yield: 44.2 %

Procedure:
A mixture of N-(3-(4-(N-tert-butylsulfamoyl)benzo[d]isothiazol-3-ylamino)propyl)-4-iodobenzamide (50 mg, 0.09 mmol), 4-methoxyphenylboronic acid (14 mg, 0.09 mmol), tetrabutylammonium bromide (29 mg, 0.09 mmol), sodium carbonate (29 mg, 0.27 mmol) and palladium (II) acetate (1 mg) in water (3 mL) was microwaved at 160° C. for 5 min. The reaction was diluted with methylene chloride and the mixture was washed successively with aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with 98:2 methylene chloride:methanol yielded N-(3-(4-(N-tert-Butylsulfamoyl)benzo[d]isothiazol-3-ylamino)propyl)-4′-methoxybiphenyl-4-carboxamide (22 mg), as a white solid. 1H NMR (300 MHz, DMSO-d6)-8.53 (t, 1H), 8.32 (d, 1H), 7.98 (d, 1H), 7.88-7.92 (m, 2H), 7.51-7.70 (m, 5H), 7.00 (d, 2H), 3.80 (s, 3H), 3.38-3.51 (m, 4H), 1.93 (t, 2H), 1.10 ppm (s, 9H). MW=553 confirmed by LC-MS, tr=4.18 min (Method B) MH+=554.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:18]3[C:13](=[C:14]([O:19]CC4C=CC=CC=4)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:19])[C:13]=3[CH:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(-n2ncc3c(OCc4ccccc4)cccc32)cc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-n2ncc3c(O)cccc32)cc1Cl
Temperature: -78 °C
Yield: 10.4 %

Procedure:
1-[3-Chloro-4-(methyloxy)phenyl]-4-[(phenylmethyl)oxy]-1H-indazole (D33) (460 mg, 1.26 mmol) was dissolved in dry DCM (15 mL) and degassed by sonication under a flow of argon. The solution was cooled to −78° C. and after 10 mins treated with BBr3 (1M in DCM, 2.52 mL, 2.52 mmol) dropwise and when the addition was complete the bath was removed and it was allowed to reach room temperature still stirring under argon. After 17 hours the mixture was partitioned between DCM (50 mL)/water (50 mL), the pH adjusted to 7 by addition of a solution of NaHCO3 and the layers separated. The aqueous phase was extracted with DCM (2×50 mL) twice and the combined organics were washed with brine (50 mL), separated and dried over MgSO4. The crude material was purified by MDAP to afford 34 mg of the title compound (E17).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1(/[CH:25]=[CH:26]/[C:27](O)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:27](=[O:28])/[CH:26]=[CH:25]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)/C=C/c1ccccc1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccccc3)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-phenyl-acrylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[CH2:5][NH:6][CH:7]1[CH:12]2[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]2)[CH:8]1[CH3:15].[Br:22][C:23]1[CH:24]=[N:25][C:26](Cl)=[N:27][CH:28]=1.C(O)(=O)C>O1CCOCC1>[Br:22][C:23]1[CH:24]=[N:25][C:26]([N:6]([CH2:5][C:4]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:3]=2[O:2][CH3:1])[CH:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH:8]2[CH3:15])=[N:27][CH:28]=1
Reactant: Clc1ncc(Br)cn1
Reactant: COc1ccc(CNC2C3CCN(CC3)C2C)c(OC)c1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1ccc(CN(c2ncc(Br)cn2)C2C3CCN(CC3)C2C)c(OC)c1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
(2,4-Dimethoxy-benzyl)-(2-methyl-1-aza-bicyclo[2.2.2]oct-3-yl)-amine (70 mg, 0.24 mmol) and 5-bromo chloropyrimidine (93 mg, 0.48 mmol) were dissolved in 1,4-dioxane (1 ml). Glacial acetic acid (42 □L, 0.72 mmol) was added and the reaction mixture was stirred under microwave radiation at 150° C. for 30 minutes. The reaction mixture was concentrated in vacuo, redissolved in EtOAc and washed with 1M aqueous sodium carbonate. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The crude reaction mixture was purified by chromatography [eluent gradient: 10-30% MeOH/Et3N (9:1) in EtOAc) to give pure (5-bromo-pyrimidin-2-yl)-(2,4-dimethoxy-benzyl)-(2-methyl-1-aza-bicyclo[2.2.2]oct-3-yl)-amine.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][C:7]([N+:16]([O-])=O)=[CH:6][N:5]=2)[CH2:3][CH2:2]1.Cl[Sn]Cl.O>C(O)C>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([NH2:16])=[CH:8][C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cnc(C2CC2)c(-c2ccccc2)c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cnc(C2CC2)c(-c2ccccc2)c1
Temperature: 80 °C
Yield: 57.1 %

Procedure:
A mixture of 2-cyclopropyl-5-nitro-3-phenylpyridine (0.25 mmol, 0.06 g) and SnCl2.H2O (0.89 mmol, 0.2 g) in ethanol (2 ml) was heated at 80° C. for 1 hour. The solvent was evaporated and the crude residue was dissolved in water. The solution neutralised with 6N NaOH aqueous solution and extracted with dichloromethane. The solid residue was purified by chromatography over SiO2 eluting with dichloromethane/methanol mixtures affording 6-cyclopropyl-5-phenylpyridin-3-amine (0.03 g, 57% of yield) of the expected product.
Reaction SMILES: [Br:1]Br.O.ClCCl.[Cl:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[OH:15]>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:1][C:12]1[CH:11]=[CH:10][C:9]([OH:15])=[C:8]([Cl:7])[C:13]=1[Cl:14]
Reactant: Oc1cccc(Cl)c1Cl
Reactant: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Oc1ccc(Br)c(Cl)c1Cl
Temperature: 10 °C

Procedure:
In a 250 mL round bottom flask 10 g of 2,3-dichlorophenol was dissolved in a solvent mixture of glacial acetic acid (16 mL) and chloroform (4 mL) and cooled to 10° C. To this was added bromine (3.45 mL) in 15 mL of glacial acetic acid dropwise while maintaining the temperature. The reaction was vigorously stirred while adding bromine and continued stirring vigorously 0.5 h after addition was finished. At this time reaction mixture was poured into a flask containing 60 mL of water and 30 mL of dichloromethane. Organic layer was separated and aqueous layer was extracted with dichloromethane (3×50 mL). The oraganic layers were combined and washed with Sat. sodium bicarbonate (3×100 mL) and brine (100 mL) and dried over sodium sulfate. The crude product (9.65 g) was carried in to the next step without any purification. 1H-NMR (400 MHz, CDCl3) δ: 7.47 and 6.89 (ABq, 2H), 5.69 (brs, 1H).
Reaction SMILES: Br[C:2]1[C:3]([C@@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH:35](B(O)O)=[CH2:36].CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C>O.CCO.CCOC(C)=O>[F:16][C:15]([F:18])([F:17])[C:12]1[CH:13]=[CH:14][C:9]([C@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:3]2[C:2]([CH:35]=[CH2:36])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1
Reactant: C=CB(O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1Br
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: C=Cc1cccnc1[C@@H](NC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a mixture of (S)-tert-butyl ((3-bromopyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)carbamate (0.4 g, 0.93 mmol) in water (2 mL) and EtOH (8 mL) were added K3PO4 (0.3 g, 1.3 mmol), vinyl boronic acid (4 mL, 9.3 mmol) and A−taPhos)2PdCl2 (Guram, A. S. et al. Org. Lett. 2006, 8, 1787; 0.13 g, 0.01 mmol). The resulting mixture was stirred at 120° C. for 1 h. Reaction progress was monitored by TLC (20% EtOAc in petroleum ether). After completion of reaction, water (50 mL) was added to the reaction mixture, and the product was extracted with DCM (3×25 mL). The combined organic layers were separated, dried over anhydrous sodium sulfate, and purified by column chromatography using silica (100-200 mesh) and using 15-30% EtOAc in petroleum ether as an eluent. In this manner, (S)-tert-butyl ((4-(trifluoromethyl)phenyl)(3-vinylpyridin-2-yl)methyl)carbamate was obtained as an off-white solid. MS (ESI pos. ion) m/z: 378.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.[CH2:31]([OH:34])[C:32]#[CH:33]>C(NCC)C.C(Cl)Cl.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.[Cu]I>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:33]=[C:32]([CH2:31][OH:34])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCNCC
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c(CO)cc3cc(CN4CCOCC4)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To a solution of N-(4-chlorobenzyl) -4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (0.15 g), PdCl2(PPh3)2 (0.0098 g) and CuI (0.0027 g) in diethylamine (5.2 mL) and CH2Cl2 (5 mL) is added propargyl alcohol (0.016 mL). The reaction is stirred at room temperature overnight, then concentrated. The crude residue is partitioned between CH2Cl2 and water. The aqueous layer is extracted with CH2Cl2 (3×). The combined organic layers are dried over Na2SO4 and condensed. The crude product is adsorbed onto silica and chromatographed (Biotage flash 40S, gradient from CH2Cl2 to 2.5% MeOH/ICH2Cl2) Product containing fractions are combined and concentrated. The resulting solid is triturated with CH2Cl2/hexanes, filtered and dried to yield 0.029 g (23%) of N-(4-chlorobenzyl)-2-(hydroxymethyl)-8-(4-morpholinylmethyl)-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide, m.p. 210-212° C.