Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[N:12]=[N:11][C:10]([C@@H:13]2[C@@H:17]([OH:18])[C@@H:16]([OH:19])[C@H:15]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][C:23]([NH:44][CH2:45][CH2:46][N:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)=[N:24][C:25]=4[NH:29][CH2:30][CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:14]2)=[N:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[N:11]1[NH:12][N:8]=[N:9][C:10]=1[C@@H:13]1[C@@H:17]([OH:18])[C@@H:16]([OH:19])[C@H:15]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][C:23]([NH:44][CH2:45][CH2:46][N:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)=[N:24][C:25]=3[NH:29][CH2:30][CH:31]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:14]1
Reactant: O[C@@H]1[C@H](O)[C@@H](c2nnn(Cc3ccccc3)n2)O[C@H]1n1cnc2c(NCC(c3ccccc3)c3ccccc3)nc(NCCN3CCCCC3)nc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: O[C@@H]1[C@H](O)[C@@H](c2nn[nH]n2)O[C@H]1n1cnc2c(NCC(c3ccccc3)c3ccccc3)nc(NCCN3CCCCC3)nc21
Temperature: 50 °C
Yield: 99.6 %

Procedure:
To 10% palladium on carbon (1.6 g) under nitrogen was added a solution of Intermediate 5 (1.67 g, 2.38 mM) in ethanol (50 ml) followed by ammonium formate (0.72 g, 11.9 mM). The mixture was heated to 50° C. for 4 h., filtered through a pad of Harborlite®. The filtrate was evaporated under reduced pressure to yield the title compound as a pale yellow solid (1.45 g).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[N:9]2[CH:10]=[C:11]([CH2:13][O:14][C:15]3[CH:36]=[CH:35][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)\[CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:17][CH:16]=3)[N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.CO.Cl>O1CCCC1>[Cl:3][C:4]1[N:9]2[CH:10]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)\[CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:35][CH:36]=3)[N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2cn3c(Cl)cccc3n2)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC/C(=N\OCc1ccc(OCc2cn3c(Cl)cccc3n2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of methyl E-4-[4-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyrate (400 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-[4-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyric acid (313 mg, yield 78%) as colorless crystals. m.p. 160-161° C.
Reaction SMILES: CC(=CC)C.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][CH:15]=[CH2:16].[OH-:25].[Na+].OO>O1CCCC1.C(Cl)Cl>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][CH2:15][CH2:16][OH:25]
Reactant: [OH-]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)c1ccccc1Br
Agent: CC=C(C)C
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CCCO)c1ccccc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.5 %

Procedure:
A solution of 2-methyl-2-butene (204 mmol, 21.68 mL) dissolved in tetrahydrofuran (150 mL) was cooled in a salt-ice bath and 1M boran-THF complex (34.1 mmol, 34.1 mL) was slowly added maintaining the temperature below 0° C. Upon complete addition the reaction mixture was left to stir for 10 minutes at 0° C. and then a tetrahydrofuran solution of (S)-tert-butyl 1-(2-bromophenyl)but-3-enylcarbamate (compound 4; 68.1 mmol, 22.23 g) was added slowly maintaining the temperature below 5° C. Once the addition was complete the cooling bath was removed and the temperature allowed to warm to room temperature and left to stir for 60 minutes. After 60 minutes the reaction mixture was cooled back to 0° C. and 4N sodium hydroxide (80 mmol, 20 mL) was slowly added at below 5° C. and this was followed by 27.5% aqueous hydrogen peroxide solution (68.1 mmol, 20 mL) keeping the temperature below 5° C., once the addition was complete the cooling bath was removed and the temperature allowed to warm to ambient temperature and left to stir overnight. The reaction mixture was diluted with ether (500 mL) then water (500 mL), the aqueous was phase separated and the aqueous re-extracted with ether (3×500 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give an white solid that was taken up in methylene chloride an loaded on to a silica pad and eluted with 40% ethyl acetate-heptane to give (S)-tert-butyl 1-(2-bromophenyl)-4-hydroxybutylcarbamate (8.08 g), MS (ES): m/z [M+H]+ 344 and 346.
Reaction SMILES: CC[C@@]1(O)C(=O)[O:7]CC2C(N3C(=CC1=2)C1N=C2C(C=CC=C2)=CC=1C3)=O.C(O)(=O)C1C=CC=CC=1.[CH2:36]1[CH2:41][CH2:40][CH:39]([N:42]=[C:43]=[N:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)[CH2:38][CH2:37]1>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH:45]1([NH:44][C:43](=[O:7])[NH:42][CH:39]2[CH2:38][CH2:37][CH2:36][CH2:41][CH2:40]2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C(O)c1ccccc1
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 38 %

Procedure:
Camptothecin (0.8 g, 0.0023 mol), benzoic acid (1.8 g, 0.014 mol), DCC (1.2 g, 0.0058 mol), and DMAP (0.3 g, 0.0025 mol) were added to 60 ml DMF in a 250 ml round-bottomed flask equipped with a mechanical stirrer. The mixture was stirred under N2 at room temperature for 72 hr. Dicyclohexyl urea formed during the reaction was removed by filtration. The filtrate was poured onto 600 ml ice water while stirring. The stirring was maintained for 30 min. The crude product was collected by filtration. The residue was chromatographically separated with THF-CH2Cl2 (1:15) as eluent. The pure product (0.4 g) was obtained as white powders by precipitation from petroleum ether. Yield 38%. Mass m/e (relative intensity): 452 (m+, 25), 330 (100), 315 (35), 302 (60), 287 (40), 169 (12), 122 (36), 105 (70), 77 (35), 69 (26); precise mass (C27H20N2O5): found, 452,137; required, 452.137.
Reaction SMILES: [NH:1]([C:8]1[C:18](=[O:19])[C:12]2[N:13]=[C:14]([CH2:16][CH3:17])[O:15][C:11]=2[C:10](=[O:20])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21]N1C(=O)CCC1=O>C(O)(=O)C>[NH:1]([C:8]1[C:18](=[O:19])[C:12]2[N:13]=[C:14]([CH2:16][CH3:17])[O:15][C:11]=2[C:10](=[O:20])[C:9]=1[Cl:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1nc2c(o1)C(=O)C=C(Nc1ccccc1)C2=O
Solvent: CC(=O)O
Product: CCc1nc2c(o1)C(=O)C(Cl)=C(Nc1ccccc1)C2=O
Reaction time: 2 h

Procedure:
A solution of 5-anilino-2-ethyl-1,3-benzoxazole-4,7-dione (1 eq.) in acetic acid is treated with N-chlorosuccinimide (1.1 eq.) at ambient temperature. The reaction medium is maintained under stirring for 2 hours before being concentrated, followed by taking up in ethanol and concentrating again. The residue is purified by medium pressure chromatography on silica in order to produce a violet-coloured powder.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:47])[C:16]([N:18]2[CH2:38][CH2:37][C@:21]3([N:25](C(OC(C)(C)C)=O)[C@H:24]([C:33]([O:35][CH3:36])=[O:34])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[CH3:46])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].[CH3:51][Si]([N-][Si](C)(C)C)(C)C.IC.C(O)(C(F)(F)F)=O>O1CCCC1>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]([N:15]([CH3:47])[C:16]([N:18]2[CH2:38][CH2:37][C@:21]3([NH:25][C@:24]([CH3:51])([C:33]([O:35][CH3:36])=[O:34])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[CH3:46])=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:49])[F:48])[CH:8]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)[C@@H]1CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1C(=O)OC(C)(C)C
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)[C@]1(C)CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl(2S,5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-1,2-dicarboxylate (Intermediate 43, 1 g, 1.421 mmol) in dry Tetrahydrofuran (THF) (16 ml) at −78° C. LiHMDS 1M in THF (2.132 ml, 2.132 mmol) was added and the reaction mixture was stirred for 10 mins at r.t. iodomethane (0.355 ml, 5.68 mmol) was then added and the reaction mixture was stirred for 30 mins at r.t. The reaction was quenched with brine (1 ml), diluted with water (10 ml) and extracted with ethyl acetate (3×30 ml). Combined organic layers were dried (Na2SO4), filtered and evaporated in vacuo. The residue was dissolved in Dichloromethane (15 ml) and the stirring solution was cooled at 0° C. TFA (5 ml, 64.9 mmol) was added and the reaction mixture was stirred at 0° C. for 1.30 h. The solvent and the excess of TFA were evaporated in vacuo. The residue was dissolved in 20 ml of ethyl acetate and washed with NaHCO3 sat. sol. (5 ml). The organic layer was dried, filtered and evaporated and the residue was purified by flash chromatography on silica gel using a Biotage SNAP 50 g as column and Cyclohexane to Cyclohexane/Ethyl acetate 1:1 as eluent affording the title compounds:
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](O)=O)=[N:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:8]=2)=[N:14][CH:15]=1
Reactant: Nc1ccccc1N
Reactant: Cc1ccc(C(=O)O)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(-c2nc3ccccc3[nH]2)nc1

Procedure:
6.2 g. of o-phenylenediamine, 7.1 g. of 5-methylpicolinic acid and 40 g. of polyphosphoric acid were stirred under nitrogen gas current at 160° C. to 180° C. for 4 hours. To the reaction mixture were added 400 ml. of water and then a concentrated aqueous solution of sodium carbonate to neutrality. The resulting crystals were filtered off, dried and recrystallized from acetonitrile or ethyl acetate to obtain 9.4 g. of colorless needles of the product (86% of theory), M.P. 229.0°-229.5° C.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:51]=[C:52]([Cl:54])[CH:53]=1)[O:31][C:32]1[C:33]([CH2:49][CH3:50])=[N:34][N:35]([CH2:39][CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:36]=1[CH2:37]O>ClCCl>[Br:1][CH2:37][C:36]1[N:35]([CH2:39][CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[N:34]=[C:33]([CH2:49][CH3:50])[C:32]=1[O:31][C:30]1[CH:29]=[C:28]([Cl:27])[CH:53]=[C:52]([Cl:54])[CH:51]=1
Reactant: CCc1nn(CCNC(=O)OC(C)(C)C)c(CO)c1Oc1cc(Cl)cc(Cl)c1
Reactant: BrBr
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1nn(CCNC(=O)OC(C)(C)C)c(CBr)c1Oc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
Bromine (160 μl, 3.12 mmol) was added dropwise to a stirred solution of triphenylphosphine (820 mg, 3.12 mmol) and imidazole (213 mg, 3.12 mmol) in dichloromethane (15 ml) at room temperature under nitrogen. A solution of the alcohol of Example 135 (1.12 g, 2.60 mmol) in dichloromethane (5 ml) was then added to the reaction. The reaction was stirred at room temperature for 2 hours, diluted with dichloromethane (50 ml), washed with brine (20 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (98:2, by volume) to provide the title compound (969 mg) as a white foam.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C@H](C2C=CC=CC=2)C)[C@@H:3]1[C:15]([NH2:17])=[O:16]>CO.[Pd]>[CH3:1][C@@H:2]1[CH2:6][CH2:5][NH:4][C@@H:3]1[C:15]([NH2:17])=[O:16]
Reactant: C[C@@H]1CCN([C@@H](C)c2ccccc2)[C@@H]1C(N)=O
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CCN[C@@H]1C(N)=O
Reaction time: 46 h

Procedure:
A mixture of (2S,3R)-3-methyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid amide (Step 1.9) (4.76 mmol) and 10% Pd on charcoal (0.947 mmol) in MeOH (20 mL) was hydrogenated for 46 h at rt. The reaction mixture was then filtered through a Fluoropore Membrane Filter (0.2 μm FG) and evaporated. The residue was dissolved in CH2Cl2 and evaporated to dryness to afford the title compound as a white solid. ESI-MS: [M+H]+ 129; TLC: Rf=0.10 (1:3 Hex/EtOAc).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([CH3:11])[C:3]=1[N+:12]([O-])=O.[H][H]>CO.[Pd]>[NH2:12][C:3]1[C:4]([CH3:11])=[CH:5][C:6]2[N:7]=[CH:8][NH:9][C:10]=2[C:2]=1[CH3:1]
Reactant: [H][H]
Reactant: Cc1cc2nc[nH]c2c(C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1cc2nc[nH]c2c(C)c1N

Procedure:
A heterogeneous mixture of 4,6-dimethyl-5-nitrobenzimidazole (410 mg, 2.14 mmol) and 10% palladium-on-carbon (50 mg) in methanol (25 mL) is treated with an atmosphere of hydrogen (1 atm, balloon) for 16 hours. The resulting mixture is filtered through Celite and rotary evaporated. The residue is purified by chromatography on silica gel (95:5 methylene chloride:methanol) to afford 5-amino-4,6-dimethylbenzimidazole as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3=[N:20][C:21](S(C)=O)=[N:22][CH:23]=[C:18]3[CH2:17][N:16]([C:27]3[C:32]([F:33])=[C:31]([O:34][CH3:35])[CH:30]=[C:29]([O:36][CH3:37])[C:28]=3[F:38])[C:15]2=[O:39])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:40]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3=[N:20][C:21]([NH2:40])=[N:22][CH:23]=[C:18]3[CH2:17][N:16]([C:27]3[C:32]([F:33])=[C:31]([O:34][CH3:35])[CH:30]=[C:29]([O:36][CH3:37])[C:28]=3[F:38])[C:15]2=[O:39])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: COc1cc(OC)c(F)c(N2Cc3cnc(S(C)=O)nc3N(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1F
Solvent: C1COCCO1
Product: COc1cc(OC)c(F)c(N2Cc3cnc(N)nc3N(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1F
Yield: 81 %

Procedure:
4-[3-(2,6-Difluoro-3,5-dimethoxy-phenyl)-7-methylsulfinyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (419 mg, 0.738 mmol) and liquid ammonia (20 mL) in dioxane (20 mL) were stirred in a sealed tube at room temperature for 24 hours. The solvent was removed under reduced pressure. The resulting residue was purified via flash chromatography eluting with a gradient of ethyl acetate:hexanes (2:1 to 5:1) to give 312 mg (81%) of the title compound: MS (APCI) 421.1, 465.2, 521.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[N:1]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:3]2[CH:4]=[CH:5][N:6]=[CH:7][C:2]=12
Reactant: Nc1cnccn1
Reactant: CCOC(=O)C(=O)CBr
Product: CCOC(=O)c1cn2ccncc2n1
Yield: 25 %

Procedure:
This derivative is obtained according to the technique described in Example 3, stage B, by reacting 2-aminopyrazine and ethyl bromopyruvate. Ethyl imidazo[1,2-a]pyrazine-2-carboxylate (m.p. 179° C., Yld=25%) is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:15][OH:16])[CH:7]=[C:8]([O:12][CH2:13][CH3:14])[C:9]=1[O:10][CH3:11])[CH3:2]>C1COCC1.O=[Mn]=O>[CH2:13]([O:12][C:8]1[CH:7]=[C:6]([CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]=1[O:10][CH3:11])[CH:15]=[O:16])[CH3:14]
Reactant: CCOc1cc(CO)cc(OCC)c1OC
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CCOc1cc(C=O)cc(OCC)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.5 %

Procedure:
To a solution of (3,5-diethoxy-4-methoxy-phenyl)-methanol (0.26 g, 1.15 mmol, 1.0 equiv) in THF (10 mL) was added activated MnO2 (1.0 g, 11.49 mmol, 10.0 equiv) and the reaction mixture stirred at rt for 4 h. Filtration through Hyflo Super Cel, concentration by evaporation under reduced pressure and purification with column chromatography on silica eluting with hexane/ethyl acetate (5:1) yielded 0.12 g (48%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.47 (t, J=7.0 Hz, 6H), 3.94 (s, 3H), 4.14 (q, J=7.0 Hz, 4H), 7.10 (s, 2H), 9.84 (s, 1H). MS (ISP): 225.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[C:8](=[O:13])[NH:7][CH2:6][CH2:5]2.C1(P([CH:27]2[CH2:32][CH2:31]CCC2)C2CCCCC2)CCCCC1.C1(B(O)O)CC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH:31]1([C:2]2[CH:3]=[C:4]3[C:9](=[C:10]([F:12])[CH:11]=2)[C:8](=[O:13])[NH:7][CH2:6][CH2:5]3)[CH2:32][CH2:27]1
Reactant: O=C1NCCc2cc(Br)cc(F)c21
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1NCCc2cc(C3CC3)cc(F)c21
Temperature: 100 °C
Reaction time: 4 h
Yield: 697.2 %

Procedure:
To a mixture of 6-bromo-8-fluoro-3,4-dihydro-2H-isoquinolin-1-one (1.6 g, 6.5 mmol), tricyclohexylphosphine (0.182 g, 0.65 mmol) and Pd(OAc)2 (0.072 g, 0.032 mmol) in 15 ml toluene placed under argon in a pressure flask was added cyclopropyl boronic acid (1.12 g, 13 mmol), potassium phosphate (6.9 g, 32.5 mmol) and 1.5 ml water. The flask was sealed and the mixture was heated under stirring for 4 hours at 100° C. After cooling the reaction mixture was diluted with ethyl acetate and the organic phase washed with brine, dried with sodium sulfate and concentrated. The residue was purified by flash chromatography (ethyl acetate) affording 0.93 g (71.5% yield) of I.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[NH:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16].[OH:18][C:19]([CH3:53])([CH3:52])[CH2:20][N:21]1[C:25]([CH3:26])=[C:24]([C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)=[O:28])[C:23](=[O:45])[N:22]1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O.[Pd]>[CH3:16][N:15]([CH3:17])[CH2:14][CH2:13][NH:12][C:7]1[C:8]2[C:3](=[C:2]([C:33]3[CH:32]=[CH:31][C:30]([NH:29][C:27]([C:24]4[C:23](=[O:45])[N:22]([C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)[N:21]([CH2:20][C:19]([OH:18])([CH3:52])[CH3:53])[C:25]=4[CH3:26])=[O:28])=[CH:35][CH:34]=3)[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CN(C)CCNc1nccc2c(Br)cccc12
Reactant: Cc1c(C(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(C(=O)Nc2ccc(-c3cccc4c(NCCN(C)C)nccc34)cc2)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Reaction time: 0.17 h
Yield: 73.4 %

Procedure:
5-Bromo-N-(2-(dimethylamino)ethyl)isoquinolin-1-amine (0.068 g, 0.2 mmol) was added to a microwave vial equipped with a stirbar, along with 1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,3-dihydro-1H-pyrazole-4-carboxamide (0.2 g, 0.3 mmol). Then 1,4-Dioxane (3 ml, 35 mmol) was added into the mixture, followed by 2M K2CO3 (0.5 ml). Then Fibrecat (2.93% Pd, 0.010 g) was added to the mixture. The vial was capped, then placed into CEM Microwave for 10 minutes at 120° C. with 80 Watts of power supplied through Powermax feature. The mixture was diluted with DCM and water, then collected the organic layer by extracting with DCM (3×10 ml). Combined organics, dried over Na2SO4, filtered and concentrated in-vacuo. The crude was purified by ISCO Amino-propyl chromatography using MeOH/DCM as the eluent. This gave the title compounds as a tan amorphous solid (85 mg). MS (ESI pos. ion) m/z: 579 (MH+). Calc'd exact mass for C34H38N6O3: 578.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[C:17]1[C:21]([CH3:22])=[CH:20][S:19][CH:18]=1)[C:11]([OH:13])=O.O[N:24]=[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][C:34]([F:37])([F:36])[F:35])[NH2:26].CCN(C(C)C)C(C)C>>[CH3:7][C:8]1[CH:9]=[C:10]([C:11]2[O:13][N:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][C:34]([F:35])([F:36])[F:37])[N:24]=2)[CH:14]=[CH:15][C:16]=1[C:17]1[C:21]([CH3:22])=[CH:20][S:19][CH:18]=1
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Reactant: Cc1cc(C(=O)O)ccc1-c1cscc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nc(-c3ccccc3OC(F)(F)F)no2)ccc1-c1cscc1C

Procedure:
Oxalyl chloride (131 μL; 1.55 mmol; 3 eq.), Intermediate 20 (120 mg; 0.52 mmol; 1 eq.), Intermediate 2 (114 mg; 0.52 mmol, 1 eq.) and DIEA (267 μL; 1.55 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 95/5) afforded the title compound as a white solid.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[CH:6]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH:13]=O)([CH3:8])[CH3:7]>C(Cl)Cl.CCCCCC.[Zn]>[Br:2][C:1]([Br:5])=[CH:13][C:12]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:10]([O:9][CH:6]([CH3:8])[CH3:7])[CH:11]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(C=O)cc1OC(C)C
Agent: [Zn]
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1ccc(C=C(Br)Br)cc1OC(C)C
Temperature: 0 °C
Reaction time: 22 h
Yield: 99.8 %

Procedure:
Carbon tetrabromide (51.3 g, 154.7 mmol) was added portion-wise to a magnetically stirred mixture of zinc dust (10.1 g, 154.5 mmol) and PP3 (40.5 g, 154.4 mmol) in CH2Cl2 (350 mL) maintained at 0° C. on an ice-salt bath. The resulting suspension was allowed to warm to room temperature and then stirred for a further 22 h. After this time the reaction mixture was re-cooled to 0° C. and isovanillin isopropyl ether (15.0 g, 77.3 mmol) was added dropwise over 2 min. The resulting mixture was allowed to stir at room temperature for 1 h then diluted with hexane (200 mL) and filtered through a No. 3 porosity sintered-glass funnel. The filtrate was concentrated on to silica gel (400-200 mesh, 30 g) and the resulting solid added to the top of a flash chromatography column (20 cm long×10 cm wide) which was subjected to gradient elution with 2:1, 1:1 then 1:2 hexane/CH2Cl2. Concentration of the appropriate fractions (Rf 0.5 in 1:1 hexane/CH2Cl2) afforded the title compound (27.0 g, 99%) as white crystalline masses, m.p. 67-69° C. νmax (KBr) 3009, 2975, 2929, 1597, 1572, 1508, 1463, 1441, 1429,1373, 1301, 1276, 1260, 1233, 1144, 1110 and 999 cm1. 1H n.m.r. δ7.38 (s, 1H), 7.24 (d, J=2.1 Hz, 1H), 7.08 (dd, J=8.4 and 2.1 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 4.53 (septet, J=6.0 Hz, 1H), 3.86 (s, 3H), 1.38 (d, J=6.0 Hz, 6H). 13C n.m.r. δ150.5 (C), 146.7(C), 136.4 (CH), 127.7(C), 122.1 (CH), 115.3 (CH), 111.3 (CH), 87.0(C), 71.4 (CH), 55.8 (CH3), 22.0 (2×CH3). Mass spectrum m/z 352 (20) 350 (40) 348 (22)(M+•), 310 (50) 308 (100) 306 (50) [(M−C3H6)+•], 295 (30), 293 (61) 291 (33) [(M−C3H6−CH3+•)+]. Anal. Calcd for C12H14Br2O2 C, 41.2; H, 4.0; Br, 45.7. Found: C, 41.1; H, 3.7: Br, 45.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]2[N:9]([CH3:12])[N:10]=[CH:11][C:3]=12.[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.CC([O-])=O.[K+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:18]2[CH:19]=[N:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[N:5]=[C:4]2[N:9]([CH3:12])[N:10]=[CH:11][C:3]=12
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cn1ncc2c(Cl)cc(Cl)nc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(Cl)c3cnn(C)c3n2)cn1
Temperature: 120 °C
Yield: 44.5 %

Procedure:
4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-b]pyridine 5 (0.5 g, 4.9 mmol) was dissolved in 1,4-dioxane (8 mL) and 6-methoxypyridin-3-ylboronic acid (0.4 g) and 1 M KOAc (8 mL) were added in a microwave tube. Nitrogen was bubbled through the solution for 1 minute. 1,1′-Bis(diphenylphosphino)ferrocenepalladium (II) chloride (1.2 g) was added and the resultant mixture was heated by microwave at 120° C. for 5 minutes. The reaction mixture was concentrated in vacuo and purified by flash chromatography (30% EtOAc in hexane) to provide 4-chloro-6-(6-methoxypyridin-3-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (0.32 g).