Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([F:16])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[I:22]I>C1COCC1.S([O-])([O-])(=O)=S.[Na+].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([I:22])=[C:10]([F:16])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: II
Reactant: COc1cc(F)cc(-c2cccc(Cl)c2)c1
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-c2cccc(Cl)c2)cc(F)c1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
A RBF was charged with 3′-chloro-3-fluoro-5-methoxy-1,1′-biphenyl (577.6 mg, 2.441 mmol) and THF (8135 μl) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 10 min, then n-butyllithium (1.8M in hexanes) (1627 μl, 2.93 mmol) was added dropwise. After 30 min, a solution of iodine (929 mg, 3.66 mmol) in THF (3 mL) was added dropwise. TLC after 5 min showed conversion to a slightly lower spot. The mixture was diluted with saturated aq. sodium thiosulfate solution and warmed to room temperature. The mixture was diluted with water and extracted with EtOAc (2×), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (25-g Ultra SNAP column, 0-5% EtOAc/Heptane) to give 3′-chloro-3-fluoro-4-iodo-5-methoxy-1,1′-biphenyl (687 mg, 1.895 mmol, 78% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) □=7.87 (td, J=1.0, 1.8 Hz, 1 H), 7.74 (td, J=1.8, 7.0 Hz, 1 H), 7.55-7.43 (m, 2 H), 7.25 (dd, J=1.8, 9.1 Hz, 1 H), 7.14-7.07 (m, 1 H), 3.97 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:61])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([C:37]5[NH:38][C:39]([C@@H:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:60])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)[CH:33]=4)[CH:28]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].COC(N[C@H](C1C=CC=CC=1)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:61])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:60])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)[CH:33]=4)[CH:28]=3)=[CH:25][CH:26]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1)c1ccccc1
Agent: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1)c1ccccc1
Yield: 58 %

Procedure:
This compound was prepared following the procedure for [1-(2-{5-[4-(6-{2-[1-(2S)-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using (R)-methoxycarbonylamino-phenyl-acetic acid (0.02 g, 0.09 mmol, 1.5 equiv.) to provide [1-(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.03 g, 58%) as a white powder. LCMS-ESI+: calc'd for C47H50N8O6: 822.4 (M+); Found: 823.8 (M+H+). 1H-NMR: 400 MHz, (CDCl3) δ: (Mixture of rotomers) 7.62-7.87 (m, 9H), 7.29-7.43 (m, 6H), 7.18 (s, 2H), 6.09 (m, 1H), 5.46 (m, 2H), 5.33 (s, 1H), 5.27 (s, 1H), 4.33 (t, 1H), 3.84 (m, 1H), 3.71 (m, 1H), 3.68 (s, 3H), 3.61 (s, 3H), 3.24 (m, 1H), 2.83-2.93 (m, 3H), 2.35 (m, 1H), 1.92-2.23 (m, 6H), 0.86-0.97 (m, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:20])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[S:28](Cl)([CH3:31])(=[O:30])=[O:29]>C(Cl)Cl>[C:14]1([CH2:13][CH2:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][O:1][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:6][CH:7]=2)=[O:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CCc1ccccc1)c1ccc(OCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccc(C(=O)CCc2ccccc2)cc1
Reaction time: 0.75 h

Procedure:
A solution of 1-[4-(2-hydroxy-ethoxy)-phenyl]-3-phenyl-propan-1-one (prepared in Example N; 6.0 g, 22.2 mmol) and triethylamine (NEt3) (4.60 mL, 33.3 mmol) in CH2Cl2 (50 mL) was cooled to 0° C. under a nitrogen atmosphere and treated with mesyl chloride (2.1 mL, 26.6 mmol). The mixture allowed to stir for 45 minutes, and then diluted with additional CH2Cl2 and washed with H2O. The organic layer was dried (MgSO4) and the solvent removed in vacuo to provide the title compound which was used without further purification. 1H NMR (DMSO-d6) δ 2.90 (t, 2 H), 3.20 (s, 3 H), 3.29 (t, 2 H), 4.32-4.34 (m, 2 H), 4.52-4.55 (m, 2 H), 7.05 (d, 2 H), 7.22-7.32 (m, 5 H), 7.95 (d, 2 H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][C:11]([OH:15])([C:13]#[CH:14])[CH3:12]>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>[CH3:10][C:11]([OH:15])([CH3:12])[C:13]#[C:14][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)O
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CC(C)(O)C#Cc1ccc(C=O)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
4-Bromobenzaldehyde (3.0 g, 16 mmol), Pd(PPh3)2Cl2 (110 mg, 0.170 mmol) and CuI (16 mg, 0.07 mmol) were placed in a Schienk flask. The flask was then evacuated and purged with argon (3 times) on the Schienk line. Then freshly distilled and degassed TEA (32 mL) was added, and after purging with argon, 2-methyl-3-butyn-2-ol (1.90 mL, 19.4 mmol) was added. The reaction mixture was stirred for 2 h at 40° C. (The progress of the reaction was monitored by GC-MS). T he reaction mixture was evaporated to dryness and then chromatographed (silica, CH2Cl2). Bulb-to-bulb distillation (93-95° C., 0.001 mm Hg) gave a pale yellowish oil (2.90 g, 95%). 1H NMR (CDCl3) δ 1.61 (s, 6H), 2.23 (brs, 1H), 7.52 (AB/2, J=8.1 Hz, 2H), 7.79 (AB/2, J=8.1 Hz, 2H), 9.02 (s, 1H); 13C NMR δ 31.9, 66.1, 81.9, 98.8, 129.8, 130.1, 132.7, 35.9, 192.3; IR (film)ν(cm−1) 790.4, 830.1, 906.3, 963.4, 1014.3, 1046.1, 1165.9, 1207.0, 1273.4, 1303.0, 1373.0, 1457.6, 1563.8, 1603.6, 1700.0, 2228.1, 2735.0, 2837.8, 2934.1, 2982.2, 3413.3; MS (EI+) m/z 188 (M+,35%), 173 (100%), 159 (10%); EI-MS obsd 188.0835, calcd exact mass 188.0837 (C12H12O2).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][O:4][NH2:5].[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=O)[C:15]([OH:17])=[O:16])[N:13]=1>>[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:5]/[O:4][CH2:3][C:2]([F:7])([F:6])[F:1])/[C:15]([OH:17])=[O:16])[N:13]=1
Reactant: NOCC(F)(F)F
Reactant: Nc1nc(C(=O)C(=O)O)cs1
Product: Nc1nc(/C(=N/OCC(F)(F)F)C(=O)O)cs1

Procedure:
N.m.r. in solvent B: 5.42 (s, 2H), 7.17 (s, 1H), 7.67 (s, 2H). 11. A suspension of the product from Footnote 10 (4.4 mM) in DMF (40 μl. at 0° C. was dissolved by the addition of 3M HCl in ether (8.8 mM). N-hydroxybenzotriazole (4.4 mM) and t-butyl 7-amino-3-azidomethyl-ceph-3-em-4-carboxylate (4.0 mM) were added to the solution, followed by dropwise addition of a solution of DCCI (4.4 mM) in CH3CN (15 ml.) during 20 minutes. The mixture was left t stir for 23 hours at 0° C. and 1 hour at room temperature. The precipitate was filtered, washed with DMF (3 ml.) and the residue evaporated to dryness. Trituration at 0° C. with aqueous NaHCO3 (5%) yielded a yellow solid which was treated at room temperature with TFA/H2O (15:1) during 2 hours. Evaporation to dryness and purification of the residue by chromatography on Dianion HP 20 resin gave the required product. 12. N.m.r. in solvent B: 3.6 (m, 2H), 4.2 (dd, 2H), 5.25 (d, 1H), 5.5 (s, 2H), 5.9 (d, 1H), 7.25 (s, 1H) 7.7 (s, 2H). 13. This molecule is not tritylated on the 14. The starting material was prepared by condensation of O-(2,2,2-trifluoroethyl)hydroxylamine with 2-(2-aminothiazol-4-yl)glyoxylic acid to give 2-(2-aminothiazol-4-yl)-2-[(Z)-2,2,2-trifluoroethoxyimino]acetic acid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[OH:34])[N:17]=2)[CH2:12]1.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37].ClC([O-])=O>C1COCC1>[F:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:34])[C:27]=1[C:18]1[N:17]=[C:16]([N:13]2[CH2:14][CH2:15][C@@H:11]([NH:10][C:36](=[O:37])[O:38][CH2:39][CH3:40])[CH2:12]2)[C:25]2[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=2)[N:19]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3c(O)cccc3F)nc2c1
Agent: O=C([O-])Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)N[C@@H]1CCN(c2nc(-c3c(O)cccc3F)nc3cc(C)ccc23)C1
Temperature: -40 °C
Yield: 93.2 %

Procedure:
At RT, diisopropyl ethylamine (130 μL, 0.74 mmol) was added to a solution of (R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (125 mg, 0.37 mmol) in THF (10 mL), and the reaction was cooled to −40° C. Ethyl chloroformate (33 μL in 0.33 mL THF, 0.34 mmol) was added dropwise over a period of 10 minutes. After addition of the chloroformate was complete, the reaction mixture was warmed to RT, quenched with H2O, and extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified via silica gel chromatography using 0-10% EtOAc in a 1:1 mixture of hexanes and CH2Cl2 to give (R)-ethyl 1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (compound 10) (130 mg, 85%). 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J=8.6 Hz, 1H), 7.58-7.57 (m, 2H), 7.38-7.29 (m, 2H), 6.76 (d, J=8.3 Hz, 1H), 6.72-6.67 (m, 1H), 4.25-4.21 (m, 1H), 4.16-4.13 (m, 2H), 4.07-3.97 (m, 3H), 3.84-3.82 (m, 1H), 2.52 (s, 3H), 2.24-2.16 (m, 1H), 2.04-2.00 (m, 1H), 1.16 (t, J=7.1 Hz, 3H) ppm. LC/MS: m/z 411.3 (M+H)+ at 2.24 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH2:4]O.C1OC2C=CC(C[Cl:19])=CC=2O1.S(Cl)(Cl)=O>CCOCC>[CH3:1][C:2]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH2:4][Cl:19]
Reactant: COc1ccc(CO)c(C)c1C
Reactant: ClCc1ccc2c(c1)OCO2
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: COc1ccc(CCl)c(C)c1C

Procedure:
1 g (6.016 mmol) of 2,3-dimethyl-4-methoxybenzyl alcohol (Aldrich, Steinheim, FRG) and 4.8 g of diisopropylaminomethylpolystyrene (polyhunig base, see Ex. 44a) in 21 ml of abs. ether are treated dropwise, at from 0° C. to 5° C. and over the space of approximately 25 min, with 0.482 ml of thionyl chloride. After the reaction has ended, the mixture is filtered with suction and the solvent and the excess reagent are removed. The residue, which is the desired title compound, is subjected, without purification, to further processing. TLC Rf (hexane:ethyl acetate 4:1)=0.59. IR(CH2Cl2) inter alia: 1599, 1485, 1466 und 1107 cm-1. 1H-NMR (200 MHz, CDCl3): 7.14 (d, 1H); 6.69 (d, 1H); 4.64 (s, 2H); 3.82, 2.34 and 2.18 (each s, each 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.IC.[C:14](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A stirred mixture of 4-bromo-2-methylbenzoic acid (6 g, 27.9 mmol), iodomethane (5.21 mL, 84 mmol) and potassium carbonate (11.57 g, 84 mmol) in DMF (60 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between water (250 mL) and 4:1 hexanes:ethyl acetate (650 mL). The organic layer was washed with water and dried over Na2SO4. The solvent was removed under vacuum to give 6.39 g of desired product as an oil in 100% yield. 1H NMR (400 MHz, CD3OD) δ ppm 7.86-7.65 (m, 7H) 7.50 (br. s., 2H) 3.88 (s, 3H) 2.56 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].CC1(C)C(C)(C)OB([C:21]2[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24])O1.C1(C)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:21]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccccc1-c1ccc(C(=O)OC)cc1C
Temperature: 25 °C
Yield: 80.6 %

Procedure:
Under a nitrogen atmosphere, to a mixture of methyl 4-bromo-3-methylbenzoate (2.291 g), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3.313 g), toluene (20 ml), water (10 ml) and tripotassium phosphate (4.246 g) was added tetrakis(triphenylphosphine)palladium(0) (0.578 g) at room temperature, and the mixture was stirred with heating under reflux overnight. The reaction mixture was cooled to room temperature, and partitioned in a separatory funnel. The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=95/5) to give the title compound (2.404 g, 81%)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][N:3]=1.[CH3:18][NH:19][C:20]1[N:25]=[C:24]([C:26]2[C:27]([O:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CO>[CH3:18][NH:19][C:20]1[N:25]=[C:24]([C:26]2[C:27]([O:32][C:33]3[CH:34]=[CH:35][C:36]([O:39][C:2]4[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)=[N:4][N:3]=4)=[CH:37][CH:38]=3)=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=[CH:22][N:21]=1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(O)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Product: CNc1nccc(-c2cccnc2Oc2ccc(Oc3nnc(-c4ccccc4)c4ccccc34)cc2)n1

Procedure:
A mixture of 1-chloro-4-phenylphthalazine (0.0900 g, 0.374 mmol), 4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenol (0.110 g, 0.374 mmol), and potassium carbonate (0.129 g, 0.934 mmol) in 1 mL DMSO was heated in a sealed tube for 1 h. Upon cooling, a white precipitate formed. The material was partitioned between water and DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give a crude solid, which was suspended in MeOH, sonicated, filtered and dried to give N-methyl-4-(2-(4-(4-phenylphthalazin-1-yloxy)phenoxy)pyridin-3-yl)pyrimidin-2-amine as a white solid. MS m/z=499 [M+H]+. Calc'd for C30H22N6O2: 498.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.C=O.[C:34](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH:26]5[CH2:27][CH2:28][N:29]([CH3:34])[CH2:30][CH2:31]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(OC4CCNCC4)cc32)nc1-c1cccc(Cl)c1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(Oc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
To a mixture of 0.041 g (0.09 mmole) 4-(3-chloro-phenyl)-2-[6-(piperidin-4-yloxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.21), 0.0135 mL of 37% aqueous formaldehyde solution, 0.0062 mL (0.11 mmole) of acetic acid and 2.1 mL of methanol-dichloromethane (2:5) was added 0.029 g (0.14 mmole) of sodium triacetoxy-borohydride. The mixture was stirred at room temperature for 18 hours. The solution was concentrated under reduced pressure. The residue was diluted with dichloromethane-ethyl acetate and washed with aqueous 1M sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 10:90-20:80) to give 0.034 g of 4-(3-chloro-phenyl)-2-[6-(1-methyl-piperidin-4-yloxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (1.22). MH+/Z=468
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@H:15]([OH:17])[CH3:16])[C:11]([O:13]C)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.CO>[C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@H:15]([OH:17])[CH3:16])[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H](CCCc1ccccc1)[C@@H](C)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](O)[C@@H](CCCc1ccccc1)C(=O)O
Temperature: 23 °C
Reaction time: 20 h
Yield: 82.7 %

Procedure:
To a solution of methyl (2R,3R)-2-(3-phenyl-1-propyl)-3-hydroxybutanoate (42.2 g, 179.5 mmol) in THF-methanol (3:1, 535 mL) is added 2 N aqueous sodium hydroxide solution (135 mL, 269.3 mmol). The solution is stirred at 23° C. for 20 h, then concentrated and extracted with hexanes (100 mL). The aqueous layer is acidified to pH 3 with saturated aqueous sodium bisulfate and is extracted with two 500-mL portions of EtOAc. The combined organic layers are dried over magnesium sulfate and concentrated under reduced pressure to provide (2R,3R)-2-(3-phenyl-1-propyl)-3-hydroxybutanoic acid as an oil (33.0 g, 83% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[NH:17][C:18]2[CH:24]=[C:23]([C:25]([OH:27])=O)[CH:22]=[CH:21][C:19]=2[N:20]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)[CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42]2[CH:43]=[CH:44][C:45]([NH:48][C:25]([C:23]3[CH:22]=[CH:21][C:19]4[NH:20][C:16]([C:3]5[CH:4]=[C:5]([C:8]6[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=6)[CH:6]=[CH:7][C:2]=5[OH:1])=[N:17][C:18]=4[CH:24]=3)=[O:27])=[CH:46][CH:47]=2)[CH2:36][CH2:35]1
Reactant: Nc1ccc(CCN2CCN(c3ccccn3)CC2)cc1
Reactant: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(=O)O)cc3[nH]2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncccc1-c1ccc(O)c(-c2nc3cc(C(=O)Nc4ccc(CCN5CCN(c6ccccn6)CC5)cc4)ccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
To a solution of 2-[2-hydroxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-3H-benzoimidazole-5-carboxylic acid (containing 1 equivalent of DMA, 44 mg, 0.1 mmol), 4-[2-(4-pyridin-2-yl-piperazin-1-yl)-ethyl]-phenylamine (28.2 mg, 0.1 mmol) and HATU (38 mg, 0.1 mmol) in DMF (1.2 mL) was added DIEA (45 mg, 0.35 mmol). The reaction mixture was stirred at room temperature for 2 h and heated at 60° C. for 3 h, and then evaporated under reduced pressure. The residue was diluted with DMSO (1.5 mL), filtered and then purified with using HPLC (TFA/H2O/CH3CN) to afford the title compound (26.6 mg, 39%). 1H NMR (MeOH-d4) δ 3.10-4.01 (12H), 3.98 (s, 3H), 6.87 (m, 1H), 7.04-7.12 (2H), 7.21 (d, J=9 Hz, 1H), 7.36 (d, J=6 Hz, 2H), 7.72-7.83 (5H), 7.89 (d, J=6 Hz, 1H), 8.09 (d, J=6 Hz, 1H), 8.17 (t, J=3 Hz, 2H), 8.26 (s, 1H), 8.37 (s, 1H). ESI-MS m/z 626.5 (MH+).
Reaction SMILES: [C:1]([CH2:5]P(=O)(OCC)OCC)([O:3][CH3:4])=[O:2].CN(C)C=O.[H-].[Na+].[CH3:21][C:22]([CH2:30][CH3:31])=[CH:23][CH2:24][CH2:25][CH2:26][C:27](=O)[CH3:28]>O>[CH3:28][C:27]([CH2:26][CH2:25][CH2:24][CH:23]=[C:22]([CH3:21])[CH2:30][CH3:31])=[CH:5][C:1]([O:3][CH3:4])=[O:2]
Reactant: CCC(C)=CCCCC(C)=O
Reactant: CCOP(=O)(CC(=O)OC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)=CCCCC(C)=CC(=O)OC

Procedure:
A mixture of 11.2 g. of diethyl carbomethoxymethylphosphonate in 100 ml. of dimethylformamide is treated with 2.4 g. of sodium hydride. The mixture is stirred until the evolution of gas ceases and then 10 g. of 7-methyl-6-nonen-2-one is added slowly with stirring, maintaining temperature below 30°. The mixture is stirred for about one hour, then diluted with water and then extracted with ether. The ethereal phase is washed with water, dried over sodium sulfate and evaporated under reduced pressure to yield methyl 3,8-dimethyldeca-2,7-dienoate as a mixture of isomers (trans,cis; trans,trans; cis,cis and cis,trans) which are separated by chromatography.
Reaction SMILES: [CH:1]([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH2:2].[CH:16]([OH:18])=[CH2:17].[N+:19]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([N+:31]([O-:33])=[O:32])[CH:30]=1)[C:25](Cl)=[O:26])([O-:21])=[O:20]>N1C=CC=CC=1.C1C=CC=CC=1>[CH:1]([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH2:2].[N+:19]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([N+:31]([O-:33])=[O:32])[CH:30]=1)[C:25]([O:18][CH:16]=[CH2:17])=[O:26])([O-:21])=[O:20]
Reactant: C=CO
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: C=Cn1c2ccccc2c2ccccc21
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: C=COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Copoly(N-vinyl carbazole-Vinyl alcohol) (II) (2.0 g) was dissolved in 50 ml of anhydrous pyridine. 3,5-Dinitrobenzoyl chloride (3.88 g) in 15 ml of anhydrous benzene was added with stirring to the pyridine solution. The resulting orange solution was stirred at room temperature for 4 hours. The small amount of solid remaining in the reaction mixture was collected on a filter and the filtrate was poured into 400 ml of methanol. The isolated polymer was purified by two precipitations from tetrahydrofuran into methanol to give 3.2 grams of a yellow powder. Nitrogen analysis demonstrated that the reaction of the alcohol groups with the acid chloride was nearly quantitative.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[C:3]#[CH:4].I[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1>>[CH3:1][C:2]1([CH3:14])[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=2)[C:13]2[CH:12]=[C:9]([C:10]#[N:11])[CH:8]=[CH:7][C:6]=2[O:5]1
Reactant: C#CC(C)(C)Oc1ccc(C#N)cc1
Reactant: O=[N+]([O-])c1ccc(I)nc1
Product: CC1(C)C=C(c2ccc([N+](=O)[O-])cn2)c2cc(C#N)ccc2O1

Procedure:
2,2-Dimethyl-4-(5-nitro-2-pyridyl)-2H-1-benzopyran-6-carbonitrile was prepared from 4-(1,1-dimethyl-2propynyloxy)benzonitrile and 2-iodo-5-nitropyridine in an analogous manner to that described in Example 6(A).