Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[C:15]([C:17]([OH:19])=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1.Cl.[OH:21][C:22]1[C:31]([N:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][NH:26][CH2:27]2>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[C:15]([C:17]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:31]([N:32]([CH3:34])[CH3:33])[C:22]=4[OH:21])[CH2:27]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2cccnc2)nc2ccccc12
Agent: Cl
Product: CN(C)c1ccc2c(c1O)CCN(C(=O)c1nc(-c3cccnc3)nc3ccccc13)C2
Yield: 7 %

Procedure:
Reaction of 2-(3-pyridinyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 87 (7% yield) as yellow oil. 1H NMR (300 MHz, CD3OD) δ 2.77 and 2.80 (2s, 6H), 2.84 and 3.07 (2t, 2H), 3.60 and 4.20 (2t, 2H), 4.50 and 5.06 (2s, 2H), 6.39 and 6.88 (2d, 1H), 7.01 and 7.22 (2d, 1H), 7.62-7.82 (m, 2H), 7.96-8.25 (m, 3H), 8.71 (m, 1H), 8.92-9.02 (2d, 1H), 9.65 and 9.73 (2s, 1H); MS (ESI) m/z 426 ([M+H]+).
Reaction SMILES: [C@@H:1]12[CH2:6][C@@H:5]1[CH2:4][C@H:3]([C:7]([NH:9][C:10]1([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)[CH2:12][CH2:11]1)=[O:8])[NH:2]2.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>>[F:23][C:24]([F:33])([F:34])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:2]1[C@@H:3]([C:7]([NH:9][C:10]2([C:13]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=3)[CH2:11][CH2:12]2)=[O:8])[CH2:4][CH:5]2[CH:1]1[CH2:6]2
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3C[C@H]4C[C@H]4N3)CC2)cc1
Reactant: FC(F)(F)c1cccc(CBr)c1
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC4CC4N3Cc3cccc(C(F)(F)F)c3)CC2)cc1
Yield: 121.8 %

Procedure:
The title compound (D146) (67 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl methyl 4-(1-((3R)-2-azabicyclo[3.1.0]hexane-3-carboxamido)cyclopropyl)benzoate (D104) (37 mg, 0.12 mmol) and 3-(Trifluoromethyl)benzyl bromide (0.029 ml, 0.19 mmol).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][O:14][C:13]3[N:17]=[CH:18][C:19]([C:21](Cl)=[O:22])=[CH:20][C:12]2=3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:24][C:25]1[C:30](O)=[CH:29][CH:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[O:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:21]1[C:19]1[CH:18]=[N:17][C:13]2[O:14][CH2:15][CH2:16][N:11]([S:8]([C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)(=[O:10])=[O:9])[C:12]=2[CH:20]=1
Reactant: O=C(Cl)c1cnc2c(c1)N(S(=O)(=O)c1ccc(F)cc1)CCO2
Reactant: Nc1ncccc1O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccccc1)N1CCOc2ncc(-c3nc4ncccc4o3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-fluorophenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonyl chloride (25 mg, 70 μmol) was dissolved in THF (0.5 mL) and placed in a 2 mL microwave vial. To this solution was added 2-aminopyridin-3-ol (8.5 mg, 77 μmol), DIPEA (26 μL, 150 μmol) and a magnetic stirrer bar and the reaction was capped. After stirring at room temperature for 1 hour, conversion to the amide was complete as shown by LCMS. To the crude reaction mixture was added Burgess reagent (83 mg, 350 μmol) and the reaction was heated for 5 minutes at 150° C. on a Biotage Initiator. The reaction mixture was diluted with DCM (3 mL) and saturated aqueous sodium bicarbonate (3 mL). The organic layer was removed and the aqueous layer extracted with DCM (2 mL). The organic layers were combined, dried with sodium sulfate, filtered and evaporated to produce a brown oil that was purified by flash column chromatography on an ISCO HPLC using a 4 gram SiO2 cartridge and a gradient of 25-100% hexanes in EtOAc. This yielded 15 mg (52%) of a yellow oil. LCMS (+ESI) m/z=413.0 [M+H]+; 1H-NMR (CDCl3) δ 9.05 (dd, 2H), 8.60 (d, 1H), 7.95 (dd, 1H), 7.82 (d, 1H), 7.78 (d, 1H), 7.35 (dd, 1H), 7.20 (dd, 2H), 4.12 (t, 2H), 3.96 (t, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:17]([O:19]CC)=[O:18])=[C:14](I)[N:15]=2)[C:8]([CH3:22])=[CH:7][N:6]=1)(=[O:3])[CH3:2].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:17]([OH:19])=[O:18])=[C:14]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[Cl:23])[N:15]=2)[C:8]([CH3:22])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccccc1Cl
Reactant: CCOC(=O)c1oc(-c2cc(NC(C)=O)ncc2C)nc1I
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1cc(-c2nc(-c3ccccc3Cl)c(C(=O)O)o2)c(C)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 2-[2-(acetylamino)-5-methylpyridin-4-yl]-4-iodo-1,3-oxazole-5-carboxylate (0.14 g, 0.33 mmol), (2-chlorophenyl)boronic acid (0.076 g, 0.49 mmol), tetrakis(triphenylphosphine)palladium(0) (0.038 g, 0.032 mmol), and cesium carbonate (0.53 g, 1.62 mmol) in 1,4-dioxane (4.5 mL) and water (0.2 mL) was subjected to microwave irradiation at 150° C. for 20 min. The reaction mixture was filtered and the filtrate was concentrated. To the residue were added MeOH (10 mL) and aqueous NaOH (0.5 M, 1.5 mL). The mixture was allowed to stir at rt for 8 h and then concentrated to give 2-[2-(acetylamino)-5-methylpyridin-4-yl]-4-(2-chlorophenyl)-1,3-oxazole-5-carboxylic acid which was used in next step without further purification.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[Br:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23]([NH2:28])[N:24]=[CH:25]2)=[CH:20][CH:19]=1.BrC1C=CC=C2C=1C=C(N)N=C2>ClCCl>[Br:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23]([N:28]=[C:1]=[S:2])[N:24]=[CH:25]2)=[CH:20][CH:19]=1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Nc1cc2ccc(Br)cc2cn1
Agent: Nc1cc2c(Br)cccc2cn1
Solvent: ClCCl
Product: S=C=Nc1cc2ccc(Br)cc2cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one 1.145 g, 4.93 mmol) in dichloromethane at room temperature was added the mixture of 7-bromoisoquinolin-3-amine and 5-bromoisoquinolin-3-amine from step B (1.0 g, 4.5 mmol). The orange solution was stirred at room temperature for 18 hours. LCMS indicated the formation of product. The deep orange solution was purified by silica gel chromatography (0-5% ethyl acetate-hexanes). The first product fractions were combined and concentrated in vacuo to afford 7-bromo-3-isothiocyanatoisoquinoline (0.27 g, 0.377 mmol, 22% yield) as a yellow solid. 1H NMR (400 MHz, Acetone) δ ppm 9.19 (1H, s), 8.41 (1H, s), 7.86-8.02 (2H, m), 7.76 (1H, s). R.T.=4.28; [M+H]+=267.04. The second product fractions were combined and concentrated in vacuo to afford 5-bromo-3-isothiocyanatoisoquinoline (0.25 g, 0.377 mmol, 21% yield) as a yellow solid. 1H NMR (400 MHz, Acetone) δ ppm 9.24 (1H, s), 8.23 (1 H, d), 8.15 (1H, d), 7.81 (1H, s), 7.64 (1H, t). LCMS: R.T.=4.61; [M+H]+=267.04.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:25][CH3:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:27]([NH2:30])[CH2:28][CH3:29].C(N(C(C)C)CC)(C)C.Cl>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:30][CH2:27][CH2:28][CH3:29])=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:25][CH3:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCN
Reactant: CCc1cc(Cc2ccc(CC(=O)Cl)cc2)nc(-c2cccc(Cl)c2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCCNC(=O)Cc1ccc(Cc2cc(CC)nc(-c3cccc(Cl)c3)n2)cc1
Reaction time: 2.5 h
Yield: 53.9 %

Procedure:
To a stirred solution of crude 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetyl chloride (˜0.20 mmol) in dichloromethane (8 mL) at 0° C. was added n-propylamine (0.082 mL, 1.00 mmol) followed by diisopropylethylamine (0.17 mL, 1.00 mmol). After stirring for 2.5 h, the reaction mixture was diluted with dichloromethane (50 mL) and water (5 mL). The mixture was acidified with 2N aqueous HCl until pH˜5. The organic layer was washed with saturated sodium chloride (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 1:1) as eluent followed by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford the title compound (0.044 g, 55%) as a white solid. MW=407.94. M.p. 123-125° C. 1H NMR (DMSO-d6, 500 MHz) δ 8.37-8.31 (m, 2H), 7.98-7.93 (m, 1H), 7.60 (dt, J=8.5, 2.0 Hz, 1H), 7.55 (t, J=7.5 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.24 (s, 1H), 7.20 (d, J=8.0 Hz, 2H), 4.09 (s, 2H), 3.34 (s, 2H), 2.97 (q, J=6.0 Hz, 2H), 2.77 (t, J=7.5 Hz, 2H), 1.43-1.34 (m, 2H), 1.26 (t, J=7.5 Hz, 3H), 0.81 (t, J=7.5 Hz, 3H); APCI MS m/z 408 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:34]=[C:33]([CH2:35][CH2:36][NH2:37])[O:32][N:31]=2)=[CH:26][CH:25]=1.O>CN1CCCC1=O>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:37][CH2:36][CH2:35][C:33]2[O:32][N:31]=[C:30]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[CH:34]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: NCCc1cc(-c2ccc(F)cc2)no1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCCc1cc(-c2ccc(F)cc2)no1
Temperature: 6 °C
Yield: 63 %

Procedure:
Under a nitrogen atmosphere, triethylamine (14.9 mL, 107 mmoL) was added to a solution of 2,4-dichloro-3-nitroquinoline (17.29 g, 71.15 mol) in anhydrous 1-methyl-2-pyrrolidinone (NMP) (100 mL). The mixture was stirred until it was homogeneous and then was cooled to 6° C. 2-[3-(4-Fluorophenyl)isoxazol-5-yl]ethylamine (14.9 mL, 107 mmol) was added dropwise over a period of 30 minutes; the temperature did not rise above 10° C. during the addition. After the reaction was stirred for 1.75 hours, deionized water (100 mL) was added. A precipitate formed, and the mixture was stirred for 30 minutes. The precipitate was isolated by filtration, and washed with deionized water until the filtrate was pH 8. The filter cake was then washed sequentially with toluene (100 mL) and a small amount of diethyl ether and dried for 18 hours to provide 27.84 g of 2-chloro-N-{2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}-3-nitroquinolin-4-amine as a bright yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12](/[CH:15]=[N:16]/[NH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][N:19]=1)[CH:11]=[CH:10]2)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.C1COCC1.O.O[Li].O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([C:15]1[N:19]3[CH:20]=[C:21]([C:22]([OH:24])=[O:23])[CH:26]=[CH:27][C:18]3=[N:17][N:16]=1)[CH:11]=[CH:10]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(N/N=C/c2ccc3cccc(C(C)(C)C)c3n2)nc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: Ic1ccccc1
Solvent: ClCCl
Product: CC(C)(C)c1cccc2ccc(-c3nnc4ccc(C(=O)O)cn34)nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.1 %

Procedure:
To a suspension of (E)-methyl 6-(2-((8-tert-butylquinolin-2-yl)methylene)hydrazinyl)nicotinate (1.78 g, 4.91 mmol) in DCM (40 mL) was added iodobenzene diacetate (1.90 g, 5.89 mmol). The reaction mixture was stirred at ambient temperature for 4 hours. The solvent was removed, and the resulting residue was suspended in 1:1 hexane/ether (50 mL) and stirred at ambient temperature for 10 minutes. The solid that formed was collected by filtration. The solid was then suspended in 1:1 THF/H2O (50 mL) and LiOH—H2O (0.82 g, 19.6 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 hours. THF was removed under reduced pressure. The resulting aqueous solution was acidified with saturated potassium hydrogen sulfate to pH˜3-4. The solid that formed was collected by filtration, washed with water, 1:1 hexane/ether (50 mL) and dried to give 3-(8-tert-butylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (1.55 g, 91.1%) as solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:31])=[C:16]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH:22]=[CH:21][N:20]=2)[CH:17]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:31])=[C:16]([NH:18][C:19]3[N:24]=[C:23]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:22]=[CH:21][N:20]=3)[CH:17]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cccnc2)n1
Reactant: O=C(O)c1ccc(O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)c2ccc(O)cc2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 4-hydroxybenzoic acid (10 mmol) and (A) (10 mmol) in DMF (40 ml) was added EDC (12.5 mmol) and HOBt (10 mmol). The reaction was stirred at RT for 4 hours and diluted with DCM (100 ml). The mixture was washed with water three times and dried with Na2SO4. The solution was evaporated and the residue was further purified by column chromatography to give the title compound (Z).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([CH3:12])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1.Br[C:14]([CH3:19])([CH3:18])[C:15](Br)=[O:16].Cl>C(Cl)Cl>[CH3:18][CH:14]1[CH2:19][C:9]2[C:10](=[C:5]([CH3:12])[CH:6]=[C:7]([CH3:11])[CH:8]=2)[C:15]1=[O:16]
Reactant: Cc1cccc(C)c1
Reactant: CC(C)(Br)C(=O)Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C)c2c(c1)CC(C)C2=O
Yield: 93 %

Procedure:
107 g (810 mmol) of AlCl3 were slowly added to a solution of 34.4 g (324 mmol) of m-xylene (99% pure) and 74 g (324 mmol) of 2-bromoisobutyryl bromide (98% pure) in 600 ml of analytical grade methylene chloride via a solids metering funnel at room temperature, while stirring vigorously, whereupon vigorous evolution of gases started. The mixture was stirred at room temperature for 15 hours, poured onto ice-water, which was acidified with 25 ml of concentrated HCl, and extracted several times with ether. The combined organic phases were washed first with a saturated NaHCOa solution and then with a saturated NaCl solution, and dried with magnesium sulfate. The oil which remained after the solvent had been stripped off under reduced pressure was distilled over a short distillation bridge. 52.4 g of the indanone 1 passed over at 81°-90° C./0.1-0.2 mbar in the form of a colorless oil, which crystallized at room temperature. The yield was 93%.
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]([O:11][C:12](=[O:26])[C:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20](Br)[CH:19]=1)([CH3:16])[CH2:14][CH3:15])([CH3:10])([CH3:9])[CH3:8].[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[NH4+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:27]([NH:34][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[Cl:24])[CH2:17][C:13]([CH3:16])([CH2:14][CH3:15])[C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:26])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: CCC(C)(Cc1ccc(Cl)c(Br)c1)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCC(C)(Cc1ccc(Cl)c(NCc2ccccc2)c1)C(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Under argon, 1.59 g (16.6 mmol) of sodium tert-butoxide were weighed out into a dry flask, and 34.6 ml of abs. toluene were added. 5.0 g (13.8 mmol) of (+/−)-tert-butyl-2-(3-bromo-4-chlorobenzyl)-2-methylbutanoate, 1.8 ml (16.6 mmol) of benzylamine, 633 mg (0.69 mmol) of tris(dibenzylidenacetone)dipalladium and 344 mg (0.55 mmol) of (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl were added in succession. The reaction mixture was then stirred at 110° C. for 2.0 h. After cooling, saturated aqueous ammonium chloride solution and ethyl acetate were added and the reaction mixture was filtered off with suction through kieselguhr. After phase separation, the organic phase was washed with sat ammonium chloride solution and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 80:1). This gave 4.44 g of the title compound in still slightly contaminated form (about 83% of theory).
Reaction SMILES: S(Cl)([Cl:3])=O.[S:5]1[C:9]2[CH:10]=[C:11]([S:14]([OH:17])(=O)=[O:15])[CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.CN(C)C=O>ClC(Cl)C>[Cl:3][S:14]([C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[CH:6][S:5][C:9]=2[CH:10]=1)(=[O:17])=[O:15]
Reactant: O=S(=O)(O)c1ccc2ncsc2c1
Reactant: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc2ncsc2c1
Reaction time: 1.5 h

Procedure:
Thionyl chloride (4 mL) was added to a suspension of the benzothiazole-6-sulfonic acid (0.60 g, 2.79 mmol) in dichloroethane (15 mL) and the reaction mixture was heated at reflux and dimethylformamide (5 mL) was added to the reaction mixture to yield a clear solution. After 1.5 hr. at reflux, the solvent was removed in vacuo and excess HCl and thionyl chloride was chased by evaporation with dichloroethane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].I[CH2:24][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27].[OH-].[Li+]>CN1CCCC1=O>[CH2:9]([O:8][C:6](=[O:7])[C:5]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])([CH2:24][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[C:4]([O:3][CH2:1][CH3:2])=[O:22])[CH3:10]
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Reactant: CCC(CC)CI
Agent: [Li+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(CC(CC)CC)(NC(=O)OCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 33 %

Procedure:
A mixture of 2-benzyloxycarbonylaminomalonic acid diethyl ester (Bladon, C. M. J. Chem. Soc. Perkin Trans. 1990, 1, 1151-1158) (1.237 g), iodo-2-ethylbutane (1.272 g) and lithium hydroxide (0.287 g) in N-methylpyrrolidone (8 mL) was stirred for 2 days at room temperature and then diluted with ice water. The aqueous solution was extracted with ether and the product purified by chromatography on silica gel to give 2-benzyloxycarbonylamino-2-(2-ethylbutyl)malonic acid diethyl ester (0.520 g).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][N:13]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17](B3OC(C)(C)C(C)(C)O3)[C:16]=2[CH2:15][NH:14]1>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:16]=3[CH:15]=[N:14][N:13]4[CH3:12])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CN1NCc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Product: Cn1ncc2c(-c3cccn4nc(Cl)nc34)cccc21

Procedure:
2-Chloro-8-(1-methyl-1H-indazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 1-methyl-2H-indazole-4-boronic acid pinacol ester in a manner analogous to Example 2c (0.36 g, 59%). MS=284 (MH)+.
Reaction SMILES: OO.[F:3][C:4]1[C:9]([F:10])=[C:8]([O:11]CC)[CH:7]=[C:6]([CH3:14])[C:5]=1OB(O)O.[Na]>C1COCC1>[F:10][C:9]1[C:4]([F:3])=[CH:5][C:6]([CH3:14])=[CH:7][C:8]=1[OH:11]
Reactant: CCOc1cc(C)c(OB(O)O)c(F)c1F
Agent: OO
Agent: [Na]
Solvent: C1CCOC1
Product: Cc1cc(O)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under cooling with an ice bath, 6.57 g of aqueous hydrogen peroxide was slowly added dropwise to the compound (10) having been dissolved in 37 mL of THF, followed by stirring at room temperature for 3 hours. Under cooling with an ice bath, 20 mL of a saturated sodium hydrogensufite aqueous solution was added thereto to terminate the reaction, and an aqueous layer was extracted with diethyl ether, which was added to the organic layer. The organic layer was washed with a saturated sodium hydrogensufite aqueous solution and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 3.84 g of 2,3-difluoro-5-methylphenol (11).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[O:12])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.O>CN(C)C=O>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:20][C:14]1[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=1[C:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[CH:6][CH:7]=1)=[O:12]
Reactant: COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccc(OCCCl)cc3)c2cc1OC
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccc(OCCN4CCCCC4)cc3)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
[4-(2-Chloro-ethoxy)-phenyl]-[2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methyl-phenyl]-methanone (compound 189) (48 mg) was dissolved in N,N-dimethylformamide to prepare a solution. Potassium carbonate (86 mg) and piperidine (52 mg) were then added to the solution, and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, and water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform methanol to give the title compound (31 mg, yield 58%).
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.N1C=CC=CC=1.ClC(Cl)([O:20][C:21](=[O:27])[O:22]C(Cl)(Cl)Cl)Cl.Cl>C(Cl)Cl>[CH:1]1[C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[C:21](=[O:20])([O-:27])[O-:22]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Agent: OCCc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C([O-])[O-]
Reaction time: 0.25 h

Procedure:
In a 250 mL 3-necked round-bottomed flask equipped with a mechanical stirrer, and a liquid addition device were placed 10 g (0.073 mol) of tyrosol, 22 ml (0.277 mol) of pyridine, 60 mL of DCM and stirred for 15 min to get a clear solution. Triphosgene (7.0 g, 0.071 mol of phosgene) was dissolved in 25 mL of DCM and the solution was introduced into the reaction flask over 2-3 hours. After the addition was complete, the 100 mL of 0.2 M aqueous HCl was added to the reaction mixture and stirred for 5 min. After allowing the layers to separate, the top aqueous layer was removed and discarded. The washing was repeated with three additional 100 portions of 0.2 M aqueous HCl. The reaction mixture was then dried over anhydrous magnesium sulfate and then precipitated with 100 mL of hexane. The resulting viscous oil was stirred with 200 mL of fresh hexane until the product solidified into a white solid. The product was transferred to a glass dish dried in a vacuum oven at 60° C. The polymer had a HPSEC polystyrene equivalent Mw of 7500 da and Mn of 5700 da (THF as mobile phase) and glass transition temperature (Tg) of 48° C. A number of oligomers and polymers ranging in Mw from 750 da to 40,000 da were prepared using this method.