Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([CH3:38])[C:29]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:37][S:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH3:38])(=[O:36])=[O:35])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccccc2C)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and o-toluenesulfonamide in accordance with Procedure 1, Method B described hereinabove. Yield (37%); 1H NMR (CD3OD) δ 11.63 (br s, 1H), 7.54 (d, J=15.7 Hz, 2H), 7.39–7.09 (m, 15H), 6.87 (d, J=8.0 Hz, 2H), 6.81 (s, 1H), 6.41 (d, J=15.7 Hz, 1H), 3.02–2.73 (s, 3H), 2.37 (q, J=7.3 Hz, 2H), 0.83 (t, J=7.3 Hz, 3H); APcI m/z: 508 (M+H+).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Si:14]([O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]O)=[CH:28][CH:27]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C.CCCCCC>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:32][C:29]2[CH:28]=[CH:27][C:26]([CH2:25][O:24][CH2:23][CH2:22][O:21][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:31][CH:30]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Reactant: CC(C)(C)[Si](C)(C)OCCOCc1ccc(CO)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)n1ncc(OCc2ccc(COCCO[Si](C)(C)C(C)(C)C)cc2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a solution of 2-tert-butyl-4-chloro-5-hydroxy-2H-pyridazin-3-one (212 mg, 1.047 mmol) in THF (15 mL) was added the product of Example 8C (475 mg, 1.570 mmol), triphenylphosphine (412 mg, 1.570 mmol), and then diisopropyl azodicarboxylate (DIAD, 304 μL, 1.570 mmol). The reaction was stirred at room temperature for 2 hours under nitrogen atmosphere. Thin layer chromatography (1:1 hexane:ethyl acetate) indicated consumption of the pyridazinone starting material and the reaction was concentrated in vacuo. The crude material was purified by flash column chromatography (90:10 pentane:ethyl acetate) to obtain a clear oil (336 mg, 66% yield). 1H NMR (600 MHz, CDCl3): 7.70 (s, 1H), 7.39 (m, 4H), 4.58 (s, 2H), 1.63 (s, 9H), 0.90 (s, 9H), 0.07 (s, 6H); HRMS calcd for C24H31D6ClN2O4Si: 509.24738, found 509.2480.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[C:7]([O:11][O:12][C:13]([CH3:19])([CH3:18])[CH2:14][CH:15]([CH3:17])[OH:16])([CH3:10])([CH3:9])[CH3:8].[CH2:20]([OH:23])[CH:21]=[CH2:22]>C(OCC)(=O)C>[C:1]([O:23][CH2:20][CH:21]=[CH2:22])(=[O:5])[C:2]([O:16][CH:15]([CH3:17])[CH2:14][C:13]([O:12][O:11][C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:18])[CH3:19])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCO
Reactant: CC(O)CC(C)(C)OOC(C)(C)C
Solvent: CCOC(C)=O
Product: C=CCOC(=O)C(=O)OC(C)CC(C)(C)OOC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A second preparation of I-4 was carried out. A 100 mL 3-necked flask equipped with a magnetic stirring bar, a nitrogen inlet line, a thermometer and an addition funnel with a side arm was charged with 25.9 g(200 mmoles) of oxalyl chloride, dry nitrogen gas was bubbled through the oxalyl chloride and the flask contents were cooled to 0° C. Then 20.0 g (97.3 mmoles) of 92.6% 3-t-butylperoxy-1,3-dimethylbutanol was added dropwise at such a rate that the temperature remained below 15° C. The addition took 30 minutes to complete. The reaction mass was then stirred for 60 minutes at 15° C. after which 50 mL of dry ethyl acetate was added. The contents were then transferred to a one-necked flask and the solvent and excess oxalyl chloride were then removed using a rotary evaporator. Obtained was 29.3 g of a light yellow oil. The oil was cooled to 10° C. and to it was added 6.0 g (103.3 mmoles) of allyl alcohol over a period of 15 minutes while a vigorous stream of dry nitrogen was swept through the reaction mass. The temperature was held below 20° C. during the addition of allyl alcohol. The reaction mixture was then stirred for 60 minutes at 15°-20° C. after which it was stripped on a rotary evaporator. Obtained was 31.7 g (>100% of theory, uncorrected) of a light yellow liquid. GC showed a single large peak, 93% by area. An IR spectrum of the product showed carbonyl bands at 1770 cm-1 and 1750 cm-1 and a peroxide (--OO--) band at 875 cm-1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:32]=1>>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[S:37]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)(=[O:39])=[O:38])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2cccnc2)c1

Procedure:
The title compound of Step B was prepared from {3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester of Step A and pyridine-3-sulfonyl chloride hydrochloride, of Preparation 2, following the method described in Example 3, Step B with a reaction time of 2 h. 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.78 (d, 1H), 8.03 (dd, 1H), 7.88 (m, 1H), 7.69 (m, 1H), 7.55 (d, 2H), 7.42 (m, 1H), 7.13 (m, 3H), 6.76 (d, 1H), 6.66 (m, 2H), 6.45 (m, 1H), 4.39 (s, 2H), 4.38 (s, 2H), 4.33 (s, 2H), 1.47 (s, 9H); MS 535(M+1).
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[C:16]1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[OH:1]
Reactant: Cc1ccccc1
Reactant: O=C(O)c1cccnc1O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cccnc1O
Reaction time: 28 h
Yield: 84 %

Procedure:
To a solution of 2-hydroxynicotinic acid (3-067-01) (50 g) in methanol (500 ml) were added conc. sulfuric acid (15 ml) and toluene (100 mL) at room temperature. After the reaction mixture was stirred for 28 h attached Dienstark reflux tube and neutralized with an aqueous potassium carbonate solution, the solvent was evaporated. To the residue were added aqueous saturated ammonium chloride solution and chloroform, and the organic layer was separated, and the aqueous layer was extracted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give 2-hydroxynicotinic acid methyl ester (3-067-02) (46 g, 84%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]3[C:13]4[CH:30]=[CH:29][N:28](S(C5C=CC(C)=CC=5)(=O)=O)[C:14]=4[N:15]=[C:16]([NH:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=4)[N:17]=3)[CH:9]=2)[CH:4]=[N:3]1.[OH-].[K+].CC(O)=O>O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]3[C:13]4[CH:30]=[CH:29][NH:28][C:14]=4[N:15]=[C:16]([NH:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=4)[N:17]=3)[CH:9]=2)[CH:4]=[N:3]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cnn(C)c5c4)nc(Nc4ccc(C(N)=O)cc4)nc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cn1ncc2ccc(Nc3nc(Nc4ccc(C(N)=O)cc4)nc4[nH]ccc34)cc21
Temperature: 70 °C
Reaction time: 20 h
Yield: 22.8 %

Procedure:
To a solution of 4-(4-(1-methyl-1H-indazol-6-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide (12 mg, 0.022 mmol) in dioxane (2 mL), aq. 1N KOH (2 mL, 2.00 mmol) was added. The mixture was stirred at 70° C. for 20 h. HOAc (1.0 mL) was added. The mixture was purified by HPLC to give the titled compound (2 mg). MS 399.2 (M+H) (Compound 23-1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1)[CH3:2].[Cl:12][C:13]1[C:14]([C:20]#[N:21])=[N:15][CH:16]=[C:17](Cl)[CH:18]=1.C([N:24](CC)CC)C>[Cu]I.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.CN(C=O)C>[CH3:10][C:7]1[C:8]2=[C:13]3[C:14](=[C:20]([NH2:21])[N:24]=[C:9]2[CH:4]=[CH:5][CH:6]=1)[N:15]=[CH:16][CH:17]=[CH:18]3.[Cl:12][C:13]1[C:14]([C:20]#[N:21])=[N:15][CH:16]=[C:17]([C:11]#[C:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[CH:18]=1
Reactant: CCN(CC)CC
Reactant: C#Cc1ccc(OCC)cc1
Reactant: N#Cc1ncc(Cl)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CCOc1ccc(C#Cc2cnc(C#N)c(Cl)c2)cc1
Product: Cc1cccc2nc(N)c3ncccc3c12
Temperature: 60 °C
Yield: 4 %

Procedure:
To a round bottom flask capped with septa was added 1-ethoxy-4-ethynylbenzene (1.1 eq), 3,5-dichloropicolinonitrile (1 eq.), triethylamine (5 eq.), and anhydrous DMF (0.2 M). Vacuumed and nitrogen flushed for three times. CuI (0.05 eq.) and bis(triphenylphosphine)dichloro-palladium(II) (0.05 eq) were added. The septum was replaced with a refluxing condenser and the flask was heated at 60° C. overnight under nitrogen atmosphere. Upon completion of the reaction as monitored by TLC, the content of the flask was loaded onto a large silica gel column pretreated with hexanes. Flash chromatography (silica gel, hexanes:EtOAc (1:4%)) afforded the product 3-chloro-5-((4-ethoxyphenyl)ethynyl)picolinonitrile.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[O:19]1[C:24]2[CH:25]=[CH:26][C:27](N)=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[O:19]1[CH2:20][CH2:21][O:22][C:23]2[CH:28]=[C:27]([NH:13][C:12]3[C:11]4[C:10](=[CH:9][CH:8]=[C:6]5[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]5=4)[N:14]=[CH:15][N:16]=3)[CH:26]=[CH:25][C:24]1=2
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc5c(c4)OCCO5)c3c2s1
Yield: 33 %

Procedure:
Prepared from VII and 1,4-benzodioxan-6-amine. Flash chromatography eluent (DCM-EtOAc, 8:2). Yield: 33%; yellow solid; mp 180-190° C.; IR (KBr) νmax/cm−1 3055, 2978, 2932, 2875, 2230, 1709, 1638, 1609, 1578, 1496, 1460, 1376, 1299, 1281, 1239, 1200, 1151, 1063, 916, 885, 814; 1H NMR (300 MHz, DMSO-d6) δ 8.37 (d, 1H, J=8.4 Hz), 7.85 (m, 1H), 7.76 (m, 1H), 6.88 (d, 1H, J=8.4 Hz), 6.56 (m, 2H), 4.25 (s, 4H); HRMS calcd for C18H12N5O2S (M+H+): 362.0712, found 362.0696.
Reaction SMILES: C([O:8][CH2:9][C:10]1([CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:14][C:13](=[O:15])[CH2:12][CH2:11]1)C1C=CC=CC=1.C(O)C.[H][H]>[Pd].O>[OH:8][CH2:9][C:10]1([CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:14][C:13](=[O:15])[CH2:12][CH2:11]1
Reactant: CCCCCCCCCCCCCCCCCCOCCC1(COCc2ccccc2)CCC(=O)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOCCC1(CO)CCC(=O)O1

Procedure:
A mixture containing 10.2 g (21.83 mmol) of the compound prepared in (e) above, 300 ml of a mixture of ethyl alcohol and water in a ratio of 9:1 and 1.5 g of 5% palladium on carbon (50% water content) was placed in a pressure bottle and hydrogenated at 40° C. under a pressure of 50 lbs. of hydrogen until uptake was complete. The catalyst was then filtered off and the filtrate concentrated in vacuo. The residue was crystallized from methanol to yield a solid.
Reaction SMILES: C(Cl)CCl.[CH3:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][C:7]=1[B:13]1[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]1.[C:22]([C:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][N:35]=1)[C:30](O)=[O:31])([CH3:26])[CH3:25])#[N:23].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O>[C:22]([C:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][N:35]=1)[C:30]([NH:10][C:9]1[CH:11]=[CH:12][C:6]([CH3:5])=[C:7]([B:13]2[O:14][C:15]([CH3:21])([CH3:20])[C:16]([CH3:19])([CH3:18])[O:17]2)[CH:8]=1)=[O:31])([CH3:26])[CH3:25])#[N:23]
Reactant: CC(C)(C#N)c1cc(C(=O)O)ccn1
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)c2ccnc(C(C)(C)C#N)c2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
EDC (1.3 equiv.) was added to a solution of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.0 equiv.), 2-(2-cyanopropan-2-yl)isonicotinic acid (1.2 equiv.), HOAt (1.3 equiv.) in DMF (0.19 M). The mixture was stirred at ambient temperature 3 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with 1M aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered, and concentrated to yield 2-(2-cyanopropan-2-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isonicotinamide in 97% yield. LCMS (m/z) (M+H)=406.2, Rt=1.10 min.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][C:16]([F:28])([F:27])[CH2:17][O:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][CH:20]=1>>[Cl:13][C:12]1[C:3]2[CH2:2][N:26]([CH2:25][C:22]3[CH:23]=[N:24][C:19]([O:18][CH2:17][C:16]([F:28])([F:15])[F:27])=[CH:20][CH:21]=3)[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: NCc1ccc(OCC(F)(F)F)nc1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: O=C1c2ccnc(Cl)c2CN1Cc1ccc(OCC(F)(F)F)nc1
Yield: 65 %

Procedure:
The title compound is prepared in 65% yield (132 mg, white solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (138 mg, 0.57 mmol, Amine-11) in a similar manner to Intermediate-2.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:24]2[C:12](=[C:13]([CH3:30])[C:14]3[N:15]([CH3:29])[C:16]4[CH:17]=[CH:18][C:19]([O:25][C:26](=[O:28])[CH3:27])=[CH:20][C:21]=4[C:22]=3[CH:23]=2)[CH:11]=[CH:10][N:9]=1)=[O:7].[Cl:32]C1C=C(C=CC=1)C(OO)=[O:37]>ClCCl>[ClH:32].[ClH:32].[CH3:31][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:24]2[C:12](=[C:13]([CH3:30])[C:14]3[N:15]([CH3:29])[C:16]4[CH:17]=[CH:18][C:19]([O:25][C:26](=[O:28])[CH3:27])=[CH:20][C:21]=4[C:22]=3[CH:23]=2)[CH:11]=[CH:10][N+:9]=1[O-:37])=[O:7]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)Oc1ccc2c(c1)c1cc3c(C(=O)NCCN(C)C)nccc3c(C)c1n2C
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(c1)c1cc3c(C(=O)NCCN(C)C)[n+]([O-])ccc3c(C)c1n2C
Product: Cl

Procedure:
The reaction of 1-[(2-dimethylaminoethyl)aminocarbonyl]-5,6-dimethyl-9-acetoxy-6H-pyrido-[4,3-b]carbazole with 3-chloroperoxybenzoic acid in dichloromethane at room temperature results in the desired product, m.p.(cap): 120° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[Se](=O)=[O:14]>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH:12]=[O:14])[CH:3]=1
Reactant: O=[Se]=O
Reactant: Cc1cc(Cl)c2ccccc2n1
Solvent: O
Product: O=Cc1cc(Cl)c2ccccc2n1
Temperature: 90 °C

Procedure:
4-Chloro-2-methylquinoline (0.4 ml, 0.5M solution in dioxane) was treated with selenium dioxide (0.2 ml, 0.9M solution in 9/1 dioxane/water) and heated to 90° C. overnight. The mixture was cooled to room temperature and diluted with water (1 ml). The mixture was then extracted with ethyl acetate (3×2 ml). The organic extract was then dried in vacuo to give 4-chloro-2-quinolinecarboxaldehyde which was carried forward without further purification. Daptomycin (1 ml, 0.1 M in dry dimethylformamide) was treated successively with 4-chloro-2-quinolinecarboxaldehyde prepared above and diluted in dry dimethylformamide (0.2 ml) and sodium triacetoxyborohydride (0.4 ml, 1.5M in dry dimethylformamide). The mixture was capped and shaken briefly. After 24 h the mixture was treated with water (0.2 ml) and loaded on an IBSIL-C8 5μ 250×20.2 mm column. The column was eluted at 25 ml/min under the gradient conditions of 30-60% acetonitrile in 5 mM ammonium phosphate buffer over 25 min followed by holding at 60% acetonitrile in 5 mM ammonium phosphate buffer for another 10 min. The desired fractions were collected and the acetonitrile was removed by evaporation. The residue was applied to a Bondesil 40μ C8 resin column, washed with water and the product eluted off with methanol. Evaporation of the methanol gave compound 285 as a yellow solid.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H][H]>C(O)C.CCOCC.[Pd]>[CH2:16]([NH:23][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: [H][H]
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: c1ccc(CNCc2ccc(Oc3ccccc3)cc2)cc1

Procedure:
4-Phenoxybenzaldehyde (10.0 g, 0.05 mol), excess benzyl amine and 1.0 g of 10% Pd/C in 200 mL of ethanol were stirred under an inert atmosphere for 16 hours followed by an atmosphere of hydrogen for 16 hours. After removal of the catalyst by filtration through Celite®, the filtrate was concentrated under reduced pressure to give the crude product as an oil. The oil was dissolved in ether and precipitated by treatment with anhydrous HCl. The solid was filtered, washed with ether, and partitioned between ethyl acetate and 1M NaOH. The ethyl acetate solution was washed with brine, dried over Na2SO4, and evaporated to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:13]=3[CH:28]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].N[C@H:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:31][OH:32]>C1(Cl)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]5[O:32][CH2:31][C@@H:30]([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)[N:2]=5)[CH:4]=4)=[CH:28][C:13]=3[C:14]=2[C:24]([NH:26][CH3:27])=[O:25])=[CH:18][CH:19]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C#N)c3)cc12
Reactant: N[C@@H](CO)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C4=N[C@H](c5ccccc5)CO4)c3)cc12
Yield: 13.2 %

Procedure:
Zinc chloride (8 mg, 0.054 mmol) was added to a stirring solution of 5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (40 mg, 0.108 mmol) and (R)-2-amino-2-phenylethanol (148 mg, 1.080 mmol) in PhCl (3 mL) at rt. It was subjected to two interactions of microwave irradiation at 200° C. for 1 hr. The material was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (7 mg, 13%). 1H NMR (500 MHz, CD3OD) δ ppm 8.33 (1H, s), 7.94-8.00 (4H, m), 7.91 (1H, d, J=7.94 Hz), 7.64-7.73 (2H, m), 7.61 (1H, t, J=7.78 Hz), 7.32-7.42 (6H, m), 7.26 (2H, t, J=8.55 Hz), 5.45 (1H, t, J=9.16 Hz), 4.94 (1H, t, J=9.31 Hz), 4.36 (1H, t, J=8.24 Hz), 2.97 (3H, s). LC-MS retention time 1.75 min; m/z (MH+): 491. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% MeOH/95% H2O/10 mM ammonium bicarbonate, Solvent B=95% MeOH/5% H2O/10 mM ammonium bicarbonate, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: PHENOMENEX® Gemini C-18, 4.6×150 mm, 3 μm, Rt=18.32 min, purity=97%; Column: Waters XBridge phenyl column 4.6×150 mm, 3.5 μm, Rt=18.11 min, purity=97%.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]([NH:15][CH:16]([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:7][C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N#N>CCN(CC)CC.O.[Cu]I.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>[C:24]1([C:30]#[C:31][C:2]2[CH:23]=[CH:22][C:5]3[C:6]([NH:15][CH:16]([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:7][C:8]4[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=4[C:4]=3[CH:3]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C#Cc1ccccc1
Reactant: CC(Nc1nc2cc[nH]c(=O)c2c2cc(Br)ccc12)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(Nc1nc2cc[nH]c(=O)c2c2cc(C#Cc3ccccc3)ccc12)C(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 9-bromo-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one (150 mg, 0.040 mmol) in Et3N (3.0 mL) was added the phenylacetylene (50 mg, 0.05 mmol), CuI (10 mg) and PdCl2(PPh3)2 (10 mg). The mixture was stirred under reflux and N2 atmosphere for 12 h. After cooling to room temperature, the mixture was diluted with water (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over magnesium sulfate, filtered, and concentrated to a crude residue that was purified by preparative TLC to afford 9-(phenylethynyl)-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one. 1H-NMR (300 MHz, MeOH): δ 10.03 (s, 1H), 8.26 (d, J=8.3 Hz, 1H), 7.70 (d, J=9.0 Hz, 1H) 7.39 (m, 1H), 6.62 (m, 4H), 3.30 (s, 1H), 1.27 (d, J=6.9 Hz, 2H), 1.03 (s, 9H). LRMS calculated for C26H25N3O [M+H]+, 396; found 396.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:7][CH2:6][N:5]([C:8]2[C:14]([F:15])=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=2[F:16])[CH2:4][CH2:3]1.[O-]S(C(F)(F)F)(=O)=O.[Li+].[O:27]1[CH2:33][C@@H:28]1[C:29]([O:31][CH3:32])=[O:30]>C(#N)C>[O:17]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]2[C:14]([F:15])=[CH:13][C:11]([NH:12][CH2:33][C@@H:28]([OH:27])[C:29]([O:31][CH3:32])=[O:30])=[CH:10][C:9]=2[F:16])[CH2:4][CH2:3]1
Reactant: Nc1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Reactant: COC(=O)[C@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: COC(=O)[C@H](O)CNc1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 56.5 %

Procedure:
A solution of 4-(1,1-dioxidothiomorpholin-4-yl)-3,5-difluoroaniline (EXAMPLE 15, Step 3, 1.30 g, 5.0 mmol) in acetonitrile (7.5 mL) is treated with lithium triflate (0.60 g, 5.0 mmol) and methyl (2R)-2,3-epoxypropanoate (0.51 g, 0.46 mL, 5.0 mmol) and heated to 70° C. for 2 h. At this time an additional amount (1.5 mmol each) of the two reagents is added and the mixture stirred for another 7 h at 70° C. The reaction mixture is then cooled to room temperature, concentrated, and purified by column chromatography (50–60% ethyl acetate-hexane) to provide the title compound (1.03 g, 57%), MS (m/z): [M+H]+=365; 1H NMR (300 MHz, CDCl3): δ 3.04 (d, 1H), 3.15 (m, 4H), 3.31–3.46 (m, 2H), 3.47–3.56 (m, 4H), 3.83 (s, 3H), 4.20 (t, 1H), 4.40 (m, 1H), 6.17 (d, 2H).