Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[NH:10][C:9]2[C:4](=[N:5][C:6]([C:11]3[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=34)=[N:7][CH:8]=2)[N:3]1[CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[CH2:28]([N:30]=C=S)[CH3:29].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>>[CH2:28]([NH:30][C:2]1[N:3]([CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:4]2[C:9]([N:10]=1)=[CH:8][N:7]=[C:6]([C:11]1[CH:12]=[N:13][N:14]3[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=13)[N:5]=2)[CH3:29]
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n(C5CCOCC5)c4n3)c2c1
Reactant: CCN=C=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCNc1nc2cnc(-c3cnn4ccc(C#N)cc34)nc2n1C1CCOCC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a suspension of the compound obtained in example 1 section d (100 mg, 0.30 mmol) in CH2C2 (2 mL), ethyl isothiocyanate (0.042 mL, 0.48 mmol), EDC.HCl (171 mg, 0.89 mmol) and DIPEA (0.25 mL, 1.49 mmol) were added. The reaction mixture was heated in a CEM Explorer microwave oven at 80° C. and 150 W for 30 min. Then, it was evaporated to dryness. The crude product thus obtained was chromatographed over silica gel using MeOH/EtOAc mixtures of increasing polarity as eluent, to afford 42 mg of the desired compound (36% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([OH:20])([CH3:19])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)=[C:4]([O:21][CH3:22])[CH:3]=1.F[B-](F)(F)F.[H+].[Br:29]N1C(=O)CCC1=O>C(#N)C>[Br:29][C:7]1[C:2]([F:1])=[CH:3][C:4]([O:21][CH3:22])=[C:5]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([OH:20])([CH3:19])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(F)ccc1-c1cnc2nc(C(C)(C)O)cnn12
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CC#N
Product: COc1cc(F)c(Br)cc1-c1cnc2nc(C(C)(C)O)cnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cold (−20° C.) solution of 2-[7-(4-fluoro-2-methoxyphenyl)imidazo[1,2-b][1,2,4]triazin-3-yl]propan-2-ol (0.4 g, 1.32 mmol) in acetonitrile (4 ml) under nitrogen was added tetrafluoroboric acid (54 wt % solution in Et2O, 0.21 ml, 1.59 mmol) and then N-bromosuccinimide (0.28 g, 1.59 mmol) slowly such that the internal temperature remained less than −10° C. After addition the cooling bath was removed and the reaction mixture was allowed to warm to room temperature. Stirring at this temperature continued for 16 h. A 40% aqueous solution of NaHSO3 (10 ml) was added and the reaction mixture extracted with EtOAc (3×50 ml). Organic extracts were washed with water (50 ml), saturated aqueous brine (50 ml), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, EtOAc) to give a quantitative yield of the title compound: 1H NMR (400 MHz, CDCl3) δ 1.71 (6H, s), 3.47 (1H, s), 3.89 (3H, s), 6.86 (1H, d, J 10.3), 8.21 (1H, d, J 7.9), 8.29 (1H, s), 8.74 (1H, s); MS (ES+) m/z 381, 383 [M+H]+.
Reaction SMILES: CN(C=O)C.[Br:6]N1C(=O)CCC1=O.[C:14]1([C:20]2[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=2[OH:30])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[Br:6][C:22]1[CH:23]=[C:24]([C:26]([CH3:27])([CH3:29])[CH3:28])[CH:25]=[C:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:21]=1[OH:30]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1ccc(O)c(-c2ccccc2)c1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Br)c(O)c(-c2ccccc2)c1
Reaction time: 48 h

Procedure:
A 20 mL DMF solution of N-bromosuccinimide (4.07 g, 22.9 mmol) was slowly added to a DMF solution (100 mL) of 2-phenyl-4-tert-butyl-phenol (4.93 g, 21.8 mmol), forming a dark green solution. After stirring in the dark for 48 h, the resultant dark red solution was poured into 500 mL of water, forming a cloudy solution. This was extracted with 95:5 hexane/toluene (3×200 mL), dried over MgSO4, filtered and the solvent removed to give 7 as a thick red oil. Yield: 6.32 g (95%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH2:11][CH2:12][CH:13]([CH3:41])[CH:14]([OH:40])[CH:15]([CH3:39])[C:16](=[O:38])[CH:17]([CH2:36][CH3:37])[CH:18]2[CH:22]([CH3:23])[CH2:21][C:20]([CH2:34][CH3:35])([CH:24]3[CH2:29][CH2:28][C:27]([CH2:31][CH3:32])([OH:30])[CH:26]([CH3:33])[O:25]3)[O:19]2)=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:42])=[C:4]([CH3:43])[CH:3]=1.CO.Cl.[N:47]([O-])=O.[Na+]>O.Cl[Cu]>[N+:1](=[C:2]1[C:10]([CH2:11][CH2:12][CH:13]([CH3:41])[CH:14]([OH:40])[CH:15]([CH3:39])[C:16](=[O:38])[CH:17]([CH2:36][CH3:37])[CH:18]2[CH:22]([CH3:23])[CH2:21][C:20]([CH2:34][CH3:35])([CH:24]3[CH2:29][CH2:28][C:27]([CH2:31][CH3:32])([OH:30])[CH:26]([CH3:33])[O:25]3)[O:19]2)=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:42])=[C:4]([CH3:43])[CH2:3]1)=[N-:47]
Reactant: O=N[O-]
Reactant: CCC(C(=O)C(C)C(O)C(C)CCc1c(N)cc(C)c(O)c1C(=O)O)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C
Agent: Cl[Cu]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(C(=O)C(C)C(O)C(C)CCC1=C(C(=O)O)C(O)=C(C)CC1=[N+]=[N-])C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C
Temperature: 25 °C

Procedure:
A solution of 5-amino-3-methyl-6-{7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-[5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahydrofuryl]heptyl}salicylic acid (1.28 g.) in 10 ml. methanol and 2 ml. of aqueous N HCl was cooled to 0° and a chilled solution of 150 mg. of NaNO2 in 1 ml. water was slowly added. To the solution was added 320 mg. of CuCl in 1 ml. of concentrated HCl. The reaction mixture was allowed to slowly warm up to room temperature and then diluted with water and extracted with ether. The ether extract was concentrated to a small volume and the crystallized product was collected by filtration, m.p. 137°-138°. [α]D -13.5° (0.7%, CH3OH).
Reaction SMILES: [C:1]1([C:7]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[O:21][C:22]2[CH:29]=[CH:28][C:25](C=O)=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30]([OH:36])(=[O:35])[CH2:31][C:32](O)=O.Cl>N1C=CC=CC=1.N1CCCCC1>[C:1]1([C:7]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[O:21][C:22]2[CH:23]=[CH:24][C:25](/[CH:32]=[CH:31]/[C:30]([OH:36])=[O:35])=[CH:28][CH:29]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(Oc2c(-c3ccccc3)c(C(F)(F)F)cc3ccccc23)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1ccc(Oc2c(-c3ccccc3)c(C(F)(F)F)cc3ccccc23)cc1
Temperature: 85 °C
Yield: 79.6 %

Procedure:
4-{[2-Phenyl-3-(trifluoromethyl)-1-naphthalenyl]oxy}benzaldehyde (183) (92 mg, 0.24 mmol) was dissolved in pyridine (3 mL). To this solution was added malonic acid (74 mg, 0.70 mmol) and 1 drop of piperidine. The reaction mixture was heated at 85° C. overnight, cooled and poured into 5 N HCl (20 mL). The mixture was extracted with EtOAc. The combined organic extract was washed with 5 N HCl, water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a light brown viscous oil, which upon trituration with 1% MeOH in hexanes, yielded 83 mg (81%) of the title compound (184) as a white solid. mp 210-211° C. 1H NMR (400 MHz, CH3OH-d4): δ 6.28 (d, J=15.9 Hz, 1H), 6.56 (d, J=8.8 Hz, 2H), 7.10-7.30 (m, 5H), 7.37 (d, J=8.7 Hz, 2H), 7.53 (d, J=16.0 Hz, 1H), 7.60-7.72 (m, 2H), 7.89 (d, J=8.1 Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 8.36 (s, 1H). LCMS (APCI): m/z 435 (M+H)+, m/z 433 (M−H)−. Anal. Calc for C26H17F3O3.⅙H2O: C, 71.39; H, 3.99. Found: C, 71.50; H, 3.94.
Reaction SMILES: [CH3:1][N:2]=[C:3]([OH:19])[C:4]1[C:5](=[C:9]([N+]([O-])=O)[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([OH:8])=[O:7].[CH2:20]([SH:24])[CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:1][N:2]=[C:3]([OH:19])[C:4]1[C:5](=[C:9]([S:24][CH2:20][CH2:21][CH2:22][CH3:23])[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: CN=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C(=O)O
Reactant: CCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCSc1cc([N+](=O)[O-])cc(C(O)=NC)c1C(=O)O

Procedure:
25.1 g (100 mmols) of 3,5-dinitrophthalic acid N-methylimide, 19.8 g (220 mmols) of n-butylmercaptan, 41.5 g (300 mmols) of anhydrous potassium carbonate and 250 ml of absolute tetrahydrofuran are kept under reflux overnight. The reaction mixture is filtered, the filtrate is evaporated and the residue is taken up in methylene chloride/2 N HCl. The extracts are washed with saturated NaCl solution, dried over sodium sulfate and evaporated. After recrystallisation from cyclohexane, 11.96 g (41% of theory) of the title imide are obtained; melting point: 106°-108° C.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C>C(O)C>[CH:14](=[N:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCCCCCCCCCCCN
Reactant: O=Cc1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCCCCCCCCCN=Cc1ccccc1

Procedure:
18.5 g (0.1 mol.) of n-dodecylamine, 10.6 g (0.1 mol.) of benzaldehyde and a catalytic amount of acetic acid were reacted in anhydrous ethanol at 60°~70° C. for 4 hours. After distilling ethanol off, the residue was further distilled under reduced pressure to obtain N-benzylidene-n-dodecylamine (II), (b.p. 160°~163° C./0.6 mmHg) as a transparent oil which includes low melting solids.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=2)[C:3]=1[N+:19]([O-:21])=[O:20].[C:22]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].[OH-].[Na+]>CC(C)=O>[OH:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:22]([O:30][CH2:31][CH3:32])=[O:29])[C:3]=2[N+:19]([O-:21])=[O:20])=[CH:11][CH:12]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Nc2ccc(CCO)cc2)n1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1nc(C)nc(Nc2ccc(CCO)cc2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.3 %

Procedure:
To a stirred solution of 2-{4-[(6-chloro-2-methyl-5-nitro-4-pyrimidinyl)amino]phenyl}ethanol (step 1, 2.0 g, 6.48 mmol) in acetone (61 ml) was added diethyl malonate (1.53 g, 9.54 mmol) at 0° C., then aqueous NaOH solution (11N, 2 ml, 22 mmol) was added dropwise over 20 min. After addition, the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (120 ml), and the pH value was adjusted to 8.0 by addition of acetic acid. The whole was extracted with ethyl acetate (100 ml×3). The organic-layer was washed with brine (50 ml), dried (MgSO4), and concentrated. Removal of excess diethyl malonate by azetropical distillation with toluene afforded 3.26 g (72%) of the title compound as a brown oil.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([NH:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:21][CH2:22][CH2:23][CH2:24][OH:25])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]>C(Cl)(Cl)Cl>[CH2:41]([O:40][C:38](=[O:39])[N:26]([C@@H:20]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)CCN[C@@H](CCCCO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)CCN(C(=O)OCc1ccccc1)[C@@H](CCCCO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a stirred solution of the material from Step 5 (8 g, 18.11 mmol) in a 2:1 mixture of chloroform and saturated aqueous NaHCO3 (271 mL) was added benzyl chloroformate (2.59 mL, 118.11 mmol). The reaction mixture was stirred at room temperature for 1 hour, partitioned and extracted with chloroform. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using EtOAc-hexanes (10 to 70%) to yield 7 g of the title compound. LCMS (M+1)=576
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])=[C:5]2[CH2:19][CH2:20]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:41]C(Br)(Br)Br>C1COCC1>[Br:41][CH2:20][CH2:19][C:5]1[C:4]2[C:8](=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=2)[NH:7][C:6]=1[Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14]
Reactant: BrC(Br)(Br)Br
Reactant: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(Cl)cc2c1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(Cl)cc2c1CCBr
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
3-(2-bromoethyl)-5,6-dichloro-2-(triethylsilyl)-1H-indole was prepared according to method D Step III with 2-(5,6-dichloro-2-(triethylsilyl)-1H-indol-3-yl)ethanol (1.7 g; 4.94 mmol) in THF (6 mL) and triphenyl phosphine (2.59 g; 9.87 mmol) and perbromomethane (3.27 g; 9.87 mmol) in THF (40 mL) pre-stirred for 30 minutes. The crude mixture was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to yield 0.548 g (27%) of 3-(2-bromoethyl)-5,6-dichloro-2-(triethylsilyl)-1H-indole as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][S:32]([N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)(=[O:34])=[O:33]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH:31][S:32]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)(=[O:34])=[O:33])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(Nc1ccccc1Br)N1CCCC1
Product: Nc1ncc(-c2ccc(-c3ccccc3NS(=O)(=O)N3CCCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 571 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and N-(2-bromophenyl)pyrrolidine-1-sulfonamide MS (ESI): mass calcd. for C20H20FN5O2S, 413.13; m/z found, 414.4 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.63 (s, 2H), 7.59 (d, J=8.4, 1H), 7.50 (m, 1H), 7.39 (m, 1H), 7.32-7.29 (m, 2H), 7.24-7.22 (m, 1H), 7.22-7.15 (m, 1H), 6.87-6.79 (m, 2H), 6.36 (s, 1H), 3.37-3.26 (m, 4H), 1.94-1.83 (m, 4H).
Reaction SMILES: [CH:1]([C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH:12]=[N:13][C:7]2=[N:6][C:5]=1[CH3:14])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26][N:13]3[C:7]4=[N:6][C:5]([CH3:14])=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9](=[O:10])[N:8]4[CH:11]=[CH:12]3)=[CH:24][CH:23]=2)=[O:21])=[CH:30][CH:31]=1
Reactant: Cc1nc2n(c(=O)c1C(C)C)CC=N2
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2n(Cc3ccc(C(=O)c4ccc(Cl)cc4)cc3)ccn2c(=O)c1C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-isopropyl-7-methylimidazo[1,2-a]pyrimidin-5-one (0.400 g, 2.23 mmol) and 4-(4-chlorobenzoyl) benzyl bromide (0.762 g, 2.46 mmol) in DMF (15.0 ml) was added potassium carbonate (0.600 g, 4.50 mmol) and the mixture was stirred at room temperature overnight. The solvent was then distilled off and the residue was purified by silica gel column chromatography (methylene chloride: acetone=20:1) to provide a colorless amorphous solid.
Reaction SMILES: F[C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:22][C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([OH:32])=[CH:27][CH:26]=2.CCOCC>COCCOCCOC>[F:13][C:11]1[CH:10]=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([O:32][C:28]2[CH:29]=[C:30]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23]([CH3:22])=[CH:31]3)[CH:12]=1
Reactant: CCOC(=O)c1ccc(F)cc1F
Reactant: Cc1cc2cc(O)ccc2[nH]1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: CCOCC
Product: CCOC(=O)c1ccc(F)cc1Oc1ccc2[nH]c(C)cc2c1

Procedure:
Ethyl 2,4-difluorobenzoate (1.14 g), K3PO4 (1.30 g) and 2-methyl-5-indolol (0.90 g) were stirred at 110° C. in diglyme (12 mL) for 24 hours. The mixture was cooled and poured into ether. The solution was washed three times with 1M NaOH solution, and with brine, and dried. The solution was then concentrated. The concentrate was chromatographed on silica gel with 10% ethyl acetate/hexanes.
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([CH3:30])=[O:29])[CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:6][CH:5]=1.[OH2:31].OO>C(O)(=O)C>[NH2:1][N:2]=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([CH3:30])(=[O:31])=[O:29])[CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:8][CH:9]=1
Reactant: CS(=O)c1ccccc1C(CC(=O)O)NC(=O)CCCCc1ccc(C=NN)cc1
Reactant: O
Agent: OO
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccccc1C(CC(=O)O)NC(=O)CCCCc1ccc(C=NN)cc1
Reaction time: 48 h

Procedure:
(±)-β-[[5-[4-(Aminoiminomethyl)phenyl]-1-oxopentyl]amino]-2-(methylsulfinyl)benzenepropanoic acid (2.5 g) was added to water (15 ml), acetic acid (5 ml) and followed by the addition of 30% H2O2 (10 mL). The oxidation was allowed to proceed for 48 hours after which the reaction mixture was purified by reverse phase chromatography (water/acetonitrile) and lyophilized to give 1.6 g of the title compound as a white solid: 1H NMR (d6 -DMSO) δ1.52 (m, 4H), 2.01 (m, 2H), 2.63 (m, 4H), 3.50 (s, 3H), 5.82 (m, 1H), 7.35 (m, 9H), 7.7 (m, 1H), 9.10 (bs, 2H), 9.20 (bs, 2H); MS (FAB) m/e 446.2 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11]Br)=[CH:2]1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:2]1
Reactant: BrCCc1coc2ccccc12
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc2c(CCN3CCNCC3)coc2c1

Procedure:
84 mmol of 2-(benzofuran-3-yl)-1-bromoethane, 67 mmol of piperazine and 56 mmol of potassium carbonate are added to 200 ml of acetonitrile. After refluxing for 4 hours, the reaction mixture is cooled and then concentrated. The residue is taken up in dichloromethane, is washed with water, dried, filtered and then concentrated under reduced pressure. Chromatography over silica gel (dichloromethane/ethanol: 90/10) allows the expected product to be isolated.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:31]([C:33]1[N:37]([CH3:38])[C:36]([C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])=[N:35][CH:34]=1)#[CH:32]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:4]([N:1]3[CH:32]=[C:31]([C:33]4[N:37]([CH3:38])[C:36]([C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])=[N:35][CH:34]=4)[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: C#Cc1cnc(C(=O)C(C)(C)C)n1C
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cnc(C(=O)C(C)(C)C)n4C)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 30 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide and 1-(5-ethynyl-1-methyl-1H-imidazol-2-yl)-2,2-dimethyl-propan-1-one in the same manner as Example 15. ESI MS m/z 622 [C31H39N7O5S+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[S:37]([NH:40][C:41]1[CH:46]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:44]=[C:43]([OH:56])[CH:42]=1)(=[O:39])=[O:38].C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[C:3]([C:45]2[CH:46]=[C:41]([NH:40][S:37]([C:31]3[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=3[F:29])(=[O:39])=[O:38])[CH:42]=[C:43]([OH:56])[CH:44]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2cc(O)cc(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)cc(NS(=O)(=O)c4ccc(F)cc4F)c3)n(-c3ccccc3)c(=O)c12
Yield: 8.6 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.18 mmol) was treated with 2,4-difluoro-N-(3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (180 mg, 0.37 mmol), sodium carbonate (2M, 200 μl, 0.40 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (30 mg, 0.04 mmol) according to the method described in Example 3 to give 10 mg (8% yield) of the title compound. Purity 94%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>ClCCl>[CH3:29][S:30]([N:1]([S:30]([CH3:29])(=[O:32])=[O:31])[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1)(=[O:32])=[O:31]
Reactant: Nc1cc(CNc2ccccc2C(=O)Nc2cccc(C(F)(F)F)c2)ccn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(c1cc(CNc2ccccc2C(=O)Nc2cccc(C(F)(F)F)c2)ccn1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49.2 %

Procedure:
193 mg (0.5 mmol) of 2-[(2-amino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamide is mixed in 3 ml of dichloromethane with 69 mg (0.6 mmol) of methanesulfonic acid chloride and 61 mg (0.6 mmol) of triethylamine and stirred together for 1.5 hours at room temperature. Then, it is washed once with dilute sodium bicarbonate solution, dried, filtered and concentrated by evaporation. The residue is chromatographed via flash chromatography (5 g of Isolute) with a gradient of cyclohexane:ethyl acetate=100:0 to 50:50 as an eluant. 80 mg (30% of theory) of 2-[(2-bismethanesulfonylamino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamide is obtained as a resin.