Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:13]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[C:20]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:21]3[CH2:24][CH2:25][CH2:26][CH2:27][N:28]3[C:36](=[O:37])[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]3=[O:38])=[CH:17][CH:16]=2)=[O:14])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[O-]S(C(F)(F)[F:50])(=O)=O.F[N+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[Br:1][C:2]1[S:3][C:4]([C:13]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([F:50])=[C:20]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[N:21]3[CH2:24][CH2:25][CH2:26][CH2:27][N:28]3[C:36](=[O:37])[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]3=[O:38])=[CH:17][CH:16]=2)=[O:14])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccccc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: F[n+]1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)Cc1cc(C(=O)c2ccc3c(F)c(-c4ccccc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Temperature: 25 °C
Yield: 18.8 %

Procedure:
To a solution of 5 (209 mg, 0.31 mmol) in 3 mL CH2Cl2 was added 1-fluoropyridinium triflate (81 mg, 0.33 mmol), and then the mixture stirred at room temperature until no 5 was detected by NMR. The resulting mixture was diluted with 40 mL Et2O, washed with brine (2×10 mL), dried over MgSO4, filtered, and then concentrated in vacuo. MPLC purification (Hex/EtOAc 9:1) gave 6 (40 mg, 19%) as a yellow amorphous solid. 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.77-7.63 (m, 6H), 7.57 (s, 1H), 7.48-7.40 (m, 5H), 4.25 (t, J=7.2 Hz, 2H), 4.16 (q, J=7.2 Hz, 2H), 3.72 (s, 2H), 3.48 (t, J=6.8 Hz, 2H), 1.65-1.61 (m, 2H), 1.50-1.44 (m, 2H), and 1.26 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 187.16, 169.94, 168.50, 143.96, 143.10, 140.65, 135.88, 135.17, 134.22, 134.17, 132.37, 132.31, 132.11, 131.68, 129.96, 129.51, 129.17, 129.13, 128.96, 128.45, 127.58, 127.38, 123.46, 121.80, 121.19, 120.18, 120.03, 116.97, 112.58, 61.52, 43.64, 37.21, 35.33, 27.32, 25.76, and 14.44; 19F NMR (376 MHZ, CDCl3) δ −174.33.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:23][CH2:22][CH2:21][N:20]2[C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4[O:37][C:36]([CH3:38])=[N:35][CH:34]=4)=[C:29]([O:39][CH3:40])[CH:28]=3)=[N:25][N:26]=[C:19]12>CN(C=O)C.C(OCC)(=O)C.[Cl-].[NH4+]>[CH3:40][O:39][C:29]1[CH:28]=[C:27]([C:24]2[N:20]3[CH2:21][CH2:22][CH2:23][C:18]([O:10][C:4]4[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=4)([C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:19]3=[N:26][N:25]=2)[CH:32]=[CH:31][C:30]=1[C:33]1[O:37][C:36]([CH3:38])=[N:35][CH:34]=1
Reactant: Oc1cc(F)c(F)c(F)c1
Reactant: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Oc2cc(F)c(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
To a mixture of 3,4,5-trifluorophenol (0.19 g) and potassium carbonate (0.50 g) in DMF (5 mL) was added ethyl 8-chloro-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (0.50 g) at room temperature, and the mixture was stirred at 100° C. for 30 min. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate and saturated aqueous ammonium chloride solution, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (0.28 g).
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:8][C:7]1[C:2]([F:1])=[C:3]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:4]=[CH:5][C:6]=1[F:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(F)ccc(-c2ccccc2)c1F
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(-c2ccccc2)c(F)c1CBr
Yield: 112.4 %

Procedure:
A stirred solution of 2,4-difluoro-3-methyl[1,1'-biphenyl] (2.2 g, 0.011 mole) and N-bromosuccinimide (1.9 g, 0.011 mole) in 100 ml of carbon tetrachloride was irradiated with a 250 watt brooder lamp for 4 hours. The reaction mixture was allowed to reflux from the heat of the lamp. The reaction mixture was then filtered, and the filter cake was washed with three portions of carbon tetrachloride. The washes and filtrate were combined and evaporated under reduced pressure to give 3-bromomethyl-2,4-difluoro[1,1'-biphenyl] (3.5 g) as an oil whose nmr spectrum was consistent with that expected for the named compound.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:24])[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=3)=[CH:9][O:10]2)=[CH:5][CH:4]=1)#[CH:2].Br[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>O1CCCC1.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)I>[C:33]([O:32][C:28]1[CH:27]=[C:26]([C:2]#[C:1][C:3]2[CH:12]=[C:11]3[C:6]([C:7](=[O:24])[C:8]([C:13]4[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=4)=[CH:9][O:10]3)=[CH:5][CH:4]=2)[CH:31]=[CH:30][N:29]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: C#Cc1ccc2c(=O)c(-c3ccc(NS(C)(=O)=O)cc3)coc2c1
Reactant: CC(C)(C)Oc1cc(Br)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)Oc1cc(C#Cc2ccc3c(=O)c(-c4ccc(NS(C)(=O)=O)cc4)coc3c2)ccn1
Temperature: 85 °C

Procedure:
N-(4-(7-ethynyl-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide (100 mg, 0.29 mmol) was combined with 4-bromo-2-tert-butoxypyridine (0.074 mg, 1.1 eq), PdCl2(PPh3)2 (10 mg, 0.05 eq), copper iodide (4 mg 0.002 eq), triphenylphosphine (6 mg 0.03 eq) and triethylamine (0.12 ml, 4.0 eq) in dry tetrahydrofuran (10 ml) and heated in microwave for 30 minutes at 85° C. Solvent was removed from the product under reduced pressure, and the residue was extracted with ethyl acetate in the presence of water. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford N-(4-(7-((2-tert-butoxypyridin-4-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide. This crude product was dissolved in dichloromethane/trifluoroacetic acid 1:1 (4 ml) and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was extracted with ethyl acetate in the presence of water. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The product was heated in acetonitrile, cooled, and the solids were filtered out. This procedure was repeated twice in order to afford N-(4-(4-oxo-7-((2-oxo-1,2-dihydropyridin-4-yl)ethynyl)-4H-chromen-3-yl)phenyl)methanesulfonamide.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-].[Li+].C[Si](Cl)(C)C.C[SiH](C)O[SiH](C)C.BrCC1C=CC(OC)=C(OC2CCCC2)C=1.[C-:47]#[N:48].[Na+]>C(#N)C.CN(C)C=O.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:10][C:47]#[N:48])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: [C-]#N
Agent: COc1ccc(CBr)cc1OC1CCCC1
Agent: C[SiH](C)O[SiH](C)C
Agent: C[Si](C)(C)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CC#N)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
To a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (20 g, 90.8 mmol) in acetonitrile (100 mL) was added lithium bromide (15 g, 173 mmol) followed by the dropwise addition of trimethylsilylchloride (17.4 mL, 137 mmol). After 15 min, the reaction mixture was cooled to 0° C., 1,1,3,3-tetramethyldisiloxane (26.7 mL, 151 mmol) was added dropwise and the resulting mixture was allowed to warm to room temperature. After stirring for 3 h, the mixture was separated into two layers. The lower layer was removed, diluted with methylene chloride and filtered through Celite. The filtrate was concentrated under reduced pressure, dissolved in methylene chloride and refiltered. The solvent was removed in vacuo to provide a light tan oil. To a solution of this crude a-bromo-3-cyclopentyloxy-4-methoxytoluene in dimethylformamide (160 mL) under an argon atmosphere was added sodium cyanide (10.1 g, 206 mmol) and the resulting mixture was stirred at room temperature for 18 h, then poured into cold water (600 mL) and extracted three times with ether. The organic extract was washed three times with water, once with brine and was dried (potassium carbonate). The solvent was removed in vacuo and the residue was purified by flash chromatography, eluting with 10% ethyl acetate/hexanes, to provide an off-white solid (17.7 g, 84%): m.p. 32°-34° C.; an additional quantity (1.3 g) of slightly impure material also was isolated.
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[CH2:3][C:4](=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:12][C@H:13]([C:18]([N:20]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH2:21][C:22]([OH:24])=[O:23])=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15].C([BH3-])#N.[Na+]>>[CH2:8]([O:7][C:5]([C@@H:4]([NH:12][C@H:13]([C:18]([N:20]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH2:21][C:22]([OH:24])=[O:23])=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15])[CH2:3][CH:2]([CH3:11])[CH3:1])=[O:6])[CH3:9]
Reactant: CCOC(=O)C(=O)CC(C)C
Reactant: CC[C@H](C)[C@H](N)C(=O)N(CC(=O)O)c1cccnc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCOC(=O)[C@H](CC(C)C)N[C@H](C(=O)N(CC(=O)O)c1cccnc1)[C@@H](C)CC

Procedure:
Ethyl 4-methyl-2-oxopentanoate and L-isoleucyl-N-(3-pyridyl)-glycine were condensed in the presence of sodium cyanoborohydride to yield N-[1-(S)-ethoxycarbonyl-3-methylbutyl]-L-isoleucyl-N-(3-pyridyl) glycine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[F:20])[NH2:16]>>[F:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: Nc1ccc(F)c(F)c1
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1ccc(F)c(F)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3,4-difluoroaniline to yield 2-[(3,4-difluorophenyl)amino]phenylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]2)=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:40][CH:37]3[CH2:38][CH2:39][CH:34]([C:31]4[CH:30]=[CH:29][C:28]([Cl:27])=[CH:33][CH:32]=4)[CH2:35][CH2:36]3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NC1CCC(c2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCC(c5ccc(Cl)cc5)CC4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.050 g, 0.13 mmol), N,N-dimethylpyridin-4-amine (0.0016 g, 0.013 mmol), and 4-(4-chlorophenyl)cyclohexanamine (0.042 g, 0.20 mmol) in DMF (1 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.031 g, 0.16 mmol), and the reaction was stirred overnight at ambient temperature. The reaction was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to yield 65 mg of the title compound (86% yield).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:21]=[CH:20][C:8]([C:9](=O)[CH2:10][CH:11]([C:16]([CH3:18])=O)[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>C(O)(=O)C>[F:22][C:23]1[CH:29]=[CH:28][C:26]([N:27]2[C:16]([CH3:18])=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[C:9]2[C:8]2[CH:20]=[CH:21][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)C(CC(=O)c1ccc(S(C)(=O)=O)cc1)C(C)=O
Reactant: Nc1ccc(F)cc1
Solvent: CC(=O)O
Product: COC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)c1C
Yield: 92 %

Procedure:
3.00 g (9.6 mmol) of methyl 2-(4-methylsulfonylphenacyl)acetoacetate [prepared as described in step (ii) above] were dissolved in 100 ml of acetic acid and 0.97 g (8.7 mmol) of 4-fluoroaniline was added to the resulting solution. The resulting mixture was then heated under reflux for 5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, a saturated aqueous solution of sodium hydrogencarbonate was added to the residue and the mixture was extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The residue was applied to a silica gel chromatography column and eluted with a 1:2 by volume mixture of ethyl acetate and hexane, to give 3.10 g of the title compound as a white powder (yield 92%), melting at 154-155° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH3:15])=[CH:10]1.Cl.[NH2:18][OH:19].N1C=CC=CC=1>CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH:13]=[CH:12][C:11]([C:14](=[N:18][OH:19])[CH3:15])=[CH:10]1
Reactant: NO
Reactant: CC(=O)c1ccn(-c2c(C)cccc2C)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(=NO)c1ccn(-c2c(C)cccc2C)c1

Procedure:
A mixture of 1-(2,6-dimethylphenyl)-3-acetyl-1H-pyrrole (20.0 g), hydroxylamine hydrochloride (25.0 g), pyridine (130 ml) in 100 ml of methanol is heated under reflux for 20 hours. Workup in the usual manner yields 1-(2,6-dimethylphenyl)-3-acetyl-1H-pyrrole oxime.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18](=[O:27])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=2)=[O:10])=[CH:5][CH:4]=1.I.CS[C:31]1[NH:32][CH2:33][CH2:34][N:35]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:31]3[NH:35][CH2:34][CH2:33][N:32]=3)=[CH:8][CH:7]=2)=[O:10])=[O:27])=[N:21][CH:22]=1
Reactant: CSC1=NCCN1
Reactant: NCc1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)cc1
Agent: I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)c1ccc(CNC2=NCCN2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.3 %

Procedure:
A mixture of [4-(aminomethyl)phenyl]-N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}carboxamide (80 mg, 0.21 mmol), 2-methylthio-2-imidazoline hydriodide (77 mg, 0.315 mmol, 1.5 equiv.) and triethyl amine (0.5 mL) in 1 mL DMF was stirred at room temperature overnight, concentrated to dryness and HPLC (C18 reversed phase) eluting with 0.1% TFA in H2O/CH3CN gave N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}{4-[(2-imidazolin-2-ylamino)methyl]phenyl}carboxamide (13.5 mg, 15%). MS found for C23H21ClN6O2 (M+H)+: 449
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[C:7](=[O:16])[C@@:6]3([CH3:22])[CH2:17][O:18][CH:19]([CH3:21])[CH2:20][N:5]3[C:4]=2[N:3]=1.[CH3:23][NH:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1)=[O:26].O1CCOCC1.C([O-])(O)=O.[Na+]>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH:13]1([CH2:12][N:8]2[C:7](=[O:16])[C@@:6]3([CH3:22])[CH2:17][O:18][C@H:19]([CH3:21])[CH2:20][N:5]3[C:4]3[N:3]=[C:2]([C:31]4[CH:30]=[CH:29][C:28]([NH:27][C:25]([NH:24][CH3:23])=[O:26])=[CH:33][CH:32]=4)[N:11]=[CH:10][C:9]2=3)[CH2:15][CH2:14]1
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CC1CN2c3nc(Cl)ncc3N(CC3CC3)C(=O)[C@@]2(C)CO1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: CNC(=O)Nc1ccc(-c2ncc3c(n2)N2C[C@@H](C)OC[C@]2(C)C(=O)N3CC2CC2)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a microwave vial containing (R)-2-chloro-5-(cyclopropylmethyl)-6a,9-dimethyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (about 0.4 mmol) was added 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (0.133 g, 0.48 mmol), Pd(dppf)Cl2-dichloromethane, 1,4-dioxane (1.2 mL) and NaHCO3 (sat., 0.6 mL). It was heated in a microwave at 100° C. for 1 hour 45 minutes and then conventionally at 100° C. (bath temperature) for 3 hours. The mixture was diluted with MeOH, passed through a microfilter. The filtrate was purified on the HPLC (40-60% of AcCN in water containing 10 mM NH4HCO3, Phenomenex Gemini 5 μm C18, 75×30 mm column) to give a mixture containing the title product, which was further purified and resolved on a ChiralPak AD-H (5 μm, 10×250 mm, 25-25% of MeOH in liquid CO2) to give the title compound as a white solid (2.1 mg) and having a retention time of 5.20 minutes on ChiralPak AD-H column (5 μm, 2.1×150 mm, 26% of MeOH in liquid CO2). 1H NMR (400 MHz, METHANOL-d6) δ ppm 0.4-0.56 (m, 4 H) 1.22 (m, 1 H) 1.34 (d, J=4 Hz, 3 H) 1.44 (s, 3 H) 2.79 (s, 3 H) 2.95 (dd, J=16, 12 Hz, 1 H) 3.73 (m, 1 H) 3.82 (m, 2 H) 3.95 (m, 1 H) 4.12 (d, J=12 Hz, 1 H) 4.35 (dd, J=12, 4 Hz, 1 H) 7.46 (d, J=8 Hz, 2 H) 8.19 m (s, 1 H) 8.20 (d, J=8 Hz, 2 H). MS [M+H] found 437.4.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH:12](I)([CH3:14])[CH3:13].[OH:16][C:17]1[C:26]([OH:27])=[C:25]2[C:20]([C:21](=[O:30])[CH2:22][C:23]([CH3:29])([CH3:28])[O:24]2)=[CH:19][CH:18]=1>COCCOCCOC>[CH:12]([O:16][C:17]1[C:26]([OH:27])=[C:25]2[C:20]([C:21](=[O:30])[CH2:22][C:23]([CH3:28])([CH3:29])[O:24]2)=[CH:19][CH:18]=1)([CH3:14])[CH3:13]
Reactant: CC(C)I
Reactant: CC1(C)CC(=O)c2ccc(O)c(O)c2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(c1O)OC(C)(C)CC2=O
Temperature: 140 °C
Yield: 90 %

Procedure:
In 50 ml of N,N-dimethyl formamide 4.2 g (20 millimoles) of 7.8-dihydroxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 5 ml of diethylene glycol dimethylether, 3.0 g (22 millimoles) of potassium carbonate and 4.2 g (2.5 ml, 25 millimoles) of isopropyl iodide are added. The reaction mixture is heated at 140° C. for 4 hours and worked up according to Example 19. Thus 4.5 g of the desired compound are obtained, yield 90%, mp.: 114°-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:22][C:23]4[CH:24]=[N:25][C:26]([O:29]C)=[CH:27][CH:28]=4)=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].C[Si](I)(C)C.CO>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:22][C:23]4[CH:28]=[CH:27][C:26](=[O:29])[NH:25][CH:24]=4)=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(Oc2ccc3c(C(=O)Nc4ccc(F)c(Cl)c4)cccc3c2)cn1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(F)c(Cl)c1)c1cccc2cc(Oc3ccc(=O)[nH]c3)ccc12
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution/suspension of N-(3-chloro-4-fluorophenyl)-6-((6-(methoxy)-3-pyridinyl)oxy)-1-naphthalenecarboxamide (167 mg, 0.39 mmol) in chloroform (4.7 mL) was added trimethylsilyl iodide (Aldrich, 221 mg, 1.10 mmol). The reaction mixture was heated at 70° C. (oil bath) for 2.5 h, cooled to RT and MeOH (1 mL) was added. After stirring for 15 min, the dark yellow solution was concentrated in vacuo and treated with concentrated aqueous NH4OH (3 mL). The title compound was isolated by filtration and dried under high vacuum. MS (ESI, pos. ion) m/z: 409.1 (M+1). Mass Calc'd for C22H14ClFN2O3: 408.81.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[CH:9][N:10]([CH:11]3[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.[CH2:14]=[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][CH:18]=1)[CH3:16].C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(C)(C)C.O1CCOCC1>[CH:11]1([N:10]2[C:4]3[CH:3]=[C:2]([NH:23][C:21](=[O:22])[C:20]4[CH:24]=[CH:25][C:17]([C:15]([CH3:16])=[CH2:14])=[CH:18][CH:19]=4)[N:7]=[CH:6][C:5]=3[CH:8]=[CH:9]2)[CH2:13][CH2:12]1
Reactant: Clc1cc2c(ccn2C2CC2)cn1
Reactant: C=C(C)c1ccc(C(N)=O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1c(C)c(C)c(P(C(C)(C)C)C(C)(C)C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1C
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: C=C(C)c1ccc(C(=O)Nc2cc3c(ccn3C3CC3)cn2)cc1
Temperature: 130 °C
Yield: 41.4 %

Procedure:
In a 500 ml pressure vessel, 6-chloro-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridine (7A, 6.2 g, 32 mmol), 4-(prop-1-en-2-yl)benzamide (6.2 g, 39 mmol), palladium(II)acetate (0.29 g, 1.3 mmol), and 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl (2.2 g, 3.9 mmol) were added. Ground-up potassium phosphate tribasic (15 g, 45 mmol) was then added, followed by 1,4-dioxane (130 ml) and t-butanol (32 ml). The vessel was purged with nitrogen for 30 min, before being sealed and heated at 130° C. for 24 hr. After cooling, 250 ml of water and 250 ml EtOAc were successively added. The layers were separated, and the aqueous layer was extracted once more with 200 ml EtOAc. Combined organic layers were dried with Na2SO4, filtered, and concentrated. The crude product was purified by normal phase column chromatography eluting with EtOAc (10-40%) in hexanes. Product-containing fractions were combined and concentrated to obtain the product N-(1-cyclopropyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(prop-1-en-2-yl)benzamide (7B, ˜4.2 g, 41%) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([C:7]([C:9]1[C:10]([CH3:18])=[N:11][N:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=12)=[O:8])[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[Cl-].[NH4+]>O.CN(C=O)C>[CH3:18][C:10]1[C:9]([C:7](=[O:8])[C:2]([C:3]([O:5][CH3:6])=[O:4])([CH3:1])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1
Reactant: CCOC(=O)CBr
Reactant: COC(=O)C(C)C(=O)c1c(C)nn2ccccc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(C)(C(=O)OC)C(=O)c1c(C)nn2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound (5.13 g) of Example 1 was dissolved into DMF (70 ml) and, after adding sodium hydride (1.00 g), the mixture was stirred for 1 hour at room temperature. This was cooled in ice bath and ethyl 2-bromoacetate (2.77 ml) was added. After stirring for 18 hours until the temperature rose to room temperature, saturated aqueous solution of ammonium chloride was added and diluted with water, which was extracted with ether. After the organic layer was washed with water and with saturated brine and dried over anhydrous sodium sulfate, solvent was distilled off under reduced pressure. The residue was purified by means of silica gel column chromatography (developing solvent, ethyl acetate:n-hexane=1:2) to obtain aimed product (4.63 g) as a yellow oily product.