Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[O:3]1.[SH:21][CH:22]([CH2:25][SH:26])[CH2:23][OH:24]>>[OH:24][CH2:23][CH:22]([SH:21])[CH2:25][S:26][CH:9]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[CH2:8][C:4]1[O:3][C:2]([CH3:1])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=1
Reactant: CC1(c2ccccc2)OC(/C=C/c2ccsc2)=CC1=O
Reactant: OCC(S)CS
Product: CC1(c2ccccc2)OC(CC(SCC(S)CO)c2ccsc2)=CC1=O

Procedure:
According to the procedure of Method A, Example 1, (E)-2-methyl-2-phenyl-5-[2-(3-thienyl)ethenyl]-3(2H)-furanone was reacted with 2,3-dimercapto-1-propanol to provide 5-[2-[(3-hydroxy-2-mercaptopropyl)thio]-2-(3-thienyl)ethyl]-2-methyl-2-phenylfuran-3(2H)-one: 1H NMR (CDCl3) δ1.65 (m, 1H) and overlapping 1.65 and 1.68 (singlets, 3H), 1.92 (br s with fine structure, 1H), 2.65-2.80 (m, 2H), 2.89 (br s with fine structure, 1H), 3.10-3.28 (m, 2H), 4.43-4.60 (m, 1H), 5.38, 5.40 and 5.41 (singlets, 1H), 7.13-7.20 (m, 2H), 7.25-7.43 (m, 6H); MS (LR-ESI) m/z 407 (M+H calcd. for C20H23NO3S3 407).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:3]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:20][CH:17]2[CH2:19][CH2:18]2)=[C:4]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1Oc1cccnc1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: Brc1ccc(CNC2CC2)c(Oc2cccnc2)c1
Reaction time: 18 h
Yield: 75.8 %

Procedure:
To a mixture of 4-bromo-2-(pyridin-3-yloxy)-benzaldehyde (2.0 g, 7.19 mmol) in DCE (75 mL) were added cyclopropylamine (0.50 mL, 7.2 mmol), acetic acid (2.16 mL, 36.0 mmol), and NaBH(OAc)3 (95%; 3.62 g, 18.0 mmol) portionwise. After 18 h, the mixture was diluted with 50 mL DCM and washed with 1 M NaOH (2×25 mL). The organic layer was dried (Na2SO4) and concentrated. FCC purification (EtOAc/DCM) gave the desired product (1.74 g, 76%). MS (ESI): mass calcd. for C15H15BrN2O, 318.04; m/z found, 319.1, 321.1 [M+H]+. 1H NMR (CDCl3): 8.42-8.39 (m, 2H), 7.31-7.26 (m, 4H), 7.00-6.99 (m, 1H), 3.84 (s, 2H), 2.11-2.07 (m, 1H), 0.43-0.40 (m, 2H), 0.36-0.33 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[N+](=[CH2:15])=[N-]>CCOC(C)=O.CCOCC>[CH3:15][O:9][C:8](=[O:10])/[CH:7]=[CH:6]/[C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:12][CH:11]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C=Cc1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)/C=C/c1ccc(O)cc1

Procedure:
To a solution of 4-hydroxycinnamic acid (0.407 g, 2.48 mmol) in EtOAc, a solution of diazomethane in Et2O was added until the yellow color persisted. Excess diazomethane was quenched by the addition of AcOH and the reaction mixture was evaporated to dryness. The residue was dissolved in EtOAc and washed with 10% aqueous HCl, saturated NaHCO3 and brine. The organic layer was dried over anhydrous MgSO4 and evaporated to dryness. The residue was purified by flash column chromatography, using a gradient from 10%-20% EtOAc in hexane, to give E-3-(4-hydroxyphenyl)acrylic acid methyl ester as a white solid (0.362 g).
Reaction SMILES: [N:1]1([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(O[C:22]1(O[Si](C)(C)C)[CH2:24][CH2:23]1)C.C(O)(=O)C.C([BH3-])#N.[Na+]>O1CCCC1.CO>[CH:22]1([N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=3)[CH2:2][CH2:3]2)[CH2:24][CH2:23]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CCOC(=O)c1ccc(N2CCCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N2CCCN(C3CC3)CC2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 117.8 %

Procedure:
A solution of ethyl 4-(1,4-diazepan-1-yl)benzoate (0.621 g, 2.5 mmol), (1-ethoxycyclopropoxy)trimethylsilane (2.51 mL, 12.50 mmol) and acetic acid (0.286 mL, 5.00 mmol) in tetrahydrofuran (50 mL), methanol (5 mL) was treated with sodium cyanoborohydride (0.393 g, 6.25 mmol) at 20° C. The resulting solution was stirred at 60° C. for 18 h. The reaction mixture was cooled, filtered and evaporated to dryness. 1N HCl (40 ml) and water (60 ml) were added and the solution extracted with ethyl acetate (3×50 ml). The aqueous layer was basified to pH 10 with solid potassium carbonate and extracted with ethyl acetate (4×50 ml). The organic extracts washed with saturated NaCl (50 ml) and dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 4-(4-cyclopropyl-1,4-diazepan-1-yl)benzoate (0.849 g, 118%) as a colourless oil.
Reaction SMILES: C(=O)(O)[O-].[Na+].[I-].[Li+].[CH2:8]([C:10]1[C:11](=[O:27])[NH:12][C:13](=[O:26])[NH:14][C:15]=1[C:16](=[O:25])[C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1)[CH3:9].C1(C)C(S(O[CH2:38][CH2:39][CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)(=O)=O)=CC=CC=1>CN(C)C=O>[CH2:41]1[CH2:42][CH2:43][CH2:44][CH:40]1[CH:39]([N:14]1[C:15]([C:16](=[O:25])[C:17]2[CH:18]=[C:19]([CH3:24])[CH:20]=[C:21]([CH3:23])[CH:22]=2)=[C:10]([CH2:8][CH3:9])[C:11](=[O:27])[NH:12][C:13]1=[O:26])[CH3:38]
Reactant: Cc1ccccc1S(=O)(=O)OCCC1CCCC1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Agent: O=C([O-])O
Agent: [I-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(C(C)C2CCCC2)c(=O)[nH]c1=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
A mixture of sodium bicarbonate (0.10 g, 1.2 mmol) and lithium iodide (13 mg, 0.1 mmol) were added to dimethylformamide solution (10 ml) of 5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione (0.27 g, 1.0 mmol) and 2-(cyclopentyl)ethyl toluenesulfonate (0.27 g, 1.0 mmol). And then, the reaction mixture was stirred at 90° C. for overnight, concentrated for removement of dimethylformamide, extracted with dichloromethane, dried, filtered and separated by column chromatography to give a white solid (90 mg).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=O)[CH2:19][CH2:18]1)([O:15][CH3:16])=[O:14].[Cl:26][C:27]1[C:28]([CH:33]([NH2:50])[C:34]2[CH:43]=[C:42]3[C:37]([CH:38]=[CH:39][C:40]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[N:41]3)=[CH:36][CH:35]=2)=[N:29][CH:30]=[CH:31][N:32]=1>C1COCC1>[CH3:16][O:15][C:13]([C@H:17]1[CH2:18][CH2:19][C@H:20]([C:23](=[O:25])[NH:50][CH:33]([C:28]2[C:27]([Cl:26])=[N:32][CH:31]=[CH:30][N:29]=2)[C:34]2[CH:43]=[C:42]3[C:37]([CH:38]=[CH:39][C:40]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)=[N:41]3)=[CH:36][CH:35]=2)[CH2:21][CH2:22]1)=[O:14]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(=O)NC(c2ccc3ccc(-c4ccccc4)nc3c2)c2nccnc2Cl)CC1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A THF solution (15 mL) of CDI (1.2 g, 7.3 mmol) and trans-4-carbomethoxycyclohexane-1-carboxylic acid (1.2 g, 6.6 mmol) was stirred at 60° C. for 16 h. The reaction mixture was charged with C-(3-chloropyrazin-2-yl)-C-(2-phenylquinolin-7-yl)-methylamine (compound of Formula IV where Q1=2-phenylquinolin-7-yl) (2.3 g, 6.6 mmol) and stirred at 60° C. for 20 h. The reaction mixture was concentrated in vacuo, taken up in EtOAc, and washed with water (2×) and brine (1×). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (20% EtOAc/Hexanes to 100% EtOAc) the desired product as an orange foam; 1H NMR (CDCl3, 400 MHz) δ 1.48-1.55 (m, 4H), 1.95-2.06 (m, 4H), 2.17-2.24 (m, 1H), 2.26-2.33 (m, 1H), 3.66 (s, 3H), 6.77 (d, 1H, J=7.6 Hz), 7.36-7.41 (m, 1H), 7.45-7.55 (m, 3H), 7.72-7.77 (m, 1H), 7.81-7.89 (m, 2H), 8.11 (d, 2H, J=7.2 Hz), 8.20-8.25 (m, 1H), 8.39 (d, 1H, J=2.4 Hz), 8.60 (d, 1H, J=2.8 Hz); MS (ES+): m/z 515.0 [MH+]; HPLC: tR=3.1 min (Micromass Platform II, nonpolar—5 min).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[C:6]([Br:8])[Br:7])[CH:3]1[C:9](Cl)=[O:10].N1C=CC=CC=1.[O:19]([C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[CH:29]([OH:32])[CH:30]=[CH2:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCOCC>[O:19]([C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[CH:29]([O:32][C:9]([CH:3]1[CH:4]([CH:5]=[C:6]([Br:7])[Br:8])[C:2]1([CH3:12])[CH3:1])=[O:10])[CH:30]=[CH2:31])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C=CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(C=C(Br)Br)C1C(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=CC(OC(=O)C1C(C=C(Br)Br)C1(C)C)c1cccc(Oc2ccccc2)c1

Procedure:
15.8 g (0.05 mole) of 2,2-dimethyl-3-(2',2'-dibromovinyl)-cyclopropanecarboxylic acid chloride are added dropwise, whilst stirring, to 5.1 g (0.05 mole) of pyridine, 100 ml of absolute ether and 11.4 g (0.05 mole) of 3-phenoxy-α-vinyl-benzyl alcohol at 0°-5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:10]=[C:9]2[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[CH:4][CH:3]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].C(=O)([O-])[O-].[K+].[K+].COCCOC>[Pd].O>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:34]=3)=[CH:3][CH:4]=2)[CH:12]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:10]=1
Reactant: CC(C)(O)c1cn(-c2ccc(Br)cc2)c(-c2c(F)cccc2F)n1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2c(F)cccc2F)n1
Temperature: 80 °C
Yield: 76.7 %

Procedure:
2-[1-(4-Bromo-phenyl)-2-(2,6-difluoro-phenyl)-1H-imidazol-4-yl]-propan-2-ol (250 mg, 0.64 mmol), (3-methylsulfonylphenyl)boronic acid (254 mg, 1.27 mmol), and potassium carbonate (398 mg, 2.88 mmol) were placed into a flask. 6 mL, of mixture of DME (1,2-dimethoxyethane) and water (9:1, V/V) was added. The flask was flushed with argon for 15 min, and then Pd catalyst (Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct, 52 mg, 0.064 mmol) was added. The mixture was heated to 80° C. overnight. After cooling to room temperature, all solvent was removed. The crude product was purified by column chromatography on silica gel (45→99% EtOAc/Hexane) to give an off-white solid (230 mg, 77% yield). 1H-NMR (400 MHz, CDCl3): δ 1.70 (s, 6H), 2.71 (s, 1H), 3.09 (s, 3H), 6.92-6.88 (m, 2H), 7.21 (s, 1H), 7.39-7.28 (m, 3H), 7.59-7.57 (m, 2H), 7.66 (t, 1H, J=7.8), 7.86-7.83 (M, 1H), 7.95-7.92 (m, 1H), 8.12 (t, 1H, J=1.7). MS (ES): 491.4 [M+Na]+
Reaction SMILES: [NH2:1][CH:2]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[C:3]([OH:5])=[O:4].C[Si](C)(C)Cl.[CH2:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24](Cl)=[O:25])[C:20](=[O:27])[C:19]1=[O:28])[CH3:17].Cl.C(N(CC)CC)C>C(Cl)Cl.O.C(N(CC)CC)C>[CH2:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]([NH:1][CH:2]([C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)[C:3]([OH:5])=[O:4])=[O:25])[C:20](=[O:27])[C:19]1=[O:28])[CH3:17]
Reactant: NC(C(=O)O)c1ccco1
Reactant: CCN1CCN(C(=O)Cl)C(=O)C1=O
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCN1CCN(C(=O)NC(C(=O)O)c2ccco2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To an ice-cooled suspension of 2.55 g of DL-α-amino-2-furylacetic acid in 35 ml of methylene chloride was added 4.81 ml of trimethylchlorosilane. To the resulting mixture was added dropwise 5.04 ml of triethylamine over a period of 10 minutes at 5° to 10° C. The reaction was allowed to proceed at 15° to 20° C. for one hour. To the reaction mixture was added over a period of 15 minutes at 5° to 10° C. 7.01 g of a mixture of 4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride and triethylamine hydrochloride, said mixture containing 58.02% of the former. The reaction was allowed to proceed at 10° to 15° C. for one hour. After addition of 20 ml of water, the reaction mixture was stirred at room temperature for one hour, then at 5° to 7° C. for 30 minutes. The precipitated crystals were collected by filtration, washed with 5 ml of methylene chloride and 5 ml of water in this order, and then dried to obtain 4.75 g of DL-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-furylacetic acid, m.p. 179°-181° C. (decomp.), yield 85.6%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([C:8]2([CH2:11][NH2:12])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[F:21][C:22]([F:33])([F:32])[C:23]1[C:24]([C:29](Cl)=[O:30])=[N:25][CH:26]=[CH:27][CH:28]=1.O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([C:8]2([CH2:11][NH:12][C:29]([C:24]3[C:23]([C:22]([F:33])([F:21])[F:32])=[CH:28][CH:27]=[CH:26][N:25]=3)=[O:30])[CH2:9][CH2:10]2)=[N:6][CH:7]=1
Reactant: NCC1(c2ncc(Br)cc2Cl)CC1
Reactant: O=C(Cl)c1ncccc1C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1(c2ncc(Br)cc2Cl)CC1)c1ncccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.3 %

Procedure:
350 mg of C-[1-(5-bromo-3-chloro-pyridin-2-yl)-cyclopropyl]-methylamine (step 3 of PREPARATION EXAMPLE 3) was dissolved in 7 ml of dichloromethane and 0.37 ml of triethylamine was added at ambient temperature. Then a solution of 308 mg 3-(trifluoromethyl)pyridine-2-carbonyl chloride (1.10 eq, 1.47 mmol, 0.) in 3 ml of dichloromethane was added dropwise. The reaction mixture was stirred at ambient temperature for 14 hours, then water was added, the phases were separated and the water phase was extracted with dichloromethane. The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated. Crude material was obtained as a brown sticky solid, which was purified by flash chromatography on silica gel with cyclohexane/ethyl acetate (2:1) as a solvent. Thus, 560 mg of N-[[1-(5-bromo-3-chloro-2-pyridyl)cyclopropyl]methyl]-3-(trifluoromethyl)pyridine-2-carboxamide was obtained as a sticky solid. 1H-NMR (CDCl3): 8.70 ppm (d, 1H), 8.45 ppm (d, 1H), 8.12 ppm (d, 1H), 7.90 ppm (s, 1H, broad), 7.83 ppm (d, 1H), 7.52 ppm (m, 1H), 3.73 ppm (d, 2H), 1.10 ppm (m, 4H).
Reaction SMILES: N1C=CC(N)=NC=1N.Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][CH2:25][O:26][C:19]=3[CH:18]=2)[C:13]([F:27])=[CH:12][N:11]=1.[F:28][C:29]([F:39])([F:38])[S:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1>>[CH2:25]1[CH2:24][O:23][C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:14]3[C:13]([F:27])=[CH:12][N:11]=[C:10]([NH:35][C:34]4[CH:36]=[CH:37][C:31]([S:30][C:29]([F:39])([F:28])[F:38])=[CH:32][CH:33]=4)[N:15]=3)=[CH:18][C:19]=2[O:26]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Nc1ccc(SC(F)(F)F)cc1
Agent: Nc1ccnc(N)n1
Product: Fc1cnc(Nc2ccc(SC(F)(F)F)cc2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 4-(trifluoromethylthio)aniline were reacted to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(4-trifluoromethylthiophenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.73 (s, 1H), 9.47 (s, 1H), 8.13 (d, 1H, J=3.6 Hz), 7.79 (d, 2H, J=9.0 Hz), 7.51 (d, 2H, J=9.0 Hz), 7.28 (d, 1H, J=2.1 Hz), 7.12 (dd, 1H, J=2.4 and 9.0 Hz), 6.83 (d, 1H, J=8.7 Hz), 4.23 (s, 4H); 19F NMR (282 MHz DMSO-d6): −12306; LCMS: purity: 97%; MS (m/e): 439(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](I)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=1)[CH:9]=2)=[O:4].[C:28]([Cu])#[N:29].C(Cl)Cl>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:28]#[N:29])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1nc(I)c2cc(Oc3ccc4ccccc4c3)ccc2c1O
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1nc(C#N)c2cc(Oc3ccc4ccccc4c3)ccc2c1O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
4-Hydroxy-1-iodo-7-(naphthalen-2-yloxy)-isoquinoline-3-carboxylic acid methyl ester (130 mg, 0.28 mmol) and CuCN (49 mg, 0.55 mmol) were suspended in DMF (1.1 mL). The resulting mixture was heated at 120° C. for 7 minutes and then cooled to room temperature. The reaction crude was poured into CH2Cl2 (30 mL) and stirred vigorously for 10 minutes at room temperature. The resulting suspension was filtered through a pad of celite and the filtrate was washed with H2O and brine sequentially. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 75 mg. MS: (−) m/z 369.24 (M−1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:19]1([C:2]2[CH:3]=[C:4]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]3=[N:6][CH:7]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: C1COCCN1
Reactant: C[Si](C)(C)CCOCn1ccc2cc(Br)cnc21
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1ccc2cc(N3CCOCC3)cnc21
Temperature: 100 °C
Yield: 53.7 %

Procedure:
A mixture of 51 (1.48 g, 4.52 mmol), morpholine (0.473 mL, 5.43 mmol), Pd2(dba)3 (0.083 g, 0.090 mmol), Xantphos (0.157 g, 0.271 mmol) and t-BuONa (0.652 g, 6.78 mmol) in toluene (15 mL) was heated at 100° C. for 2.5 hours. The mixture was cooled and poured into brine and extracted with AcOEt. The organic layer was washed with brine, dried (MgSO4), and concentrated. The residue was purified by means of SGC with hexane: AcOEt as eluent to afford 52 (0.81 g, 54%) as a tan syrup. 1H NMR (400 MHz, CDCl3) δ 0.00 (s, 9H), 0.94-1.00 (m, 2H), 3.18-3.23 (m, 4H), 3.57-3.63 (m, 2H), 3.96-4.02 (m, 4H), 5.70 (s, 2H), 6.50 (d, J=0.35 Hz, 1H), 7.38 (d, J=0.35 Hz, 1H), 7.55 (d, J=0.26 Hz, 1H), 8.24 (d, J=0.26 Hz, 1H).
Reaction SMILES: I([O-])(=O)(=O)=O.Cl[O-].[Na+].[O:9]=[C:10]1[CH2:17][C:14]([CH3:16])([CH3:15])[CH2:13]C(C)=[CH:11]1.[C:19](=[O:22])([O-])[O-:20].[Na+].[Na+]>C(Cl)Cl>[O:9]=[C:10]([CH3:11])[CH2:17][C:14]([CH3:16])([CH3:15])[CH2:13][C:19]([OH:20])=[O:22]
Reactant: O=C([O-])[O-]
Reactant: CC1=CC(=O)CC(C)(C)C1
Agent: [Na+]
Agent: [O-]Cl
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: CC(=O)CC(C)(C)CC(=O)O

Procedure:
The above oxidation procedure was repeated, except that in place of periodate there was utilized sodium hypochlorite. There was added slowly about 2700 parts of an aqueous 5% sodium hypochlorite solution to a solution of 56 parts of isophorone in about 200 parts of methylene chloride. An exothermic reaction resulted causing the methylene chloride to reflux. The organic phase was analyzed shortly after the addition was complete and it was found that all of the isophorone had reacted. The aqueous layer was made basic with sodium carbonate and the reaction mixture was filtered. The aqueous phase was washed with methylene chloride and then acidified by slowly adding it to a 2 phase mixture of concentrated hydrochloric acid and methylene chloride. The organic phase was separated and the aqueous phase was extracted with several portions of fresh methylene chloride. Upon combining the various organic layers which were dried and evaporated, there was obtained 37.7 parts of 5-keto-3,3-dimethylhexanoic acid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[C:5]([CH:14]=[O:15])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:22][CH2:23][CH2:24]Br.O>CN(C=O)C>[Br:22][CH2:23][CH2:24][O:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[C:5]([CH:14]=[O:15])=[CH:4][CH:3]=1
Reactant: COc1cccc2c(O)ccc(C=O)c12
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c(OCCBr)ccc(C=O)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
4-hydroxy-8-methoxynaphthalene-1-carbaldehyde (1 g, 5 mmol) was dissolved in DMF (15 mL). To this mixture potassium carbonate (3.4 g, 25 mmol) and 1,2-dibromoethane (4 mL, 50 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. Water. (150 mL) was added and the resulting mixture was extracted with ethyl acetate (3×90 mL). The combined organic extracts were washed with saturated sodium chloride (100 mL), dried (MgSO4) and evaporated in vacuo to afford 1.13 g (74%) of 4-(2-bromoethoxy)-8-methoxynaphthalene-1-carbaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9](I)[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=1)[CH2:5]2.[C-:27]#[N:28].[Na+].CCCCCC.CCOC(C)=O>C(#N)C.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.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:27]#[N:28])[C:8]2[C:7](=[O:12])[N:6]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:18][CH:19]=3)[CH2:5][C:4]=2[CH:3]=1
Reactant: [C-]#N
Reactant: O=C1c2c(I)cc(Cl)cc2CN1Cc1ccc(Oc2ccccc2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#Cc1cc(Cl)cc2c1C(=O)N(Cc1ccc(Oc3ccccc3)cc1)C2
Temperature: 80 °C
Reaction time: 18 h
Yield: 57.7 %

Procedure:
A mixture of 5-chloro-7-iodo-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.675 g, 1.42 mmol), Pd(PPh3)4 (0.162 g, 0.14 mmol), sodium cyanide (0.089 g, 1.85 mmol), and CuI (0.027 g, 0.14 mmol) in acetonitrile (5 mL) was stirred at 80° C. for 18 h. Workup and silica gel column chromatography using 2:1 hexanes-ethyl acetate (typically 2:1 hexane-EtOAc) afforded 6-chloro-3-oxo-2-(4-phenoxy-benzyl)-2,3-dihydro-1H-isoindole-4-carbonitrile (0.307 g, 58%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.32 (s, 2H), 4.77 (s, 2H), 6.95-7.38 (m, 9H), 7.63 (s, 1H), 7.75 (s, 1H). GC-MS: m/z 374 (M)+, 297 (M−77)+, 281 (M-93)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:35])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27](=[O:34])(=[O:33])[NH:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:17][N:16]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[C:29]([NH:28][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:35])=[N:16][CH:17]=1)(=[O:34])=[O:33])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C2CCCN2C(=O)OC(C)(C)C)nc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C2CCCN2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-[5-(2-tert-Butylsulfamoyl-phenyl)-pyridin-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.92 g, 1.83 mmol) was dissolved in 30 mL DCM, added 10 mL trifluoroacetic acid and stirred at ambient temperature for one hour. Concentrated solution, redissolved in CHCl3 and reconcentrated. Repeated co-concentration twice to yield title compound as an oil. (quant. yield) APCI (AP−): 401.1 (M−H)−.