Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH2:11][CH:12]([CH3:15])[CH2:13][OH:14].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[N:11]/[CH:12]([CH3:15])[CH2:13][OH:14])=[CH:5][CH:4]=1
Reactant: CC(N)CO
Reactant: COc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(/C=N/C(C)CO)cc1

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-methoxybenzaldehyde (54.4 g, 400.00 mmol, 1.00 equiv), 2-aminopropan-1-ol (30 g, 400.00 mmol, 1.00 equiv), 4-methylbenzenesulfonic acid (3.84 g, 20.21 mmol, 0.05 equiv), toluene (300 mL). The resulting solution was heated to reflux for overnight in an oil bath. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with 3×50 mL of hexane. The resulting solids were collected by filtration. This resulted in 63 g (82%) of (E)-2-(4-methoxybenzylideneamino)propan-1-ol as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:13]([C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=3)[NH:14][C:15](=O)[CH2:16][O:17][CH3:18])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.O>O1CCCC1.CCOCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:13]([C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=3)[NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COCC(=O)NC(c1nccn1C)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COCCNC(c1nccn1C)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 0 °C
Reaction time: 48 h
Yield: 41703.7 %

Procedure:
Borane-methyl sulphide complex (5 ml) was added dropwise to a solution of the acetamide (3.3 g) prepared as above in tetrahydrofuran (100 ml) and the mixture stirred for 2 days. Ice-water was added cautiously and the resulting mixture basified. The basified mixture was extracted with ether and the extracts washed and dried. Removal of the ether gave a residue which was dissolved in ether. Hydrogen chloride gas was passed through the solution to give a hydrochloride of N-{[1-(3,4-dichlorophenyl)cyclobutyl][1-methylimidazol-2-yl]methyl}-2-methoxyethylamine containing 1.8 moles of hydrochloride and 1.6 moles of water which decomposed when heated to 150° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH3:17])[N:10]=2)[N:3]=1.[CH3:18][O-:19].[Na+].[Na].C(Cl)(Cl)Cl>CO>[CH3:18][O:19][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH3:17])[N:10]=2)[N:3]=1
Reactant: CCCc1cccc(-c2nc(C)cc(Cl)n2)n1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCc1cccc(-c2nc(C)cc(OC)n2)n1
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 4-chloro-6-methyl-2-(6-n-propyl-2-pyridinyl)pyrimidine (1 g) in methanol (10 ml), was added sodium methoxide prepared from methanol (10 ml) and metallic sodium (0.11 g). After being left to stand at room temperature for two hours, the solution was concentrated under reduced pressure. To the residue obtained, was added chloroform (100 ml). The mixture was washed twice with water (30 ml each) and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure to obtain 4-methoxy-6-methyl-2-(6-n-propyl-2-pyridinyl)pyrimidine (0.93 g, yield: 95 %).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:18]3[CH:26]=[CH:27][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:29][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:44](Cl)(=[O:46])[CH3:45]>CN(C)C=O>[C:44]([NH:33][S:30]([C:28]1[CH:27]=[CH:26][C:18]2[N:19]([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)[C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:14][CH:13]=3)=[N:16][C:17]=2[CH:29]=1)(=[O:32])=[O:31])(=[O:46])[CH3:45]
Reactant: NS(=O)(=O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Reactant: CC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(=O)NS(=O)(=O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 23.8 %

Procedure:
A solution of intermediate 69 (0.023 g, 0.05 mmol) in N,N-dimethylformamide (0.200 mL) and lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran) (0.050 ml, 0.05 mmol) was cooled to 0° C. Acetyl chloride (0.005 ml, 0.06 mmol) was added. The reaction mixture was stirred at rt for 1.5 h. At this time, more lithium bis(trimethylsilyl)amide solution (0.050 ml, 0.05 mmol) and acetyl chloride (0.010 ml, 0.014 mmol) were added. The reaction was stirred at rt overnight and concentrated. The crude material was purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.05% trifluoroacetic acid) to afford the product as a white solid (0.006 g, 18%). 1H NMR (CDCl3) δ 8.52 (br s, 1H), 8.15 (br s, 1H), 7.84 (br m, 1H), 7.61 (br m, 2H), 7.47-7.29 (br m, 5H), 7.22 (br m, 2H), 5.18 (s, 2H), 4.46 (m, 1H), 2.30 (br m, 4H), 2.01 (br m, 2H), 1.82 (br m, 1H), 1.37 (br m, 3H); ESI-MS m/e 504.1 (M+1); HPLC purity (ELSD) 100%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([NH:10][C:11]([NH:13][CH2:14][CH2:15][OH:16])=S)[C:2]1=2.[Na]>C(O)C.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[O:16]1[CH2:15][CH2:14][N:13]=[C:11]1[NH:10][C:9]1[C:2]2[O:1][CH:5]=[CH:4][C:3]=2[CH:6]=[CH:7][CH:8]=1
Reactant: OCCNC(=S)Nc1cccc2ccoc12
Agent: CC(=O)[O-]
Agent: [Hg+2]
Agent: [Na]
Solvent: CCO
Product: c1cc(NC2=NCCO2)c2occc2c1

Procedure:
5.4 g of N-benzo[b]furan-7-yl-N'-2-hydroxyethylthiourea in 300 ml of ethanol are boiled under reflux and are treated with a solution of 1.12 g of sodium in 25 ml of ethanol. The hot mixture is treated with 8.1 g of mercury(II) acetate over 1/2 minute, refluxed for 15 minutes and then filtered. The filtrate is evaporated to dryness. The residue is partitioned between 40 ml of 1 N hydrochloric acid and 40 ml of methylene chloride. The aqueous phase is treated with active charcoal, filtered and made alkaline with concentrated ammonia solution. The resultant precipitate is filtered, dried and recrystallised from ethyl acetate to give the title compound in free base form. M.Pt. 124°-6°.
Reaction SMILES: O.[CH:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([C:14]=2[C:16]([OH:18])=O)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>>[CH:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([C:14]=2[C:16]([Cl:21])=[O:18])=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c2ccccc2nc2ccccc12
Solvent: O
Product: O=C(Cl)c1c2ccccc2nc2ccccc12

Procedure:
A mixture of 9-acridinecarboxylic acid hydrate (7.3 g, 30 mmole), and thionyl chloride (50 ml, 0.685 mole) was heated at reflux in a round bottom flask equipped with a reflux condenser, a drying tube, and a stirring bar. The reaction mixture was heated further for one hour after the dissolution occurred, the cooled and evaporated to remove any excess thionyl chloride. The residue was directly utilized in the subsequent reaction without further purification.
Reaction SMILES: C(O[C@@H:6]1[O:20][C@H:19]([C@@H:21]([CH2:27][O:28][C:29](=[O:32])[CH2:30][CH3:31])[O:22][C:23](=[O:26])[CH2:24][CH3:25])[C@H:13]([O:14][C:15](=[O:18])[CH2:16][CH3:17])[C@H:7]1[O:8][C:9](=[O:12])[CH2:10][CH3:11])(=O)CC.[NH:33]1[CH:40]=[CH:39][C:37](=[O:38])[NH:36][C:34]1=[O:35].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>CC#N>[C:9]([O:8][C@@H:7]1[C@@H:13]([O:14][C:15](=[O:18])[CH2:16][CH3:17])[C@@H:19]([C@@H:21]([CH2:27][O:28][C:29](=[O:32])[CH2:30][CH3:31])[O:22][C:23](=[O:26])[CH2:24][CH3:25])[O:20][C@H:6]1[N:33]1[CH:40]=[CH:39][C:37](=[O:38])[NH:36][C:34]1=[O:35])(=[O:12])[CH2:10][CH3:11]
Reactant: CCC(=O)OC[C@@H](OC(=O)CC)[C@H]1O[C@@H](OC(=O)CC)[C@H](OC(=O)CC)[C@H]1OC(=O)CC
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: CCC(=O)OC[C@@H](OC(=O)CC)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(=O)CC)[C@H]1OC(=O)CC
Temperature: 60 °C
Yield: 98 %

Procedure:
To a suspension of 1,2,3,5,6-penta-O-propanoyl-β-D-glucofuranose (2.0 g, 4.3 mmol) and uracil (730 mg, 6.5 mmol) in CH3CN (30 mL) was added N,O-bis(trimethylsilyl)acetamide (6.4 mL, 26.1 mmol) dropwise. The mixture was heated at 60° C. for 1 h by which time the suspension had dissolved. The mixture was cooled to 0° C. and trimethylsilyl trifluoromethanesulfonate (1.6 mL, 8.7 mmol) was added dropwise. After 5 h reflux, the solution was concentrated in vacuo to half the volume and cooled in an ice-bath. Saturated aqueous NaHCO3 (60 mL) was added and the mixture extracted with CH2Cl2 (60, 2×30 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Flash silica chromatography of the residue, eluting with 1% CH3OH in CHCl3, gave 1-(2,3,5,6-tetra-O-propanoyl-β-D-glucofuranosyl)uracil as a colourless syrup (2.1 g, 96%), [α]D22=+14.6 (c 1.0 in CHCl3), (Found: C. 52.7; H, 6.1; N, 5.7. C22H30N2O11 requires C, 53.0; H, 6.1; N 5.6%); δH (CDCl3) 9.34 (1H, s, NH), 7.47 (1H, d, J 8.2, 6-H), 6.06 (1H, d, J 2.0, 1′-H), 5.82 (1H, d, J 8.2, 5-H), 5.45 l1H, d, J 3.3, 3′-H), 5.36 (1H, ddd, J 9.6, 5.4 and 2.4, 5′-H), 5.07 (1H, d, J 2.0, 2′-H), 4.61 (1H, dd, J 12.3 and 2.4, 6′a-H), 4.38 (1H, dd, J 9.6 and 3.3, 4′-H), 4.11 (1H, dd, J 12.3 and 5.4, 6′b-H), 2.45 (2H, qd, J 7.5 and 1.5, CH2), 2.36 (2H, q, J 7.5, CH2), 2.35 (2H, q, J 7.5, CH2), 2.29 (2H, q, J 7.5, CH2), 1.18 (3H, t, J 7.5, CH3), 1.15 (3H, t, J 7.5, CH3), 1.12 (3H, t, J 7.5, CH3), 1.10 (3H, t, J 7.5, CH3); δC (CDCl3) 174.3, 173.4, 172.8, 172.3 (4×C═O), 163.2 (3-C), 150.4 (2-C), 139.4 (6-C), 103.5 (5-C), 89.7 (1′-C), 80.6 (2′-C), 79.3 (4′-C), 73.5 (3′-C), 67.1 (5′-C), 63.2 (6′-C), 27.7, 27.6, 27.6, 27.5 (4×CH2), 9.4, 9.1, 9.1, 9.0 (4×CH3); m/z (FAB) 499.191398 (MH+, C22H31N2O11 requires 499.192785).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:11][C:12]1[N:17]=[C:16]([NH:18][C@@H:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:20][CH:21]=O)[C:15]([F:27])=[CH:14][N:13]=1.[CH3:28]COC(C)=O.[NH4+].[Cl-]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:11][C:12]1[N:17]=[C:16]([NH:18][C@H:19]([CH2:20][CH:21]=[CH2:28])[C:23]([CH3:26])([CH3:25])[CH3:24])[C:15]([F:27])=[CH:14][N:13]=1
Reactant: CC(C)(C)[C@@H](CC=O)Nc1nc(Cl)ncc1F
Reactant: CCOC(C)=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CC[C@@H](Nc1nc(Cl)ncc1F)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl(triphenyl)phosphonium bromide (0.983 g, 2.753 mmol) in THF (40 mL) was added LiHMDS (2.753 mL of 1 M solution, 2.753 mmol). The reaction mixture was stirred at room temperature for 1 hour. A solution of (3R)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-4,4-dimethyl-pentanal (0.550 g, 2.118 mmol) in THF (20 mL) was added to the reaction mixture resulting in significant precipitate formation. The reaction mixture was stirred at room temperature for 45 minutes. The reaction mixture was diluted into EtOAc and aqueous saturated NH4Cl solution. The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (EtOAc/Hexanes) to afford 180 mg of desired product: 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J=2.8 Hz, 1H), 5.76-5.60 (m, 1H), 5.05-4.91 (m, 2H), 4.82 (t, J=22.1 Hz, 1H), 4.26-4.11 (m, 1H), 2.58-2.48 (m, 1H), 2.07-1.92 (m, 1H), 0.94 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.60 minutes (M+H) 258.38.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([CH3:7])[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:41][C:42]([C:44]([F:47])([F:46])[F:45])=[O:43].[F:48][CH:49]([F:78])[CH2:50][NH:51][C:52]1[N:53]=[C:54]2[CH2:76][CH:75]([CH3:77])[NH:74][CH2:73][C:55]2=[N:56][C:57]=1[N:58]1[CH2:63][CH2:62][CH:61]([O:64][C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][C:66]=2[F:72])[CH2:60][CH2:59]1>CN(C=O)C>[F:78][CH:49]([F:48])[CH2:50][NH:51][C:52]1[N:53]=[C:54]2[CH2:76][CH:75]([CH3:77])[N:74]([C:4](=[O:6])[C@@H:3]([O:2][CH3:1])[CH3:7])[CH2:73][C:55]2=[N:56][C:57]=1[N:58]1[CH2:59][CH2:60][CH:61]([O:64][C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][C:66]=2[F:72])[CH2:62][CH2:63]1.[C:42]([OH:43])([C:44]([F:47])([F:46])[F:45])=[O:41]
Reactant: CC1Cc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CN1
Reactant: CO[C@@H](C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H](C)C(=O)N1Cc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc2CC1C
Reaction time: 2 h

Procedure:
A solution of (S)-2-methoxypropanoic acid (1.9 mg, 0.018 mmol), DIPEA (7.0 mg, 0.054 mmol), and HATU (6.9 mg, 0.018 mmol) in DMF (90 μL) was stirred at room temperature for 10 min then treated with N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (10 mg, 0.018 mmol). The resulting reaction mixture was stirred for 2 h. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (5 mg) as a white solid. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) 6 ppm 1.17 (t, J=6.7 Hz, 1.4H), 1.27 (dd, J=6.7, 2.7 Hz, 1.6H), 1.33 (dd, J=11.5, 6.7 Hz, 1.4H), 1.38 (dd, J=6.7, 2.7 Hz, 1.6H), 1.92-2.03 (m, 2H), 2.09-2.19 (m, 2H), 2.58 (m, 0.6H), 2.64 (m, 0.4H), 2.95-3.05 (m, 2H), 3.08-3.10 (m, 0.5H), 3.12-3.14 (m, 0.5H), 3.35 (s, 3H), 3.37-3.44 (m, 2H), 3.71-3.86 (m, 2H), 4.03 (t, J=18.3 Hz, 1H), 4.30-4.41 (m, 1H), 4.43-4.50 (m, 1H), 4.70-4.83 (m, 1H), 5.08 (m, 0.5H), 5.21 (m, 0.5H), 5.89-6.21 (m, 1H), 6.84-6.91 (m, 1H), 6.99 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 525.9.
Reaction SMILES: [F:1][C:2]1([F:7])[CH2:4][CH:3]1[CH2:5][OH:6].[H-].[Na+].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](F)[N:12]=1.O>O1CCOCC1.CN(C=O)C>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:6][CH2:5][CH:3]2[CH2:4][C:2]2([F:7])[F:1])[N:12]=1
Reactant: OCC1CC1(F)F
Reactant: Fc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: FC1(F)CC1COc1cccc(Br)n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To 307 mg (2.84 mmol) (2,2-difluorocyclopropyl)methanol in 1,4-dioxane (10 mL) is added 69 mg (2.84 mmol) sodium hydride and 500 mg (2.84 mmol) 2-bromo-6-fluoropyridine. The mixture is stirred for 2 h at 90° C. Water and DMF are added and the mixture is filtered and concentrated in vacuo. The residue is purified by HPLC (C18 RP Sunfire, acetonitrile/water (+0.1% TFA)) to yield the desired product.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:27])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:26])([C:14]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)=[O:15])[CH2:6][CH2:5]2.[O:28]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][NH:16][C:14](=[O:15])[C:7]([OH:28])([CH3:26])[CH2:6][CH2:5][C:4]2[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=2[CH3:27])=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCc1ccc(O)cc1)O2
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCc2ccc(O)cc2)=C(C)C1=O
Yield: 14.4 %

Procedure:
Oxidation as described in protocol B, using 100 mg 6-hydroxy-N-(4-hydroxyphenethyl)-2,5,7,8-tetramethylchroman-2-carboxamide (0.271 mmol) and 325 mg CAN (0.595 mmol) yielded 15 mg of N-(4-hydroxyphenethyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].I[CH:29]([CH3:31])[CH3:30].[H-].[Na+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH:29]([CH3:31])[CH3:30])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(C(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (2.00 g) and 2-iodopropane (2.8 mL) in N,N-dimethylformamide (20 mL) was added 60% sodium hydride (0.34 g), and the mixture was stirred at room temperature for 15 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.23 g, 10%).
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.O[NH:28][C:29]([C:31]1[C:32]2[CH:33]=[CH:34][C:35]([NH:41][C@H:42]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:44][CH2:43]3)=[N:36][C:37]=2[CH:38]=[CH:39][CH:40]=1)=[NH:30]>C(#N)C>[C@H:42]1([NH:41][C:35]2[CH:34]=[CH:33][C:32]3[C:37](=[CH:38][CH:39]=[CH:40][C:31]=3[C:29]3[N:28]=[C:1]([CH3:2])[O:4][N:30]=3)[N:36]=2)[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44][CH2:43]1
Reactant: CC(=O)O
Reactant: N=C(NO)c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: Cc1nc(-c2cccc3nc(N[C@@H]4CCc5ccccc54)ccc23)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.9 %

Procedure:
To a stirred solution of acetic acid (127 mg, 2.12 mmol) in acetonitrile (8.5 ml) was added at room temperature 1-hydroxy-benzotriazole (403 mg, 2.98 mmol) and N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimid-hydrochloride (465 mg, 2.43 mmol). The mixture was allowed to stir for 3 h at room temperature and N-hydroxy-2-((R)-indan-1-ylamino)-quinoline-5-carboxamidine (450 mg, 1.41 mmol) was added together with acetonitrile (7.5 ml). The mixture was allowed to stir for 2 h at room temperature, evaporated to dryness and diluted with acetic acid (14 ml). The reaction mixture was allowed to stir for 2 h at 100° C., evaporated, poured into saturated NaHCO3 solution (50 ml) and extracted with ethyl acetate (3×80 ml). The combined organic layers were washed with brine (2×50 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (ethyl acetate/heptane) to yield the title compound as light yellow solid (130 mg, 18%).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[OH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[NH:3][C:2]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][OH:21])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: OCc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CO)[nH]c2c1
Yield: 93 %

Procedure:
A solution (0.04 M) of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (prepared as described in WO2004/087714) in DME/EtOH 5:2 was treated with [2-(hydroxymethyl)phenyl]boronic acid (1.2 eq), Na2CO3 (6 eq) and Pd(PPh3)4 (0.1 eq) at 80° C. After 1 h the mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, then dried and concentrated under reduced pressure. The residue was purified by flash chromatography on SiO2 (7:3 PE/EtOAc) to give the title compound (93%) as a solid. MS (ES+) m/z 364 (M+H+).
Reaction SMILES: Cl.C(N=C=[N:6][CH2:7][CH2:8][CH2:9][N:10]([CH3:12])C)C.[CH:13]([C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([OH:23])=O)[C:16]=1[CH3:24])=[O:14].ON1C2C=CC=CC=2N=N1.N1CCC(N)C1>O.CN(C=O)C.C(N(CC)CC)C>[NH:10]1[CH2:9][CH2:8][CH:7]([NH:6][C:21]([C:17]2[C:16]([CH3:24])=[C:15]([CH:13]=[O:14])[NH:19][C:18]=2[CH3:20])=[O:23])[CH2:12]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CCNC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1[nH]c(C=O)c(C)c1C(=O)NC1CCNC1
Temperature: 0 °C
Yield: 68 %

Procedure:
1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (268.1 g, 1.4 mol), triethylamine (280.0 mL), 5-formyl-2,4-dimethyl-1H-pyrrole-3-formic acid (167.0 g, 1.0 mol) and 1-hydroxybenzotriazole (189.2 g, 1.4 mol) were added to DMF (500 mL) with stirring at about 0° C. and stirred for 1.5 hrs, then pyrrolidine-3-amine (1.2 mol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 120 mL of water and 100 mL of saturated salt water were added, and the mixture was extracted with 10% methanol/dichloromethane (300 mL×3), the combined organic phase was washed with saturated salt water (300 mL×3), dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The residue was then chromatographed on silica gel (eluted with methanol/ethyl acetate=1/1) to give 159.8 g (680 mmol) of N-(pyrrolidin-3-yl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide as an off-white solid. Yield 68.0%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH:26][C:27](=[O:29])[CH3:28])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1.[K].[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.O>CN(C)C=O>[O:36]=[C:34]1[C:33]2[C:32](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:31](=[O:41])[N:35]1[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH:26][C:27](=[O:29])[CH3:28])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(=O)Nc1nc(-c2ccc(CCCBr)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1nc(-c2ccc(CCCN3C(=O)c4ccccc4C3=O)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of N-{4-[4-(3-bromopropyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide (82 mg) in N,N-dimethylformamide (0.82 ml) was added phthalimide potassium salt (30.8 mg), and the mixture was stirred for 2 hrs. at 50° C. The reaction mixture was cooled to 20° C., then water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with brine, dried over magnesium sulfate and evaporated to give a crude material (92.0 mg). The crude material was purified by preparative thin-layer chromatography over silica gel to give N-{4-{4-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]phenyl}-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide.