Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2=[N:15][C:16]3[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:17]=3[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]2=3)[CH2:10][C@@H:9]1[CH2:30][C:31]([OH:33])=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[CH3:46][CH:47](O)[CH2:48][C:49]([OH:52])([CH3:51])[CH3:50]>CN(C=O)C.CN(C)C1C=CN=CC=1>[Cl:29][C:27]1[CH:26]=[CH:25][C:17]2[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@@H:9]([CH2:30][C:31]([O:33][C@@H:47]([CH2:48][C:49]([OH:52])([CH3:51])[CH3:50])[CH3:46])=[O:32])[CH2:10]3)=[N:15][C:16]=2[CH:28]=1
Reactant: CC(O)CC(C)(C)O
Reactant: CC(C)(C)OC(=O)N1CCN(C2=Nc3cc(Cl)ccc3Oc3ccccc32)C[C@@H]1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: C[C@H](CC(C)(C)O)OC(=O)C[C@H]1CN(C2=Nc3cc(Cl)ccc3Oc3ccccc32)CCN1C(=O)OC(C)(C)C
Temperature: 50 °C

Procedure:
(S,E)-2-(1-(tert-butoxycarbonyl)-4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)acetic acid (300 mg, 0.60 mmol) can be dissolved in DMF (0.25M). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.9 mmol), and 4-Dimethylaminopyridine (0.3 mmol) may be added respectively at room temperature under nitrogen. After about fifteen minutes R-(−)-2-Methyl-2,4-pentanediol (0.60 mmol) may be added and the mixture heated to about 50° C. under nitrogen. The product can be worked up as usual and purified by flash chromatography using 10% Acetone/Dichloromethane as the eluent to give (S)-tert-butyl 4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-2-(2-((R)-4-hydroxy-4-methylpentan-2-yloxy)-2-oxoethyl)piperazine-1-carboxylate as a white foam. The (S)-tert-butyl 4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-2-(2-((R)-4-hydroxy-4-methylpentan-2-yloxy)-2-oxoethyl)piperazine-1-carboxylate may be dissolved in anhydrous THF and cooled in a dry ice acetone bath under nitrogen. A 2.0M solution of Butyl lithium in cyclohexane (about 1 mole equivalent) may be added dropwise under nitrogen. After about 15 minutes, iodomethane (about 1 mole equivalent) may be added dropwise under nitrogen. After about one hour, a 2.0M solution of Butyl lithium in cyclohexane (about 1 equivalent) may be added dropwise under nitrogen. After about 15 minutes, iodomethane (about 1 equivalent) may be added dropwise under nitrogen. After about one hour the solution may be concentrated under vacuum to give (S)-tert-butyl 4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-2-(1-((R)-4-hydroxy-4-methylpentan-2-yloxy)-2-methyl-1-oxopropan-2-yl)piperazine-1-carboxylate as a white foam. The (S)-tert-butyl 4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-2-(1-((R)-4-hydroxy-4-methylpentan-2-yloxy)-2-methyl-1-oxopropan-2-yl)piperazine-1-carboxylate may be dissolved in dichloromethane (about 1.1 ml) and cooled in an ice bath. Trifluoroacetic acid (about 0.5 ml) may be added dropwise under nitrogen and slowly allowed to reach room temperature while running overnight. The mixture may be concentrated under vacuum and purified by flash chromatography using 10% Acetone/Dichloromethane as the eluent to give Compound EK.
Reaction SMILES: C(OC[N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:16]=[C:17]([CH:44]=[CH:45][CH:46]=2)[C:18]([NH:20][C@@H:21]2[CH2:25][CH2:24][CH2:23][C@@H:22]2[C:26]([N:28]2[CH2:33][CH2:32][C@@:31]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)([OH:34])[C:30]([CH3:43])([CH3:42])[CH2:29]2)=[O:27])=[O:19])=[N:11]1)C1C=CC=CC=1.C(O)C1C=CC=CC=1>CO>[Cl:41][C:38]1[CH:37]=[CH:36][C:35]([C@@:31]2([OH:34])[CH2:32][CH2:33][N:28]([C:26]([C@H:22]3[CH2:23][CH2:24][CH2:25][C@H:21]3[NH:20][C:18](=[O:19])[C:17]3[CH:44]=[CH:45][CH:46]=[C:15]([C:12]4[N:11]=[N:10][NH:14][N:13]=4)[CH:16]=3)=[O:27])[CH2:29][C:30]2([CH3:42])[CH3:43])=[CH:40][CH:39]=1
Reactant: CC1(C)CN(C(=O)[C@H]2CCC[C@H]2NC(=O)c2cccc(-c3nnn(COCc4ccccc4)n3)c2)CC[C@]1(O)c1ccc(Cl)cc1
Solvent: OCc1ccccc1
Solvent: CO
Product: CC1(C)CN(C(=O)[C@H]2CCC[C@H]2NC(=O)c2cccc(-c3nn[nH]n3)c2)CC[C@]1(O)c1ccc(Cl)cc1

Procedure:
Example 24 was prepared from 3-(2-(benzyloxymethyl)-2H-tetrazol-5-yl)-N-((1R,2S)-2-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidine-1-carbonyl)cyclopentyl)benzamide using similar conditions as described in Example 22. MS (ESI+)=523 (M)+. 1H NMR (CD3OD, 500 MHz) (NMR shows several rotamers) (NMR indicates contamination with 0.5 eq. (mol) of benzyl alcohol—chemical shifts for contaminant not reported) δ 8.46 (s, 0.3H), 8.39 (s, 0.7H), 8.24 (d, J=8.0 Hz, 0.3H), 8.20 (d, J=8.0 Hz, 0.7H), 7.97 (d, J=8.3 Hz, 0.3H), 7.91 (d, J=8.3 Hz, 0.7H), 7.73 (t, J=7.8 Hz, 0.3H), 7.67 (t, J=7.7 Hz, 0.7H), 7.45 d, J=8.8 Hz, 1.4H), 7.33 d, J=8.8 Hz, 0.6H), 7.28 (d, J=8.5 Hz, 1.4H), 7.19 (d, J=8.5 Hz, 0.6H), 4.79 (q, J=7.4 Hz, 0.7H), 4.62-4.54 (m, 0.6H), 4.15-4.06 (m, 0.7H), 4.02 (d, J=12.7 Hz, 0.7H), 3.66-3.51 (m, 2.3H), 3.18-3.06 (m, 0.3H), 2.94 (d, J=12.4 Hz, 0.7H), 2.71 (td, J=13.5, 4.7 Hz, 0.7H), 2.49 (td, J=13.3, 4.4 Hz, 0.3H), 2.29-1.80 (m, 5H), 1.76-1.63 (m, 1H), 1.53 (d, J=14.0 Hz, 0.7H), 1.50-1.44 (m, 0.3H), 0.80 (s, 0.8H), 0.77-0.68 (m, 5.2H). [LCMS method: Inj. Vol.=10 uL; Start % B=0; Final % B=100; Gradient Time=2 min; Flow Rate=5 ml/min; Wavelength=220 nm; Solvent A=10% MeOH-90% H2O-0.1% TFA; Solvent B=90% MeOH-10% H2O-0.1% TFA; Column 1=Sunfire S5 C18 4.6×30 mm (2 min grad); Retention Time=1.90 minutes.]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([N:12]([CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20](O)=[O:21])[CH:16]=1)[CH3:13])(=[O:11])=[O:10].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:35]1[CH2:39][CH2:38][N:37]=[C:36]1[C:40]1[CH:45]=[CH:44][C:43]([CH2:46][NH:47][CH3:48])=[CH:42][CH:41]=1.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:9]([N:12]([CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20]([N:47]([CH2:46][C:43]2[CH:44]=[CH:45][C:40]([C:36]3[NH:37][CH2:38][CH2:39][N:35]=3)=[CH:41][CH:42]=2)[CH3:48])=[O:21])[CH:16]=1)[CH3:13])(=[O:10])=[O:11]
Reactant: CNCc1ccc(C2=NCCN2)cc1
Reactant: CN(Cc1cc(C(=O)O)co1)S(=O)(=O)c1c(Cl)cccc1Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc(C2=NCCN2)cc1)C(=O)c1coc(CN(C)S(=O)(=O)c2c(Cl)cccc2Cl)c1

Procedure:
5-({[(2,6-dichlorophenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (51 mg, 0.14 mmol) was dissolved in DMF (1 mL) and CDI (34 mg, 0.21 mmol) was added. The mixture was stirred until acid activation was complete. 1-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylmethanamine.HCl (32 mg, 0.14 mmol) and DIPEA (0.074 mL, 0.42 mmol) were sonicated in DMF (0.5 mL) for 15 min. 0.5 mL of activated acid solution was added to 0.25 mL of amine solution and the reaction was stirred at ambient temperature for 18 h, then microwaved (120° C., 200 W) for 2×20 min. The reaction was concentrated, dissolved in DCM and washed with water (3×1.5 mL) and saturated brine (1 mL)). The organic layer was dried over MgSO4 and solvents were removed in vacuo. A portion of the crude product was purified using prep method A.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][C:16]2[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:6]([CH:14]=1)[C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8].C(N)(N)=[O:24].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][C:16]2[C:17]([F:22])=[N+:18]([O-:24])[CH:19]=[CH:20][CH:21]=2)=[C:6]([C:7](=[O:8])[N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:14]=1
Reactant: NC(N)=O
Reactant: CCN(CC)C(=O)c1cc(Br)ccc1Oc1cccnc1F
Agent: OO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCN(CC)C(=O)c1cc(Br)ccc1Oc1ccc[n+]([O-])c1F
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-N,N-diethyl-2-(2-fluoropyridin-3-yloxy)benzamide (1.4 g, 3.81 mmol) and urea peroxide (1.076 g, 11.44 mmol) in 10 mL of DCM at 0 C was added dropwise trifluoroacetic anhydride (1.601 mL, 11.44 mmol) and the resulting reaction was stirred overnight. LCMS showed only less than 50% of desired conversion. The mixture was evaporated to dryness, quenched with Sat. NaHCO3, extracted with EA, dried over Na2SO4, filtered and evaporated to dryness. CC (DCM to DCM/EA=3:1 to DCM/MeOH=100:2 to 100:5 to 100:10) gave 3-(4-bromo-2-(diethylcarbamoyl)phenoxy)-2-fluoropyridine 1-oxide as an off white solid.
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:8]([CH2:12][NH:13][CH3:14])=[CH:9][CH:10]=[CH:11][C:2]1=2.Cl.[O:16]=[C:17]1[NH:26][C:25]2[N:24]=[CH:23][C:22](/[CH:27]=[CH:28]/[C:29]([OH:31])=O)=[CH:21][C:20]=2[CH2:19][CH2:18]1>>[O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:8]([CH2:12][N:13]([CH3:14])[C:29](=[O:31])[CH:28]=[CH:27][C:22]3[CH:23]=[N:24][C:25]4[NH:26][C:17](=[O:16])[CH2:18][CH2:19][C:20]=4[CH:21]=3)=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: CNCc1cccc2c1OCCCO2
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: Cl
Product: CN(Cc1cccc2c1OCCCO2)C(=O)C=Cc1cnc2c(c1)CCC(=O)N2
Yield: 78.9 %

Procedure:
According to the procedure of Example 35g (3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-ylmethyl)-methyl-amine (239 mg, 1.24 mmol) and (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3yl)acrylic acid hydrochloride (318 mg, 1.25 mmol), were coupled to give crude product. Purification by column chromatography (silica gel, 5% MeOH/CH2Cl2) gave the title compound (385 mg, 79%) as a yellow solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 10.66-10.63 (m, 1H), 8.36-8.32 (m, 1H), 8.07-8.03 (m, 1H), 7.51-7.46 (m, 1H), 7.30-721 (m, 1H), 6.93-6.88 (m, 2H), 6.78-6.76 (m, 1H), 4.76-4.59 (m, 2H), 4.13-4.06 (m, 4H), 3.11-2.84 (m, 5H), 2.54-2.52 (m, 2H), 2.11-2.07 (m, 2H); ESI MS m/e 394 [C22H23N3O4+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][O:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].[Cl:22][C:23]1[N:28]=[C:27](Cl)[C:26](=[O:30])[N:25]([CH2:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C:24]=1[CH3:42].C(N(CC)CC)C>C(OCC)(=O)C>[C:14]([O:13][C:12]([NH:11][CH2:10][CH2:9][O:8][CH2:7][C:6]1[CH:5]=[C:4]([CH:21]=[CH:20][CH:19]=1)[CH2:3][CH2:2][NH:1][C:27]1[C:26](=[O:30])[N:25]([CH2:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C:24]([CH3:42])=[C:23]([Cl:22])[N:28]=1)=[O:18])([CH3:17])([CH3:15])[CH3:16]
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCOCc1cccc(CCN)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(Cl)nc(NCCc2cccc(COCCNC(=O)OC(C)(C)C)c2)c(=O)n1CC(=O)OCc1ccccc1
Yield: 45.1 %

Procedure:
A mixture of tert-butyl 2-{[3-(2-aminoethyl)benzyl]oxy}ethylcarbamate (preparation 105) (270 mg, 0.92 mmol), benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (300 mg, 0.92 mmol), and triethylamine (140 ml, 1.01 mmol) in ethyl acetate was heated under reflux overnight. The cooled suspension was diluted with ethyl acetate, then washed with hydrochloric acid (2N), NaHCO3 solution, brine, then dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate:pentane (40:60) as eluant, and triturated with ether, to give the title compound as a white solid, (243 mg, 45%). Re-purifiing the ether filtrate by column chromatography on silica gel provided an additional (176 mg, 33%) of the desired product.
Reaction SMILES: [C:1]1(=O)O[C:5](=[O:6])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[C:13]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1CBr)#[N:14].C(N(CC)CC)C>C(#N)C>[O:6]=[C:5]1[C:4]2[C:3](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]2[CH2:1][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[C:13]=2[NH:14]1
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: N#Cc1ccccc1CBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=c1[nH]c2c(c3ccccc13)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of homophthalic anhydride (324 mg, 2.0 mmol) in acetonitrile (15 mL) was added 2-cyanobenzyl bromide (431 mg, 2.0 mmol, 1.0 eq) and triethylamine (5 mL). The reaction was stirred under inert atmosphere at room temperature for 30 minutes, after which time a yellow precipitate appeared. The reaction mixture was then heated at reflux for 18 h and the resulting white precipitate was filtered, washed using acetonitrile (3×8 mL) and dried under vacuum to provide Compound 13a as a white crystalline solid. Yield=150 mg (32%).
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[CH2:3][CH2:4][OH:5].[C:8](OC(=O)C)(=[O:10])[CH3:9]>C(Cl)Cl>[C:8]([O:5][CH2:4][CH2:3][C:2]([OH:7])([CH3:6])[CH3:1])(=[O:10])[CH3:9]
Reactant: CC(C)(O)CCO
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)OCCC(C)(C)O
Reaction time: 5 h

Procedure:
A solution of 16 mL 3-methylbutane-1,3-diol in 10 mL methylene chloride with a catalytic amount of 4-dimethylpyridine was cooled to 0° C. Acetic anhydride (4.084 g, 40 mmol) was then added drop wise and the solution was stirred for 5 hours. An additional 10 mL of methylene chloride was added and the solution was washed with 10% aqueous ammonium chloride (2×20 mL), 5% sodium carbonate (2×20 mL) and brine (1×20 mL), dried over sodium sulfate and evaporated to dryness to yield a clear, yellow liquid. (2.402 g) 1H NMR (400 MHz, CDCl3): δ 1.24 (s, 6H), 1.56 (b, 1H), 1.80-1.83 (t, J=6.8, 2H), 2.02 (s, 3H), 4.22 (t, J=6.9, 2H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]=1.[NH3:25]>CN(C=O)C>[F:1][C:2]([F:24])([F:23])[CH2:3][N:4]=[C:5]([NH2:25])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]=1
Reactant: N
Reactant: CCOC(=O)CCCSc1nccc(NC(=S)NCC(F)(F)F)n1
Solvent: CN(C)C=O
Product: CCOC(=O)CCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 4-[4-(3-[2,2,2-trifluoroethyl]thioureido)pyrimid-2-ylthio]butyrate (0.25 g.), DMF (2 ml.), saturated ethanolic ammonia (5 ml.) and yellow mercuric oxide (0.2 g.) was stirred at room temperature for 2 hours and then filtered. The filtrate was evaporated to dryness and the residue recrystallised from EtOAc to give ethyl 4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyrate, m.p. 120°-122°.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.C(N(CC)CC)C.Cl.[NH2:21][OH:22]>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:21][OH:22]
Reactant: NO
Reactant: O=Cc1ccc2ccccc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ON=Cc1ccc2ccccc2c1
Temperature: 35 °C
Yield: 98.2 %

Procedure:
To a mixture of 7.8 g of 2-naphthalaldehyde and 7.1 ml of triethylamine in 100 ml of methylene chloride was added 3.54 g of hydroxylamine hydrochloride and the mixture heated at 35° C. for three hours. The organic reaction solvent was washed with water, dried and concentrated to give 8.4 g of product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:4][N:3]=1.[Na].[CH2:18]([OH:20])[CH3:19]>>[Cl:1][C:2]1[N:7]=[C:6]([O:20][CH2:18][CH3:19])[C:5]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:4][N:3]=1
Reactant: CCO
Reactant: Cc1ccc(Cc2cnc(Cl)nc2Cl)cn1
Agent: [Na]
Product: CCOc1nc(Cl)ncc1Cc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a stirred solution of 8.1 g (32 mmol) of 2,4-dichloro-5-[(6-methyl-3-pyridinyl)methyl]pyrimidine prepared as in Example 1 in 200 ml of ethanol at 10° was added dropwise over 1 hour a solution of 0.8 g (35 mg-atom) of sodium metal in 100 ml of ethanol. The resulting mixture was stirred for 18 hours at room temperature, concentrated, and the resulting oil dissolved in 100 ml of ethyl acetate. The resulting solution was washed with water, dried over sodium sulfate, filtered and concentrated to give 7.6 g (0.0288 mmol, 90%) of 2-chloro-4-ethoxy-5-[(6-methyl-3-pyridinyl)methyl]pyrimidine; MS(FD)m/e 263 parent ion.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.[C:29]([O:33][C:34]([N:36]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[C:37]1[C:46]2[C:41](=[CH:42][C:43]([NH:47][CH:48]([C:52]3[CH:57]=[C:56]([CH3:58])[C:55]([CH2:59][CH2:60][OH:61])=[C:54]([CH3:62])[CH:53]=3)[C:49]([OH:51])=O)=[CH:44][CH:45]=2)[CH:40]=[CH:39][N:38]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30].[N+:70]([C:73]1[CH:74]=[C:75]([CH:86]=[CH:87][CH:88]=1)[CH2:76][NH:77][CH2:78][C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])([O-:72])=[O:71]>CCOC(C)=O>[C:29]([O:33][C:34]([N:36]([C:63]([O:65][C:66]([CH3:68])([CH3:67])[CH3:69])=[O:64])[C:37]1[C:46]2[C:41](=[CH:42][C:43]([NH:47][CH:48]([C:52]3[CH:57]=[C:56]([CH3:58])[C:55]([CH2:59][CH2:60][OH:61])=[C:54]([CH3:62])[CH:53]=3)[C:49]([N:77]([CH2:78][C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[CH2:76][C:75]3[CH:86]=[CH:87][CH:88]=[C:73]([N+:70]([O-:72])=[O:71])[CH:74]=3)=[O:51])=[CH:44][CH:45]=2)[CH:40]=[CH:39][N:38]=1)=[O:35])([CH3:31])([CH3:32])[CH3:30]
Reactant: CC(C)(C)OC(=O)CNCc1cccc([N+](=O)[O-])c1
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)O)cc(C)c1CCO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(CC(=O)OC(C)(C)C)Cc2cccc([N+](=O)[O-])c2)cc(C)c1CCO
Temperature: 60 °C
Reaction time: 3 h
Yield: 42.2 %

Procedure:
EDCI (142 mg, 0.74), HOAt (101 mg, 0.74 mmol), and triethylamine (0.18 mL, 1.35 mmol) were added to a solution of 50C (380 mg, 0.67 mmol) and 52C (197 mg, 0.74 mmol) in that order. The reaction mixture was stirred at 60° C. for 3 h. The solution was diluted with EtOAc, washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude solid was purified by flash chromatography (0% to 100% EtOAc in hexanes) to afford 52D (230 mg, 42%) as a yellow solid. MS (ESI) m/z 814.9 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[N:9]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])(=[O:19])=[O:18])[C:8]1=[O:30].O>N1C=CC=CC=1>[Cl:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[O:28][CH3:29])(=[O:19])=[O:18])[C:8](=[O:30])[C:7]2([NH:6][C:1]([CH2:2][CH3:3])=[O:4])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37]
Reactant: CCC(=O)Cl
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3Cl)c3cc(Cl)ccc32)c(OC)c1
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)NC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.08 g of propionyl chloride is added to a solution of 0.33 g of the compound obtained in EXAMPLE 3 in 3 ml of pyridine and the reaction mixture is stirred for 1 hour at RT. It is poured into water, extracted with AcOEt, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (98/2; v/v) as the eluent to give the expected product after crystallization from a DCM/iso ether mixture. m=0.18 g. M.p.=188° C.
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.C[Si]([C:13]#[N:14])(C)C.N12CCCN=C1CCCCC2>C1COCC1>[C:13]([C:2]1[CH:3]=[C:4]([CH3:7])[CH:5]=[CH:6][N:1]=1)#[N:14]
Reactant: Cc1cc[n+]([O-])cc1
Reactant: C[Si](C)(C)C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.4 %

Procedure:
To a suspension of 4-picoline N-oxide (13.64 g, 0.124 mole) in 82 ml of THF, under an inert atmosphere, was added trimethylsilyl cyanide (20.1 ml, 0.15 mole) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (4.4 ml, 0.028 mole). After stirring at 25° C. for 12 hours, the reaction mixture was heated to reflux. After 4.5 hours, the solvent was removed under reduced pressure and the crude sample was eluted with methylene chloride through a pad of Florisil®. The solvent was removed under reduced pressure to provide (8.7 g, 60%) of 2-cyano-4-methyl pyridine, a white crystalline solid: mp 88–89° C. Anal. Calc'd. for C7H6N2: C, 71.17; H, 5.12; N, 23.71. Found: C, 70.17; H, 5.12; N, 23.44.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:15]=[C:14]([N:16]([CH3:18])[CH3:17])[N:13]=[C:12]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.Cl[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[CH:37]=1>O1CCOCC1>[CH3:43][O:42][C:38]1[CH:37]=[C:36]([CH:41]=[CH:40][CH:39]=1)[CH2:35][N:22]1[CH2:23][CH2:24][N:19]([C:12]2[N:11]=[C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:15]=[C:14]([N:16]([CH3:18])[CH3:17])[N:13]=2)[CH2:20][CH2:21]1
Reactant: COc1cccc(CCl)c1
Reactant: COc1cccc(Nc2cc(N(C)C)nc(N3CCNCC3)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1cccc(CN2CCN(c3nc(Nc4cccc(OC)c4)cc(N(C)C)n3)CC2)c1
Yield: 71.3 %

Procedure:
A solution of N4-(3-methoxyphenyl)-N6,N6-dimethyl-2-(1-piperazinyl)-4,6-pyrimidinediamine (36 mg, 0.1 mmol), DIPEA (52 mg, 0.4 mmol), and 1-(chloromethyl)-3-methoxybenzene (20 mg, 0.13 mmol) in 5 mL of dioxane was stirred at 100° C. for 16 h. The crude product was concentrated in vacuo and treated with saturated NaHCO3 (50 mL) and extracted with CH2Cl2 (3×50 mL). The organic layer washed with brine (2×100 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product (32 mg, 70%).
Reaction SMILES: Br[CH:2]1[C:7](=O)[CH2:6][CH2:5][CH2:4][CH:3]1[C:9]([O:11][CH3:12])=[O:10].[C:13]([NH2:21])(=[S:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO>[C:14]1([C:13]2[S:20][C:2]3[CH:3]([C:9]([O:11][CH3:12])=[O:10])[CH2:4][CH2:5][CH2:6][C:7]=3[N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(=S)c1ccccc1
Reactant: COC(=O)C1CCCC(=O)C1Br
Solvent: CCO
Product: COC(=O)C1CCCc2nc(-c3ccccc3)sc21

Procedure:
A soln. of methyl 2-bromo-3-oxocyclohexanecarboxylate (100 mg, 0.43 mmol) and thiobenzamide (64 mg, 0.47 mmol) in EtOH (2 mL) was stirred at 85° C. overnight. Subsequently, the mixture was quenched with aq. sat. NaHCO3 and extracted with EtOAc. The comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo. Purification by means of CC (2-15% EtOAc/Hept) provided a yellow oil.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].Cl[S:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([OH:36])[CH:28]=1)(=[O:26])=[O:25]>>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[CH2:10][NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][S:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([OH:36])[CH:28]=2)(=[O:26])=[O:25])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: CCCCc1oc2ccccc2c1CNc1ccc(O)cc1
Product: CCCCc1oc2ccccc2c1CNc1ccc(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)cc1
Yield: 68.2 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using 4-[(2-butyl-benzofuran-3-ylmethyl)-amino]-phenol (0.500 g, 1.69 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.401 g, 1.69 mmol). Purification on 2% H3PO4 /MeOH treated silica gel, eluting with 25% EtOAc/hexane gave 0.571 g (85%) of the title compound as a dark yellow solid, mp 75-77° C. 1H NMR (DMSO-d6) δ 0.86 (t, 3 H), 1.31 (sextet, 2 H), 1.60 (quintet, 2 H), 2.80 (t, 2 H), 4.23 (s, 2 H), 6.54 (d, 2 H), 6.72 (d, 2 H), 7.14-7.22 (m, 2 H), 7.26-7.30 (m, 2 H), 7.45 (dd, 1 H), 7.58 (dd, 1 H), 7.95 (d, 1 H). IR (KBr) 3400, 2950, 1600, 1510 and 1380 cm-1. mass spectrum (-ESI) m/z 494 (M-H).