Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[CH:4]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6][CH2:5]1)#[C-:2].C[O-].[Na+].[F:33][C:34]([F:47])([F:46])[C:35]([C:38]1[CH:45]=[CH:44][C:41]([CH:42]=[O:43])=[CH:40][CH:39]=1)([OH:37])[CH3:36]>CO.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[F:33][C:34]([F:46])([F:47])[C:35]([C:38]1[CH:45]=[CH:44][C:41]([C:42]2[O:43][CH:2]=[N:1][C:3]=2[CH:4]2[CH2:5][CH2:6][N:7]([S:10]([C:13]3[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=3)(=[O:11])=[O:12])[CH2:8][CH2:9]2)=[CH:40][CH:39]=1)([OH:37])[CH3:36]
Reactant: CC(O)(c1ccc(C=O)cc1)C(F)(F)F
Reactant: [C-]#[N+]C(C1CCN(S(=O)(=O)c2ccc(C)cc2)CC1)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CCC(c3ncoc3-c3ccc(C(C)(O)C(F)(F)F)cc3)CC2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
4-(Isocyano(tosyl)methyl)-1-tosylpiperidine (260 mg, 0.73 mmol) was dissolved in MeOH (6 mL) and treated with sodium methoxide (1.0 M solution in MeOH, 0.7 mL), and 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzaldehyde (159 mg, 0.73 mmol) was then added. After being stirred at 80° C. for 2 h, the mixture was then cooled to r.t. and diluted with ethyl acetate (80 mL) and saturated aqueous NaHCO3 (30 mL). The separated organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (15% EtOAc/hexane) to provide 1,1,1-trifluoro-2-(4-(4-(1-tosylpiperidin-4-yl)oxazol-5-yl)phenyl)propan-2-ol as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.69-7.65 (m, 2H), 7.51-7.49 (m, 2H), 7.36-7.33 (m, 4H), 3.90 (d, J=11.7 Hz, 2H), 3.30-3.28 (s, 1H), 2.79 (tt, J=3.9 Hz, 11.7 Hz, 1H), 2.45 (s, 3H), 2.37 (td, J=2.3 Hz, 12.1 Hz, 2H), 2.17-2.07 (m, 2H), 1.85 (d, J=12.1 Hz, 2H), 1.80 (s, 3H); MS (ESI) 495.1 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:4][CH2:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:26]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:27][C:28](ON1C(=O)CCC1=O)=[O:29]>CN(C=O)C.CCN(CC)CC>[NH:26]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:27][C:28]([NH:2][C@H:3]([C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[CH2:4][CH2:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:29]
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a stirred solution at 0° C, of HCl.H-Glu(OBzl)-OBzl (1.82 g, 5 mmol) in DMF (35 ml), Et3N (0.7 ml) was added dropwise followed by Boc-Gly-OSu (1.5 g, 5.5 mmol). The mixture was stirrred at 0° C for 2 hr and at room temperature overnight; pH 8 was maintained by addition of a few drops of Et3N. The reaction mixture was then evaporated to a small volume and H2O was added. The precipitated oil was extracted with EtOAc and the organic phase was washed with 1 M AcOH, water, and dried (Na2SO4). Evaporation provided an oil which was purified on a Silica gel 60 column using CHCl3 :MeOH (5:1) as eluant. The pooled fractions containing (XVIII) were evaporated yielding colorless oil which failed to crystallize, 1.62 g (67%) homogeneous on tlc [α]D25 -15.0° (c 2, MeOH). Anal. Calcd for C26H32N2O7 (484.558): C, 64.45; H, 6.66; N, 5.78. Found: C, 64.23; H, 6.72; N, 5.66. Compound XVIII was also prepared from Boc-Gly-Glu(OBzl)-OH via the cesium salt procedure of Wang et al, supra.
Reaction SMILES: [O:1]1[CH2:18][C@H:2]1[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[CH:7]=[C:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][C:21]=1[F:32]>CO>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:27][CH2:28][N:29]([CH2:18][C@H:2]([OH:1])[CH2:3][O:4][C:5]3[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=3[CH:7]=[C:8]3[CH2:13][CH2:12][O:11][C:9]3=[O:10])[CH2:30][CH2:31]2)=[CH:22][C:21]=1[F:32]
Reactant: Fc1cc(C2CCNCC2)ccc1Cl
Reactant: O=C1OCCC1=Cc1ccccc1OC[C@@H]1CO1
Solvent: CO
Product: O=C1OCCC1=Cc1ccccc1OC[C@@H](O)CN1CCC(c2ccc(Cl)c(F)c2)CC1
Yield: 33.7 %

Procedure:
By the reaction in same manner as in Example 307 using (S)-α-(2′-(2,3-epoxypropan-1-yloxy)benzylidene)-γ-butyrolactone (1.0 g) and 4-(4-chloro-3-fluorophenyl)piperidine (0.8 g) in methanol (50 ml), the title compound (0.58 g), melting point 114–115° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH:10]([CH3:12])[CH3:11].[O:13]=O.Cl>C1(C)C=CC=CC=1.C(OP(OCC)OCC)C.CN(C)C=O>[OH:13][C:10]([C:3]1[N:2]([CH3:1])[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=1)([CH3:12])[CH3:11]
Reactant: O=O
Reactant: CC(C)c1ncc([N+](=O)[O-])n1C
Agent: CCOP(OCC)OCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cn1c([N+](=O)[O-])cnc1C(C)(C)O
Yield: 23.8 %

Procedure:
A total of 45 ml of a 2.25-N solution of sodium tert.amylate in toluene and 11.2 ml of triethylphosphite were added to a solution, cooled to -15°, of 8.5 g of 1-methyl-2-isopropyl-5-nitroimidazole in 85 ml of dimethylformamide. A strong oxygen stream was conducted through this mixture for 6 hours at a temperature of -10° to -15° while stirring vigorously. The mixture was then neutralized by the addition of 45 ml of 2-N hydrochloric acid and concentrated on a rotary evaporator at 50°/12 Torr. The residue was taken up in 250 ml of water and the aqueous solution extracted 3 times with 250 ml portions of dichloromethane. The combined dichloromethane extracts were washed with a small amount of water and concentrated to dryness. The residue was then taken up in ethyl acetate and chromatographed on 600 g of silica gel with ethyl acetate. After evaporation of the solvent on a rotary evaporator and crystallization from isopropyl ether, there were obtained 2.2 g of 2-(2-hydroxy-2-propyl)-1-methyl-5-nitroimidazole, melting point 106°-108°. The yield was 23.8%.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12](Br)=[N:11][C:10]=1[Br:15])[CH:2]=[CH2:3].C[Sn](C)(C)[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=[O:27])[CH3:26])[CH:19]=1.[Cl-].[Li+]>O1CCOCC1.[Cu]I>[CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=[O:27])[CH3:26])[CH:19]=2)=[N:11][C:10]=1[Br:15])[CH:2]=[CH2:3]
Reactant: C=CCn1ccnc1-c1sc(Br)nc1Br
Reactant: CC(=O)Nc1cc([Sn](C)(C)C)ccn1
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=CCn1ccnc1-c1sc(-c2ccnc(NC(C)=O)c2)nc1Br
Temperature: 115 °C
Yield: 54.1 %

Procedure:
To a solution of 5-(1-allyl-1H-imidazol-2-yl)-2,4-dibromo-1,3-thiazole (5.00 g, 14.3 mmol) in 1,4-dioxane (133 mL) was added N-[4-(trimethylstannyl)pyridine-2-yl]acetamide (5.14 g, 17.2 mmol), lithium chloride (1.82 g, 43.0 mmol), copper (I) iodide (0.818 g, 4.30 mmol) and tetrakis (triphenylphosphine)palladium(0) (1.24 g, 1.07 mmol). The flask was purged with argon and then the mixture was heated at 115° C. for 4 hours. The reaction was allowed to cool to room temperature, and then the solvent was evaporated in vacuo. Column chromatography was performed to yield the title compound (3.13 g, 54%). LCMS: (FA) ES+ , 406. 1H NMR (400 MHz, d6-DMSO) δ: 10.77 (s, 1H), 8.66-8.61 (m, 1H), 8.49-8.44 (m, 1H), 7.61-7.56 (m, 1H), 7.49-7.45 (m, 1H), 5.98-5.87 (m, 1H), 5.19-5.12 (m, 1H), 4.95-4.88 (m, 1H), 4.70-4.64 (m, 2H), 2.13 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C-:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=O)=[O:7])=[CH:4][CH:3]=1.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26].S(=O)(=O)(O)O.O>C(O)(=O)C>[C-:14]1([C:12]2[CH2:11][CH2:10][CH2:9][C:8]=2[C:6](=[O:7])[C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:18]=[CH:17][CH:16]=[CH:15]1.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26]
Reactant: O=C(CCCCC(=O)[c-]1cccc1)c1ccc(Cl)cc1
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: c1cc[cH-]c1
Solvent: CC(=O)O
Solvent: O
Product: O=C(C1=C([c-]2cccc2)CCC1)c1ccc(Cl)cc1

Procedure:
5-(4-Chlorobenzoyl)pentanoyl ferrocene (8.2g; 0.02 mole) and 5% (v/v) concentrated sulphuric acid in glacial acetic acid (200 ml) were stirred at room temperature for one hour, the mixture was poured into water extracted with chloroform (3 × 100 mls.). The combined extracts were washed with saturated aqueous sodium bicarbonate, and water, dried (magnesium sulphate) and evaporated under vacuum to yield a red-brown oil which crystallized from pentane at 0°-5°. The solid was filtered off to yield pure 1-ferrocenyl-2(4-chlorobenzoyl)cyclopent-1-ene; 2.5g (35%) mp 121°-3°.
Reaction SMILES: C([Cl:4])C=C.[CH3:5][SiH:6]([CH3:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:5][Si:6]([CH3:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[Cl:4]
Reactant: C[SiH](C)c1ccccc1
Reactant: C=CCCl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: C[Si](C)(Cl)c1ccccc1
Temperature: 42.5 °C
Yield: 96 %

Procedure:
To a 500 ml glass flask equipped with a stirring machine, a thermometer, a reflux condenser and a dropping funnel, there were added 91.8 g (1.2 mole) of allyl chloride and 0.03 g of palladium acetate, the temperature of the mixture was raised up to 40 to 45° C., then 136.3 g (1.0 mole) of dimethylphenylsilane was dropwise added to the mixture over 3 hours through the dropping funnel to carry out the reaction of the allyl chloride and the dimethylphenylsilane and the reaction mixture was aged at 50° C. for 3 hours. The reaction solution obtained after the aging was distilled to give a distillate having a boiling point range of from 80 to 84° C./16 mmHg. Thus, 163.9 g of dimethylphenylchlorosilane having a purity of 99.9% was obtained. The yield of the product was found to be 96.0%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH2:19][CH3:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Br:22][C:23]1[N:24]=[C:25]([CH3:31])[NH:26][C:27]=1[C:28](O)=[O:29].CCN(C(C)C)C(C)C.C(Cl)CCl>>[Br:22][C:23]1[N:24]=[C:25]([CH3:31])[NH:26][C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:21])=[O:29]
Reactant: CCc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: Cc1nc(Br)c(C(=O)O)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C)nc3Br)c2F)c1
Yield: 63.2 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-ethylbenzonitrile (0.053 g, 0.174 mmol), 4-bromo-2-methyl-1H-imidazole-5-carboxylic acid (0.036 g, 0.174 mmol) and DIEA (0.061 mL, 0.348 mmol) were combined and treated with EDC (0.067 g, 0.348 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness and partitioned between EtOAc and water. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted with 0 to 10% CH3OH/DCM to give 4-bromo-N-({4-chloro-3-[(3-cyano-5-ethylphenyl)oxy]-2-fluorophenyl}methyl)-2-methyl-1H-imidazole-5-carboxamide (0.054 g, 0.110 mmol, 63.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6+1 drop D2O) δ ppm 7.40-7.51 (m, 2H), 7.32 (t, J=7.83 Hz, 1H), 7.14 (d, J=6.73 Hz, 2H), 4.47 (s, 2H), 2.62 (q, J=7.51 Hz, 2H), 2.24 (s, 3H), 1.12 (t, J=7.49 Hz, 3H). LC-MS (ES−) m/z 488.97, 490.93, 492.87 [M−1]. LC-MS (ES+) m/z 491.10, 493.10, 495.07 [M+H].
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.Cl[CH2:18][C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.N>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH2:12][CH2:13][N:14]([CH2:18][C:19]2[NH:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:15][CH:16]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: C1=C(c2cc3ccccc3s2)CCNC1
Agent: Cl
Agent: N
Product: C1=C(c2cc3ccccc3s2)CCN(Cc2nc3ccccc3[nH]2)C1

Procedure:
The title compound was prepared in a analogous manner to Example 1 using 4-(benzothiophen-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride and 2-chloromethylbenzimidazole, m.p. 241° C. (dec.); (Found: C, 72.44; H, 5.41; N, 11.83. C12H19N3S.0.1H2O requires C, 72.63; H, 5.57; N, 2.10%); δH (DMSO-d6) 2.62 (2H, br s, tetrahydropyridinyl CH2), 2.77 (2H, m, tetrahydropyridinyl CH2), 3.24 (2H, d, J 2.8 Hz, tetrahydropyridinyl CH2), 3.87 (2H, s, NCH2Ar), 6.23 (1H, br s, CH=CR), 7.10-7.42 (1H, m, ArH), 7.45 (1H, d, J 8 Hz, ArH), 7.74 (1H, d, J 8 Hz, ArH), 7.76 (1H, dd, J 8, 2 Hz, ArH), 7.86 (1H, dd, J 8, 2 Hz, ArH), and 12.32 (1H, br s, NH); m/z (CI+, NH3) 346 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)=[N:5][C:6]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:7][C:8]=1[S:9]([CH3:11])=O)#[N:2].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32]CS.C1CCN2C(=NCCC2)CC1>COCCOC>[C:1]([C:3]1[C:4]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)=[N:5][C:6]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:7][C:8]=1[S:9][CH2:11][CH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=1)#[N:2]
Reactant: SCCc1ccccn1
Reactant: CS(=O)c1nc(NC(=O)c2ccccc2)nc(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(SCCc2ccccn2)nc(NC(=O)c2ccccc2)nc1-c1ccco1

Procedure:
From N-(5-cyano-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl)-benzamide, 2-pyridylethylmercaptan and DBU in DME. ES-MS m/e (%): 428 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([CH2:9][CH:10]1[CH2:19][C:18](=[O:20])[C:17]2[C:12](=[CH:13][C:14]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:15][CH:16]=2)[O:11]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:31][Mg]Cl>C1COCC1>[C:1]([O:5][C:6](=[O:30])[N:7]([CH2:9][CH:10]1[CH2:19][C:18]([OH:20])([CH3:31])[C:17]2[C:12](=[CH:13][C:14]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:15][CH:16]=2)[O:11]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CC1CC(=O)c2ccc(S(=O)(=O)c3ccccc3)cc2O1)C(=O)OC(C)(C)C
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CN(CC1CC(C)(O)c2ccc(S(=O)(=O)c3ccccc3)cc2O1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
To a solution of (7-benzenesulfonyl-4-oxo-chroman-2-ylmethyl)-methyl-carbamic acid tert-butyl ester (216 mg, 0.5 mmol) in THF (25 mL) at 0° C. was added MeMgCl (3.0 M in THF, 0.208 mL). The mixture was allowed to warm at room temperature and was stirred for 6 hours. The reaction was quenched by addition of water and it was concentrated in vacuo. The aqueous residue was extracted with DCM and the organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (DCM/MeOH, 97/3) to give (7-benzenesulfonyl-4-hydroxy-4-methyl-chroman-2-ylmethyl)-methyl-carbamic acid tert-butyl ester (214 mg, 96% yield) as yellow crystalline solid.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([NH:8][C:9]2[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=2)[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].[Cl:23]N1C(=O)CCC1=O>ClCCl.O1CCOCC1>[Cl:23][C:10]1[C:11](=[O:14])[CH2:12][CH2:13][C:9]=1[NH:8][C@@H:7]1[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]([CH3:22])([CH3:21])[C@H:2]1[OH:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC2=CC(=O)CC2)[C@@H]1O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC2=C(Cl)C(=O)CC2)[C@@H]1O

Procedure:
A solution of 150 mg of the title compound of example 5 in 5 ml of dichloromethan and 5 ml of dioxan is mixed with 77 mg of N-chloro-succinimide. After 50 minutes at room temperature the solution is poured on water and the organic components are extracted with dichloromethane/ethanol. Recristallisation of the raw product obtained after concentration yields white crystalls of the title compound having a m.p. of 288°-89° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:24])([CH3:23])[CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][C:3]([CH3:24])([CH3:23])[CH2:2][NH:1][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CN
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CNC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
A solution containing 1-(3-amino-2,2-dimethylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.05 mmol) and triethylamine (470 μL, 3.36 mmol) in 1-methyl-2-pyrrolidinone (30 mL) was cooled to 0° C. Benzoyl chloride (345 μL, 3.05 mmol) was slowly added dropwise. The reaction mixture was allowed to slowly warm to ambient temperature overnight. The reaction mixture was combined with 1% aqueous sodium bicarbonate solution (150 mL) and then stirred overnight. A fine white precipitate was isolated by filtration and washed with hexanes. The material was dissolved in dichloromethane, methanol and toluene. The solution was concentrated under vacuum. The material was purified by column chromatography (60 g silica gel eluting with 7.5% methanol in dichloromethane) and then dried in a vacuum oven at 50° C. for 2 days to provide 0.82 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2,2-dimethylpropyl}benzamide as an off white powder, m.p. 103-125° C. Analysis: Calculated for C25H29N5O2.0.30H2O: % C, 68.72; % H, 6.83; % N, 16.03; Found: % C, 68.50; % H, 6.55; % N, 16.02.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.N1C=CC=CC=1.Cl.Cl.Cl.[NH:50]1[CH2:54][CH2:53][CH:52]([C:55]2[CH:60]=[N:59][CH:58]=[CH:57][N:56]=2)[CH2:51]1>C(#N)C>[F:17][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([N:50]2[CH2:54][CH2:53][CH:52]([C:55]3[CH:60]=[N:59][CH:58]=[CH:57][N:56]=3)[CH2:51]2)=[O:16])=[CH:7][CH:8]=1
Reactant: c1cnc(C2CCNC2)cn1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCC(c2cnccn2)C1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
5-[4-(Trifluoromethyl)phenyl]isoxazole-4-carboxylic acid (30 mg, 0.12 mmol) was dissolved in acetonitrile (1.5 mL) followed by the addition of o-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (52 mg, 0.16 mmol), pyridine (60 μL, 0.72 mmol) and 2-pyrrolidin-3-yl-pyrazine trihydrochloride (36 mg, 0.14 mmol), and stirred at 60° C. for 30 min. The residue was purified on reversed phase HPLC to yield the title compound (26 mg). HRMS (ESI, pos. ion) m/z calcd for C19H15F3N4O2: 388.1147, found 388.1152.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[OH:50][CH2:51][C@H]1[C@H](O)CCN1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][C@@H:51]([OH:50])[C@@H:27]2[CH2:26][OH:25])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OC[C@@H]1NCC[C@H]1O
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CC[C@@H](O)[C@@H]2CO)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (2S,3R)-2-(hydroxymethyl)pyrrolidin-3-ol and isolated as light-yellow gum (9.6 mg, 49%). MS(m/e): 417.4 (MH+).
Reaction SMILES: C[O:2][C@:3]1([C@@H:24]2[CH2:28][S:27][C:26](=[O:29])[N:25]2CC2C=CC(OC)=CC=2)[CH2:8][C@H:7]([O:9][C:10](=[O:18])/[CH:11]=[C:12](/[CH3:17])\[CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:6][C@@H:5]([CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23])[O:4]1.CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[OH:2][C@:3]1([C@@H:24]2[CH2:28][S:27][C:26](=[O:29])[NH:25]2)[CH2:8][C@H:7]([O:9][C:10](=[O:18])/[CH:11]=[C:12](/[CH3:17])\[CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:6][C@@H:5]([CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23])[O:4]1
Reactant: C=CCCC[C@@H]1C[C@@H](OC(=O)/C=C(/C)CCC=C)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: C=CCCC[C@@H]1C[C@@H](OC(=O)/C=C(/C)CCC=C)C[C@](O)([C@@H]2CSC(=O)N2)O1

Procedure:
Application of the method shown in Example 46, with the modification that (Z)-((2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl)-3-methylhepta-2,6-dienoate was substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, afforded the title compound.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)C>[CH2:32]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: O=C(NCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NCC1CCN(Cc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1

Procedure:
To a solution of 0.58 g (1.5 mM) of N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (7.5 mM) of triethylamine in ethanol was added 0.19 ml (1.6 mM) of benzyl bromide at room temperature, and the mixture was refluxed under nitrogen for 6 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with methylene chloride. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The resulting crude product was purified by column chromatography (methanol/ethyl acetate 40%) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][NH:10][C:11](=[O:12])[C:3]=12.Cl[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16].CCN(CC)CC>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][N:10]=[C:11]([O:12][CH2:14][C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[C:3]=12
Reactant: Cc1cc(C)c2c(=O)[nH]sc2n1
Reactant: O=C(CCl)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c2c(OCC(=O)N3CCOCC3)nsc2n1
Temperature: 40 °C
Yield: 9.3 %

Procedure:
Pyridinothiazolone 4 (200 mg, 1.22 mmol), was treated with 2-chloro-1-morpholinoethanone (225 mg, 1.25 mmol) and Et3N (370 mg, 3.66 mmol) in anhydrous CH2Cl2 (25 mL) at reflux (40° C.) for 24 h, and then washed with 1 M HCl(aq). The organic phase was dried over MgSO4, filtered, concentrated, and purified by flash chromatography on a silica gel column with elution of EtOAc/hexane (1:1) to give the title compound (35 mg, 9% yield) in addition to the main N-alkylation product 19 (55%).