Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.CS[C:32]1[S:33][CH2:34][CH2:35][N:36]=1.Cl.C([O-])(O)=O.[Na+]>COCCO>[S:33]1[CH2:34][CH2:35][N:36]=[C:32]1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][CH:7]=1
Reactant: CSC1=NCCS1
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Product: CC(=O)Nc1nc(CCc2ccc(NC3=NCCS3)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 120 °C
Reaction time: 1.3 h
Yield: 58.4 %

Procedure:
A mixture of N-{4-[2-(4-aminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}-acetamide (200 mg), 2-(methylsulfanyl)-4,5-dihydro-1,3-thiazole (62 mg), concentrated HCl (0.064 ml) and 2-methoxyethanol (3 ml) was stirred at 120° C. for 1.3 hours under N2 atmosphere. After cooled to r.t., the reaction mixture was made basic with saturated NaHCO3. The mixture was extracted with AcOEt. The organic layer was dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by preparative silica gel chromatography with CHCl3/MeOH (10:1) as an eluent to give N-{4-{2-[4-(4,5-dihydro-1,3-thiazol-2-ylamino)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (139.8 mg) as a pale yellow amorphous substance.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:26][CH2:27][CH3:28]>>[NH2:24][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:17][CH2:18][N:19]([CH2:26][CH2:27][CH3:28])[CH2:20][CH2:21]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCNCC3)c2n1
Reactant: CCCI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCN(CCC)CC3)c2n1

Procedure:
Prepared similarly to Example 24 from 2-(butyloxy)-8-(methyloxy)-9-(4-piperidinylmethyl)-9H-purin-6-amine and 1-iodopropane.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][C@H:21]([OH:28])[C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:29])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1(C2C=CN=CC=2)CCCC1.[CH3:41][C:42]([CH3:48])([CH2:46][CH3:47])[C:43](Cl)=[O:44]>N1C=CC=CC=1.CCOCC>[CH3:41][C:42]([CH3:48])([CH2:46][CH3:47])[C:43]([O:28][C@@H:21]1[C@@:19]2([CH3:20])[C@@H:15]([CH2:16][CH2:17][C:18]2=[O:29])[C@H:14]2[C@@H:23]([C@:24]3([CH3:27])[C@H:11]([CH2:12][CH2:13]2)[CH2:10][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH2:26][CH2:25]3)[CH2:22]1)=[O:44]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2C[C@H](O)[C@]2(C)C(=O)CC[C@@H]32)C1
Reactant: CCC(C)(C)C(=O)Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCC(C)(C)C(=O)O[C@H]1C[C@H]2[C@@H](CC[C@@H]3C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@]32C)[C@@H]2CCC(=O)[C@@]12C
Temperature: 85 °C
Reaction time: 3 h

Procedure:
3α-tert-butyldimethylsilyloxy-12α-hydroxy-5β-androstan-17-one (5.9 g), 4-pyrrolidinopyridine (0.30 g) and 2,2-dimethylbutyryl chloride (6 ml) are dissolved in pyridine (30 ml) and the solution warmed to 85° C., stirred at that temperature for about 3 hours, cooled, diluted with ether and washed with water, then 0.5M hydrochloric acid. The organic solution is dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography in a gradient of 20% to 30% ether in hexane to give the desired product.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5](=O)[CH:6]([O:9][CH3:10])[O:7][CH3:8].O.[NH2:14]N>CO>[CH3:8][O:7][CH:6]([O:9][CH3:10])[C:5]1[CH:4]=[CH:3][NH:2][N:14]=1
Reactant: COC(OC)C(=O)C=CN(C)C
Reactant: NN
Solvent: O
Solvent: CO
Product: COC(OC)c1cc[nH]n1
Reaction time: 8 h

Procedure:
A mixture of 5 g of 4-dimethylamino-1,1-dimethoxy-3-butene-2-one, 1.7 ml of hydrazine monohydrate and 15 ml of methanol was stirred for 8 hours under heat refluxing. The reaction mixture was concentrated under reduced pressure to obtain 4.07 g of 3-(dimethoxymethyl)-1H-pyrazole of the formula:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[N+:10]([C:13]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][N:14]=1)([O-:12])=[O:11].C(=O)(O)[O-].[Na+]>CO.C(Cl)Cl>[N+:10]([C:13]1[C:18]([O:19][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:17][CH:16]=[CH:15][N:14]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ncccc1O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CCCOc1cccnc1[N+](=O)[O-]
Yield: 76 %

Procedure:
This compound was prepared from ethyl 4-bromobutyrate 2 and 2-nitro-3-pyridinol (39) via the procedure of Step (A), supra. Following flash chromatography (silica gel; 1.5% methanol/methylene chloride eluant) a dilute sodium bicarbonate wash of an ether solution of the product was necessary to remove traces of starting phenol. The product (40) was obtained in 76% yield as a pale yelow oil.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[C:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:4]1([N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:19]=[CH:18][C:17]([C:27]3[CH:28]=[CH:29][C:24]([C:21](=[O:23])[CH3:22])=[CH:25][CH:26]=3)=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 80 °C
Yield: 75.8 %

Procedure:
4-Bromotriphenylamine (2.0 g, 6.17 mmol), 4-acetylphenylboronic acid (1.12 g, 6.8 mmol), dichlorobis(triphenylphosphine)palladium(II) (130 mg, 0.185 mmol) and sodium carbonate (460 mg, 4.32 mmol) were added into a solvent mixture of acetonitrile and water (1:1, v/v, 80 mL), and heated under nitrogen at 80° C. for 3 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature and added with water (80 mL), followed by the separation of the organic layer with dichloromethane (150 mL×3). The organic layer was filtered, dried and evaporated, and the resulting organic residue was purified by column chromatogram (silica gel, hexane: EtOAc=4:1) to obtain the title compound (1.7 g).
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][C:7]([OH:13])=[C:6]([O:14][CH2:15][CH2:16][OH:17])[CH:5]=1)([O-:3])=[O:2].[CH3:18]N>C(O)C.C(N)=O>[CH3:18][NH:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([O:14][CH2:15][CH2:16][OH:17])=[C:7]([OH:13])[CH:8]=1
Reactant: O=[N+]([O-])c1cc(O)c(OCCO)cc1[N+](=O)[O-]
Reactant: CN
Solvent: CCO
Solvent: NC=O
Product: CNc1cc(O)c(OCCO)cc1[N+](=O)[O-]
Temperature: 95 °C

Procedure:
A mixture consisting of 0.115 mol (28.2 g) of 4,5-dinitro-2-(β-hydroxyethoxy)phenol, prepared in Example 3, in 300 ml of a 33% strength solution of methylamine in absolute ethanol and 100 ml of formamide is heated to 95° C. for 6 hours in an autoclave (pressure 5-6 kg/cm2). After the reaction mixture has been cooled, the expected product crystallizes. It is recrystallized from formamide. It melts at 210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([OH:21])=O)=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:21])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: Cc1ccc(Cl)c(Nc2c(C(=O)N3CCC(c4ccccc4)CC3)cnc3c(C(=O)O)cnn23)c1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 36.6 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-chloro-5-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (40 mg, 0.08 mmol) obtained in step 4 and ethanesulfonamide (36 mg, 0.33 mmol), the title compound (17 mg, 36%) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:21]([NH2:22])=[CH:20][C:19]([C:23]([CH3:26])([CH3:25])[CH3:24])=[N:18]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl[C:30]([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31]>CCOC(C)=O.C1CCCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([N:17]2[C:21]([NH:22][C:30]([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31])=[CH:20][C:19]([C:23]([CH3:26])([CH3:25])[CH3:24])=[N:18]2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(C2CCN(C(=O)OCc3ccccc3)CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(C2CCN(C(=O)OCc3ccccc3)CC2)n1
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
To a solution of Intermediate 16b (550 mg, 1.54 mmol) in aqueous NaOH solution (1M, 3.85 mL, 3.85 mmol) and EtOAc (5 mL) at RT, was added 2,2,2-trichloroethyl chloroformate (0.32 mL, 2.31 mmol) over 2 min, then the mixture stirred vigorously for 30 min. The aqueous layer was extracted with EtOAc (10 mL), then the combined organics washed with brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to leave a yellow-brown oil. FCC, using 0-30% EtOAc in cyclohexane, gave the title compound as a white foam (337 mg, 41%). LCMS (Method 3): Rt 4.81 min, m/z 531, 533 [MH+].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][CH2:9][C@@H:10]([O:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)[C:16]([OH:18])=O)[CH3:11].[NH2:30][C:31]1[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:11][C@H:10]([O:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)[C:16]([NH:30][C:31]1[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=1)=[O:18])[CH2:9][O:8][CH3:7]
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: Cc1cnc(N)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2cnc(C)cn2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.9 %

Procedure:
Oxalyl chloride (2.1 mL, 24.0 mmol) was added to a solution of 3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acid (6.32 g, 20.0 mmol) in DCM (100 mL) and the mixture stirred at RT for 4 hours. The mixture was evaporated in vacuo to a residue, which was taken up in DCM (25 mL) and added to a stirred mixture of 2-amino-5-methylpyrazine (2.29 g, 21.0 mmol) and pyridine (1.94 mL, 24.0 mmol) in DCM (100 mL) at 5° C.-10° C. The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo. The residue was partitioned between water (50 mL) and ethyl acetate (150 mL), the organic layer washed with brine, dried (MgSO4) and evaporated to a residue, which was chromatographed on silica, eluting with 50% ethyl acetate in isohexane, to give the desired compound (7.0 g). 1H NMR δ (CDCl3): 1.3 (d, 3H), 2.5 (s, 3H), 3.3 (s, 3H), 3.4-3.5 (m, 2H), 4.5 (m, 1H), 5.0 (s, 2H), 6.7 (s, 1H), 7.0 (s, 1H), 7.05 (s, 1H), 7.35 (m, 5H), 8.05 (s, 1H), 8.3 (s, 1H) and 9.5 (s, 1H). m/z 408 (M+H)+.
Reaction SMILES: [Br:1][C@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([OH:5])=O.[NH2:14][C:15]1[C:24]([S:25][CH3:26])=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2.C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>C1(C)C=CC=CC=1>[CH3:26][S:25][C:24]1[C:15]([NH:14][C:3](=[O:5])[C@H:2]([Br:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][CH:18]=[CH:17]2
Reactant: CSc1ccc2ncccc2c1N
Reactant: CCCCCCCC[C@@H](Br)C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: Cc1ccccc1
Product: CCCCCCCC[C@@H](Br)C(=O)Nc1c(SC)ccc2ncccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.1 %

Procedure:
(R)-2-Bromodecanoic acid (210 mg, 0.83 mmol), 5-amino-6-methylthioquinoline (160 mg, 0.84 mmol) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ, 223 mg, 0.90 mmol) were stirred in 6 ml of toluene at 0° C. The reaction was allowed to warm to rt and stirred under N2 for 18 hours. The reaction was quenched with 100 ml of 10% citric acid and extracted with ethyl acetate (3×50 ml). The organic phase was washed with 0.5N NaHCO3, brined and dried over Na2SO4. Purification by silica gel column chromatography (eluent: 100% CHCl3) yielded 120 mg (34% yield) of the desired product: 1H NMR (CDCl3) δ8.85 (1H, d, J=3 Hz), 8.09 (1H, d, J=9 Hz), 8.08 (1H, d, J=9 Hz), 7.98 (1H, bs), 7.65 (1H, d, J=9 Hz), 7.42 (1H, dd, J=9, 9 Hz), 4.61 (1H, dd, J=8, 8 Hz), 2.58 (3H, s), 2.33 (1H, m), 2.21 (1H, m), 1.76-121 (12H, m), 0.88 (3H, m).
Reaction SMILES: C(=S)([O-])N.[NH2:5][C:6]1[S:7][C:8]2[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][C:9]=2[N:10]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[S:18]>N1C=CC=CC=1>[O:15]=[C:14]1[C:8]2[S:7][C:6]([NH:5][C:17](=[S:18])[O:19][CH2:20][CH3:21])=[N:10][C:9]=2[CH2:11][CH2:12][CH2:13]1
Reactant: CCOC(=S)Cl
Reactant: Nc1nc2c(s1)C(=O)CCC2
Agent: NC([O-])=S
Solvent: c1ccncc1
Product: CCOC(=S)Nc1nc2c(s1)C(=O)CCC2

Procedure:
The desired thiocarbamate is obtained in analogy with the preparation of Z-13 b, starting from 101 g of 2-amino-5,6-dihydro-4H-benzothiazol-7-one (602 mmol) in 3.4 l of pyridine and 75 g of ethyl chlorothioformate (602 mmol). Yield: 84 g
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27]O)=[CH:23][CH:22]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1.[CH2:31]([N:33](CC)[CH2:34][CH3:35])[CH3:32].N1CC=CC1>C(Cl)Cl.CN(C=O)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][N:33]4[CH2:34][CH:35]=[CH:32][CH2:31]4)=[CH:23][CH:22]=3)=[N:17][CH:18]=2)=[CH:11][CH:12]=1
Reactant: CCN(CC)CC
Reactant: OCCOc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Agent: C1=CCNC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CC=CC4)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
23 μL (0.29 mmol) methanesulphonic acid chloride are added dropwise to a solution, cooled to 0° C., of 85 mg (0.24 mmol) 2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethanol and 41 μL (0.29 mmol) triethylamine in 10 mL DCM and the reaction mixture is stirred for 1 h at this temperature. 46 μL (0.58 mmol) 2,5-dihydro-1H-pyrrole are added dropwise, the mixture is heated to RT and stirred overnight. 1 mL of DMF is added and the mixture is heated for 8 h to 70° C. The mixture is evaporated down i. vac., the residue is combined with water, extracted exhaustively with EtOAc and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography on silica gel (EtOAc/MeOH/NH3 95:5:0.5).
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[SH:32])([CH2:24][CH3:25])[CH3:23].N1CCCCC1>ClCCl>[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32][C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8])([CH2:24][CH3:25])[CH3:23]
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: CCC(C)c1ccccc1S
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CCC(C)c1ccccc1SC1=C(O)CC(c2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 1.6 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 1.7 mmol of 2-sec-butylbenzenethiol, and 1.7 mmol of piperidine in 25 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 161°-162° C.). 1H NMR (DMSO-d6) δ 0.81 (t, 3 H), 1.15 (d, 3 H), 1.43-1.64 (m, 2 H), 2.98 (m, 1 H), 3.77 (s, 2 H), 5.65 (dd, 1 H), 6.47 (t, 1 H), 6.92 (t, 1 H), 7.07 (d, 1 H), 7.34-7.48 (m, 10 H), 12.4 (bs, 1 H).
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:20][O:21][CH2:22]Br>CN(C=O)C>[F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([O:8][CH2:20][O:21][CH3:22])=[N:6][CH:7]=1
Reactant: COCBr
Reactant: CN(C)C=Nc1nc(O)ncc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCOc1ncc(F)c(N=CN(C)C)n1
Yield: 18.5 %

Procedure:
N′-(5-Fluoro-2-hydroxypyrimidin-4-yl)-N,N-dimethylformamidine (100 mg, 0.54 mmol), cesium carbonate (196 mg, 0.60 mmol), and bromomethyl methyl ether (75 mg, 0.6 mmol) were shaken together in DMF (3 mL) at ambient temperature for 4 hours. The reaction mixture was partitioned between ethyl acetate and water, dried over magnesium sulfate, filtered and evaporated to yield a colorless oil which was placed directly onto a silica gel column and eluted with ethyl acetate in petroleum ether (0-80% gradient) to isolate 23 mg, 0.1 mmol (19%) of the title compound as a colorless oil: 1H NMR (CDCl3) δ 8.66 (s, 1H), 8.05 (d, J=2.6 Hz, 1H), 5.46 (s, 2H), 3.53 (s, 3H), 3.17 (s, 3H), 3.16 (s, 3H); HPLC-MS (ESI) m/z 229 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:23][C:24]1[N:25]=[N:26][N:27]([CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)[CH:28]=1.N1(C2CCCCCCCCCC2)CCCCCCCCCN1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([N:31]4[CH2:32][CH2:33][CH:29]([N:27]5[CH:28]=[C:24]([CH3:23])[N:25]=[N:26]5)[CH2:30]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1cn(C2CCNC2)nn1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Agent: Cl
Solvent: CC#N
Product: Cc1cn(C2CCN(c3c(F)c(C)c4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)C2)nn1

Procedure:
A suspension of 50 mg (0.168 mmol) of 1-cyclopropyl-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-(4-methyl-1,2,3-triazol -1-yl)pyrrolidine hydrochloride (79 mg, 0.421 mmol) and 64 mg (0.421 mmol) of DBU (diazabicyloundecane) in dry acetonitrile (5 ml) was refluxed under nitrogen for 46 h. The yellow solution was concentrated to dryness and the residue was triturated with acetonitrile and thus separated solid was filtered. The supernatant was evaporated to dryness and water was added to the residue and separated solid was collected (30 mg, 43%), m.p. 232°-234° C. 1H NMR (TFA) δ: 9.26 (s, 1H), 8.37 (s, 1H), 5.78-5.58 (m, 1H) 4.85-4.1 (m, 5H), 3.0-2.7 (m, 5H), 2.68 (s, 3H), 1.65-1.15 (m, 4H). Anal. calcd. for C21H21F2N5O3 : C, 58.74; H, 4.93; N, 16.31. Found: C, 58.14; H, 5.06; N, 16.08.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([CH3:25])[N:18]=2)[CH2:13][CH2:12]1)=[O:10].[C:26]([N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34])(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:33][CH2:32][N:31]([C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([CH3:25])[N:18]=3)[CH2:13][CH2:12]2)=[O:10])[C:30]1=[O:34])(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Cl)cc3Br)CC2)nc1C
Product: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3nc(C)c(C)cc3C)CC2)C1=O
Yield: 61.6 %

Procedure:
Using (2-bromo-4-chlorophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (846 mg) described in Preparation Example 257 and 1-acetylimidazolidin-2-one (384 mg) and by the reaction and treatment in the same manner as in Preparation Example 234, the title compound (579 mg) was obtained.
Reaction SMILES: [CH:1]1([C:6]([OH:32])([CH2:22][C:23]2[O:24]C(C)(C)O[C:27](=[O:29])[CH:28]=2)[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:19]#[N:20])[CH2:18][CH2:17][CH2:16]3)=[C:11]([F:21])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(O)(CC2OC(C)(C)OC(=O)C=2)CCC2C=CC(C3(C#N)CC3)=C(F)C=2)CCCC1>>[CH:1]1([C:6]2([CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4([C:19]#[N:20])[CH2:18][CH2:17][CH2:16]4)=[C:11]([F:21])[CH:10]=3)[CH2:22][C:23](=[O:24])[CH2:28][C:27](=[O:29])[O:32]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(CCc2ccc(C3(C#N)CCC3)c(F)c2)C2CCCC2)O1
Agent: CC1(C)OC(=O)C=C(CC(O)(CCc2ccc(C3(C#N)CC3)c(F)c2)C2CCCC2)O1
Product: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)CC(=O)O3)cc2F)CCC1

Procedure:
The desired product was prepared analogously to Example A(86) step 5 substituting 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-cyclobutanecarbonitrile (1.00 g, 2.2 mmol) from step 3 below in place of 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile. Yield: 0.477 g, 57%.
Reaction SMILES: [CH3:1][Si:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][O:5][CH2:6][C:7]1([C:16]2[NH:17][CH:18]=[CH:19][N:20]=2)[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=[S:13](=[O:15])=[O:14].C([N-]C(C)C)(C)C.[Li+].[I:31]N1C(=O)CCC1=O>>[CH3:1][Si:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][O:5][CH2:6][C:7]1([C:16]2[NH:20][C:19]([I:31])=[CH:18][N:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=[S:13](=[O:15])=[O:14]
Reactant: C[Si](C)(C)CCOCC1(c2ncc[nH]2)C=CC=CC1=S(=O)=O
Reactant: O=C1CCC(=O)N1I
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: C[Si](C)(C)CCOCC1(c2ncc(I)[nH]2)C=CC=CC1=S(=O)=O

Procedure:
According to the foregoing reaction scheme 1, 1-[[2-(trimethylsilyl)ethoxy]methyl]- imidazole (1) is treated with n-BuLi at -78° C. and reacted with phenyl disulfide to afford 1-[[2-(trimethylsilyl)ethoxy]methyl]-2-thiophenyl-imidazole (2). 1-[[2-(trimethylsilyl)ethoxy]methyl]-2-thiophenyl-imidazole (2) is oxidized with 2 equivalents of m-chloroperbenzoic acid to give 1-[[2-(trimethylsilyl)ethoxy]methyl]-2-sulfonylphenyl-imidazole (3). 1-[[2-(trimethylsilyl)ethoxy]methyl]-2-sulfonylphenyl-imidazole (3). is deprotonated with lithium diisopropylamide at -78° C. and treated with N-iodosuccinimide to afford 1-[[2-(trimethylsilyl)ethoxy]methyl]-2-sulfonylphenyl-5-iodo-imidazole (4). The corresponding grignard reagent of (4) is prepared by treatment with 1 equivalent of t-butyl magnesium chloride at 0° C. in anhydrous CH2Cl2 for 30 minutes and then reacted with 1,4-cyclohexanedione mono-ethylene ketal (5) to provide alcohol (6). The sulfonylphenyl protecting group is removed by treatment of (6) in methanol at 0° C. in the presence of 4 equivalents of sodium phosphate buffer with excess 2-3% Na(Hg) to give alcohol (7). Alcohol (7) is dehydrated by heating in THF/2 drops of water in the presence of a catalytic amount of PPTS to give olefin (8). The SEM protecting group is removed by treatment of (8) with n-butyl ammonium flouride at 60° C. to provide olefin (9). Catalytic hydrogenation of (9) over Pd(C) affords cyclohexane (10). Ketal deprotection of (10) proceeds smoothly with 5% HCl in THF at room temperature to give (1H -4(5)-imidazoyl)-4-cyclohexanone (11). The N-methoxy oxime is prepared by treatment of ketone (11) with N-methoxyl amine and TEA in dichloromethane to give (12). Finally, TBAH reduction of oxime (12) affords the (1H-(4,5)-imidazoyl)-4-cyclohexyl-N-methoxylamine (13). ##STR12##