Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]([C@@H:11]2[O:31][C@H:30]([CH2:32][O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@@H:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:12]2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]=1[CH2:8][C:9]#[N:10])#[N:2].C(O)C.[SH2:44]>C(N(CC)CC)C>[NH2:10][C:9]1[NH:2][C:1](=[S:44])[C:3]2[N:4]=[CH:5][N:6]([C@@H:11]3[O:31][C@H:30]([CH2:32][O:33][CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C@@H:21]([O:22][CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C@@H:12]3[O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:7]=2[CH:8]=1
Reactant: N#CCc1c(C#N)ncn1[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: S
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1cc2c(ncn2[C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)c(=S)[nH]1

Procedure:
A mixture of 8 g of 4-cyano-5-cyanomethyl-1-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)imidazole, 250 ml of ethanol saturated at 0° C. with hydrogen sulfide, and 2.5 g of triethylamine is kept in a steel bomb for 48 hours at ambient temperature. The reaction solution is evaporated in vacuo to a yellow foam which is coevaporated with ethanol several times to provide 6-amino-1,5-dihydro-1-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-4H-imidazo[4,5-c]pyridine-4-thione.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[C:24]1[S:25][C:26]2[C:27]([N:32]=1)=[N:28][CH:29]=[CH:30][CH:31]=2.O>CC#N>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([O:15][C:24]3[S:25][C:26]4[C:27]([N:32]=3)=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: Clc1nc2ncccc2s1
Reactant: CCOC(=O)c1cc2ccc(O)cc2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cc2ccc(Oc3nc4ncccc4s3)cc2o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.6 %

Procedure:
To a solution of 6-hydroxy-benzofuran-2-carboxylic acid ethyl ester (2.0 g, 10 mmol) in MeCN (100 mL) added Cs2CO3 (6.3 g, 19 mmol) followed by 2-chloro-thiazolo[4,5-b]pyridine hydrochloride (2.0 g, 10 mmol) and the reaction mixture was stirred (rt, 12 h). The reaction mixture was treated with H2O (50 mL) and the solid was filtered to afford the title compound as a beige solid (2.3 g, 69%). MS (ESI): mass calcd. for C17H12N2O4S, 340.1; m/z found, 341.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.58 (dd, J=4.8, 1.6, 1H), 8.04 (dd, J=7.9, 1.6, 1H), 7.75-7.69 (m, 2H), 7.55 (d, J=0.8, 1H), 7.42 (dd, J=8.6, 2.1, 1H), 7.22 (dd, J=7.9, 4.8, 1H), 4.46 (q, J=7.1, 2H), 1.44 (t, J=7.1, 3H).
Reaction SMILES: [OH-].C[N+](C)(C)C.[C:7]([OH:11])(=[O:10])[CH2:8][OH:9].Br[CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15]>CN(C)C=O>[OH:9][CH2:8][C:7](=[O:11])[O:10][CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15]
Reactant: O=C(O)CO
Reactant: COC(=O)C(C)Br
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)C(C)OC(=O)CO
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Tetramethylammonium hydroxide (25% in methanol) was added to a stirring solution of glycolic acid (3.8 g, 50 mmol) in 5 mL dimethylformamide cooled on ice until a pH of 7 was indicated by moistened pH paper. Methyl 2-bromopropionate (6.1 mL, 55 mmol) was added and the reaction was stirred at room temperature for 5 d. The reaction mixture was filtered, the solids were washed with ethyl ether, and the combined filtrate and ether solution was washed with 5% NaCl/5% NaHCO3. Sufficient ethyl ether was added to effect rapid separation of the phases, the aqueous phase was extracted with CH2Cl2, and the organic phases were combined and dried with MgO4. The solvent was removed and the resulting residue was distilled under reduced pressure to give the title compound: b.p. 64° C./0.05 mm Hg; 1H NMR δ 1.53 (d, 3H, J=7.2 Hz), δ 2.78 (bs, 1H), δ 3.77 (s, 3H),δ 4.24 (d, 1H, J=17.4 Hz) δ 4.31 (d, 1H, J=17.4 Hz), δ 5.22 (q, 1H, J=7.1 Hz), HRMS calcd for C6H9O5Tms (M--CH3) 219.0688, obsd 219.0708.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[O:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:18]3[N:38]=[CH:39][C:40]([C:41]4[CH:42]=[N:43][C:44]5[C:49]([CH:50]=4)=[CH:48][CH:47]=[CH:46][CH:45]=5)=[C:17]3[N:16]=2)[CH2:11][CH2:10]1>CC#N>[Br:8][C:20]1[C:15]([N:12]2[CH2:11][CH2:10][O:9][CH2:14][CH2:13]2)=[N:16][C:17]2[N:18]([N:38]=[CH:39][C:40]=2[C:41]2[CH:42]=[N:43][C:44]3[C:49]([CH:50]=2)=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:19]=1[N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:36])[CH3:37])[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Solvent: CC#N
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of NBS (20.6 mg, 0.116 mmoL) in CH3CN (1 mL) was added to a mixture of 5-morpholino-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (70.0 mg, 0.116 mmoL) in CH3CN (6 mL). After stirring at room temperature for 10 min, the reaction mixture was concentrated and purified by column chromatography to afford 6-bromo-5-morpholino-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine. LCMS tR=2.91 Min (5 min run, UV254nm). Mass calculated for, M+ 684.2, observed LC/MS m/z 685.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:26])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:24][CH3:25])[CH:18]=4)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.C(OC([N:34]1[CH2:39][CH2:38][O:37][CH:36]([CH2:40]O)[CH2:35]1)=O)(C)(C)C.P(CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:26])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:40][CH:36]5[O:37][CH2:38][CH2:39][NH:34][CH2:35]5)=[C:19]([O:24][CH3:25])[CH:18]=4)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Reactant: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1O
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OCC1CNCCO1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Dissolve 2-(4-chloro-phenyl)-5-(4-hydroxy-3-methoxy-phenyl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (103 mg, 0.267 mmol), 2-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (Pharmacore, CAS: 135065-69-9) (70 mg, 0.324 mmol), and PBu3 (84 μl, 0.324 mmol) in dry toluene (1.2 mL). Cool to 0° C. then add 1,1′-(azodicarbonyl)piperidine (84 μl, 0.324 mmol). Let stir for 10 min at 0° C., then warm to ambient temperature overnight. Reaction mixture thickens and turns gel like. Add hexanes and collect solid via vacuum filtration. Wash the solid with hexanes several times. Dissolve the crude material in dry CH2Cl2 (500 μL) and TFA (200 μl) and stir overnight. Add 1N NaOH until the reaction is pH=10 and extract with EtOAc (3×10 mL). Dry the combined organic portions with Na2SO4, filter, and concentrate to give the title compound. MS (ES+) 486.0 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]#[N:17])=[N:14][CH:15]=2)[CH:6]=[CH:7][CH:8]=1.[OH:18][C:19]1[C:24]([CH2:25][CH2:26][CH3:27])=[C:23](O)[CH:22]=[CH:21][C:20]=1[C:29](=[O:31])[CH3:30]>>[C:29]([C:20]1[CH:21]=[CH:22][C:23]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([S:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]#[N:17])=[N:14][CH:15]=3)[CH:6]=[CH:7][CH:8]=2)=[C:24]([CH2:25][CH2:26][CH3:27])[C:19]=1[OH:18])(=[O:31])[CH3:30]
Reactant: N#Cc1ccc(Sc2cccc(CO)c2)cn1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Product: CCCc1c(OCc2cccc(Sc3ccc(C#N)nc3)c2)ccc(C(C)=O)c1O
Yield: 42.5 %

Procedure:
Using the method of Preparation 166 using 5-(3-(hydroxymethyl)phenylthio) picolinonitrile (1.70 g, 7.02 mmol) and 1-(2,4-dihydroxy-3-propylphenyl)ethanone (1.36 g, 7.02 mmol) affords the title compound (1.25 g, 43%). MS (APCI-neg) m/z (rel intensity): 417 (M−H, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([O:15][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=c1ccn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)COc1cc2c(=O)ccn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
10-bromo-2-hydroxy-4H-pyrido[3,2,1-jk]carbazole-4-one (2.5 g) obtained in Example 59 was suspended in dimethyl sulfoxide (120 ml), and potassium carbonate (2.2 g) was added to the suspension. The mixture was stirred at room temperature for 30 minutes and t-butyl bromoacetate (1.4 ml) was added to the mixture. The mixture was stirred at room temperature for 12 hours, and the reaction mixture was poured into ice water (900 ml), and the crystals precipitated were recovered by filtration. The crude crystals were purified by silica gel flash column chromatography (eluent: methylene chloride containing 2% methanol) to obtain the title compound (1.9 g, 68%).
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[CH:11]=3)[CH:7]=[CH:6][C:5]=12.C1C(=O)N([Br:25])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[O:14][C:13]([CH3:15])([CH3:16])[C:12](=[O:17])[C:11]=3[Br:25])[CH:7]=[CH:6][C:5]=12
Reactant: CC1(C)OC(c2ccc3nsnc3c2)=CC1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC1(C)OC(c2ccc3nsnc3c2)=C(Br)C1=O
Reaction time: 2 h
Yield: 63.9 %

Procedure:
To a stirred solution of 5-(benzo[c][1,2,5]thiadiazol-5-yl)-2,2-dimethylfuran-3(2H)-one (0.5 g, 2.164 mmol) in CHCl3 (15 mL), NBS (0.462 g, 2.590 mmol) was added portionwise at RT. The reaction mixture was then stirred for 2 h and diluted with DCM (10 mL). The combined organic layers were washed with water (5 mL) and brine (10 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(benzo[c][1,2,5]thiadiazol-5-yl)-4-bromo-2,2-dimethylfuran-3(2H)-one (0.45 g, 69%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:23][C@@:22]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:25])[CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6][C@@H:5]1[O:27][C:28](=[O:31])[CH2:29]I)[CH3:2].[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33].O>C(Cl)Cl>[CH2:32]([N:34]([CH2:29][C:28]([O:27][C@@H:5]1[C@@H:4]([O:3][CH2:1][CH3:2])[CH2:23][C@@:22]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:25])[CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)=[O:31])[CH2:35][CH3:36])[CH3:33]
Reactant: CCNCC
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1OC(=O)CI
Solvent: O
Solvent: ClCCl
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1OC(=O)CN(CC)CC
Temperature: 25 °C

Procedure:
2β-Ethoxy-3α-iodoacetoxy-5α-pregnane-11,20-dione (460 mg) was dissolved in methylene chloride (25 ml) and diethylamine (1 ml) added to the solution. The mixture was stirred at room temperature for one-half hour. The mixture was poured into water and the organic layer washed with water (100 ml.), dried over anhydrous sodium sulphate and evaporated to a red oil (410 mg.) which was purified by preparative T.L.C. using ethyl acetate/petrol (2/1) run twice. The main band (RF 0.4) gave title compound (230 mg) as a pale yellow oil [α]D + 100° (c = 0.9).
Reaction SMILES: Cl[C:2]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([CH3:22])=[N:19][CH:18]=4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[N:9][N:10]=[C:3]12.[F:30][C:31]1[CH:32]=[C:33]([OH:38])[CH:34]=[C:35]([F:37])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[F:30][C:31]1[CH:32]=[C:33]([CH:34]=[C:35]([F:37])[CH:36]=1)[O:38][C:2]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([CH3:22])=[N:19][CH:18]=4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[N:9][N:10]=[C:3]12
Reactant: Oc1cc(F)cc(F)c1
Reactant: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Oc2cc(F)cc(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 38.6 %

Procedure:
A mixture of ethyl 8-chloro-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (671 mg), 3,5-difluorophenol (220 mg), potassium carbonate (667 mg) and DMF (6 mL) was stirred at 100° C. for 1 hr, the reaction mixture was diluted with ethyl acetate, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and purified by silica gel chromatography (NH, ethyl acetate). The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (317 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[N+]=[N-])[CH:6]=[CH:7][CH:8]=1.[FH:12]>CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[F:12])[NH2:9]
Reactant: F
Reactant: COc1cccc(N=[N+]=[N-])c1
Solvent: CCCCCC
Product: COc1cc(N)ccc1F
Reaction time: 10 h

Procedure:
A solution of 10.73g. (0.07 mole) of 3-methoxyphenylazide in 100 ml. of hexane was added to 20 ml. of concentrated hydrofluoric acid and the reaction mixture, contained in a bomb, was aged for 10 hours at room temperature with agitation. The reaction mixture was then cooled, vented, and poured from the bomb. The bomb was then rinsed with 50 ml. of water, followed by 20 ml. of dichloromethane. The reaction mixture poured from the bomb was blown down under nitrogen, and then combined with the bomb rinsings, and this mixture was cooled and brought to a pH of about 12 with KOH pellets. The mixture was extracted three times with 50 ml. of dichloromethane per extraction, and the combined extracts were dried over MgSO4 and concentrated to 7.31g. (53%) of a dark oil. An aliquot of this product was distilled under reduced pressure to obtain a pale yellow oil with a b.p. of 150°-152° C. at 50 mm. Hg. Structure of the final product as 3-methoxy-4-fluoroaniline was confirmed by mass spectroscopy.
Reaction SMILES: Cl.Cl.[CH:3]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.[Cl:21][C:22]1[N:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1>>[ClH:21].[CH:3]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH:15]3[CH2:20][CH2:19][N:18]([C:22]4[N:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=4)[CH2:17][CH2:16]3)=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: O=C(C1CCNCC1)N1CCN(C2CCC2)CC1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Agent: Cl
Product: O=C(C1CCN(c2ccc(C(F)(F)F)nn2)CC1)N1CCN(C2CCC2)CC1

Procedure:
The title compound (E190) was prepared from 1-cyclobutyl-4-(piperidine-4-carbonyl)-piperazine (free base compound from D7) and 3-chloro-6-trifluoromethyl-pyridazine (A. J. Goodman, S. P. Stanforth and B. Tarbit, Tetrahedron, 1999, 55(52), 15067-15070) using the method described in Example 88. LCMS electrospray (+ve) 398 (MH+). 1H NMR δ [MeOH-d4]: 1.86-2.02 (6H, m), 2.33-2.37 (4H, m), 2.78-2.89 (1H, m), 2.91-3.12 (2H, m), 3.23.3.28 (1H, m), 3.44-3.54 (6H, m), 3.71-3.75 (1H, m), 4.30-4.42 (2H, m), 4.67-4.70 (2×m, 1H), 7.95 (1H, d, J=10 Hz) and 8.00 (1H, d, J=10 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH:31][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCN(CCN)CC1
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Solvent: C1COCCO1
Product: CN1CCN(CCNC(=O)Nc2cc(CN3C(=O)N(c4ccc(C(C)(C)C)cc4)C(=O)C3(C)C)ccn2)CC1

Procedure:
A solution of 100 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9 in 2 mL of dioxane and 48 μl of 1-(2-aminoethyl)-4-methylpiperazine is heated by microwave at 130° C. for 15 minutes. The reaction mixture is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica, eluting with a gradient (100/0 to 75/25 by volume) of dichloromethane and methanol/aqueous ammonia (6/1 by volume) to give 75 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-3-[2-(4-methylpiperazin-1-yl)ethyl]urea, the characteristics of which are as follows:
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:14])[N:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1.CO.N.C(Cl)Cl>>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[Cl:27])[CH2:20][NH:19][CH2:18][CH2:17][CH2:16][NH:15][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:14])[N:3]=1
Reactant: NCCCNCc1ccc(Cl)c(Cl)c1
Reactant: COc1cc(Cl)nc2cccc(Cl)c12
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1cc(NCCCNCc2ccc(Cl)c(Cl)c2)nc2cccc(Cl)c12
Temperature: 100 °C

Procedure:
A mixture of 2,5-dichloro-4-methoxyquinoline (0.12 g, 0.53 mmol) and N-(3-aminoprop-1-yl)-3,4-dichlorobenzylamine (0.37 g) was heated at 100° C. for 8 h. The resulting mixture was submitted to column chromatography (silica gel, MeOH:NH3:CH2Cl2 10:1:150→10:1:100) to give the title compound as a colourless film, (93 mg, 41%). δH (CDCl3) 1.70-1.87 (m, 3H+H2O), 2.74 (t, J=6.3, 2H), 3.54-3.65 (m, 2H), 3.72 (s, 2H), 3.91 (s, 3H), 5.22 (br, t, 1H), 5.90 (s, 1H), 7.10-7.17 (m, 2H), 7.28-7.37 (m, 2H), 7.40-7.45 (m, 2H); MS (ES+) 424 (MH+, 37%), 249 (100).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:3][CH:2]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:8]2[CH2:9][CH2:10][CH2:11][CH:7]2[C:4]2[CH:5]=[CH:6][C:1]([CH3:12])=[CH:2][CH:3]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(C2CCCN2)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: Cc1ccc(C2CCCN2S(=O)(=O)c2ccc(F)cc2)cc1

Procedure:
The title compound, white solid, m.p. 112° C. and MS: m/e=319 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-p-tolyl-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20](=[O:27])[NH:21][C:22]2[NH:23][CH:24]=[CH:25][N:26]=2)=[CH:14][CH:13]=1)(C)(C)C.[ClH:29]>>[ClH:29].[ClH:29].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([NH:21][C:22]2[NH:26][CH:25]=[CH:24][N:23]=2)=[O:27])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(OCC(=O)Nc2ncc[nH]2)cc1
Agent: Cl
Product: NCCCCc1ccc(OCC(=O)Nc2ncc[nH]2)cc1

Procedure:
(4-{4-[1H-Imidazol-2-yl-carbamoyl)methoxy]phenyl}butyl)carbamic acid tert-butyl ester 34 (950 mg, 2.45 mmol) was treated with HCl (4 M in dioxane, 24 mL, 96 mmol) at room temperature for 12 h. The reaction mixture was concentrated in vacuo and further co-evaporated with dichloromethane and methanol, and dried under high vacuum. The desired product was obtained as a white solid (779 mg, 98%) and used directly without further purification. 1H NMR (300 MHz, CD3OD) δ 1.59-1.74 (m, 4H), 2.55-2.67 (m, 2H), 2.85-2.98 (m, 2H), 4.80 (s, 2H), 7.00 (d, 2H), 7.18 (d, 2H), 7.19 (s, 2H). m/z (ESI): 289 [C15H20N4O2+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH3:32]I>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH3:32])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:27])([F:28])[F:29])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.5 %

Procedure:
Add 4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (16.03 g; 1.00 equiv; 38.77 mmoles) in 40 mL of dimethyl sulfoxide (DMSO) to a solution of potassium hydroxide (1.5 equiv; 58.16 mmoles; 3.26 g) in 200 mL of DMSO. After 5 min at RT, add methyl iodide (1.1 equiv; 42.65 mmoles; 2.66 mL) in one portion. Stir at RT for two hours, then pour the mixture into ice water. Filter the solid, wash with water, and dry under reduced pressure. Triturate the solid in hot heptane, filter and dried under reduced pressure to give 4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (8.7 g; 52.49% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.O>C(O)C>[CH3:11][C:6]1[CH:5]=[C:4]([NH:12][CH2:19][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:23])[F:24])=[CH:22][CH:21]=2)[CH:3]=[C:2]([CH3:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(N)cc(C)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CCO
Product: Cc1cc(NCc2ccc(C(F)(F)F)cc2)cc(C)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 85 %

Procedure:
3,5-Dimethyl-4-nitro-phenylamine (3.95 g) and 4-trifluoromethyl-benzaldehyde (4.87 mL) were dissolved in ethanol (50 mL) and refluxed for 16 h. The reaction mixture was poured into water (75 mL) and the precipitate collected by filtration. Sodium cyanoborohydride (3.1 g) and acetic acid (7.0 mL) were added to the precipitate dispersed in methanol (130 mL) and stirred for 60 minutes. The reaction mixture was filtered, water (350 mL) was added and the organic solvent was removed in vacuo. The product was allowed to precipitate at 25° C. and collected by filtration and washed with water (300 mL) to furnish 6.7 g (85% yield) of the title compound as a yellow solid. LC-MS (m/z) 325 (MH+); tR=2.00, (UV, ELSD) 92%, 93%. 1H NMR (500 MHz, CDCl3): 2.30 (s, 6H), 4.45 (broad, 3H), 6.25 (s, 2H), 7.45 (d, 2H), 7.60 (d, 2H).