Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]([O:20][CH3:21])=[O:19])=[C:12]([CH3:22])[CH:11]=1)C1C=CC=CC=1.[H][H]>C1COCC1.CO.[Pd]>[CH3:21][O:20][C:18]([CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([OH:23])=[O:8])=[CH:11][C:12]=1[CH3:22])=[O:19]
Reactant: COC(=O)C=Cc1ccc(C(=O)OCc2ccccc2)cc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(C(=O)O)cc1C
Yield: 99.9 %

Procedure:
A mixture of 4-(2-methoxycarbonyl-vinyl)-3-methyl-benzoic acid benzyl ester (11.6 g, 37.4 mmol) and Pd/C (5%, 1.5 g) in THF (300 mL) and methanol (100 mL) is stirred under 60 psi of hydrogen overnight. Catalyst is filtered off, filtrate is concentrated giving the title compound (8.3 g, 100%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[N:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([O:17][CH2:24][C:23]([O:22][CH2:21][CH3:20])=[O:25])=[C:11]2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OCCBr
Reactant: Cc1cc2c(O)ccnc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccnc2c1cc(C)n2Cc1ccccc1

Procedure:
A mixture of 1-benzyl-2-methyl-1H-pyrrolo[2,3-b]pyridin-4-ol 7 (0.30 g, 1.26 mmol), 2-bromoethylacetate (1.05 g, 6.29 mmol) and K2CO3 (2.0 g) in anhydrous acetone (15 mL) were heated at reflux for 6 h under N2. After cooling, the mixture was filtered through celite and the filtrate was concentrated to yield a syrup. It was then re-dissolved in ethyl acetate and washed with water (10×2 mL), brine and dried (Na2SO4). The solvent was removed under reduced pressure, and the residue was chromatographed on a silica gel column eluting with 40% ethylacetate in hexanes afforded the title compound 8 as an amorphous white solid. Yield: 0.25 g, 61%; ESI MS: m/z 325.0 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9].[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:31])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=2)=[CH:13][C:12]=1[NH:32][C:33](=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=1>>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:31])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH:20]=2)=[CH:13][C:12]=1[NH:32][C:33](=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH:8]2[CH2:2][CH2:3][CH2:4][N:5]([CH3:9])[CH2:6][CH2:7]2)[CH:35]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(O)c1
Reactant: CN1CCCC1CCCl
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(OC2CCCN(C)CC2)c1

Procedure:
As described hereinbefore in Example 7, 2-(2-chloroethyl)-N-methylpyrrolidine was reacted with N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-hydroxybenzamide and the reaction product was purified by column chromatography on silica using a 9:1 mixture of methylene chloride and methanol as eluent. There was thus obtained N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-[2-(N-methylpyrrolidin-2-yl)ethoxy]benzamide (Example 7, Compound No. 32). On further elution an isomeric by-product was obtained. There was thus obtained the title compound NMR Spectrum: (DMSOd6) 1.6 (m, 1H), 1.79 (m, 3H), 2.04 (m, 2H), 2.17 (s, 3H), 2.24 (s, 3H), 2.52 (m, 4H), 3.18 (t, 4H), 3.76 (t, 4H), 4.66 (m, 1H), 7.1 (m, 2H), 7.21 (d, 1H), 7.4 (m, 4H), 7.5 (d, 1H), 7.56 (m, 1H), 7.78 (d, 1H), 9.83 (s, 1H), 10.11 (s, 1H); Mass Spectrum: M+H+543.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH2:35]([NH2:39])[CH:36]([CH3:38])[CH3:37]>>[F:34][C:20]1[C:19]([C:9]2[N:10]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:39][CH2:35][CH:36]([CH3:38])[CH3:37])[N:7]=2)=[CH:24][CH:23]=[CH:22][C:21]=1[NH:25][S:26]([C:29]1[O:30][CH:31]=[CH:32][CH:33]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccco1
Reactant: CC(C)CN
Product: CC(C)CNc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccco3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-furansulfonamide (150 mg, 0.287 mmol) and isobutylamine (0.288 mL, 2.87 mmol) the title compound was obtained as a light yellow solid (88 mg, 55% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.56 (s, 1H), 7.77-7.91 (m, 2H), 7.30-7.41 (m, 1H), 7.16-7.32 (m, 2H), 7.10 (d, J=1.1 Hz, 1H), 7.03 (d, J=3.4 Hz, 1H), 6.54 (dd, J=3.3, 1.7 Hz, 1H), 3.66 (t, J=4.6 Hz, 4H), 3.41 (t, J=4.5 Hz, 4H), 2.97 (br. s., 2H), 1.78 (dt, J=13.4, 6.7 Hz, 1H), 0.73-0.87 (m, 7H). MS (ESI): 559.0 [M+H]+.
Reaction SMILES: [NH:1]=[C:2]1[C:6]([CH3:13])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5][C:4](=[S:14])[N:3]1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.N[OH:24]>CO>[OH:24][N:1]=[C:2]1[C:6]([CH3:13])([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:5][C:4](=[S:14])[N:3]1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NO
Reactant: CC1(c2ccccc2)SC(=S)N(Nc2ccccc2)C1=N
Agent: Cl
Solvent: CO
Product: CC1(c2ccccc2)SC(=S)N(Nc2ccccc2)C1=NO
Yield: 52.2 %

Procedure:
A solution of 4-imino-5-methyl-5-phenyl-3-phenylaminothiazolidine-2-thione (0.31 g) and hydroxylamine hydrochloride (0.16 g) in methanol (15 ml) was refluxed for 6 hrs followed by solvent evaporation. The residue was purified by column chromatography (ethyl acetate-n-hexane, ⅓) to yield 4-hydroxyimino-5-methyl-5-phenyl-3-phenylamino-thiazolidine-2-thione (0.17 g) having a melting point of 83-84° C.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[S:11][C:10]([NH2:12])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:15][O:16][CH2:17][CH2:18]Br>C(OCC)(=O)C>[F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[S:11][C:10](=[NH:12])[N:9]([CH2:18][CH2:17][O:16][CH3:15])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: Nc1ncc(Cc2ccc(F)cc2)s1
Reactant: COCCBr
Solvent: CCOC(C)=O
Product: COCCn1cc(Cc2ccc(F)cc2)sc1=N
Temperature: 85 °C
Reaction time: 12 h
Yield: 80.8 %

Procedure:
A mixture of 5-(4-fluoro-benzyl)-thiazol-2-ylamine (330 mg, 1.59 mmol) and 2-bromoethyl methyl ether (0.50 mL, 5.34 mmol) was heated to 85° C. and stirred for 12 hours. The mixture was cooled to ambient temperature, diluted with 20 mL of ethyl acetate and washed with saturated aqueous NaHCO3. The layers were separated and the aqueous phase was extracted with 2×20 mL ethyl acetate and the combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (SiO2, 50% ethyl acetate in dichloromethane containing 0.5% Et3N) afforded 342 mg of the title compound: MS (LC/MS) m/z 267 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][C:25]=3[O:32][CH2:33][CH3:34])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:43][S:44]([CH2:47][CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)(=[O:46])=[O:45]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:35])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:53]3[CH2:54][CH2:55][N:50]([CH2:49][CH2:48][CH2:47][S:44]([CH3:43])(=[O:45])=[O:46])[CH2:51][CH2:52]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][C:25]=3[O:32][CH2:33][CH3:34])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(C#N)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1
Reaction time: 0.5 h

Procedure:
A solution of rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(4-cyano-2-ethoxy-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (˜175 mg, 0.26 mmol) in dichloromethane (10 mL) and triethylamine (0.35 g, 3.34 mmol) at 0° C. was treated with 1-(3-methanesulfonylpropyl)piperazine (0.11 g, 0.39 mmol, prepared as described in Fotouhi, N. et a. WO 2005110996) for 0.5 h. The reaction was washed with cold water, dried over anhydrous magnesium sulfate, filtered and evaporated to give a solid. Trituration with ether and filtration gave the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C35H40N5O4SCl2 [(M+H)+] 696.2173, observed 696.2167.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[CH3:7])=[O:5].[CH3:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1)=O>>[Br:25][C:21]1[CH:20]=[C:19]([C:17]([CH3:16])=[C:6]([CH3:7])[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Product: CCOC(=O)C(C)=C(C)c1cccc(Br)c1

Procedure:
To a suspension of potassium tert-butoxide (183.1 g, 1.63 mol) in toluene (1400 ml) under an atmosphere of nitrogen was slowly added triethyl 2-phosponopropionate (361.1 g, 1.52 mol) with ice cooling at such a rate that the internal temperature was maintained at approximately 20° C. The resultant yellow solution was stirred at room temperature for 3 h after which time it was cooled in an ice bath. To this cooled solution was added a solution of 3-bromoacetophenone (274.2 g, 1.38 mol) in toluene (400 ml) at such a rate that the internal temperature did not rise above 20 ° C. The resultant red-brown solution was then stirred at room temperature for 18 h. After this time, more potassium tert-butoxide (38.7 g, 0.34 mol) was added, and the resultant mixture was stirred at room temperature for an additional 20 h. The reaction was quenched by the cautious addition of water (2000 ml), and the layers were separated. The organic layer was washed with water (4×2000 ml), and was then concentrated in vacuo to give the crude product as a brown oil (344 g) which was distilled under reduced pressure to give the impure title compound (2:3 mixture of geometric isomers) as a colourless liquid (212 g) which was contaminated with small amounts of triethyl 2-phosphonopropionate and 3-bromoacetophenone. In the present synthetic route the impure title compound was taken forward into the next step without any further purification. However, purification, for example using flash chromatography eluting with 5% ethyl acetate in hexane, affords the analytically pure title compound as a clear colourless oil.
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][C:5]([NH2:7])=[NH:6].C([O:10][C:11](=O)[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=O)C.O>CN(C=O)C>[OH:10][C:11]1[CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[N:4]=[C:5]([NH2:7])[N:6]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: N=C(N)N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(O)cc(-c2ccc(F)cc2)n1
Reaction time: 0.5 h
Yield: 51 %

Procedure:
Into an oven-dried three neck round bottom, equipped with reflux condenser and nitrogen inlet, and two addition funnels with stoppers, were added oven-activated 5 Å molecular sieves under a stream of dry nitrogen. Sodium hydride (95%) 3.03 grams (0.126 mole) was added to the room temperature flask followed by 40 mL of dry DMF. Stirring was initiated to achieve a suspension of the solids. A solution of guanidine hydrochloride, 11.9 grams (0.125 mole) dissolved in 40 mL of dry DMF was added dropwise via addition funnel over 0.25 hours and stirring was continued for 0.5 hours at room temperature. 3-(4-Fluorophenyl)-3-oxo-propionic ethyl ester, 26.28 grams (0.125 mole) was dissolved in 75 mL of dry DMF and added to the reaction flask via dropper funnel over 0.25 hours. The mixture was then heated at reflux overnight. The mixture was filtered hot and concentrated to afford a heterogeneous mixture. Water, 100 mL, was added and a solid that formed was filtered off and dried. The solid was recrystallized from methanol to afford 4-hydroxy-6-(4-fluorophenyl)pyrimidin-2-amine (51% yield). Hydroxy-pyrimidine compounds were used in the procedure of Method G.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][N:11]([CH2:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[C:8]([Cl:27])[N:7]=[C:6]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])[CH2:2][CH2:3][CH3:4].C1C(=O)N([Cl:42])C(=O)C1>C(#N)C>[CH2:1]([N:5]1[C:9]([CH2:10][N:11]([CH2:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[C:21]3[Cl:42])[CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])=[C:8]([Cl:27])[N:7]=[C:6]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(-c2ccccc2C)nc(Cl)c1CN(CCC(C)C)Cc1ccc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CCCCn1c(-c2ccccc2C)nc(Cl)c1CN(CCC(C)C)Cc1ccc2[nH]cc(Cl)c2c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
To a solution of (3-Butyl-5-chloro-2-o-tolyl-3H-imidazol-4-ylmethyl)-(1H-indol-5-ylmethyl)-(3-methyl-butyl)-amine (150 mg, 0.31 mmol) in 5 ml of anhydrous acetonitrile cooled to 0° C. is added NCS (44 mg, 0.33 mmol, 1.05 eq.), the resulting mixture is stirred at 40° C. overnight. The solvent is evaporated; the residue is purified through flash chromatography to give 112 mg of (3-butyl-5-chloro-2-o-tolyl-3H-imidazol-4-ylmethyl)-(3-chloro-1H-indol-5-ylmethyl)-(3-methyl-butyl)-amine as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.39 (1H, S), 7.52 (1H, S), 7.11˜7.36 (6H, m), 6.98 (1H, d, J=2.4 Hz), 3.67 (2H, m), 3.65 (2H, s), 3.54 (2H, s), 2.52 (2H, t, J=7.2 Hz), 2.11 (3H, s), 1.62 (1H, m), 1.45 (2H, q, J=6.9 Hz), 1.10 (2H, m), 0.84 (6H, d, J=6.6 Hz), 0.73 (2H, m), 0.47 (3H, t, J=6.9 Hz); MS (+VE) m/z 511 (M+1).
Reaction SMILES: N([C:3]([CH:5]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])N.Cl.C(O)(=[O:40])C>>[C:7]1([CH2:6][CH:5]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([NH:22][S:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:28][CH:27]=4)(=[O:24])=[O:25])=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[C:3]([OH:40])=[O:4])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NNC(=O)C(Cc1ccccc1)n1ccc2cc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)ccc21
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)C(Cc1ccccc1)n1ccc2cc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)ccc21
Temperature: 80 °C

Procedure:
To N-[1-(1-hydrazinocarbonyl-2-phenyl-ethyl)-1H-indol-5-yl]-4-trifluoro methoxy-benzenesulfonamide (0.07 g, 0.13 mmol) in acetic acid at ambient temperature under a laboratory atmosphere was added conc. HCl (1 ml) then the reaction vessel was capped. The dark red mixture was heated at 80° C. for 15 hours (the vessel was periodically uncapped then recapped to release pressure build up with in the vessel). The reaction was cooled to ambient temperature and concentrated in vacuo to a dark red powder. The crude product was subjected to gradient RP-HPLC (H2O: CH3CN) and the title compound was isolated as a red powder (0.06 g, 91% yield): MS (ESI) m/z 505, MS (ESI) m/z 503.
Reaction SMILES: [O:1]=[C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]2[C:4]([S:5][C:6]3[CH:20]=[C:19]([CH2:21][C:22]([OH:24])=O)[CH:18]=[CH:17][C:7]=32)=[N:3]1.[C:25](N1C=CN=C1)([N:27]1C=CN=[CH:28]1)=O.CNC>O1CCCC1>[CH3:25][N:27]([CH3:28])[C:22](=[O:24])[CH2:21][C:19]1[CH:18]=[CH:17][C:7]2[N:8]3[C:9]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[CH:10][C:2](=[O:1])[N:3]=[C:4]3[S:5][C:6]=2[CH:20]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1ccc2c(c1)sc1nc(=O)cc(-c3ccccc3)n12
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1ccc2c(c1)sc1nc(=O)cc(-c3ccccc3)n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
A solution of 3 g of 2-oxo-4-phenyl-2H-pyrimido[2,1-b]benzothiazole-8-acetic acid in 40 ml of tetrahydrofuran and 2 g of 1,1'-carbonyldiimidazole were admixed. The mixture was stirred at room temperature for 1 hour until dissolution took place. Excess dimethylamine (30% in ethanol) was added and the mixture was stirred for a further 40 minutes. The solvent was then removed under vacuo and the residue was taken up in dichloromethane and washed with water, bicarbonate solution water then dried over MgSO4, filtered and evaporated to dryness to obtain 1.1 g of N,N-dimethyl-2-oxo-4-phenyl-2H-pyrimido[2,1-b]benzothiazole-8-acetamide as a pale buff solid which was purified by flash chromatography on silica. It had a melting point of 238°-40° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]2=[O:21])=[CH:7][C:6]=1[CH:22]=[C:23]([Cl:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(#N)C>[CH3:1][N:2]([CH3:3])[C:15](=[O:16])[C:14]1[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=1[C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([Cl:4])=[C:6]([CH:22]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[Cl:29])[CH:7]=1)=[O:21]
Reactant: CCOC(=O)C(Cl)=Cc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl
Reactant: CNC
Solvent: CC#N
Product: CCOC(=O)C(Cl)=Cc1cc(NC(=O)C2=C(C(=O)N(C)C)CCCC2)ccc1Cl
Reaction time: 20 h

Procedure:
1.39 ml of a 40% strength by weight aqueous dimethylamine solution were added to a solution of 3.9 g of N-[4-chloro-3-(2-chloro-2-ethoxycarbonylethenyl)phenyl]-3,4,5,6-tetrahydrophthalimide in 100 ml of acetonitrile at about 20° C. The mixture obtained was stirred for a further 20 hours at 20°-25° C., after which the solid formed was separated off, washed with petroleum ether and finally dried. Mp.: 161°-164° C.
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C=CC=CC=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:42])=[C:30]([C:32]2[CH:33]=[CH:34][C:35]([C:38]([O:40][CH3:41])=[O:39])=[N:36][CH:37]=2)[CH:31]=1.C1C(=O)N([Br:50])C(=O)C1>CCOC(C)=O>[Br:50][CH2:42][C:29]1[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][C:30]=1[C:32]1[CH:33]=[CH:34][C:35]([C:38]([O:40][CH3:41])=[O:39])=[N:36][CH:37]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(-c2cc(Cl)ccc2C)cn1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(-c2cc(Cl)ccc2CBr)cn1

Procedure:
Solid benzoyl peroxide (496 mg, 2.0 mmol) was added to a benzene solution (50 mL) of methyl 5-(5-chloro-2-methylphenyl)picolinate (3.6 g, 13.6 mmol) and NBS (2.7 g, 15.0 mmol) and the resulting mixture was refluxed. After 16 h the resulting mixture was cooled, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]([C@H:21]1[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]1)[C:8](=[O:20])[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1.[H][H]>CO.[C].[Pd]>[CH3:28][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]([C@H:21]1[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]1)[C:8](=[O:20])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1
Reactant: [H][H]
Reactant: COc1cc(C=CC(=O)N(CCCCN(C)C)[C@H]2CC[C@H](C)CC2)ccc1O
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)N(CCCCN(C)C)[C@H]2CC[C@H](C)CC2)ccc1O

Procedure:
0.05 g of 10% palladium-carbon was added to a solution of 1 g of N-(4-dimethylaminobutyl)-N-(trans-4-methylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (Example 75) in 60 ml of methanol. Under normal-pressure hydrogen gas, the solution was reacted for 16 hours, while it was vigorously stirred. After reaction, the catalyst was filtered out, and the solvent was removed in vacuo from the filtrate, yielding 0.92 g of N-(4-dimethylaminobutyl)-N-(trans-4-methylcyclohexyl)-3-(4-hydroxy-3-methoxyphenyl)propionamide (a compound of the present invention) as a pale yellow oily oil, which had the following physiochemical properties:
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=4)[C@H:16]([CH2:26][O:27]CC4C=CC=CC=4)[O:15][C:14]3=[O:35])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=4)[C@H:16]([CH2:26][OH:27])[O:15][C:14]3=[O:35])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C1O[C@@H](COCc2ccccc2)[C@H](c2cc(F)cc(F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1O[C@@H](CO)[C@H](c2cc(F)cc(F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Reaction time: 2 h

Procedure:
The title compound was obtained as a colorless oil from 1-((E)-3-(benzyloxy)prop-1-enyl)-3,5-difluorobenzene by the same method that is described for Example 39. (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-((benzyloxy)methyl)-4-(3,5-difluorophenyl)oxazolidin-2-one (Example 96) was placed into a 25 mL round bottom flask and dissolved in 7 mL ethanol:ethyl acetate (1:1) and treated with palladium on carbon (10% by weight, 73 mg). The vessel was sealed with a rubber septum and charged with hydrogen. The reaction was stirred for 2 h, then filtered on celite, evaporated to dryness and purified on silica gel (20-30% ethyl acetate/hexanes) to give the title compound as a colorless oil that solidified on standing. 1H NMR (acetone-d6) δ (ppm) 7.53 (d, J=9.1 Hz, 2H), 7.37 (d, J=9.0 Hz, 2H), 7.21-7.16 (m, 2H), d, J=6.15 Hz, 2H), 7.02-6.93 (m, 5H), 5.58 (d, J=5.4 Hz, 1H), 4.55 (t, J=5.8 Hz, 1H), 4.45 (ddd, J=5.6, 3.7, 3.6), 3.97 (ddd, J=12.3, 5.6, 3.8 Hz, 1H), 3.90 (ddd, J=12.3, 5.6, 3.8 Hz, 1H); HPLC-MS calculated C22H16ClF2NO4 (M+H+): 432.1, found: 432.0.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[CH3:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@H:27]3[CH2:29][O:28]3)=[CH:21][C:19]=2[N:20]=1>C(O)C>[OH:28][C@H:27]([CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:18]2[S:17][C:16]([CH3:15])=[N:20][C:19]=2[CH:21]=1)[CH2:29][N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][C@@H:2]1[CH3:1]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cc1nc2cc(OC[C@H]3CO3)ccc2s1
Solvent: CCO
Product: Cc1nc2cc(OC[C@@H](O)CN3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)ccc2s1

Procedure:
A solution of tert-butyl (3S)-3-methylpiperazinecarboxylate (3 g, 15 mmol) and 2-(2R)-methyl-5-(oxiran-2-ylmethoxy)benzothiazole, (3.3 g, 15 mmol), a compound of formula (5), was refluxed in ethanol for 24 hours. The solvent was removed under reduced pressure, and the residue was chromatographed on silica gel, eluting with methanol/dichloromethane 1/15, to yield tert-butyl (3S)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazinecarboxylate, a compound of formula (8).