Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[CH:18]=[C:17]([CH2:19][CH3:20])[NH:16][N:15]=3)=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH3:21])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.CCN=C=NCCCN(C)C>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH:1]1([C:5]2[C:13]([C:14]3[CH:18]=[C:17]([CH2:19][CH3:20])[NH:16][N:15]=3)=[CH:12][C:8]([C:9]([N:23]3[CH2:28][CH2:27][CH:26]([C:29]4[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=[O:10])=[C:7]([CH3:21])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: CCc1cc(-c2cc(C(=O)O)c(C)cc2C2CCC2)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)n[nH]1
Temperature: 30 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of 4-cyclobutyl-5-(5-ethyl-1H-pyrazol-3-yl)-2-methylbenzoic acid (compound 445.3, 130 mg, 0.460 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL) were added 4-(Piperidin-4-yl)benzonitrile hydrochloride (1.5, 102 mg, 0.460 mmol, 1.00 equiv), EDCI (176 mg, 0.920 mmol, 2.00 equiv), and 4-dimethylaminopyridine (112 mg, 0.920 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at 30° C., and then diluted with 40 mL of ethyl acetate. The mixture was washed with 3×40 mL of brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (59.0% CH3CN up to 73.0% in 6 min, up to 100.0% in 7 min, down to 59.0% in 1 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 150 mg (72%) of the title compound as a white solid. m/z (ES+) 453 (M+H)+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14](F)([F:32])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])=[CH:19][CH:18]=1.C(O)(=O)C>CCCCCC.O1CCCC1>[F:13][C:14]([F:32])=[CH:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])=[CH:21][CH:22]=1
Reactant: O=C(Cc1ccccc1)c1ccc(OCC(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: O=C(Cc1ccccc1)c1ccc(OC=C(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Butyllithium (190 ml; 1.6N) in hexane was added, dropwise, to diisopropylamine (30.4 g; 0.3 mol) in tetrahydrofuran (400 ml) kept under nitrogen at 0° C. The mixture was stirred for 30 minutes at 0° C. and then cooled to -70° C. At this temperature benzyl 4-(2,2,2-trifluoroethoxy)phenyl ketone, dissolved in tetrahydrofuran (70 ml) was slowly added, dropwise, to the reaction mixture. The solution became deep red. The mixture was then stirred at -70° C. for an hour and acetic acid (20 ml) was added, dropwise, without allowing the temperature of the reaction mixture to rise above -65° C. The mixture was then warmed to room temperature and added to ice-water (2000 ml). It was extracted with diethyl ether (3×500 ml) and the purified organic phase washed with sodium hydrogen carbonate, dried over magnesium sulphate and concentrated in a rotary evaporator. The residue was recrystallised from ethanol to give pure benzyl 4-(2,2-difluorovinyloxy)phenyl ketone.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].[C:14]1([N:20]2[CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:23](=[O:31])[NH:22][C:21]2=[O:32])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:32]=[C:21]1[N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:23](=[O:31])[N:22]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: O=C1NC(=O)N(c2ccccc2)C1c1ccccc1
Reactant: COC(=O)CCCCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCCCCCCCN1C(=O)C(c2ccccc2)N(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.2 %

Procedure:
Diethyl axodicarboxylate (1.39 g, 8 mmol) in THF (5 mL, was added dropwise to a stirred solution of methyl 9-hydroxynonanoate (1.50 g, 8 mmol), 3,4-diphenylimidazolidine-2,5-dione (2.02 g, 8 mmol) obtained according to the procedure of K. C. Joshi, et al., J. Het. Chem., 18, 1651-1653 (1981) and triphenylphosphine (2.10 g, 8 mmol) in THF (35 mL). The mixture was stirred at room temperature for 72 hours, the THF removed in vacuo and the residue triturated with a mixture of hexanes and diethyl ether. The mixture was filtered, the filtrate concentrated and subjected to chromatography on a column of silica gel using a mixture of hexanes and ethyl acetate (3:2) as eluent. Elution gave methyl 2,5-dioxo-3,4-diphenyl-1-imidazolidinenonanoate (2.78 g, 82%), mp 69°-72° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1([CH3:22])[CH2:15][C:14]2[NH:13][CH:12]=[C:11]([CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:10]=2[CH2:9][CH2:8]1.[OH-].[K+].CN(C)[CH:27]=[O:28]>>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][CH2:16][C:11]1[C:10]2[CH2:9][CH2:8][C:7]([CH3:22])([CH3:6])[CH2:15][C:14]=2[NH:13][C:12]=1[CH:27]=[O:28]
Reactant: CN(C)C=O
Reactant: CN(C)CCCc1c[nH]c2c1CCC(C)(C)C2
Agent: [K+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)CCCc1c(C=O)[nH]c2c1CCC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Phosphorus oxychloride (0.5 mL, 5.1 mmol) was added dropwise to ice-cooled dimethylformamide (1.1 mL, 14.1 mmol) and then stirred at room temperature for 30 minutes. A solution of [3-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-dimethyl-amine (1.1 g, 4.6 mmol) in dimethylformamide (2 mL) was added dropwise at −5° C. The mixture was stirred at room temperature overnight. Ice cubes were added to the reaction mixture followed by the addition of 10 N potassium hydroxide to pH 11–12 and stirring for one hour. The mixture was extracted with ethyl acetate and the extract washed with brine and concentrated. The residue was chromatographed (5%-10% methanol in dichloromethane) to give 650 mg of 3-(3-dimethylamino-propyl)-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde as a brown solid. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 11.25 (br s, 1H, NH), 9.41 (s, 1H, CHO), 2.62 (t, 2H, CH2), 2.36 (t, 2H, CH2), 2.30 (s, 2H, CH2), 2.21 (t, 2H, CH2), 2.12 (s, 6H, 2×CH3), 1.60 (m, 2H, CH2), 1.46 (t, 2H, CH2), 0.93 (s, 6H, 2×CH3). MS m/z 262 [M+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:31]([OH:34])(=[O:33])[CH3:32].[O:35]1[C:39]([CH:40]=O)=[CH:38][C:37]2[CH:42]=[CH:43][CH:44]=[CH:45][C:36]1=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClC(Cl)C.C(=O)(O)[O-].[Na+]>>[C:31]([OH:34])(=[O:33])[CH3:32].[O:35]1[C:39]([CH2:40][NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[N:14][C:15]=4[NH2:17])[N:10]([C@H:18]4[CH2:23][CH2:22][C@@H:21]([N:24]5[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]5)[CH2:20][CH2:19]4)[N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:38][C:37]2[CH:42]=[CH:43][CH:44]=[CH:45][C:36]1=2
Reactant: O=Cc1cc2ccccc2o1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4cccc(N)c4)c4c(N)ncnc43)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4cccc(NCc5cc6ccccc6o5)c4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 11.8 %

Procedure:
A mixture of cis-3-(3-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.107 g, 0.263 mmol, 1 equiv), glacial acetic acid (0.06 mL, 1.0 mmol, 3.8 equiv), benzo[B]furan-2-carboxaldehyde (0.1 g, 0.3 mmol, 1 equiv), sodium triacetoxyborohydride (0.212 g, 1.0 mmol, 3.8 equiv), and dichloroethane (2 mL) was stirred at ambient temperature for 4.5 h. Aqueous sodium bicarbonate was added, the organic layer was separated, and the aqueous layer was extracted with two portions of CH2Cl2 (10 mL each). The combined organic extracts were dried over MgSO4, filtered, and concentrated to afford a yellow oil which was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 10%-60% acetonitrile-0.1M ammonium acetate over 20 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give cis-3-{3-[(benzo[b]furan-2-ylmethyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine monoacetate salt as a white solid (0.017 g, 0.031 mmol): 1H NMR (d6 DMSO, 400 MHz): δH 8.22 (1H, s), 7.51-7.58 (2H, m), 7.22-7.28 (3H, m), 6.98 (1H, s), 6.79-6.84 (2H, m), 6.59-6.62 (1H, m), 4.76-4.81 (1H, m), 4.50 (2H, d, J=5.6 Hz), 2.19-2.24 (14H, m), 2.05-2.07 (2H, m), 1.91 (3H, s), 1.60-1.75 (4H, m); RP-HPLC (Delta Pak C18, 5 μm, 300 Å, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 13.99 min. MS: MH+ 537.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](F)(=[O:31])=[O:30])=[CH:25][C:24]=1[NH2:33].[I-].C([NH3+])(C)(C)C>ClCCl>[NH2:33][C:24]1[CH:25]=[C:26]([S:29]([O:13][C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:31])=[O:30])[CH:27]=[CH:28][C:23]=1[O:22][CH3:21]
Reactant: COc1cc(O)cc(OC)c1OC
Reactant: COc1ccc(S(=O)(=O)F)cc1N
Agent: CC(C)(C)[NH3+]
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Oc2cc(OC)c(OC)c(OC)c2)cc1N
Reaction time: 8 h
Yield: 35 %

Procedure:
A solution of 3,4,5-trimethoxyphenol (505.7 mg, 2.75 mmol) in dichloromethane (28 mL) was treated sequentially with triethylamine (1.2 mL), 4-methoxymetanilyl fluoride (572.5 mg, 2.75 mmol), and tert-butylammonium iodide (106 mg, 0.287 mmol), stirred overnight, and washed once with 1M Na2CO3. The organic layer was separated, dried (MgSO4), filtered, and concentrated. Chromatography of the concentrate on silica gel with 40% ethyl acetate/hexanes provided 356 mg of the desired compound.
Reaction SMILES: Cl.Cl.C(NN=C(C1C=C(C(=NNC(=N)N)C)C=C(C=1)N[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C)(=N)N.[C:32]([C:35]1[CH:36]=[C:37]([CH:39]=[C:40]([C:42](=[O:44])[CH3:43])[CH:41]=1)[NH2:38])(=[O:34])[CH3:33].N1C=CC=CC=1.C(Cl)(=O)C1C=CC=CC=1>O1CCCC1.O>[C:16]([NH:38][C:37]1[CH:39]=[C:40]([C:42](=[O:44])[CH3:43])[CH:41]=[C:35]([C:32](=[O:34])[CH3:33])[CH:36]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=NNC(=N)N)c1cc(NC(=O)c2ccccc2)cc(C(C)=NNC(=N)N)c1
Reactant: CC(=O)c1cc(N)cc(C(C)=O)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc(NC(=O)c2ccccc2)cc(C(C)=O)c1
Reaction time: 1 h

Procedure:
Compound 26, FIG. 7E.26: A solution of 3,5-diacetylaniline (0.885 g) in tetrahydrofuran (10 mL) containing 0.45 mL pyridine was treated with 0.65 mL benzoyl chloride. The mixture was stirred 1 hr, then treated with I mL water and stirred 15 min. The mixture was then diluted with 40 mL water and stirred 30 min. Filtration and washing with water and isopropanol gave colorless needles of N-benzoyl-3,5-diacetylaniline, 1.36 g, mp 188-189° C. A suspension of N-benzoyl-3,5-diacetylaniline (0.844 g) in aq. 87.5% ethanol (8 mL) containing 0.73 g aminoguanidine hydrochloride and a trace of HCl was heated at reflux for 18 hr. Cooling and filtration gave 1.357 g of N-benzoyl-3,5-diacetylaniline bis(amidinohydrazone) dihydrochloride (Compound 26), mp 268-72° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:14][CH3:15])[C:10]=1[N+:11]([O-])=O)[C:5]([OH:7])=[O:6].CC(O)=O.[H][H]>CO>[NH2:11][C:10]1[C:9]([O:14][CH3:15])=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: [H][H]
Reactant: COc1cc(C(=O)O)cc(F)c1[N+](=O)[O-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(C(=O)O)cc(F)c1N

Procedure:
A solution of 3-fluoro-5-methoxy-4-nitrobenzoic acid (obtained above), HOAc (5 mL) and MeOH (5 mL) was hydrogenated using a hydrogen balloon overnight. The solution was then filtered through celite and concentrated to a red solid (590 mg, 66%). [M+H] calc'd for C8H8FNO3, 186. found 186.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20](O)=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.[CH:23]1([C:26]2[O:30][N:29]=[C:28]([CH2:31][NH2:32])[CH:27]=2)[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:17])([F:19])[F:18])=[CH:12][N:11]=[C:10]([C:20]([NH:32][CH2:31][C:28]3[CH:27]=[C:26]([CH:23]4[CH2:25][CH2:24]4)[O:30][N:29]=3)=[O:21])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Reactant: NCc1cc(C2CC2)on1
Product: O=C(NCc1cc(C2CC2)on1)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example D) and 5-cyclopropyl-3-isoxazolemethanamine (CAS Registry No. 1060817-49-3) as starting materials; LC-MS (UV peak area/ESI) 98.6%, 452.0979 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32]>>[CH3:40][O:39][C:35]1[CH:34]=[C:30]([CH:29]=[C:28]([O:27][CH3:26])[C:36]=1[O:37][CH3:38])[C:31]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1)=[O:32]
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Product: COc1cc(C(=O)/C=C/c2cn(C(=O)c3cc(OC)c(OC)c(OC)c3)c3ccccc23)cc(OC)c1OC

Procedure:
Substantially the same procedure as in Example 3 was repeated using Compound 1 (1.69 g) obtained in Example 1 and 3,4,5-trimethoxybenzoyl chloride (2.31 g) except that the obtained crude crystals were recrystallized from a mixed solvent of ethanol and acetone, to give Compound 59 (1.22)
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16](COC)[C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:4](=[O:25])[NH:3]1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].Cl.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:26]([N:3]1[C:4](=[O:25])[CH:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:14])=[O:15])=[CH:9][CH:8]=2)[NH:6][C:2]1=[O:1])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: COCN(c1nccs1)S(=O)(=O)c1ccc(C2NC(=O)NC2=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=C1NC(c2ccc(S(=O)(=O)Nc3nccs3)cc2)C(=O)N1Cc1ccccc1
Temperature: 65 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
A suspension of 4-(2,5-dioxo-imidazolidin-4-yl)-N-methoxymethyl-N-thiazol-2-yl-benzenesulfonamide (0.1 mmol), benzyl bromide (0.2 mmol), and potassium carbonate (0.1 mmol) in DMF (5 mL) was stirred at 65° C. for 4 h. The reaction mixture was acidified with 6N HCl aqueous solution and was stirred for 30 min before neutralized with saturated NaHCO3. The mixture was extracted with ethyl acetate and organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by reverse phase HPLC to give 4-(1-benzyl-2,5-dioxo-imidazolidin-4-yl)-N-thiazol-2-yl-benzenesulfonamide (0.04 mmol).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[N:7][NH:8][CH:9]=1.C(N(CC)CC)C.Br[C:18]([C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])([Cl:28])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C(Cl)(Cl)Cl>[C:29]([C:18]([C:6]1[C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:9][NH:8][N:7]=1)([Cl:28])[C:19]([NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:20])(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: OCCCc1cn[nH]c1
Reactant: CC(C)(C)C(=O)C(Cl)(Br)C(=O)Nc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)C(Cl)(C(=O)Nc1ccccc1)c1n[nH]cc1CCCO
Reaction time: 1 h
Yield: 87.4 %

Procedure:
56.7 g of 4-(3-hydroxypropyl)pyrazole and 45.5 g of triethylamine were dissolved in 500 ml of chloroform and, under cooling with ice, a solution of 88.8 g of α-bromo-2-pivaloyl-2-chloroacetanilide in 300 ml of chloroform was dropwise added thereto in about 1 hour. After completion of the dropwise addition, the solution was stirred for 2 hours, and the reaction solution was washed twice with 300 ml of dilute hydrochloric acid, then twice with 500 ml of water. The reaction solution was dried with anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain 88.2 g of oily α-pivaloyl-α-[4-(3-hydroxypropyl)pyrazolyl]-2-chloroacetanilide. (Yield: 78%)
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=3)[CH:17]=[C:16]([O:30][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:40])C.[OH-].[Na+].Cl>C(O)C>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][CH2:31][O:30][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:41])=[O:3])=[C:8]([CH3:40])[CH:9]=3)[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][OH:29])=[CH:26][CH:27]=3)[CH:17]=2)=[CH:38][CH:37]=1
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (270 mg; 0.46 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried, evaporated to dryness and purified by prep HPLC (method B). Yield: 218 mg (85%). HPLC-MS: m/z: 559.1 (M+H)+; Rt: 2.61 min.
Reaction SMILES: [CH3:1][S:2]S(C)(=O)=O.[N+](C1C=CC=CC=1)([O-])=O.[S:16]1[CH:20]=[CH:19][N:18]2[CH:21]=[N:22][CH:23]=[C:17]12.Cl>Cl[Ti](Cl)Cl.ClCCl>[CH3:1][S:2][C:23]1[N:22]=[CH:21][N:18]2[CH:19]=[CH:20][S:16][C:17]=12
Reactant: CSS(C)(=O)=O
Reactant: c1cn2cncc2s1
Agent: Cl[Ti](Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O=[N+]([O-])c1ccccc1
Product: CSc1ncn2ccsc12
Reaction time: 0.33 h

Procedure:
To 200 ml of dichloromethane cooled at 0° C., 35 ml of trichlorotitanium and 40 g of methyl methanethiolsulfonate were added and the mixture was stirred at the same temperature for 20 min. The mixture was added dropwise to 1 L of nitrobenzene containing 26 g of imidazo[5,1-b]thiazole at 5 to 10° C. and stirred at the same temperature for five hr. The reaction was stopped by adding 400 ml of 0.5N hydrochloride, followed by filtration to remove insolubles. The mixture was washed with 200 ml of dichloromethane and 200 ml of water. The organic layer was removed and the aqueous layer was washed with 800 ml of dichloromethane twice. After the pH of the aqueous layer was adjusted to 4.0, the extraction three times with dichloromethane. The organic layer was dried and the solvent was removed to give 19.8 g of 7-Methylthioimidazo[5,1-b]thiazole.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@@H:15]([CH2:17][O:18]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@H:14]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][O:45][CH2:46][C@@H:47]([CH3:51])[CH2:48][O:49][CH3:50])=[CH:40][CH:39]=2)[C@@H:13]([O:52][CH2:53][C:54]2[CH:55]=[CH:56][C:57]3[O:62][CH2:61][C:60](=[O:63])[N:59]([CH2:64][CH2:65][CH2:66][O:67][CH3:68])[C:58]=3[CH:69]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O1CCCC1.CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][C@H:13]([O:52][CH2:53][C:54]2[CH:55]=[CH:56][C:57]3[O:62][CH2:61][C:60](=[O:63])[N:59]([CH2:64][CH2:65][CH2:66][O:67][CH3:68])[C:58]=3[CH:69]=2)[C@@H:14]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][O:45][CH2:46][C@@H:47]([CH3:51])[CH2:48][O:49][CH3:50])=[CH:40][CH:39]=2)[C@H:15]([CH2:17][OH:18])[CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCN1C(=O)COc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COCCCN1C(=O)COc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](CO)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reaction time: 15 h

Procedure:
A solution of 8.526 mmol of (3R,4R,5S)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl) -phenyl]-3-[4-(3-methoxy-propyl)-3-oxo-3,4-dihydro-2H-benzo [1,4]oxazin-6-ylmethoxy]-5-trityloxymethyl-piperidine-1-carboxylic acid benzyl ester in 20 ml of tetrahydrofuran and 80 ml of methanol is treated with 12.789 mmol of toluene-4-sulfonic acid.monohydrate. After stirring for 15 hours, the reaction mixture is basified with saturated aqueous sodium bicarbonate solution and concentrated under reduced pressure to remove most of the methanol and tetrahydrofuran. The residue is extracted with dichloromethane (3×)—the combined organic layers are washed successively with water and brine, dried with sodium sulfate and evaporated. The title compound is obtained as a yellow oil from the residue by flash chromatography (SiO2 60F). Rt=4.86 (gradient I).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:11]([CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]2)[CH2:12][CH2:13][CH3:14])[CH3:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(OCC)(=O)C>[N:32]1([C:38]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:11]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:20][CH2:21]3)[CH2:12][CH2:13][CH3:14])[CH3:10])=[CH:4][CH:3]=2)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: CCCN(CC1CCN(S(C)(=O)=O)CC1)C(C)Cc1ccc(N)cc1
Reactant: O=C(Cl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCN(CC1CCN(S(C)(=O)=O)CC1)C(C)Cc1ccc(NC(=O)N2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-[2-(4-aminophenyl)-1-methylethyl]-N-propyl-(1-methanesulfonyl-piperidin-4-ylmethyl)amine (60 mg) was dissolved in ethyl acetate (1 ml) and saturated potassium carbonate (1 ml). The mixture was cooled in an ice bath to 0° C. and morpholine-4-carbonyl chloride (0.03 ml) was added. After stirring for 30 minutes, the layers were separated. The organic layer was dried over magnesium sulfate, filtered, and the solvent removed to give N-{2-[4-(morpholine-4-carbonylamino)phenyl]-1-methylethyl]-N-propyl-(1-methanesulfonylpiperidin-4-ylmethyl)amine (90 mg) as a foam, M+H 481.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].[Br:17]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[Br:17][C:10]1[CH:9]=[CH:8][C:7]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:11]=1
Reactant: COCCOc1ccccc1OCCOC
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1ccc(Br)cc1OCCOC
Yield: 99.6 %

Procedure:
1,2-Bis(2-methoxyethoxy)benzene (8.1 g, 31.9 mmol) and N-bromosuccinimide (6.2 g, 35 mmol) were stirred in 50 mL DMF at room temperature overnight. The reaction was diluted with 200 mL EtOAc and washed with 1N NaOH and water. The organic layer was dried over magnesium sulfate and concentrated to give 9.7 g (92%) of 4-bromo-1,2-bis(2-methoxyethoxy)benzene.