Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[N:12]([CH2:15]O)[C:11](=[O:17])[O:10]2)=[CH:5][CH:4]=1.S(Cl)([Cl:20])=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][Cl:20])[C:11](=[O:17])[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2oc(=O)n(CO)c2=O)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(-n2oc(=O)n(CCl)c2=O)cc1

Procedure:
2-(4-Methoxyphenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione (0.03 mole) dissolved in chloroform (40 ml) and thionyl chloride (0.06 mole) dissolved in chloroform (10 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 2 hours. After this time the reaction mixture is stripped of solvent under reduced pressure, leaving a residue. This residue is dissolved in toluene, and the toluene solution is stripped of solvent and unreacted starting materials to yield the desired product 2-(4-methoxyphenyl)-4-chloromethyl-1,2,4-oxadiazolidin-3,5-dione as the residue.
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]2[C:33]3[C:32](=[O:34])[NH:31][C:30]([C:35]([O:37]CC)=O)=[N:29][C:28]=3[S:27][CH:26]=2)[CH:22]=[CH:23][CH:24]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:83]2[CH:87]=[N:86][C:85]([O:88][CH2:89][CH2:90][O:91][C:92]3[CH:93]=[C:94]([CH2:98][NH2:99])[CH:95]=[CH:96][CH:97]=3)=[N:84]2)C=CC=CC=1>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]2[C:33]3[C:32](=[O:34])[NH:31][C:30]([C:35]([NH:99][CH2:98][C:94]4[CH:95]=[CH:96][CH:97]=[C:92]([O:91][CH2:90][CH2:89][O:88][C:85]5[N:86]=[CH:87][NH:83][N:84]=5)[CH:93]=4)=[O:37])=[N:29][C:28]=3[S:27][CH:26]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1nc2scc(-c3cccc(OC)c3)c2c(=O)[nH]1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: COc1cccc(-c2csc3nc(C(=O)NCc4cccc(OCCOc5nc[nH]n5)c4)[nH]c(=O)c23)c1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-(3-methoxyphenyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 74 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (117.5 mg, 50%).
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH2:6][O:5][CH2:4]1)[CH3:2].C([Li])CCC.C(O[B:29]1[O:33][C:32]([CH3:35])([CH3:34])[C:31]([CH3:37])([CH3:36])[O:30]1)(C)C>C1COCC1>[CH2:1]([C:3]1([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[S:16][C:17]([B:29]3[O:33][C:32]([CH3:35])([CH3:34])[C:31]([CH3:37])([CH3:36])[O:30]3)=[CH:18][CH:19]=2)[CH2:4][O:5][CH2:6]1)[CH3:2]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CCC1(COCCCCCCc2cccs2)COC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC1(COCCCCCCc2ccc(B3OC(C)(C)C(C)(C)O3)s2)COC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a stirred solution of 3-ethyl-3-(6-thiophen-2-yl-hexyloxymethyl)-oxetane (6.0 g, 21.28 mmol) in dry THF (70 ml) is added n-butyllithium (2.5 M in hexanes, 8.10 ml, 21.28 mmol) dropwise at −78° C. under nitrogen. After complete addition, the mixture is allowed to warm to room temperature, with stirring, over 2 h, followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.96 g, 21.28 mmol). The resultant mixture is stirred overnight at room temperature. The reaction is quenched with water, and the reaction mixture is extracted with ethyl acetate (3×70 ml). The combined organic extracts are washed with water, brine, and dried over sodium sulphate. The solvent is removed under reduced pressure and the residue is purified by column chromatography on silica, eluting with petroleum ether/ethyl acetate (9:1), to give a yellow oil (6.28 g, 72%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.45 (d, J=3.4 Hz, 1H, Ar—H), 6.85 (d, J=3.4 Hz, 1H, Ar—H), 4.44 (d, J=5.8 Hz, 2H, OCH2), 4.36 (d, J=5.8 Hz, 2H, OCH2), 3.51 (s, 2H, OCH2), 3.45 (t, J=6.4 Hz, 2H, OCH2), 2.83 (t, J=7.6 Hz 2H, ArCH2), 1.32-1.77 (m, 22H, CH2 and CH3), 0.88 (t, J=7.4 Hz, 3H, CH3); δ (ppm) 153.5 (quat.), 145.6 (quat.), 137.3 (CH), 125.9 (CH), 83.9 (quat.), 78.6 (OCH2), 73.4 (OCH2), 71.5 (OCH2), 43.4 (quat.), 31.6 (CH2), 30.1 (CH2), 29.4 (CH2), 28.8 (CH2), 26.8 (CH2), 25.9 (CH2), 24.8 (CH3), 8.2 (CH3); MS (m/e): 408 (M+, 0.5%), 223 (27), 165 (30), 141 (35), 123 (100), 97 (52).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:25][CH2:26][C:27](O)=[O:28])[C:10]([NH:12][C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH:14]=2)=[O:11])=[CH:4][CH:3]=1.C(OCC)(=O)C.Cl.[CH2:37]([NH2:39])[CH3:38].[Cl-].[NH4+]>C(N(CC)CC)C.ClCCl>[CH2:37]([NH:39][C:27]([CH2:26][NH:25][C@@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:10]([NH:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH:14]=1)=[O:11])=[O:28])[CH3:38]
Reactant: Cn1nc(-c2ccncc2)cc1NC(=O)[C@H](Cc1ccc(F)cc1)NCC(=O)O
Reactant: CCN
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)CN[C@@H](Cc1ccc(F)cc1)C(=O)Nc1cc(-c2ccncc2)nn1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.2 %

Procedure:
To a 25 ml flask was added 2-((S)-3-(4-fluorophenyl)-1-(1-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-ylamino)-1-oxopropan-2-ylamino)acetic acid 103.2 (145 mg, 0.36 mmole), 50% propylphosphoric anhydride in ethyl acetate (348 mg, 0.55 mmole), 0.2 ml of triethylamine and 3 ml of dichloromethane. After 20 min, ethylamine hydrochloride (60 mg, 0.73 mmole) was added to the mixture. The reaction was stirred at room temperature for 4 days. The solution was poured into saturated ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was chromatographed on silica gel to give 103.3 (69 mg, 44% yield) as colorless amorphous. LCMS ESI (pos.) m/e: 425 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 9.91 (s, 1H), 8.58 (dd, J=17.9, 6.2 Hz, 2H), 7.63 (dd, J=19.5, 6.2 Hz, 2H), 7.25 (dd, J=9.2, 6.0 Hz, 2H), 7.05 (t, J=7.7 Hz, 2H), 6.82 (s, 1H), 5.79 (brs, 1H), 3.81 (s, 3H), 3.46 (dd, J=8.6, 4.7 Hz, 1H), 3.31-3.17 (m, 3H), 3.21 (d, J=2.8 Hz, 2H), 2.92 (dd, J=14.1, 8.6 Hz, 1H), 1.09 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21]Br)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31][C:32]([F:48])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH2:41].C(=O)(O)[O-].[Na+].[I-].[Na+]>CS(C)=O.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21][NH:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][O:34][CH2:33][C:32]([F:31])([F:48])[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: NCCCCCCOCC(F)(F)c1ccccc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCCCCOCC(F)(F)c1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 140 °C

Procedure:
To a solution of (8-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)quinolin-2(1H)-one (V) (4.80 g, 9.83 mmol) and 6-(2,2-Difluoro-2-phenylethoxy)hexyl]amine (IV) (3.04 g, 11.8 mmol) in dimethylsulfoxide (13.5 mL) was added sodium bicarbonate (2.49 g, 29.4 mmol) and sodium iodide (2.22 g, 14.8 mmol). The mixture was heated at 140° C. for 2 hours. After cooling, the reaction was diluted with water (40 mL) and extracted with diethyl ether (2×20 mL). The combined organic extracts were washed with water (2×10 mL) and brine (20 mL), dried (Na2SO4), and the solvent removed under reduced pressure. The title compound was obtained (6.40 g, 98%) as oil.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH3:11])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:12]Br.O.[OH-].[K+]>C(O)(=O)C>[Br:12][C:9]1[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]([CH3:11])[C:8]=1[NH2:10]
Reactant: Cn1nc(C(C)(C)C)cc1N
Reactant: BrBr
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cn1nc(C(C)(C)C)c(Br)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a solution of 3-tert-butyl-1-methyl-1H-pyrazol-5-amine (10 g, 65.3 mmol) in acetic acid (90 mL) was added bromine (10.4 g, 65.26 mmol) in acetic acid (10 mL). The solution was stirred at rt for 30 min, and then water (100 mL) was added. The reaction mixture was basified to pH 9 using KOH (1.0 M ice cold solution). The resulting brown solid was filtered, collected, and purified by silica gel flash chromatography using 10 to 30% ethyl acetate in hexanes to afford 13.2 g (87%) of the title compound (white solid).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>>[OH:29][C:23]([C:25]([F:28])([F:27])[F:26])=[O:24].[OH:29][C:23]([C:25]([F:28])([F:27])[F:26])=[O:24].[N:16]1[CH:15]=[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=12
Reactant: CC(C)(C)OC(=O)N1CCC(c2cnc3ccccn23)CC1
Solvent: O=C(O)C(F)(F)F
Product: c1ccn2c(C3CCNCC3)cnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 100 mg of 1-(t-butoxycarbonyl)-4-(imidazo[1,2-a]pyridin-3-yl)piperidine from Step A was added 2 mL TFA. The reaction was stirred at rt for 1 h. The mixture was concentrated under reduced pressure to afford 180 mg of a viscous oil.
Reaction SMILES: [CH3:1][C@@:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]2[OH:9].[Cr](O[Cr](O)(=O)=O)(O)(=O)=O.N1C=CC=CC=1>C(Cl)Cl.C(OCC)C>[CH3:1][C@@:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3]2=[O:9]
Reactant: C[C@@]12CCC(CC1O)C2
Agent: O=[Cr](=O)(O)O[Cr](=O)(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@]12CCC(CC1=O)C2
Reaction time: 72 h
Yield: 64.5 %

Procedure:
79.6 g (0.63M) of the optically active alcohol (V) obtained in 1-4) above was dissolved in 300 ml of methylene chloride and the resulting solution was added dropwise to a suspension of 304 g (0.81M) of pyridine dichromate in 700 ml of methylene chloride at room temperature. Then the resulting mixture was stirred for three days. The obtained reaction mixture was diluted with 1 l of diethyl ether and filtered through celite. The filtrate was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was distilled under reduced pressure to give 50.4 g (theoretical yield: 64.5%) of the aimed compound (VI) as a colorless oily material. b.p.: 70° C./20 mmHg.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:47][C:48]1[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][C:49]=1[N+:55]([O-:57])=[O:56]>CN(C=O)C>[CH3:47][C:48]1[CH:54]=[CH:53][C:51]([NH:52][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=2)=[CH:50][C:49]=1[N+:55]([O-:57])=[O:56]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
A solution of 3-(trifluoromethyl)benzoic acid (8 g, 42.1 mmol), HATU (19.20 g, 50.5 mmol) and DIPEA (13.91 mL, 84 mmol) in DMF (350 mL) was stirred for 15 min at rt. 4-methyl-3-nitroaniline (6.40 g, 42.1 mmol) was added and stirred overnight at 60° C. After cooling to room temperature the reaction was quenched with H2O. After stirring for 10 minutes the resulting precipitate was collected and washed with water to give compound N-(4-methyl-3-nitrophenyl)-3-(trifluoromethyl)benzamide 66 (12 g, 88%). (m/z)=325 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[O:25]COCC[Si](C)(C)C)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.C(O)(=O)C.Cl>C1COCC1.C(OCC)(=O)C.O>[NH2:14][C:11]1[N:10]=[CH:9][C:8]([C:7]2[CH:6]=[CH:5][C:4]([C:15]3[C:16]([OH:25])=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=3)=[CH:3][C:2]=2[F:1])=[CH:13][N:12]=1
Reactant: C[Si](C)(C)CCOCOc1cc(C(F)(F)F)ccc1-c1ccc(-c2cnc(N)nc2)c(F)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ncc(-c2ccc(-c3ccc(C(F)(F)F)cc3O)cc2F)cn1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-[3-fluoro-4′-(trifluoromethyl)-2′-{[2-(trimethylsilyl)ethoxy]-methoxy}-biphenyl-4-yl]pyrimidin-2-amine in 14 mL of THF were added water (1.40 mL), acetic acid (1.40 mL) and hydrochloric acid (0.43 mL, 6 N). The reaction was stirred overnight at 65° Celsius, before diluting with ethyl acetate (20 mL) and water (20 mL). The aqueous layer was extracted with ethyl acetate (3×30 mL) and the combined organic extracts dried over Na2SO4, and concentrated to dryness. The crude product was purified by FCC to provide the title compound. MS (ESI): mass calcd. for C17H11F4N3O, 349.08; m/z found, 350.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.61 (s, 2H), 7.61-7.48 (m, 4H), 7.23-7.19 (dd, J=8.3, 1.8, 1H), 7.19-7.17 (d, J=1.6, 1H).
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[NH:8][NH2:9]>>[C:12]([O:11][C:7]([NH:8][NH:9][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1CCCC1
Product: CC(C)(C)OC(=O)NNC1CCCC1
Temperature: 67.5 °C
Yield: 46.3 %

Procedure:
Cyclopentanone (5.000 g, 59.44 mmol; CAS #120-92-3, purchased from Aldrich) was dissolved in hexanes (90 mL). t-Butyl carbazate (7.860 g, 59.47 mmol) was added and the mixture was heated at 65-70° C. for 1 hour. The mixture was cooled and concentrated in vacuo. The residue was taken up in isopropanol (25 mL)-ether (25 mL)-hexanes (50 mL) and chilled. The crystalline material was collected by filtration to give N′-cyclopentyl-hydrazinecarboxylic acid tert-butyl ester (5.51 g; 47%). A second crop (2.62 g, 22%) was collected from the mother liquor.
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:22][OH:23])[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([O:27][CH2:28][CH2:29]Br)(=[O:26])[CH3:25].[H-].[Na+].[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([C@@:8]1([CH2:22][O:23][CH2:25][C:24]([O:27][CH2:28][CH3:29])=[O:26])[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CO)(C(=O)OC(C)(C)C)CC1=O
Reactant: CC(=O)OCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)COC[C@]1(C(=O)OC(C)(C)C)CC(=O)N([C@H](C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.5 %

Procedure:
(3S)-3-Hydroxymethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (2.0 g, 6.26 mmol) and bromoethyl acetate (2.09 g, 12.52 mmol) were dissolved in tetrahydrofuran (40 mL). Sodium hydride (0.33 g, 7.51 mmol) was added at 0° C., and the mixture was stirred at room temperature for 18 hours. A saturated ammonium chloride solution (100 mL) was added to the reaction solution at 0° C., followed by extraction with ethyl acetate (300 mL). The organic layer was washed with water (100 mL) and brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (40% ethyl acetate/hexane) to give 1.74 g of the title compound as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Br[CH2:9][C:10]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)([C:12]1[N:13]=[C:14]([CH3:17])[S:15][CH:16]=1)[OH:11]>CN(C)C=O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:10]([C:12]2[N:13]=[C:14]([CH3:17])[S:15][CH:16]=2)([OH:11])[CH2:9][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:19][CH:20]=1
Reactant: c1nc[nH]n1
Reactant: Cc1nc(C(O)(CBr)c2ccc(F)cc2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(C(O)(Cn2cncn2)c2ccc(F)cc2)cs1
Yield: 28.8 %

Procedure:
At 10° C., a solution of 4.1 g (0.06 mol) of 1,2,4-triazole in 30 ml of dimethylformamide is added dropwise and with stirring to a suspension of 1.8 g (0.06 mol) of sodium hydride in 20 ml of dimethylformamide, and, after an hour, a solution of 12.6 g (0.04 mol) of 2-bromo-1-(4-fluorophenyl)-1-(2-methylthiazol-4-yl)-ethanol in 30 ml of dimethylformamide is likewise added dropwise at 0° C. and with stirring. When the addition is complete, the mixture is stirred for an hour at 20° C., for a further two hours at 70° C., for two hours at 90° C. and for a further hour at 110° C. For working up, the reaction mixture is cooled and evaporated in vacuo, the residue is taken up in 300 ml of dichloromethane, the solution is washed twice using 200 ml of water each time, dried over sodium sulphate and concentrated in vacuo the residue is chromatographed over silica gel (eluent: dichloromethane/methanol 10:1), and the product thus obtained is crystallized by stirring with 150 ml of diisopropyl ether. 3.5 g (29% of theory) of 1-(4-fluorophenyl)-1-(2-methylthiazol-4-yl)-2-(1,2,4-triazol-1-yl)-ethanol of melting point 120° C. are obtained.
Reaction SMILES: O.[NH2:2][NH2:3].C(N(CC)CC)C.[Cl:11][C:12]1[N:17]=[C:16]([Cl:18])[C:15]([F:19])=[C:14](Cl)[N:13]=1>CO>[Cl:11][C:12]1[N:17]=[C:16]([Cl:18])[C:15]([F:19])=[C:14]([NH:2][NH2:3])[N:13]=1
Reactant: Fc1c(Cl)nc(Cl)nc1Cl
Reactant: NN
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: NNc1nc(Cl)nc(Cl)c1F
Reaction time: 8 h
Yield: 36.6 %

Procedure:
To hydrazine monohydrate (289 μL, 5.96 mmol) and triethylamine (830 μL, 5.96 mmol) in MeOH (15 mL) was added a solution of 2,4,6-trichloro-5-fluoropyrimidine (1.0 g, 4.96 mmol) in MeOH (15 mL), and the mixture was stirred overnight. When the reaction was complete as determined by LCMS, the solution was concentrated in vacuo, and the resulting crude product was purified by RP-HPLC to provide 2,4-dichloro-5-fluoro-6-hydrazinopyrimidine (358 mg, 32%). LCMS: (M+H)+: 196.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][O:17][CH2:18][C:19]([O:21]C)=[O:20])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH-].[K+:30]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][O:17][CH2:18][C:19]([O-:21])=[O:20])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1.[K+:30]
Reactant: COC(=O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Yield: 56 %

Procedure:
16.8 g (0.0417 mole) of methyl 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetate (prepared in the manner described above in Example 1.3) are dissolved in 65 ml of absolute ethanol. 42 ml of a 1 N ethanolic solution of potassium hydroxide are then added thereto and the reaction mixture is heated under reflux for 4 hours. It is then cooled and the precipitate removed by filitration, after washing with diethyl ether. The filtrate is evaporated to dryness and the evaporation residue is triturated with diethyl ether aand left to crystallize, 10.5 g of hydroscopic potassium 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetate being obtained. The yield is 56% of theory; M.P. 161°-163° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][CH2:28][C@@H:29]([OH:34])[C@H:30]([OH:33])[CH2:31][OH:32])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[OH:34][C@@H:29]([C@H:30]([OH:33])[CH2:31][OH:32])[CH2:28][O:27][C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([N:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[N:26]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc(OC[C@@H](O)[C@H](O)CO)c3ccccc3n2)CC1
Agent: [Pd]
Solvent: CO
Product: OC[C@@H](O)[C@H](O)COc1nc(N2CCNCC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-[4-(Benzyloxycarbonyl)piperazin-1-yl]-4-[(2R,3R)-(2,3,4-trihydroxybutan-1-yl)oxy]quinazoline (1.5 g) is dissolved in methanol (40 ml), and thereto is added 1% palladium/carbon (0.15 g), and the mixture is stirred under hydrogen atmosphere and under atmospheric pressure at room temperature for 20 hours. The reaction mixture is filtered, and the filtrate is evaporated to dryness under reduced pressure to give4-[(2R,3R)-(2,3,4-trihydroxybutan-1-yl)oxy]-2-(1-piperazinyl)quinazoline (1.0 g). A part of this product is recrystallized from ethanol to give a product having the following physical properties.
Reaction SMILES: Br[CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)=[O:4].[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC.O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH:2]([C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)=[O:4])[CH:22]([C:20]#[N:21])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:14][CH:15]=1
Reactant: O=C(c1cccc(Cl)c1)C(Br)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C#N)C(Cc1ccc(Cl)cc1)C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
To a solution of 2-bromo-1-(3-chlorophenyl)-3-(4-chlorophenyl)propan-1-one (358 mg, 1 mmol) in DMF (3 mL) was added ethyl 2-cyanoacetate (226 mg, 2 mmol), followed by K2CO3 (276 mg, 2 mmol). The reaction was stirred at RT for 2 h then diluted with EA (10 mL) and water (3 mL). The organic layer was washed with brine (3 mL), dried over Na2SO4 and concentrated to give ethyl 3-(4-chlorobenzyl)-4-(3-chlorophenyl)-2-cyano-4-oxobutanoate (300 mg, 77% yield) as a yellow solid. LCMS: MH+ 390 and TR=2.334 min. Used without further purification.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.Cl[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:29](=[O:30])[C:28]([CH:31]([CH3:33])[CH3:32])=[C:21]2[S:22](=[O:27])(=[O:26])[CH2:23][CH2:24][CH2:25][N:20]2[C:19]1=[O:34].[I-].[Na+]>CN(C)C=O.O>[N:12]1[CH:11]=[CH:10][N:9]2[C:4]([S:3][CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:29](=[O:30])[C:28]([CH:31]([CH3:33])[CH3:32])=[C:21]4[S:22](=[O:27])(=[O:26])[CH2:23][CH2:24][CH2:25][N:20]4[C:19]3=[O:34])=[CH:5][CH:6]=[CH:7][C:8]=12
Reactant: Sc1cccc2nccn12
Reactant: CC(C)c1c2n(c(=O)n(CCCCCl)c1=O)CCCS2(=O)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1c2n(c(=O)n(CCCCSc3cccc4nccn34)c1=O)CCCS2(=O)=O
Reaction time: 0.5 h

Procedure:
To a suspension of 0.152 g (3.8 mmol) of 60% oily sodium hydride in 20 ml of N,N-dimethylformamide, 0.57 g (3.8 mmol) of 5-mercaptoimidazo[1,2-a]pyridine was added at room temperature, followed by stirring for 30 minutes. To this mixture, 1.22 g (3.5 mmol) of 7-(4-chlorobutyl)-9-isopropyl-1,1-dioxo-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione and 0.57 g (3.8 mmol) of sodium iodide were added, followed by stirring at 100° C. for 3 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate 3 times. The organic layer was washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=25/1) to yield 1.11 g (68.6%, white powder) of the desired product.