Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:14].C(N(CC)CC)C.[CH2:22]([OH:26])[CH:23]([CH3:25])[CH3:24]>>[OH:13][C:12]1[C:3]([CH2:2][O:26][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:14])[CH2:7][CH2:6][CH2:5]2
Reactant: CC(C)CO
Reactant: O=C1CCCc2c1ccc(O)c2CCl
Solvent: CCN(CC)CC
Product: CC(C)COCc1c(O)ccc2c1CCCC2=O
Temperature: 108 °C

Procedure:
To a solution of 5-Chloromethyl-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one, prepared as described Chem. Pharm. Bull. 25(11)2988-3002(1077), (0.211 g, 0.001 mol) and triethylamine (0.167 ml, 0.0012 mol, Mallinckrodt) contained in a 16×125 mm screw top glass tube, was added isobutyl alcohol (3 ml, Aldrich Chemical). The tube was capped with a teflon lined cap and placed on an orbital mixing heat block at reflux temperature (˜108° C.) for 16 hrs. The reaction mixture was concentrated in vacuo to a pink-red syrup. On addition of ethyl ether, a pinkish solid precipitated from the syrup. Washed mixture with 5% citric acid, brine, and dried organic phase over anhydrous sodium sulfate. Evaporated mixture in vacuo to yield a red-pink powder, 0.210 g, 85% crude yield. Low resolution mass spectroscopy (APCI) 249 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4]([Cl:16])[C:3]=1[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:18](Cl)=[O:19].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>C(#N)C>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([CH:17]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([N:8]3[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]3)=[CH:5][C:4]=2[Cl:16])[C:18]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:19])=[CH:26][CH:25]=1
Reactant: O=C(Cl)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Reactant: C1CCNC1
Solvent: CC#N
Product: O=C(C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl)N1CCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 36.2 %

Procedure:
A mixture of 2.28 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetylchloride, 4,5 parts of pyrrolidine and 40 parts of acetonitrile was stirred for 17 hours at room temperature. After evaporation in vacuo, the residue was taken up in water and the mixture was acidified with hydrochloric acid. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was dried in vacuo for 48 hours at 110° C., yielding 0.8 parts (36.2%) of 1-[2-(4-chlorophenyl)-2-[2,6-dichloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)phenyl]acetyl]pyrrolidine; mp. 153.9° C. (intermediate 35).
Reaction SMILES: [C:1]([C:3]1([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=2[CH2:21][CH3:22])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)#[N:2].C(O)(=[O:25])C.S(=O)(=O)(O)O>O>[CH2:21]([C:13]1[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=1[C:3]1([C:1]([NH2:2])=[O:25])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[CH3:22]
Reactant: CCc1ccc([N+](=O)[O-])cc1C1(C#N)Cc2ccccc2C1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCc1ccc([N+](=O)[O-])cc1C1(C(N)=O)Cc2ccccc2C1
Temperature: 0 °C
Yield: 71 %

Procedure:
To a mixture of the compound (1.16 g) obtained in Example 25b and acetic acid (10 ml), water (2 ml) and concentrated sulfuric acid (20 ml) were added sequentially. The reaction mixture was heated under reflux for 13 h, cooled, put into ice water and subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (870 mg) (yield, 71%).
Reaction SMILES: S(Cl)(Cl)=O.CO.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1.[C:19]([O-])(O)=O.[Na+]>C(OCC)(=O)C>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:13]=1
Reactant: Nc1ccc(CCC(=O)O)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)CCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
Thionyl chloride (14.6 ml, 200 mmol, 3.3 equiv) was added dropwise to a solution of dry methanol (60 ml, 1453 mmol, 24 equiv) at −10° C. After stirring for 10 minutes, 3-(4-aminophenyl)propanoic acid (10.0 g, 61 mmol) was added to give a yellow suspension. The solution stirred for 1 hour and was slowly warmed to room temperature. The resulting solution was concentrated to give a yellow solid. The solid was suspended in ethyl acetate, and NaHCO3 (aq.) was added until the salt dissolved fully. Solid sodium bicarbonate was added to give pH 8.The layers were separated and the organics were washed with brine (aq.). The resulting solution was dried over MgSO4, filtered, and concentrated to give a yellow solid (10.6 g, 98%). 1H NMR (300 MHz, CDCl3) 7.00 (d, J=8.3 Hz, 2H), 6.63 (d, J=8.3 Hz, 2H), 3.67 (s, 3H), 3.59 (bs, NH2, 2H), 2.85 (t, J=7.6 Hz, 2H), 2.58 (t, J=8.3 Hz, 2H). 13C NMR (300 MHz, CDCl3) 173.8, 144.9, 130.7, 129.3, 115.5, 51.8, 36.4, 30.4. M.S. (ESI) m/z=180.102 (M+H).
Reaction SMILES: ClN1C(=O)CCC1=O.CSC.[OH:12][CH:13]([CH:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)[CH3:19])[CH2:14][C:15](=[O:17])[CH3:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:35][C:34]([F:36])([F:37])[C:31]1[CH:30]=[CH:29][C:28]([O:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][CH:18]([CH3:19])[C:13](=[O:12])[CH2:14][C:15](=[O:17])[CH3:16])=[CH:22][CH:23]=2)=[CH:33][CH:32]=1
Reactant: CC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CSC
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-chlorosuccinimide (0.40 g, 3 mmol) in toluene (10 ml) at -10° under argon is added dimethylsulfide (0.3 ml, 4 mmol). The mixture is cooled to -25°, and 4-hydroxy-5-[4-(4-trifluoromethylphenoxy)phenoxy]-2-hexanone (2 mmol) in several ml of toluene is added dropwise. After 2 hours at -25°, the mixture is cooled to -60°, and a solution of 0.31 g (3 mmol) of triethylamine in several ml of toluene is added dropwise. The reaction mixture is allowed to slowly warm to RT and is quenched by the addition of 5 ml of water. The mixture is poured into ether, and the organic fraction is then separated, washed with 5% HCl, water and brine, and dried over sodium sulfate. Solvent is removed and the residue is purified by prep. TLC to give 5-[4-(4-trifluoromethylphenoxy)phenoxy]-2,4-hexanedione (IX; Z is trifluoromethyl, Y is hydrogen, W is oxygen, R1 is methyl and R2 is methyl).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:16]([OH:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:50][O:51][C:52](=[O:77])[C@@H:53]([NH:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=1[C:69](=[O:76])[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[CH2:54][C:55]1[CH:60]=[CH:59][C:58](O)=[CH:57][CH:56]=1>C1COCC1>[CH3:50][O:51][C:52](=[O:77])[C@@H:53]([NH:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=1[C:69](=[O:76])[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[CH2:54][C:55]1[CH:56]=[CH:57][C:58]([O:18][CH:16]([C:3]2[C:2]([CH3:1])=[CH:11][C:10]3[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=3[CH:4]=2)[CH3:17])=[CH:59][CH:60]=1
Reactant: Cc1cc2c(cc1C(C)O)C(C)(C)CCC2(C)C
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(OC(C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1)Nc1ccccc1C(=O)c1ccccc1

Procedure:
A solution of 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-ethanol (184 mg; 0.75 mmol), triphenylphosphine (268 mg; 1.0 mmol), diethyl azodicarboxylate (0.161 ml; 1.0 mmol) and (2S)-2-((2-benzoylphenyl)amino)-3-(4-hydroxyphenyl)-propionic acid methyl ester (190 mg; 0.5 mmol) in THF (10 ml) was stirred at 0° C. for 1.5 hours and for 16 hours at room temperature. The reaction mixture was evaporated and the residue was purified on column chromatography using methylene chloride as eluent. Yield 118 mg.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:24][CH2:23][C@:12]34[C:13]5[C:14]6[O:22][C@H:11]3[C:10](=[O:25])[CH2:9][CH2:8][C@@:7]4([CH2:26][CH3:27])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[O:20]C)[CH2:3][CH2:2]1.Cl.N1C=CC=CC=1.N>O>[CH:1]1([CH2:4][N:5]2[CH2:24][CH2:23][C@:12]34[C:13]5[C:14]6[O:22][C@H:11]3[C:10](=[O:25])[CH2:9][CH2:8][C@@:7]4([CH2:26][CH3:27])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[OH:20])[CH2:2][CH2:3]1
Reactant: CC[C@@]12CCC(=O)[C@@H]3Oc4c(OC)ccc5c4[C@@]31CCN(CC1CC1)[C@@H]2C5
Agent: Cl
Agent: N
Solvent: O
Solvent: c1ccncc1
Product: CC[C@@]12CCC(=O)[C@@H]3Oc4c(O)ccc5c4[C@@]31CCN(CC1CC1)[C@@H]2C5

Procedure:
3.25 g (8.9 mMol) of the compound of example 1 and 10 g of pyridine hydrochloride are heated for 3 hours to 190° C., then taken up in water after cooling, rendered basic with conc. ammonia, and extracted three times with methylene chloride. Flash-chromatography with ethyl acetate/hexane 1:5 yields the title compound as colorless crystals. Recrystallization from ether/pentane yields an analysis-pure product: M.p.: 157°-158° C.
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC(CN3CCN(C(OC(C)(C)C)=O)CC3)=CC=2N=1.[O:31]1[CH2:36][CH2:35][N:34]([C:37]2[C:38]3[S:52][C:51]([CH2:53][N:54]4[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]4)=[CH:50][C:39]=3[N:40]=[C:41]([C:43]3[CH:44]=[N:45][C:46]([NH2:49])=[N:47][CH:48]=3)[N:42]=2)[CH2:33][CH2:32]1.[CH3:60][S:61]([CH2:64][C:65](O)=[O:66])(=[O:63])=[O:62]>>[NH2:49][C:46]1[N:47]=[CH:48][C:43]([C:41]2[N:42]=[C:37]([N:34]3[CH2:33][CH2:32][O:31][CH2:36][CH2:35]3)[C:38]3[S:52][C:51]([CH2:53][N:54]4[CH2:55][CH2:56][N:57]([C:65](=[O:66])[CH2:64][S:61]([CH3:60])(=[O:63])=[O:62])[CH2:58][CH2:59]4)=[CH:50][C:39]=3[N:40]=2)=[CH:44][N:45]=1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)cn1
Agent: CC(C)(C)OC(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CS(=O)(=O)CC(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
The HCl salt of 5-(4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (100 mg) was then reacted with methanesulfonylacetic acid via General Procedure B to generate 56 mg of 101. MS (Q1) 533.2 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Reaction time: 1.5 h
Yield: 57.1 %

Procedure:
Periodinane (36.1 g, 85.2 mmol) was added to 4-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (15.0 g, 65.5 mmol) in CH2Cl2 (230 mL) and stirred for 90 min. Diethyl ether (560 ml) was added and precipitates were removed by extraction with 10% Na2S2O3/saturated NaHCO3 (1:1, 350 mL). The organic layer was washed with 0.5 M NaOH solution and brine. The organic phase was dried and concentrated under reduced pressure to yield 4-(2-Oxo-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (8.50 g, 57%).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28](=[O:29])[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([NH:30][C:31](=[O:40])[CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:17][CH:18]=2)[C:13]1=[O:41])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28](=[O:29])[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([NH:30][C:31](=[O:40])[CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:17][CH:18]=2)[C:13]1=[O:41]
Reactant: COC(=O)CCCCC(=O)Nc1ccc2c3c(n(CCCNC(=O)OC(C)(C)C)c(=O)c2c1)-c1ccccc1C3=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)CCCCC(=O)Nc1ccc2c3c(n(CCCN)c(=O)c2c1)-c1ccccc1C3=O

Procedure:
Compound 21 (0.030 g, 0.053 mmol) was treated with trifluoroacetic acid (0.25 mL) in chloroform (3 mL) for 2 h at room temperature. The solvent was removed on a rotary evaporator and the residue was then basified with 2 N NH3 in methanol to get the free amine, which was purified by silica gel column chromatography, eluting with chloroform-methanol, 9.2:0.8, to yield the product 26 (0.015 g, 55%) as a red solid: mp 153-155° C. IR (KBr) 2947, 1739, 1705, 1693, 1661, 1570, 1530, 1431, 1197, 760, 665 cm−1; 1H NMR (CD3OD, 300 MHz) δ 8.51 (d, J=2.4 Hz, 1H), 8.34 (d, J=9.0 Hz, 1H), 7.70 (dd, J=2.4, J=9.0 Hz, 1H), 7.60 (t, J=9.0 Hz, 1H), 7.51 (m, 2H), 7.31 (m, 1H), 4.55 (t, J=4.5 Hz, 2H), 3.67 (s, 3H), 3.13 (m, 2H), 2.39 (m, 4H), 2.26 (m, 2H), 1.70 (m, 2H); 13C NMR (DMSO-d6, 125 MHz) δ 190.0, 173.3, 171.3, 162.3, 154.4, 138.3, 136.6, 134.2, 133.9, 130.9, 127.0, 125.6, 123.5, 123.4, 123.3, 122.5, 116.5, 107.2, 51.2, 42.1, 38.2, 36.0, 33.0, 30.9, 24.4, 24.0; ESIMS (m/z, relative intensity) 462 (MH+, 100); HRESIMS calcd for C26H27N3O5 462.2023 (MH+). found 462.2031 (MH+); HPLC purity: 98.5% (1% TFA in MeOH—H2O, 70:30).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]=[C:11]=[S:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.C([O:16][C:17](=O)[CH2:18][NH:19][CH3:20])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:17](=[O:16])[CH2:18][N:19]([CH3:20])[C:11]3=[S:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: S=C=Nc1ccc2c(c1)CCC2
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CC(=O)N(c2ccc3c(c2)CCC3)C1=S
Yield: 73.5 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 7.7 g of indan-5-yl-isothiocyanate, 6.7 g of sarcosine ethyl ester hydrochloride, 12 g of triethyl amine, and 300 mL of chloroform. Crystallization from ethyl acetate afforded the title compound (7.9 g) as a tan solid, m.p. 158-160° C. Anal. Calcd. for C13H14N2O S: C, 63.39; H, 5.73; N,11.37. Found: C, 63.30; H, 5.81; N, 11.31. Mass spectrum (EI, M.+) m/z 246.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][CH:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1B1OC(C)(C)C(C)(C)O1.Br[C:29]1[CH:48]=[CH:47][C:32]([O:33][CH2:34][C:35]2([CH3:46])[O:39][C:38]3=[N:40][C:41]([N+:43]([O-:45])=[O:44])=[CH:42][N:37]3[CH2:36]2)=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>>[F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][CH:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[C:29]1[CH:48]=[CH:47][C:32]([O:33][CH2:34][C:35]2([CH3:46])[O:39][C:38]3=[N:40][C:41]([N+:43]([O-:45])=[O:44])=[CH:42][N:37]3[CH2:36]2)=[CH:31][CH:30]=1
Reactant: CC1(COc2ccc(Br)cc2)Cn2cc([N+](=O)[O-])nc2O1
Reactant: CC(=O)NCC1CN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)NCC1CN(c2ccc(-c3ccc(OCC4(C)Cn5cc([N+](=O)[O-])nc5O4)cc3)c(F)c2)C(=O)O1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To an oven dried round bottom flask was charged N-{3-[3-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (78 mg, 0.2 mmol), 2-(4-Bromo-phenoxymethyl)-2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazole (prepared similarly as described by Sasaki, H. et al: Journal of Medicinal Chemistry (2006), 49(26), 7854-7860; 71 mg, 0.2 mmol), Ph(PPh3)4 (23 mg, 0.02 mmol) and K2CO3 (55 mg, 0.4 mmol). The flask was flushed with nitrogen and was added 3 mL degassed DMF/H2O (10/1, v/v). The resulting mixture was stirred at 80° C. for 3 hours before it was cooled down and partitioned into 50 mL EtOAc/50 mL water. The organic layer was washed with brine and dried over Na2SO4, concentrated, and purified by column chromatography (CH2Cl2/MeOH, v/v, 20:1 to 10:1) gave the titled compound (70 mg) as off-white solid. ESI MS m/z 526 (M+H). 1H NMR (400 MHz, CD3OD) δ 7.86 (s, 1H), 7.52-7.59 (m, 1H), 7.45-7.52 (m, 3H), 7.32-7.38 (m, 1H), 6.96-7.02 (m, 2H), 4.76-4.84 (m, 1H), 4.51 (d, J=6.8 Hz, 1H), 4.38 (d, J=6.8 Hz, 1H), 4.27 (d, J=6.8 Hz, 1H), 4.18 (d, J=6.8 Hz, 1H), 3.89 (s, 1H), 3.83 (dd, J=6.8, 9.2 Hz, 1H), 3.55-3.59 (m, 2H), 1.96 (s, 3H), 1.77 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][C:8]1([C:14]#[N:15])[CH:13]=[CH:12][CH2:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2]>O.CO.[Pd]>[C:1]([O:5][C:6](=[O:16])[CH2:7][C:8]1([C:14]#[N:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC1(C#N)C=CCC=C1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CC1(C#N)CCCCC1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 56.5 %

Procedure:
Added 5% Pd/C, 50% H2O catalyst (94.0 mg, 22.1 μmol) to a solution of (1-cyanocyclohexa-2,5-dienyl)acetic acid t-butyl ester (0.50 g, 2.3 mmol) in MeOH (10 mL). After shaking the reaction mixture under 20 psi H2 at room temperature for 18.5 hours, the pressure was slowly released. The reaction was filtered and concentrated under reduced pressure. Flash chromatography (SiO2, 1:3 hexane:CH2Cl2-100% CH2Cl2) afforded 0.29 g (56%) of product as an oil.
Reaction SMILES: C([Li])CCC.C[C:7](C)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][C:9](=[O:15])[CH2:10]P(=O)([O-])[O-].CCOCC.[CH:28]([C@H:30]1[C@H:37]([O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:36][C@H:35]2[C@@H:31]1[CH2:32][C:33](=[O:47])[O:34]2)=O>CCCCCC.C(O)(=O)C.O1CCCC1>[O:15]=[C:9]([CH2:8][CH2:7][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)/[CH:10]=[CH:28]/[C@H:30]1[C@H:37]([O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:36][C@H:35]2[C@@H:31]1[CH2:32][C:33](=[O:47])[O:34]2
Reactant: CC(C)(CC(=O)CP(=O)([O-])[O-])c1ccccc1
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: O=C(/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)CCc1ccccc1
Reaction time: 0.08 h

Procedure:
At 20° under argon, 20 ml. of a 2-molar butyllithium solution in hexane was added dropwise to a solution of 11.2 g. of dimethyl-2-oxo-4-phenylbutylphosphonate in 400 ml. of ether. The mixture was stirred for 5 minutes and then 600 ml. of ether was added thereto and the mixture again stirred for 5 minutes at 20°. Thereafter, a solution of 9.26 g. of (1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo[3,3,0]octan-3-one [J. Amer. Chem. Soc. 96, 5865 (1974)] in 150 ml. of tetrahydrofuran was added dropwise to this mixture, and the latter was agitated for 30 minutes at 20°. 6 ml. of glacial acetic acid was added thereto, and the mixture was evaporated under vacuum. The residue was taken up in 600 ml. of methylene chloride, shaken twice with respectively 100 ml. of saturated sodium bicarbonate solution, twice with respectively 100 ml. of water, dried over magnesium sulfate, and evaporated under vacuum. After recrystallization from isopropyl ether/methylene chloride, 11 g. of the title compound was obtained as colorless crystals; m.p. 119°-120°.
Reaction SMILES: [C:1]1([C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.I[CH2:31][CH2:32][CH2:33][O:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1.O>C1COCC1.CCCCCC>[C:19]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH2:31][CH2:32][CH2:33][O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ICCCOC1CCCCO1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2CCCOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 310 mg (1 mmol) of 1-triphenylmethylimidazole (K H. Buchel et al.; Drugs Made in Germany, 1972, 15, 77) in 12 ml of dry THF is cooled to 0° under nitrogen and treated with 0.647 ml (1.1 mmol) of 1.7 M solution of n-BuLi in hexane. The solution is stirred at room temperature for 1 hour, then recooled to 0° and treated with 405 mg (1.5 mmol) of 1-iodo-3-(tetrahydropyran-2-yloxy)propane dissolved in 2 ml of dry THF. The reaction mixture is allowed to warm to room temperature overnight, then poured into water and extracted with ethyl acetate. The organic extract is rinsed with brine and dried (MgSO4). Removal of solvents in vacuo affords the title A compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10](Cl)=[O:11].[Cl:13][C:14]1[C:19]([NH2:20])=[C:18]([Cl:21])[N:17]=[CH:16][N:15]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([NH:20][C:19]1[C:14]([Cl:13])=[N:15][CH:16]=[N:17][C:18]=1[Cl:21])=[O:11]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: O=C(Cl)Cc1c(Cl)cccc1Cl
Product: O=C(Cc1c(Cl)cccc1Cl)Nc1c(Cl)ncnc1Cl
Temperature: 130 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a mixture of 2,6-dichlorophenyl acetic acid (100 g, 487 mmol) and DMF (1.5 mL) in toluene (600 mL) was added thionyl chloride (116 g, 974 mmol). The resulting mixture was stirred at rt. After 12 h, the solution was concentrated to provide 2,6-dichloro-phenylacetyl chloride as colorless oil. MS (ESI): mass calcd. for C8H5Cl3O, 221.94; m/z found, 223.0 [M+H]+. 1H NMR (CDCl3): 7.33 (d, J=8.1 Hz, 2H), 7.29-7.24 (m, 1H), 4.56 (s, 2H). A suspension of the crude 2,6-dichloro-phenylacetyl chloride and 4,6-dichloro-pyrimidin-5-ylamine (76 g, 463 mmol) was heated neat to 130° C. After 1 h, the resulting solid was cooled, collected by filtration, and washed with cold MeOH (400 mL) to provide the title compound as a solid (135 g, 84%). MS (ESI): mass calcd. for C12H7Cl4N3O, 348.9; m/z found, 350.0 [M+H]+. 1H NMR ((CD3)2SO): 10.59 (s, 1H), 8.86 (s, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.37-7.33 (m, 1H), 4.13 (s, 2H).
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:29]3[CH2:35][CH2:34][CH2:33][N:32]([CH3:36])[CH2:31][CH2:30]3)=[O:28])[CH2:10]2)=CC=1.FC(F)(F)C(O)=O.[F:46][C:47]([F:53])([F:52])[S:48]([OH:51])(=[O:50])=[O:49]>C1(OC)C=CC=CC=1>[F:46][C:47]([F:53])([F:52])[S:48]([OH:51])(=[O:50])=[O:49].[F:46][C:47]([F:53])([F:52])[S:48]([OH:51])(=[O:50])=[O:49].[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27]([N:29]2[CH2:35][CH2:34][CH2:33][N:32]([CH3:36])[CH2:31][CH2:30]2)=[O:28])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCCN(C)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CN1CCCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
620 mg of (2S, 4S)-4-(4-methoxybenzylthio)-2-(4-methyl-1-homopiperazinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 5) were suspended in 1.23 ml of anisole, and the suspension was placed on an ice bath. Whilst the suspension was still on the ice bath, 6.2 ml of trifluoroacetic acid and 200 μl of trifluoromethanesulfonic acid were added to it, and the resulting mixture was stirred for 1 hour at room temperature. At the end of this time, the mixture was treated in a similar manner to that described in Example 1(1), to give 640 mg of the title compound.