Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)O)=[CH:4][CH:3]=1.C[Si](I)(C)C.[I-].[Na+].Cl[Si](C)(C)C.[OH-].[Na+]>C(#N)C.ClCCl.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:10]2[S:14][CH:13]=[N:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)c1cncs1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)I
Agent: [I-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Fc1ccc(Cc2cncs2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
(4-Fluorophenyl)(thiazol-5-yl)methanol from step (i) was reduced with trimethylsilyliodide using a slight modification of published procedure (See reference: Tetrahedron 1995, 51 (41), 11043-11062.) A dry three-necked flask equipped with an addition funnel and a nitrogen inlet was charged with sodium iodide (6.78 g, 47.8 mmol) and acetonitrile (10 mL). Then, chlorotrimethylsilane (6.0 mL, 48 mmol) was added via syringe and the reaction mixture was allowed to stir at ambient temperature for about 15 min. At that time, the bright yellow mixture was cooled to 0° C. and a solution of (4-fluorophenyl)(thiazol-5-yl)methanol (2.00 g, 9.56 mmol) in acetonitrile (40 mL) and dichloromethane (50 mL) was added dropwise over the course of an hour. The reaction mixture was allowed to warm to room temperature over 16 h and then heated to 40° C. for 72 h. Then the solution was cooled back down to 5° C. for work-up. A solution of NaOH (5 N, 10 mL, 50 mmol) was added and the reaction mixture cooled to rt before it was diluted with EtOAc and stirred for an additional 10 min. The layers were separated and the aqueous layer extracted with another portion of EtOAc. The combined organic layers were washed with a solution of saturated aqueous Na2S2O3.5H2O, water, and brine, dried over MgSO4, and concentrated. The resulting residue was purified by flash chromatography, eluting with 10-30% EtOAc/hexanes to afford the product (1.26 g, 6.50 mmol, 68% yield). MS (M+H)+ 194.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:10]1[N:11]=[C:12]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[S:13][CH:14]=1)[C:7]([OH:9])=O)[C:2]#[CH:3].C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[NH2:33][CH:34]1[C:59](=[O:60])[N:36]2[C:37]([C:56]([OH:58])=[O:57])=[C:38]([CH2:41][S:42][C:43]3[N:47]([CH2:48][C:49]([C:53]([OH:55])=[O:54])=[N:50][O:51][CH3:52])[N:46]=[N:45][N:44]=3)[CH2:39][S:40][C@H:35]12.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O1CCCC1.O.CC(C)=O.CN(C)C=O>[CH2:1]([O:4][N:5]=[C:6]([C:10]1[N:11]=[C:12]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[S:13][CH:14]=1)[C:7]([NH:33][CH:34]1[C:59](=[O:60])[N:36]2[C:37]([C:56]([OH:58])=[O:57])=[C:38]([CH2:41][S:42][C:43]3[N:47]([CH2:48][C:49]([C:53]([OH:55])=[O:54])=[N:50][O:51][CH3:52])[N:46]=[N:45][N:44]=3)[CH2:39][S:40][C@H:35]12)=[O:9])[C:2]#[CH:3]
Reactant: C#CCON=C(C(=O)O)c1csc(NC(=O)C(F)(F)F)n1
Reactant: CON=C(Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1)C(=O)O
Agent: C[N+](C)=CCl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=NOC)C(=O)O)CS[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
2-(2-Propynyloxyimino)-2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]acetic acid (syn isomer) (1.05 g) was added at 0° C. to vilsmeier reagent which had been prepared from N,N-dimethylformamide (0.31 g) and phosphoryl chloride (0.65 g) in ethyl acetate (1.2 ml) and tetrahydrofuran (7.4 ml), and the mixture was stirred at the same temperature for 30 minutes to afford the activated solution. The activated solution was added dropwise at -5° to 0° C. to a solution of 7-amino 3-[1-(2-carboxy-2-methoxyiminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (1.40 g) in water (10 ml) and acetone (8 ml), adjusted to pH 8.0 with sodium bicarbonate and the mixture was stirred at the same temperature for 35 minutes. To the resultant mixture was added ethyl acetate (10 ml), and the aqueous layer was separated from the mixture. To the aqueous solution was added ethyl acetate (70 ml) and the mixture was adjusted to pH 1.8 with 10% hydrochlonic acid with stirring, and the ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated. The residue was pulverized with diisopropyl ether to give 7-[2-(2-propynyloxyimino)-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-[1-(2-carboxy-2-methoxyiminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer: in the 7-position) (2.05 g).
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12]CO)([CH3:4])([CH3:3])[CH3:2].C([Si](C)(C)OCCCCC#CCOC(=O)C)(C)(C)C.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:1]([Si:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12])([CH3:15])[CH3:16])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCCC#CCO
Agent: CC(=O)OCC#CCCCCO[Si](C)(C)C(C)(C)C
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: C#CCCCCO[Si](C)(C)C(C)(C)C
Reaction time: 18 h

Procedure:
7-(tert-Butyl-dimethyl-silanyloxy)-hept-2-yn-1-ol (27); and Acetic acid 7-(tert-butyl-dimethyl-silanyloxy)-hept-2-ynyl ester (28, FIG. 4). A solution of 7-(tert-Butyl-dimethyl-silanyloxy)-hept-2-yn-1-ol (27) (4.507 g, 21 mmol) in pyridine (20 mL) was treated with acetic anhydride (3.0 mL, 31.8 mmol). After 18 hours, the solvent was evaporated and the residue co-evaporated with toluene. The residue was used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH3:18].[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>CN(C=O)C.C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][C:14]1[N:15]=[CH:16][NH:17][C:13]=1/[CH:12]=[C:5]1\[C:6](=[O:11])[NH:7][C:8]2[C:4]\1=[CH:3][C:2]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:10][CH:9]=2
Reactant: C#C[Si](C)(C)C
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(C#C[Si](C)(C)C)cc21
Temperature: 90 °C

Procedure:
(Z)-5-Bromo-1,3-dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (0.17 g, 0.56 mmol) (from Example 99) was dissolved in 3 mL DMF and 3 mL triethylamine. The solution was degassed for 30 minutes by bubbling argon through the solution. At this time (trimethylsilyl)acetylene (0.3 mL, 2.1 mmol) (Aldrich), CuI (34 mg) (Aldrich) and (Ph3P)2PdCl2 (34 mg) (Aldrich) were added and the reaction flask sealed. The reaction was heated, under argon, at 90° C. for 18 hours. After cooling, the mixture was filtered through Celite® (Fisher Scientific) and residue washed extensively with hot EtOAc and CH3CN. Combined filtrate and washing was concentrated under reduced pressure and the product was purified via flash column chromatography (SiO2, 230-400 mesh) with 5% MeOH in CH2Cl2. (Yield 0.1 g, 56%).
Reaction SMILES: [NH:1]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[CH2:9][CH2:8]2)[C:2]1=[O:18].[H-].[Na+].S(OCC)(O[CH2:25][CH3:26])(=O)=O.Cl>CN(C)C=O>[CH2:25]([N:1]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[CH2:9][CH2:8]2)[C:2]1=[O:18])[CH3:26]
Reactant: O=C1CCC2(CCC(=O)c3ccccc32)C(=O)N1
Reactant: CCOS(=O)(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)CCC2(CCC(=O)c3ccccc32)C1=O
Reaction time: 0.08 h
Yield: 128.8 %

Procedure:
To 24.3 grams (0.1 M) of 2,3-dihydrospiro-[naphthalene-1(4H),3'-piperidine]-2',4,6'-trione in 300 milliliters of dry dimethylformamide maintained under nitrogen atmosphere was added with stirring 4.37 grams (0.1 M) of a 55 per cent suspension of sodium hydride in mineral oil. After stirring for five minutes, 16.0 grams (0.1 M) of diethyl sulfate were added in one portion. The slightly exothermic reaction mixture was allowed to stir for a short time and concentrated hydrochloric acid was added dropwise until the reaction mixture was slightly acidic. The reaction solvent was removed under reduced pressure at steam bath temperature and the resulting oil extracted into ether. The ether extracts were washed with 5 percent sodium hydroxide solution, water, and then dried (MgSO4). After filtration, the ether was removed, leaving a residue, which was recrystallized from diethyl ether to give 34.9 grams (64%) of 1'-ethyl-2,3-dihydrospiro-[naphthalene-1(4H),3'-piperidine]-2',4,6'-trione, melting point 85.5°-89° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[N:9][C:8]([C@@H:20]([NH:22][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][N:27]3C1CCCCO1)[CH3:21])=[C:7]2[F:38]>Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][CH2:13][N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[N:9][C:8]([C@@H:20]([NH:22][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][NH:27]3)[CH3:21])=[C:7]2[F:38]
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc(CCN2CCOCC2)c2c(Cl)cccc2c1F
Agent: Cl
Solvent: CO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc(CCN2CCOCC2)c2c(Cl)cccc2c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of N—((S)-1-(8-chloro-4-fluoro-1-(2-morpholinoethyl)isoquinolin-3-yl)ethyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine 84 (60 mg, 0.11 mmol) in hydrogen chloride/methanol solution (4 N, 20 mL) was stirred at RT for 0.5 h and then concentrated in vacuo. The residue was suspended in water (20 mL), neutralized with concentrated ammonium hydroxide to adjust the pH to 8-9 and then extracted with DCM (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (2-10% MeOH-DCM) to afford the product (S)—N-(1-(8-chloro-4-fluoro-1-(2-morpholinoethyl)isoquinolin-3-yl)ethyl)-9H-purin-6-amine 85. ESI-MS m/z: 456.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH2:4][N:18]1[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]1
Reactant: O=Cc1ccc(N2CCCC2)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N3CCCC3)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
A 100 mL round-bottom flask was charged with 2-chloro-4-(pyrrolidin-1-yl)benzaldehyde (0.600 g, 2.86 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (0.590 g, 3.15 mmol, 1.10 equiv), 1,2-dichloroethane (15 mL). The mixture was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (1.80 g, 8.49 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with H2O (10 mL), extracted with dichloromethane (3×10 mL). The organic layers were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide 0.900 g (83% yield) of tert-butyl 4-[[2-chloro-4-(pyrrolidin-1-yl)phenyl]methyl]piperazine-1-carboxylate as colorless oil. LCMS (ESI, m/z): 380 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:31]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:32])[C:22]=2[N:21]=[C:20]1[CH2:33][CH2:34][CH2:35][CH3:36]>>[NH2:32][C:23]1[C:22]2[N:21]=[C:20]([CH2:33][CH2:34][CH2:35][CH3:36])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][NH:14][S:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)(=[O:12])=[O:11])[C:31]=2[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:24]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1

Procedure:
According to the general method of Example 5, 3-nitrobenzenesulfonyl chloride and 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine were combined. N1-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-nitro-1-benzenesulfonamide was isolated as the hydrochloride salt (white solid), m.p. 176.0–178.2° C. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (very broad s, 2H), 8.49–8.42 (m, 2H), 8.21–8.17 (m, 2H), 8.06 (t, J=5.7 Hz, 1H), 7.88–7.81 (m, 2H), 7.71 (t, J=7.7 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 4.56 (t, J=7.3 Hz, 2H), 2.94 (t, J=7.7 Hz, 2H), 2.86 (m, 2H), 1.81 (m, 4H), 1.60–1.42 (m, 4H), 0.96 (t, J=7.3 Hz, 3H); IR (KBr) 3096, 2954, 2869, 2771, 1671, 1607, 1528, 1351, 1335, 1163, 1128, 1083, 879, 758, 735, 672, 661 cm−1; MS (EI) m/e 496.1897 (496.1893 calcd for C24H28N6O4S). Anal calcd for C24H28N6O4S*HCl*H2O: C, 52.31; H, 5.67; N, 15.25. Found: C, 52.26; H, 5.46; N, 15.09.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(C)(C)C.C(N(CC)CC)C.Cl.[NH:29]1[CH2:34][CH2:33][CH:32]([O:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:31][CH2:30]1>C(OCC)(=O)C.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([N:29]1[CH2:30][CH2:31][CH:32]([O:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:33][CH2:34]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)COC1CCNCC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)COC1CCN(C(=O)[C@H](C)NC(=O)OC(C)(C)C)CC1
Temperature: 2.5 °C
Yield: 95.4 %

Procedure:
47.3 g (250 mmol) of (S)-2-tert.-butoxycarbonylamino-propionic acid (Fluka) were dissolved in 560 ml of ethyl acetate (Fluka) while stirring and under argon, cooled to 0-5° C. and treated with 31.0 ml (250 mmol) of pivaloyl chloride (d=98; Fluka). The light yellowish solution was treated dropwise within 30 minutes with 35.0 ml (250 mmol) of triethylamine (d=0.726; Fluka), with the temperature being held in the range of 0-5° C. A white suspension formed. The white precipitate was filtered off through a pre-cooled, sintered glass filter (G3) and the filter cake was washed with 140 ml of cold ethyl acetate (0 to 5° C.). To the combined filtrates, a light yellow solution, were added 55.9 g (17. HCl; 250 mmol) of ethyl (piperidin-4-yloxy)-acetate hydrochloride and 66.6 g of K3PO4.3H2O (250 mmol; Merck). The white suspension was treated with 500 ml of deionised water at 5 to 10° C. under argon and while stirring vigorously, with the temperature rising to 20° C. The colourless two-phase system was stirred at 20 to 25° C. for two hours. The aqueous phase was separated and the organic phase was washed with 500 ml of a 1M sodium bicarbonate solution. The organic phase was dried over about 50 g of sodium sulphate, filtered and the filter cake was washed with about 100 ml of ethyl acetate. The combined filtrates were evaporated in a rotary evaporator at 50°/20 mbar, giving 85.5 g (95 wt. %) of ethyl (S)-[1-(2-tert.-butoxycarbonylamino-propionyl)-piperidin-4-yloxy]-acetate as a crude product in the form of a clear, yellowish oil (HPLC analysis: 88.9% (area).
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4]>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Pd+2].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P(=O)(O)(O)O.O1CCOCC1>[CH3:5][C:3]([CH2:2][CH:1]=[CH:1][CH:2]=[C:3]([CH3:5])[CH3:4])=[CH2:4]
Reactant: C=CC(=C)C
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)/C=C(/C)[O-]
Solvent: C1COCCO1
Product: C=C(C)CC=CC=C(C)C
Reaction time: 50 h

Procedure:
50 ml of distilled isoprene, 1 kg of dioxane, 5 g (16.5 mmol) of palladium acetylacetonate, 23.1 g (82.5 mmol) of tricyclohexylphosphine and 1.9 g (16.5 mmol) of 85% phosphoric acid in a four-necked flask are held under reflux under an argon atmosphere until the internal temperature exceeds 90°C. 1 kg of isoprene is then added dropwise at an oil-bath temperature of 120°C in such a manner that the internal temperature does not fall below 88°C (ca 30 ml/hour) but remains in the range of 90°-95°C. After 50 hours, the isoprene addition is terminated, the product now consisting essentially of 2,7-dimethyl-1,3,7-octatriene. The mixture is left to react for a further 40 hours, the internal temperature rising to 105°-108°C. The dioxane is now removed on a rotary evaporator at 40°C/20 mm Hg. The black-coloured residual oil is steam-distilled, 780 g of distillate being obtained. The residue (trimers and polymers) amounts to 215 g. By fractional distillation of the oil on a Raschig-ring column at 63°C/10 mm Hg, there are obtained 550 g of 2,7-dimethyl-1,4,6-octatriene; nD20 =1.4885. Odour: fatty, green, soapy, terpene-like.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:15].CC(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C.[C:39]([O:43][C:44](=[O:65])[NH:45][CH2:46][C:47]1[CH:64]=[CH:63][C:50]2[N:51]([CH2:56][CH2:57][CH2:58][S:59]([CH3:62])(=[O:61])=[O:60])[C:52]([CH2:54]Cl)=[N:53][C:49]=2[CH:48]=1)([CH3:42])([CH3:41])[CH3:40]>C1COCC1>[C:39]([O:43][C:44](=[O:65])[NH:45][CH2:46][C:47]1[CH:64]=[CH:63][C:50]2[N:51]([CH2:56][CH2:57][CH2:58][S:59]([CH3:62])(=[O:60])=[O:61])[C:52]([CH2:54][N:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:13](=[O:14])[N:4]([CH2:3][C:2]([F:1])([F:16])[F:17])[C:5]3=[O:15])=[N:53][C:49]=2[CH:48]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: O=c1[nH]c2ccccc2c(=O)n1CC(F)(F)F
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)nc(CCl)n2CCCS(C)(=O)=O
Agent: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc2c(c1)nc(Cn1c(=O)n(CC(F)(F)F)c(=O)c3ccccc31)n2CCCS(C)(=O)=O
Temperature: 23 °C
Reaction time: 12 h
Yield: 17.8 %

Procedure:
A slurry of 3-(2,2,2-trifluoro-ethyl)-1H-quinazoline-2,4-dione (88 mg, 0.36 mmol) in THF (20 ml) was treated with BTPP (0.33 ml, 1.08 mmol) and stirred for 15 min at 23° C. [2-Chloromethyl-1-(3-methanesulfonyl-propyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (150 mg, 0.36 mmol) was added and the mixture stirred at 23° C. for 12 h. The solvent was removed and the residue triturated with water. The residue was chromatographed to give 40 mg (18%) of [2-[2,4-dioxo-3-(2,2,2-trifluoro-ethyl)-3,4-dihydro-2H-quinazolin-1-ylmethyl]-1-(3-methanesulfonyl-propyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH2:7][C:8]1[S:9][C:10]([CH3:17])=[CH:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14]>N1C=CC=CC=1>[C:13]([C:12]1[CH:11]=[C:10]([CH3:17])[S:9][C:8]=1[NH:7][C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:5])([O:15][CH3:16])=[O:14]
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)c1cc(C)sc1N
Solvent: c1ccncc1
Product: COC(=O)c1cc(C)sc1NC(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
Cyclopropanecarboxylic acid chloride (10.9 g, 0.105 mol) was added dropwise during 40 min. to a stirred solution of methyl 2-amino-5-methyl-3-thiophene-carboxylate (prepared by the method of Gewald, Chemische Berichte, 99, 94, (1966)), (17.1 g, 0.1 mol) in anhydrous pyridine (100 ml) kept at 0° C. The reaction mixture was stirred below 10° C. for the next 4 hours, at room temperature overnight, and finally under reflux for 1.5 hours. The excess of pyridine was evaporated under reduced pressure and the residue was dissolved in CHCl3 (200 ml) and extracted in turn with 2N--HCl, H2O, 2N--NaOH and H2O. The dried (Na2SO4) organic solution was evaporated and the residue was recrystallised from EtOH to yield the amide as yellow crystals (11.1 g, 46%), m.p. 121°-123° C.
Reaction SMILES: F[C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:26])[CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:5].[C:31](C1C=CC(C(Cl)=O)=CC=1)#[N:32]>>[C:31]([C:29]1[CH:28]=[CH:27][C:3]([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][C:13](=[O:26])[CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[O:5])=[CH:2][CH:30]=1)#[N:32]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: O=C(CNC(=O)OCc1ccccc1)Nc1ccccc1C(=O)c1ccccc1F
Product: N#Cc1ccc(C(=O)c2ccccc2NC(=O)CNC(=O)OCc2ccccc2)cc1
Yield: 76 %

Procedure:
According to the method used for the synthesis of the compound 28a, the titled compound (551 mg) is synthesized by using tert-butyl((2-trimethylstannylphenyl)-(2-(3-m-tolylureido)acethyl)amino)acetate (1.0 g) and 4-cyanobenzoylchloride (289 mg). Yield 76%.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:12][O:13][C:14]1[CH:15]=[C:16](OB(O)O)[CH:17]=[CH:18][CH:19]=1>>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(OB(O)O)c1
Reactant: Brc1cnc2ccccc2c1
Product: COc1cccc(-c2cnc3ccccc3c2)c1
Reaction time: 19 h
Yield: 70 %

Procedure:
The compound is prepared by the reaction of 3-bromoquinoline (200 mg, 0.96 mmol, 1.06 eq) and 3-methoxyphenylboric acid (138 mg, 0.91 mmol, 1 eq) according to method A in 19 h. Purification by column chromatography with a mixture of hexane/ethyl acetate 3/1 yields the desired product in a yield of 70% (147 mg).
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=O)(C)C.CCN=C=NCCCN(C)C.[CH:28]1[CH:29]=[CH:30][C:31]2N(O)N=[N:34][C:32]=2[CH:33]=1.NC1C=CC=CC=1>CN(C=O)C.CCOCC>[C:32]1([NH:34][C:14]([CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[O:16])[CH:33]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Nc1ccccc1)C1CNCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 135.6 %

Procedure:
To a stirred solution of 4-{[(1,1-dimethylethyl)oxy]carbonyl}-2-morpholinecarboxylic acid (500 mg, 2.16 mmol) in dry DMF (2 mL) at 0° C. were added EDCI (456 mg, 2.38 mmol), HOBT (331 mg, 2.16 mmol) and aniline (0.22 mL, 2.38 mmol). The solution was stirred at room temperature overnight. The solvent was evaporated and the resulting residue was poured onto water and extracted with EtOAc (2×) and CH2Cl2 (2×). The combined organics were washed with brine and dried (MgSO4), filtered and evaporated. To this crude material dissolved in CH2Cl2/CH3OH (3 mL/0.3 mL) was added TFA (1.5 mL), and the reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated and dried in vacuo to afford a light brown oil. Et2O and hexanes were added and a precipitate crashed out. The mixture was sonicated and filtered to afford the title compound (604 mg). LC-MS (ES) m/z=207 [M+H]+.