Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(CC)C.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH3:22])=[O:12])([CH3:9])([CH3:8])[CH3:7].CON(C)[C:26](=[O:30])[CH2:27][CH2:28][CH3:29]>C1CCCCC1.C1COCC1>[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH2:22][C:26](=[O:30])[CH2:27][CH2:28][CH3:29])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CCCC(=O)N(C)OC
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCCC(=O)Cc1c(NC(=O)OC(C)(C)C)cccc1OC
Temperature: -60 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A solution of 50 mL (65 mmol) of 1.3M sec-butyl lithium in cyclohexane was added slowly to N-tert-butoxycarbonyl-3-methoxy-2-methylaniline (7.7 g, 32.5 mmol) in 100 mL of THF keeping the temperature below −40° C. with a dry ice-ethanol bath. The bath was removed and the temperature allowed to rise to −10° C. and then the bath replaced. After the temperature said cooled to −60° C., 4.3 g (32.5 mmol) of N-methoxy-N-methylbutanamide in an equal volume of THF was added dropwise. The reaction mixture was stirred 1 hour, the cooling bath removed and stirred an additional 22 hours. It was then poured into a mixture of 200 mL of ether and 200 mL of 0.5N HCl. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated at reduced pressure to give 9.9 g of crude 1-[2-(tert-butoxycarbonylamino)-6-methoxyphenyl]-2-pentanone. This material was dissolved in 100 mL of methylene chloride and 20 mL of trifluoroacetic acid and stirred for a total of 23 hours. The mixture was washed with water, dried (MgSO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 2.19 g of 4-methoxy-2-propyl-1H-indole as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][C:19]([S:22](=[O:26])(=[O:25])[NH:23][CH3:24])=[CH:18][CH:17]=1.[OH-].[Na+]>CO.O>[CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][C:19]([S:22](=[O:26])(=[O:25])[NH:23][CH3:24])=[CH:18][CH:17]=1
Reactant: CNS(=O)(=O)c1ccc(C2Nc3ccc(C(=O)OC)cc3CC2(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNS(=O)(=O)c1ccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)cc1
Yield: 21.8 %

Procedure:
To a round bottom flask, a mixture of methyl 3,3-dimethyl-2-(4-(N-methylsulfamoyl) phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (190 mg, 0.49 mmol) in methanol (20 mL), and water (2 mL) was treated with a solution of sodium hydroxide (332 mg, 8.3 mmol) in water (3 mL). The resultant mixture was heated for reflux for 1.5 hours. The methanol was removed under vacuum. The residue was acidified with 2M hydrochloric acid to pH=5-6. The precipitates were collected by filtration, purified by preparative Thin layer chromatography (silica gel, petroleum ether/ethyl acetate=1:1) to afford 3,3-dimethyl-2-(4-(N-methylsulfamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (40 mg, yield: 21.9%). MS (ES+APCI) M+1=375.1.
Reaction SMILES: [ClH:1].[C:2]1([CH3:14])[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.O.[OH-].[Na+].[CH2:18]=O>C(O)=O>[ClH:1].[CH3:18][N:10]1[CH2:11][CH:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:14])=[CH:7][CH:6]=3)([CH2:13]2)[CH2:9]1
Reactant: Cc1ccc(C23CNCC2C3)cc1
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: Cc1ccc(C23CC2CN(C)C3)cc1

Procedure:
A mixture of 4.19 g. of 1-(p-tolyl)-3-azabicyclo[3.1.0]hexane hydrochloride and 20 ml. of water is made basic with sodium hydroxide. This mixture is extracted with ether and the ether is evaporated to give an oil. This oil is combined with 40 ml. of 97% formic acid and 35 ml. of 37% formaldehyde and the solution is heated on a steam bath for 2 hours. The solution is cooled, made basic with sodium hydroxide and extracted with ether. The extract is dried over magnesium sulfate, filtered, and the filtrate is saturated with hydrogen chloride. The precipitated crystals are collected and recrystallized from isopropyl alcohol to give 3-methyl-1-(p-tolyl)-3-azabicyclo[3.1.0]hexane hydrochloride as colorless crystals, m.p. 197°-198° C.
Reaction SMILES: FC(F)(F)C(O)=O.[I:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][NH:13][CH2:12]2.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>N1C=CC=CC=1>[I:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH2:12]2
Reactant: Ic1ccc2c(c1)CNC2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A mixture of the product of Step A (0.77 g; 2.15 mmol) and (BOC)2O (0.7 g; 3.2 mmol) in anhydrous pyridine (3 ml) was stirred for 1 h at ˜70° C. After removing solvents under reduced pressure, the residue was diluted to 20 ml with Et2O. The insoluble material was filtered off, and filtrate was washed with diluted HCl (5 ml), saturated NaHCO3 (5 ml), brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2; CH2Cl2:hexane 1:1) to give title compound (0.58 g; 78%) as creamy oil. 1H-NMR (CDCl3) 1.49 (5, 9H); 4.58-4.63 (m, 4H); 6.9-7.04 (m, 1H); 7.5-7.63 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][OH:21])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][O:21][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: OCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
In analogy to example 15.1, 4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol and methane sulfonyl chloride were converted to yield Methanesulfonic acid 4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl ester as a light yellow oil, MS: 391 (M, 1Cl).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[N:6]([C:7]2[S:8][C:9]3[CH2:15][CH2:14][O:13][C:12]4[CH:16]=[C:17]([CH:20]5[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]5)[CH:18]=[CH:19][C:11]=4[C:10]=3[N:33]=2)[C:5](=[O:34])[NH:4][C:3]1=[O:35]>FC(F)(F)C(O)=O.ClCCl>[NH:23]1[CH2:22][CH2:21][CH:20]([C:17]2[CH:18]=[CH:19][C:11]3[C:10]4[N:33]=[C:7]([N:6]5[C:2]([CH3:36])([CH3:1])[C:3](=[O:35])[NH:4][C:5]5=[O:34])[S:8][C:9]=4[CH2:15][CH2:14][O:13][C:12]=3[CH:16]=2)[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)OCCc2sc(N4C(=O)NC(=O)C4(C)C)nc2-3)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)NC(=O)N1c1nc2c(s1)CCOc1cc(C3CCNCC3)ccc1-2
Yield: 30 %

Procedure:
tert-Butyl 4-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-8-yl)-tetrahydropyridine-1(2H)-carboxylate was stirred in 50% trifluoroacetic acid in dichloromethane to give 514. Yield 30%. MS(ESI+):413.2. 1H NMR (500 MHz, DMSO) δ 8.23 (s, 1H), 8.17 (d, J=8.2, 1H), 7.02 (d, J=8.2, 1H), 6.85 (d, J=1.6, 1H), 4.30 (t, J=4.9, 2H), 3.22-3.20 (m, 3H), 2.88 (t, J=11.2, 2H), 2.75 (t, J=12.0, 1H), 1.89 (d, J=12.5, 2H), 1.67 (d, J=12.9, 7H)
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[O:11][CH:12]=[C:13]([F:15])[CH:14]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23].[B:26](OC(C)C)([O:31]C(C)C)[O:27]C(C)C.Cl>C1COCC1.C(OCC)C>[Si:5]([O:8][CH2:9][C:10]1[O:11][C:12]([Si:22]([CH3:25])([CH3:24])[CH3:23])=[C:13]([F:15])[C:14]=1[B:26]([OH:31])[OH:27])([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:7])[CH3:6]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(F)co1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1oc([Si](C)(C)C)c(F)c1B(O)O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 59.2 %

Procedure:
tert-Butyl-(4-fluorofuran-2-ylmethoxy)dimethylsilane (prepared according to Heffernan et al, US2008 0058395, 6.75 g) was dissolved in anhydrous THF (100 mL), under an atmosphere of nitrogen and cooled to −78° C. n-Butyllithium (2.5M in hexanes, 11.74 mL) was added and the mixture was stirred at −78° C. for 10 minutes. Chlorotrimethylsilane (3.19 g) was added and the mixture was stirred at −78° C. for 40 minutes. Further n-butyllithium (2.5M in hexanes, 11.74 mL) was added and the mixture was stirred at −78° C. for 40 minutes, before triisopropyl borate (11.04 g) was added. The resultant mixture was stirred at −78° C. for 5 minutes then allowed to warm to room temperature. 1M aqueous hydrochloric acid (100 mL) and diethyl ether (50 mL) were added and the mixture was stirred vigorously for 5 minutes. The layers were separated and the organic layer was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-20% to give 2-(tert-butyldimethylsilanyloxymethyl)-4-fluoro-5-trimethylsilanylfuran-3-yl-boronic acid (6.01 g) as a brown oil which was used without further characterisation.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3][CH2:2]1.[CH:18]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[CH2:19]>C(#N)C>[N:23]1[CH:24]=[CH:25][C:20]([CH2:18][CH2:19][N:3]2[CH2:2][CH2:1][C:6]3([CH2:11][CH2:10][CH:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:7]3)[CH2:5][CH2:4]2)=[CH:21][CH:22]=1
Reactant: C=Cc1ccncc1
Reactant: CCOC(=O)CC1CCC2(CCNCC2)CC1
Solvent: CC#N
Product: CCOC(=O)CC1CCC2(CC1)CCN(CCc1ccncc1)CC2

Procedure:
A solution of 0.48 g (2.0 mmol) of the intermediate from Example 1, Step C and 0.21 g (2.0 mmol) 4-vinylpyridine in 6 ml acetonitrile were heated at 80° C. over night. The solvent was removed under reduced pressure, and the remaining solid title compound was purified by stirring several times with tert.-butylmethylether, filtered with suction, and dried in vacuo.
Reaction SMILES: [K].[CH3:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9].[CH2:10](Cl)[CH:11]=[CH2:12]>O>[CH3:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:12][CH:11]=[CH2:10]
Reactant: COCCOCCO
Reactant: C=CCCl
Agent: [K]
Solvent: O
Product: C=CCOCCOCCOC
Temperature: 10 °C
Reaction time: 8 h

Procedure:
1,700 mls of dried peroxide free tetrahydrofuran, available from Fisher Scientific Company, 15 Jet View Drive, P.O. Box 8740, Rochester, NY 14624 and 158.7 g potassium metal, available from Fisher Scientific, are charged under dry nitrogen into a 5,000 ml three-neck round bottom flask equipped with mechanical stirrer. The solution is chilled to 10° C., using an icewater bath, and 494 ml of diethylene glycol monomethyl ether, available from Chemical Samples Company, 4692 Kenny Road, Columbus, OH 43221, is added dropwise. The potassium metal reacts within 24 hours at which time 350 mls of allyl chloride available from Aldrich, 159 Forest Street, Metuchen, NJ 08840, is added dropwise at such a rate to maintain a gentle reflux. After the reaction is allowed to continue overnight, one liter of distilled water is added to the reaction vessel to dissolve the precipitated salts. The tetrahydrofuran layer is washed three times with a salt water solution (270 g NaCl to 1 liter H2O) to remove excess alcohol. The tetrahydrofuran is removed with a water aspirator and the product is distilled at reduced pressure. 410 g of diethylene glycol allyl methyl ether is obtained (b.p. 109° C./30 mm). The analytical data is consistent with a product of the general formula:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: COc1ccc(O)c(Br)c1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOc1ccc(OC)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
A mixture of 2-bromo-4-methoxyphenol (available from Betapharma Inc.) (1.50 g, 7.39 mmol), 1-bromobutane (available from Aldrich) (0.95 mL, 8.87 mmol), and cesium carbonate (3.13 g, 9.60 mmol) in DMF (40 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 4.1 (1.49 g, 78% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.15 (d, J=2.7 Hz, 1H), 6.84 (d, J=9.0 Hz, 1H), 6.80 (dd, J=3.1, 9.0 Hz, 1H), 3.97 (t, J=6.5 Hz, 2H), 3.76 (s, 3H), 1.79 (m, 2H), 1.53 (m, 2H), 0.98 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[Cl:8][C:9](Cl)([O:11]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>C(OCC)C>[Cl:8][C:9]([O:5][CH:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])=[O:11]
Reactant: CC(O)C(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(OC(=O)Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a mixture of 1,1,1-trifluoro-2-propanol (114.1 mg, 1.0 mmol, Matrix Scientific) and triphosgene (98 mg, 0.33 mmol, Aldrich) in ethyl ether (10 mL) at −40° C. was added pyridine (80 μL, 1.0 mmol, EMD) in ethyl ether (1.0 mL) dropwise. The reaction mixture was warmed to 0° C. and stirred for 6 h. The flask containing the above reaction mixture was put into a refrigerator overnight and then filtered. The filtrate was concentrated in vacuo in ice both to give a colorless oil which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1[S:22]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:24])=[O:23]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cc(Cl)c(Cl)cc2Cl)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2,4,5-trichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (51.0 mg) with purity >90%. MS (pos) m/z 429.0. 431.0.
Reaction SMILES: [C:1]([NH:8][S:9]([C:12]1([CH:15]=O)[CH2:14][CH2:13]1)(=[O:11])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:17]([O-])([O-])=O.[K+].[K+].C/C(/[O-])=C(/P(OC)(OC)=O)\[N+]#N>CO>[C:1]([NH:8][S:9]([C:12]1([C:15]#[CH:17])[CH2:14][CH2:13]1)(=[O:11])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)C1(C=O)CC1
Agent: COP(=O)(OC)/C([N+]#N)=C(/C)[O-]
Agent: [K+]
Solvent: CO
Product: C#CC1(S(=O)(=O)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a stirred solution of compound 80 (230 mg, 0.92 mmol) in MeOH (5 mL) at 0° C. was added K2CO3 (255 mg, 1.84 mmol), and Ohira-Bestmann reagent (215 g, 1.10 mmol) (Tetr. Lett. 2008, 49, 4454). The mixture was stirred at room temperature for 16 hrs and was concentrated under reduced pressure. Water, EtOAc, and citric acid were added to bring pH to 4-5. Organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield compound 81 in 85% yield.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[CH2:12][C:13]1[C:14](=[O:19])[CH2:15][C@@H:16]([OH:18])[CH:17]=1)C1C=CC=CC=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CN=C1.[Si:45](Cl)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]>C(Cl)Cl>[Si:45]([O:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[CH2:12][C:13]1[C:14](=[O:19])[CH2:15][C@@H:16]([O:18][CH:28]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:17]=1)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C1=COCCC1
Reactant: O=C1C[C@@H](O)C=C1Cc1cccc(OCc2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(CC2=C[C@H](OC3CCCCO3)CC2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
(R)-2-(3-(benzyloxy)benzyl)-4-hydroxycyclopent-2-enone (0.5 g, 1.7 mmol) and dihydropyrane (0.34 g, 4 mmol) was dissolved in CH2Cl2 (5 ml), p-toluenesulfonic acid (0.2 g) was added to the solution at 10° C., and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was washed with sat. NaHCO3 aq., dried over MgSO4, and evaporated. The resulting residue was dissolved in EtOH (5 ml) under hydrogen, Pd/C (0.15 g) was added to the solution and the mixture was stirred at room temperature for 2 hrs. After the reaction was completed, the reaction mixture was filtered to remove the Pd/C and the filtrate was evaporated. The resulting residue was dissolved in EtOAc (5 ml), imidazole (0.24 g, 3.5 mmol) and tert-butyldimethylsilyl chloride (0.38 g, 2.55 mmol) was added to the solution and the mixture was stirred at 50° C. for 4 hrs. After the reaction was completed, the reaction mixture was filtered to remove the precipitate and washed with NaHCO3 and extracted with EtOAc. The organic layer was dried over MgSO4, and evaporated. The residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent to give (4R)-2-(3-(tert-butyldimethylsilyloxy)benzyl)-4-(tetrahydro-2H-pyran-2-yloxy)cyclopent-2-e none as yellow oil: 0.47 g (yield: 69%,)
Reaction SMILES: [C:1]1([N:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:19])[CH2:9][C:8]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21](O)C>>[C:1]1([N:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]([CH3:21])[C:10](=[O:19])[CH2:9][C:8]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Product: CN1C(=O)CC(=O)N(c2ccccc2)c2cc(Cl)ccc21

Procedure:
Starting from 1-phenyl 8-chloro 1,2,4,5-tetrahydro 2,4-dioxo 3H-1,5-benzodiazepine (obtained according to the example XI) and from a methyl halide, and operating according to the example X, there is obtained 1-phenyl 5-methyl 8-chloro 1,2,4,5-tetrahydro 2,4-dioxo 3H-1,5-benzodiazepine, melting at 166°-168° C after recristallisation in 50% ethanol.
Reaction SMILES: C(O)(C)(C)C.[Li].[CH3:7][C@:8]12[CH2:24][CH2:23][C@H:22]3[C@@H:13]([CH2:14][CH2:15][C:16]4[CH:17]=[C:18]([OH:25])[CH:19]=[CH:20][C:21]=43)[C@@H:12]1[CH2:11][CH:10]=[CH:9]2>C1COCC1.N.CO>[CH3:7][C@:8]12[CH2:24][CH2:23][C@H:22]3[C@@H:13]([CH2:14][CH2:15][C:16]4[C@@H:21]3[CH2:20][CH2:19][C:18](=[O:25])[CH:17]=4)[C@@H:12]1[CH2:11][CH:10]=[CH:9]2
Reactant: C[C@@]12C=CC[C@H]1[C@@H]1CCc3cc(O)ccc3[C@H]1CC2
Agent: N
Agent: [Li]
Solvent: CC(C)(C)O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@@H]3[C@H]1CC2
Reaction time: 8 h

Procedure:
To estra-1,3,5(10), 16-tetraene-3-methyl ether (551.5 mg., 2.055 mmol) in 8.6 ml of anhydrous THF, approximately 30 ml of anhydrous ammonia, and 6.76 g of t-butyl alcohol was added lithium wire (0.24 g, 35 mg-atom) cut in small pieces. The reaction mixture was refluxed 41/2 h under argon, after which methanol (2.3 ml) was added and the ammonia was allowed to boil off overnight. The residue was dissolved in 25 Ml of methanol and was acidified to approximately Ph 1 with 5N HCI. After heating in an oil bath between 55 and 70 C. for 15 min. the cooed hydrolysis mixture was partitioned between 25 ml of water and 50 ml of ethyl acetate and the aqueous phase was extracted with 25 ml of ethyl acetate. The combined organic extracts were washed with 25 ml of saturated sodium bicarbonate and 25 ml of brine, dried over magnesium sulfate, and filtered. Removal of solvent under reduced pressure yielded 0.57 g of oily residue which was purified by flash chromatography on silica gel (eluent: 15% ethyl acetate/hexane) followed by recrystallization from pentane to give crystals (206.1 mg, 39%) homogeneous to TLC, m.p. 67-71 C.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:14]=[CH:13]C(C)=[C:11]([F:16])[CH:10]=1.S(=O)(=O)(O)O>[O-2].[O-2].[O-2].[Cr+6].C(O)(=O)C>[Br:8][C:9]1[CH:14]=[CH:13][C:6]([CH:5]=[O:7])=[C:11]([F:16])[CH:10]=1
Reactant: Cc1ccc(Br)cc1F
Reactant: CC(=O)OC(C)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(=O)O
Product: O=Cc1ccc(Br)cc1F
Reaction time: 0.25 h

Procedure:
To a stirred mixture of glacial acetic acid (88 ml.), acetic anhydride (90 g.) and 4-bromo-2-fluorotoluene (10 g.) at -10° was added concentrated sulphuric acid (12 ml.) over 20 minutes, keeping the temperature around 0°. Solid chromium trioxide (14.7 g.) was added over 40 minutes keeping the temperature below 5°. The mixture was stirred for 15 minutes. The mixture was poured onto ice (300 g.) and stirred. The mixture was extracted with ether (2×300 ml.). The organic extracts were washed with 2% sodium carbonate solution (2×100 ml.). After evaporation the crude diacetate was treated with a mixture of water (30 ml.), ethanol (30 ml.) and conc sulphuric acid (3 ml.) and the mixture refluxed for 1 hour. After cooling the product was extracted into ether, dried and evaporated. Recrystallisation from hexane yielded the title product. Nuclear magnetic resonance (NMR) was as follows. 7.6, 3H, M; 10.0, 1H, s.
Reaction SMILES: [CH2:1]([C:10]1[C:15]2[N:16]3[CH2:22][CH2:21][CH2:20][N:19]=[C:17]3[S:18][C:14]=2[CH:13]=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[CH2:31]Cl>C(#N)C>[Cl-:23].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[CH2:31][N+:19]1[CH2:20][CH2:21][CH2:22][N:16]2[C:15]3[C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:11][CH:12]=[CH:13][C:14]=3[S:18][C:17]=12
Reactant: ClCc1c(Cl)cccc1Cl
Reactant: CCCCCCCCCc1cccc2c1N1CCCN=C1S2
Solvent: CC#N
Product: CCCCCCCCCc1cccc2c1N1CCC[N+](Cc3c(Cl)cccc3Cl)=C1S2
Product: [Cl-]

Procedure:
A mixture of 1.9 parts of 3,4-dihydro-6-nonyl-2H-pyrimido[2,1-b]benzothiazole, 3.4 parts of 1,3-dichloro-2-(chloromethyl)benzene and 24 parts of acetonitrile is stirred and refluxed for 8 hours. The reaction mixture is evaporated and the residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 2.8 parts of 1-(2,6-dichlorophenylmethyl)-3,4-dihydro-6-nonyl-2H-pyrimido[2,1-b]benzothiazolium chloride; mp. 174.6° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.Br[CH2:10][CH:11]1[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:10][CH:11]2[CH2:13][CH2:12]2)[CH:5]=[CH:4][N:3]=1
Reactant: BrCC1CC1
Reactant: Oc1ccnc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1cc(OCC2CC2)ccn1
Temperature: 120 °C
Yield: 69.1 %

Procedure:
To a solution of 2-bromopyridin-4-ol (1.6 g, 9.2 mmol) and (bromomethyl)cyclopropane (1.61 g, 12.0 mmol) in DMF (12 mL) in a microwave vial was added cesium carbonate (4.19 g, 12.9 mmol). The vial was sealed and heated in a microwave reactor at 120° C. for 4 h. The reaction mixture was cooled to room temperature, quenched with water and extracted with EtOAc (2×). The combined organics were washed with sat'd NaCl then dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (20-50% EtOAc/heptane) to give 1.45 g (69%) of 2-bromo-4-cyclopropylmethoxy-pyridine as a yellow oil.