Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=3[CH3:22])[C:6]=2[CH:5]=[C:4]([NH2:23])[CH:3]=1.[OH-].[Na+].Br[CH2:27][CH2:28][O:29][CH2:30][CH2:31]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[C:13]=3[CH3:22])[C:6]=2[CH:5]=[C:4]([N:23]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:3]=1
Reactant: Cc1c(Cn2cnc3c(Br)cc(N)cc32)cccc1C(F)(F)F
Reactant: BrCCOCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Product: Cc1c(Cn2cnc3c(Br)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Temperature: 110 °C
Yield: 18.9 %

Procedure:
Into a 100 ml round bottomed flask with 4-bromo-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-amine (2.28 g, 5.93 mmol), tetrabutylammonium iodide (0.110 g, 0.297 mmol) was added 6N sodium hydroxide (14.84 ml, 89 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (1.480 ml, 11.87 mmol). The reaction was heated to 110° C. for 2 h, cooled to room temperature and the mixture was extracted with EtOAc. The combined organic phase was washed with Brine (20 mL) and concentrated. The residue was purified on a silica gel cartridge and eluted with a gradient of 0% ethyl acetate/hexanes to 80% over 10 column volumes. The appropriate fractions were collected and evaporated to yield 4-(4-bromo-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-yl)morpholine (508 mg, 1.118 mmol, 18.84% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.40 (s, 3H) 3.00-3.09 (m, 4H) 3.76-3.81 (m, 4H) 5.26 (s, 2H) 6.54 (d, J=2.02 Hz, 1H) 6.85 (d, J=7.58 Hz, 1H) 7.13-7.21 (m, 2H) 7.57 (d, J=7.83 Hz, 1H) 7.68 (s, 1H); LC/MS: MS (ES+) m/e 455 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]2)[CH2:3][CH2:4][CH2:5][N:6]([CH2:10][CH2:11][Cl:12])[CH2:7][CH2:8][Cl:9].[BH4-].[Na+].Cl.[OH-].[Na+]>CO.O>[OH:1][CH:2]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]2)[CH2:3][CH2:4][CH2:5][N:6]([CH2:10][CH2:11][Cl:12])[CH2:7][CH2:8][Cl:9]
Reactant: O=C1CCc2cc(C(=O)CCCN(CCCl)CCCl)ccc2N1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1CCc2cc(C(O)CCCN(CCCl)CCCl)ccc2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.5 Grams of 6-{1-oxo-4-[di-(2-chloroethyl)-amino]butyl}-3,4-dihydrocarbostyril was dissolved in 80 ml of methanol, with stirring at a room temperature condition 1.6 g of sodium borohydride was added gradually to the mixture in 15 minutes and further stirred at a room temperature for 2 hours. To the reaction mixture was added 5 ml of concentrated hydrochloric acid was added and the reaction mixture was concentrated under a reduced pressure to dryness. The residue thus obtained was dissolved in 10 ml of water, the pH of the solution was adjusted to 6-7 by adding 2N-sodium hydroxide aqueous solution and stirred to precipitate crystals. The crystals were collected by filtration washed with water and dried to obtain 1.4 g of 6-{1-hydroxy-4-[bis(2-chloroethyl)amino]-butyl}-3,4-dihydrocarbostyril in colorless powdery product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH3:14]O>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:10][CH3:14])=[O:9])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: CO
Product: COC(=O)c1cccc(S(C)(=O)=O)c1
Yield: 99 %

Procedure:
To a stirred solution of 3-(methylsulfonyl)benzoic acid (1) (1.5 g, 7.5 mmol) in methanol (25 mL) sulfuric acid (1.5 mL) was added and the reaction mixture was heated to reflux for 8 h. On completion, solvent was removed, diluted with water (40 mL) and extracted with ethyl acetate (60 mL×3). The combined organic layer was washed saturated sodium bicarbonate solution, brine, dried over sodium sulphate and concentrated to afford the title compound 2 (1.6 g, 99%) which was used for further reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15][CH3:16])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[NH:20][NH2:21]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(O)C>[CH2:24]([O:23][C:19]([NH:20][N:21]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][S:15][CH3:16])=[CH:10][CH:9]=1)[C:5]1[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)NN
Reactant: CSCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CCOC(=O)NN=C(c1ccc(Cl)cc1)c1ccc(CSC)cc1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
An ethanol solution (100 ml) of 4-chloro-4'-methylmercaptomethylbenzophenone (8.3 g), ethyl carbazate (10 g) and pyridinium p-toluenesulfonate (0.1 g) was heated for 16 hours with refluxing. After cooling to a room temperature, the reaction mixture was poured into ice water, and then the precipitated crystals were collected by filtration, and washed with water. After air-drying, 4-chloro-4'-methylmercaptomethylbenzophenone ethoxycarbonylhydrazone (9.4 g) was obtained as an isomer mixture.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([CH3:14])[CH:13]=1)[O:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[Cl:15][S:16]([C:13]1[C:12]([CH3:14])=[CH:11][C:4]([O:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[CH:3][C:2]=1[CH3:1])(=[O:18])=[O:17]
Reactant: COC(=O)COc1cc(C)cc(C)c1
Reactant: O=S(=O)(O)Cl
Product: COC(=O)COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 26 %

Procedure:
Methyl (3,5-dimethylphenoxy)acetate (19.4 g, 0.10 mol) was added dropwise over ca. 30 min to rapidly stirred chlorosulfonic acid (58 g, 0.50 mol) that was cooled in a −20° C. bath. After an additional 20 min, the mixture was allowed to slowly warm to room temperature. After 2 hr, the mixture was poured slowly into 400 mL of ice/water. This suspension was extracted with 400 mL of dichloromethane, and the organic layer was washed with water and concentrated. The residue was purified by flash silica gel chromatography (hexanes→dichloromethane) to yield 7.6 g (27%) of the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[CH2:8][CH3:9].C(OCC)(=O)C.[OH-].[Na+]>O1CCCC1.O>[CH2:7]([C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]2[CH:24]=[CH:23][C:19]([CH2:20][OH:21])=[CH:18][CH:17]=2)[CH2:14][CH2:15]1)[CH2:8][CH3:9]
Reactant: CCC[C@H]1CC[C@H](c2ccc(C(=O)Cl)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCC[C@H]1CC[C@H](c2ccc(CO)cc2)CC1
Temperature: 0 °C

Procedure:
Into a three-necked flask having a 1 l capacity was added lithium aluminum hydride (5.7 g, 0.15 mol), and cooled down to 0° C., followed by dropwise adding tetrahydrofuran (100 ml) and a solution of 4-(trans-4'-n-propylcyclohexyl)benzoyl chloride (53.0 g, 0.2 mol) in tetrahydrofuran (100 ml) in this order, agitating the mixture at room temperature for 3 hours, again cooling it down to 0° C., adding ethyl acetate (10 ml), water (10 ml) and 2N NaOH aqueous solution (10 ml) in this order, heating the mixture under reflux for 30 minutes, cooling the resulting material, filtering, adding saturated NaCl aqueous solution (100 ml) and ethyl acetate (100 ml), removing the aqueous layer, washing the resulting organic layer with water till the washing water became neutral, drying over anhydrous sodium sulfate, removing a drying agent, concentrating under reduced pressure, recrystallizing from heptane solvent and drying to obtain the captioned compound (35.8 g). Its structure was confirmed by NMR spectra.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[CH3:6][CH2:7][C:8]([O:10]O)=[O:9]>>[C:1]([O:5][O:10][C:8](=[O:9])[CH2:7][CH3:6])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)O
Reactant: CCC(=O)OO
Product: CCC(=O)OOC(=O)CC

Procedure:
Two side reactions could in theory occur in the extraction column, namely the reaction of hydrogen peroxide with sulphuric acid to form Caro's acid and the reaction of propionic acid with perpropionic acid to give propionyl peroxide. However the simultaneous extraction into the organic phase constituted by the propylene dichloride has the general effect of minimising these side reactions.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1Cl.[CH2:12]([CH2:14][NH2:15])[OH:13]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:15][CH2:14][CH2:12][OH:13]
Reactant: O=[N+]([O-])c1cccc(Br)c1Cl
Reactant: NCCO
Solvent: CCO
Product: O=[N+]([O-])c1cccc(Br)c1NCCO

Procedure:
A solution of 1-bromo-2-chloro-3-nitrobenzene (0.34 g, 1.4 mmol) and ethanolamine (0.22 mL, 3.5 mmol) in dry ethanol (3.8 mL) was irradiated in a microwave oven at 135° C. for 180 min. After the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, the organic phase was washed with potassium bisulfate (0.1 M), water and brine, dried over Na2SO4 and concentrated. Purification was performed using flash chromatography on a silica column and 25% ethyl acetate in heptane as an eluent to yield 2-[(2-bromo-6-nitrophenyl)amino]ethanol as red oil, 0.24 g (65%). 1H NMR (400 MHz, DMSO-D6) δ ppm 3.13 (q, J=5.2 Hz, 2H) 3.51 (q, J=5.1 Hz, 2H) 4.87 (t, J=5.1 Hz, 1H) 6.18 (t, J=5.1 Hz, 1H) 6.80 (t, J=8.1 Hz, 1H) 7.84 (dd, J=7.8, 3.3 Hz, 2H).
Reaction SMILES: O=[C:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4][CH:3]1[C:17]([O:19][CH3:20])=[O:18].Cl.[CH3:22][O:23][NH2:24]>N1C=CC=CC=1>[CH3:22][O:23][N:24]=[C:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4][CH:3]1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)CC1=O
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CN(C(=O)OCc2ccccc2)CC1C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.2 %

Procedure:
A solution of 1-benzyl 3-methyl 4-oxopyrrolidine-1,3-dicarboxylate (12 g, 43.2 mmol) in pyridine (50 mL) at 0° C. was added O-METHYLHYDROXYLAMINE HYDROCHLORIDE (5.51 g, 66.0 mmol) which was stirred for 10 minutes, and then it was warmed up to RT and stirred for 16 hrs. The reaction mixture was concentrated to yield a crude product which was partitioned in 300 mL of 1N HCl and 300 mL of EtOAc. The organic layer was washed with 100 mL of brine. The combined aqueous phases were extracted with 200 mL of EtOAc. The combined organic phases were dried over Na2SO4. Filtration and concentration to yield the product (12.6 g, 95% yield).
Reaction SMILES: [C@@H:1]1([N:10]2[CH2:17][CH2:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@H:4]([OH:5])[C@@H:2]1[OH:3].[BH4-].[Na+]>>[OH:15][CH:14]1[CH2:16][CH2:17][N:10]([C@@H:1]2[O:7][C@H:6]([CH2:8][OH:9])[C@H:4]([OH:5])[C@@H:2]2[OH:3])[C:11](=[O:12])[NH:13]1
Reactant: O=C1CCN([C@@H]2O[C@H](CO)[C@H](O)[C@@H]2O)C(=O)N1
Agent: [BH4-]
Agent: [Na+]
Product: O=C1NC(O)CCN1[C@@H]1O[C@H](CO)[C@H](O)[C@@H]1O

Procedure:
In the manner given in Example 2C 1-β-D-lyxofuranosyl-dihydrouracil was reduced with sodium borohydride to give 4-hydroxy-1-β-D-lyxofuranosyl-tetrahydro-2(1H)-pyrimidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([CH:41]=[CH:42][CH:43]=4)[C:35](N(OC)C)=[O:36])[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-:44].[Li+]>CO.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([CH:41]=[CH:42][CH:43]=4)[C:35]([OH:36])=[O:44])[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: CON(C)C(=O)c1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-(5-{2-[(R)-1-(4-chloro-benzenesulfonyl)-piperidin-3-ylamino]-pyrimidin-4-yl}-imidazo[2,1-b]thiazol-6-yl)-N-methoxy-N-methyl-benzamide (0.57 g, 0.089 mmol) in a mixture of methanol (1.0 mL) and tetrahydrofuran (THF) (3.0 mL) was added a solution of lithium hydroxide (0.075 g, 0.179 mmoL) in water (1.0 mL). The mixture was stirred at room temperature for 48 hours. Solvent was removed to dryness. Residue was dissolved into a mixture of dichloromethane (20 mL) and 1.0 N HCl (1.0 mL). Organic layer was separated, washed with water (5 mL×4), dried over sodium sulfate and concentrated to dryness. The residue was dried further under high vacuum at 45° C. for 24 hours to provide 0.45 g (85%) as a yellow solid. M.p.=190-195° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.70 (br. s, 1H), 8.16(bs, 1H), 8.12 (d, J=5.2 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.78-7.83 (m, 1H), 7.77-7.74 (m, 2H), 7.68-7.65 (m, 2H), 7.58 (t, J=8.0 Hz, 1H), 7.41 (d, J=4.4 Hz, 1H), 7.17 (d, J=6.8 Hz, 1H), 6.37 (d, J=5.2 Hz, 1H), 3.92 (br. s, 1H), 3.75-3.71 (m, 1H), 3.48-3.45 (m, 1H), 2.49-2.43 (m, 1H), 2.32 (t, J=10.4 Hz, 1H), 1.90-1.82 (m, 2H), 1.59-1.56 (m, 1H), 1.39-1.32 (m, 1H). LCMS: 596 [M+H].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][CH:10]=[CH2:11])=[CH:4][C:3]=1[F:13].CCOC(C)=O.[CH3:20][N:21](C=O)C>[Pd].[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][CH:10]=[CH2:11])=[CH:4][C:3]=1[F:13])#[N:21]
Reactant: C=CCC(O)c1ccc(Br)c(F)c1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Solvent: CCOC(C)=O
Product: C=CCC(O)c1ccc(C#N)c(F)c1
Temperature: 80 °C
Reaction time: 168 h

Procedure:
A solution of the crude product from Step G (39.1 mmol) and Zn(CN)2 (4.59 g, 39.1 mmol) in 50 mL of DMF was degassed by bubbling argon through the mixture for 30 minutes. Tetrakis(triphenylphosphine)palladium (3.15 g, 2.73 mmol) was added, and the reaction was heated to 80° C. The solution was stirred over the course of 7 days, twice adding additional portions (2.0 mmol) of palladium catalyst. After cooling to room temperature, the solution was poured into EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography (10-15% EtOAc/hexane) provided the titled compound along with some of the aryl bromide starting material.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:8][C:9]([F:20])([F:19])[CH2:10][CH2:11][Si:12](OC)([O:15][CH3:16])[O:13][CH3:14].[SiH4].CCCCCC>C(OCC)C.CCCCCC>[F:20][C:9]([F:8])([F:19])[CH2:10][CH2:11][Si:12]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([O:13][CH3:14])[O:15][CH3:16]
Reactant: CO[Si](CCC(F)(F)F)(OC)OC
Reactant: Cl[Mg]C1CCCC1
Agent: [SiH4]
Solvent: CCCCCC
Solvent: CCOCC
Product: CO[Si](CCC(F)(F)F)(OC)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under nitrogen, a 500 ml Schlenk flask was cooled to room temperature, charged with 150 ml of diethyl ether and cyclopentylmagnesium chloride (0.055 mol, 27.7 ml) and warmed slightly to 30° C. A 100 ml Schlenk flask was purged with nitrogen and charged with 75 ml hexane and 3,3,3-trifluoropropyltrimethoxy silane (10 ml, 0.0504 mol). The silane/hexane solution was added dropwise via cannula to the Grignard/diethyl ether mixture producing a white cloudy mixture. After addition (1.25 hrs.), the Grignard containing flask was rinsed once with 25 ml of hexane. The reaction mixture was stirred at room temperature for one hour.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1I.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Sc1ccccc1
Reactant: Cc1cc(C)c(I)c(C)c1
Product: Cc1cc(C)c(Sc2ccccc2)c(C)c1

Procedure:
The general procedure was used to convert 2,4,6-trimethyliodobenzene and thiophenol to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (444 mg, 97% yield). 1H NMR (300 MHz, CDCl3) δ 7.20 (m, 2H; Hb, Hb′), 7.09 (m, 3H; Hc, Hc′, Hd), 6.96 (m, 2H; Ha, Ha′) 2.44 (s, 6H; ortho methyl protons), 2.37 (s, 3H, para methyl protons). 13C NMR (75 MHz, CDCl3) δ 143.67 (C2, C6), 139.21 (C4), 138.35 (C1), 129.29 (C10), 128.81 (C11, C15), 127.20 (C12, C14), 125.39 (C3, C5), 124.41 (C13), 21.67 (C7, C8), 21.10 (C9). Anal. Calcd. for C15H16S: C, 78.90; H, 7.06; S, 14.04; Found C, 78.76; H, 7.23; S, 14.10.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=1.C(CC(C1C=CC(F)=CC=1)C(C1C=CC=C(F)C=1)C(OC)=O)#N>C1(C)C=CC=CC=1>[C:9]([CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH:21]([C:18]1[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=1)[CH2:22][C:23]([O:25][CH3:26])=[O:24])#[N:10]
Reactant: N#CCc1cccc(F)c1
Reactant: COC(=O)C=Cc1ccc(F)cc1
Agent: COC(=O)C(c1cccc(F)c1)C(CC#N)c1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)CC(c1ccc(F)cc1)C(C#N)c1cccc(F)c1
Temperature: 65 °C
Reaction time: 15 h

Procedure:
Under protective gas (Ar), 0.767 g (5.0 mmol) of (3-fluorophenyl)acetonitrile and 0.1 ml of sodium methoxide solution (30% in methanol) were added to 0.820 g (4.55 mmol) of methyl 3-(4-fluorophenyl)acrylate in 15.0 ml of toluene, and the mixture was stirred in a closed vessel at 65° C. for 15 h. The solvent was removed under reduced pressure, the residue was taken up in ethyl acetate and the mixture was washed twice with in each case 25 ml of water. The combined organic phases were dried over sodium sulphate and the solvent was removed under reduced pressure. Chromatography of the residue on silica gel (ethyl acetate/heptane=20:80) gave 0.950 g (57% of theory) of an erythro/threo diastereomer mixture of methyl 4-cyano-(3-fluorophenyl)-3-(4-fluorophenyl)butanoate (erythro:threo=54:46 according to integration of the methyl singlets in the 1H-NMR in CDCl3 at 3.66 and 3.56 ppm).
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:47])[N:29]([CH:44]([CH3:46])[CH3:45])[CH2:30][C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:47])[N:29]([CH:44]([CH3:45])[CH3:46])[CH2:30][C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[N:27]=2)[CH2:20]1
Reactant: CC(C)N(CC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)N(CC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 82.8 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-{4-[N-isopropyl-N-(p-nitrobenzyloxycarbonylmethyl)carbamoyl]-1,3-thiazol-2-yl}azetidine (1.81 g, 2.69 mmol) (obtained as described in Reference Example 48(4)) in anhydrous tetrahydrofuran (90 ml) were added acetic acid (0.18 ml, 3.23 mmol) and a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (3.23 ml, 3.23 mmol) in an ice bath. The mixture was stirred in the ice bath for 2 hours. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride:ethyl acetate (1:1) as the eluant to afford 3-hydroxy-1-{4-[N-isopropyl-N-(p-nitrobenzyloxycarbonylmethyl)carbamoyl]-1,3-thiazol-2-yl}azetidine (968 mg, yield 83%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:17][N:16]4[CH:12]([CH2:13][CH2:14][CH2:15]4)[CH2:11][C:7]=3[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:17][N:16]4[CH:12]([CH2:13][CH2:14][CH2:15]4)[CH2:11][C:7]=3[N:8]2[S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:4][CH:3]=1
Reactant: Brc1ccc2c3c([nH]c2c1)CC1CCCN1C3
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(Br)cc42)CN2CCCC2C3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
A solution of 8-Bromo-2,3,5,10,11,11a-hexahydro-1H-indolizino[7,6-b]indole (150 mg, 0.52 mmol) in THF (3 mL) was treated sequentially with NaH (31 mg, 0.77 mmol) and TsCl (0.12 g, 0.61 mmol). The reaction mixture was stirred at room temperature under argon overnight. After the mixture was concentrated, the residue was purified by flash column chromatography (silica gel, 5% CH3OH in CH2Cl2) to give 8-bromo-10-tosyl-2,3,5,10,11,11a-hexahydro-1H-indolizino[7,6-b]indole (0.11 g, 48%) as a yellow solid. 8-bromo-10-tosyl-2,3,5,10,11,11a-hexahydro-1H-indolizino[7,6-b]indole (0.11 g, 0.22 mmol) was reacted according to the procedure of Example 2 (step b) to give a yellow solid in 40% (50 mg). The yellow solid was dissolved in CH2Cl2, and NaOH (177 mg, 4.43 mmol) was added. The reaction mixture was stirred at room temperature under argon for 3 h. After the mixture was concentrated, the residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) to give a white solid (30 mg, 83%). The white solid was dissolved in CH3OH (1 mL) and was treated with 2 N HCl in Et2O (1 mL). The resulting solid was isolated by filtration and dried under vacuum to give the title compound (30 mg, 92%) as an off-white powder: mp 270-273° C.; 1H NMR (500 MHz, CD3OD) δ 7.61 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.47-7.31 (m, 6H), 7.04 (dd, J=8.5, 2.0 Hz, 1H), 6.36-6.34 (m, 1H), 6.16 (d, J=2.5 Hz, 1H), 5.20 (s, 2H), 4.89 (d, J=14.0 Hz, 1H), 4.36 (d, J=14.0 Hz, 1H), 3.90-3.85 (m, 2H), 3.49-3.36 (m, 2H), 3.10 (dd, J=15.5, 11.0 Hz, 1H), 2.60-2.55 (m, 1H), 2.36-2.21 (m, 2H), 1.96-1.92 (m, 1H); ESI MS m/z 412 [M+H]+; HPLC (Method A)>99% (AUC), tR=12.7 min.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[NH:20]1[CH2:23][CH2:22][CH2:21]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:20]4[CH2:23][CH2:22][CH2:21]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: C1CNC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCC3)c(F)cc2c1=O
Temperature: 110 °C
Yield: 41.3 %

Procedure:
A mixture of 0.6 g (2.2 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.25 g (4.4 mmol) of azetidine and 1 ml of triethylamine in 8 ml of pyridine is heated to 110° C. in a closed vessel for 2 hours. The mixture is allowed to cool and is filtered and the product is washed with water, ethanol and ether. 0.275 g of 1-cyclopropyl-6-fluoro-7-(1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point 291°-4° C., is thereby obtained.