Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)=[O:4].C(N(C(C)C)CC)(C)C.[CH:26]1[CH:31]=[CH:30][C:29]([C@H:32]([NH2:35])[CH2:33][OH:34])=[CH:28][CH:27]=1>CN(C=O)C>[OH:16][C:8]1[CH:7]=[CH:6][C:5]([C@@H:3]([OH:4])[CH2:2][NH:35][C@@H:32]([C:29]2[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=2)[CH2:33][OH:34])=[CH:10][C:9]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: N[C@H](CO)c1ccccc1
Reactant: CS(=O)(=O)Nc1cc(C(=O)CBr)ccc1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1cc([C@@H](O)CN[C@H](CO)c2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 6.7 %

Procedure:
A solution of N-[5-(bromoacetyl)-2-hydroxyphenyl]methanesulfonamide (J. Med. Chem. 1967, 10, 462-72) (1.15 g) in dry DMF (30 mL) was treated with diisopropylethylamine (1.06 mL) and (S)-phenylglycinol (474 mg) and the reaction mixture stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo and the residue re-suspended in methanol (50 mL). The reaction mixture was cooled to 0° C. and treated with CaCl2 (1.27 g). The reaction mixture was stirred at 0° C. for 30 min prior to portionwise addition of NaBH4 (218 mg) ensuring that the temperature did not rise above 10° C. After complete addition the reaction mixture was allowed to warm to room temperature and stirred for a further 74 h. The reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc and water. The organic phase was dried and concentrated in vacuo. The mixture was purified by chromatography (SPE, gradient from DCM to DCM-MeOH—NH3(aq) 100:10:1) afforded the title compound (85 mg). LCMS RT=2.48 min
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH:13]([O:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:14][N:15]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[NH2:3][CH2:12][CH:13]([O:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:14][NH2:15]
Reactant: CC(C)(C)OC(=O)NCCOC(CN1C(=O)c2ccccc2C1=O)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCOC(CN)CN
Temperature: 42.5 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
A 20 L 4-neck round-bottom flask was flushed with N2. Then charged a solution of tert-butyl 2-(1,3-bis(1,3-dioxoisoindolin-2-yl)propan-2-yloxy)ethylcarbamate (919 g, 1.9 mol, 1.0 eq) in ethanol (12000 mL, 13.0 v), followed by dropwise addition of hydrazine hydrate (602 g, 12.0 mol, 6.3 eq) with stirring at 40-45° C. over 30 min. The resulting mixture was stirred for 7 hours at 40-45° C. in an oil bath. The reaction progress was monitored with LCMS. The reaction mixture was cooled to 20˜30° C. and filtered. The filtrate was concentrated under vacuum to give 424.0 g (97.5%) of tert-butyl 2-(1,3-diaminopropan-2-yloxy)ethylcarbamate as a brown oil.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([OH:9])[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18].CCN(CC)CC>C(Cl)Cl>[F:1][C@H:2]1[C@H:8]([O:9][S:26]([C:23]2[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:25][CH:24]=2)(=[O:27])=[O:28])[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](F)CC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
trans-tert-butyl 4-fluoro-5-hydroxyazepane-1-carboxylate (12.36 g, 52.98 mmol) was dissolved in CH2Cl2 (110 mL). The solution was cooled to 0° C., 4-nitrobenzene-1-sulfonyl chloride (14.09 g, 63.58 mmol) was added and the mixture was stirred for 10 minutes. NEt3 (11.08 mL, 79.48 mmol) was added and the mixture was slowly warmed to ambient temperature over 1 hour and stirred for an additional 2 hours. The mixture was diluted with CH2Cl2 and washed with water followed by 1N KHSO4 (2×50 mL), then with saturated aqueous NaHCO3 (50 mL) and brine, and the combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified via column chromatography (10 to 70% MTBE/hexanes) to provide 18.4 g of the product (84%) as a single isomer and as a faint orange powder.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[N:10]=[C:6]2[N:5]=[C:4]([CH3:16])[CH:3]=1.[SH-:17].[Na+]>O>[SH:17][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[N:10]=[C:6]2[N:5]=[C:4]([CH3:16])[CH:3]=1
Reactant: COC(=O)Cc1nc2nc(C)cc(Cl)n2n1
Reactant: [SH-]
Agent: [Na+]
Solvent: O
Product: COC(=O)Cc1nc2nc(C)cc(S)n2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.7 %

Procedure:
The product obtained in Step 4 (2 g) and sodium hydrosulfide (1.22 g) were dissolved in 35 ml of water, the solution was stirred at room temperature for 1.5 hours under a nitrogen stream, and the insoluble matters were filtered off. The filtrate was cooled to 0° C., its pH was lowered to 1-2 with 6N hydrochloric acid, the slurry was stirred at that temperature for 30 minutes, and the crystals thus formed were collected by filtration, washed with 30 ml of water and dried, affording 1.44 g of the objective compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][N:12]=[C:13]([C:20](=[O:22])[CH3:21])[CH2:14][C:15](OCC)=[O:16])[C:5]([OH:7])=[O:6].C(O)C.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15](=[O:16])[CH2:14][C:13]([C:20](=[O:22])[CH3:21])=[N:12]1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CC(=NNc1ccc(C(=O)O)cc1C)C(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)C1=NN(c2ccc(C(=O)O)cc2C)C(=O)C1

Procedure:
To a solution of a 5 g. (34 mmoles) of 3-methyl-4-[N′-(2-ethoxycarbonyl-1-acetylethylidene)hydrazino]benzoic acid in 25 ml. of ethanol and 25 ml. of water was added with stirring 34.3 ml. of a 1 M sodium carbonate solution. The mixture was stirred at room temperature for 24 hours. The resulting mixture was acidified to pH 3 with 6 M hydrochloric acid and the resulting solid was collected by filtration, washed with water and dried. The 3-methyl-4-(3-acetyl-5-oxo-2-pyrazolin-1-yl)benzoic acid has melting point of >250° C.
Reaction SMILES: CS(O[CH:6]1[CH2:10][O:9][CH:8]2[CH:11]([O:14][CH3:15])[CH2:12][O:13][CH:7]12)(=O)=O.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C.C([O-])(O)=O.[Na+]>[N:16]([CH:6]1[CH2:10][O:9][CH:8]2[CH:11]([O:14][CH3:15])[CH2:12][O:13][CH:7]12)=[N+:17]=[N-:18]
Reactant: COC1COC2C(OS(C)(=O)=O)COC12
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1COC2C(N=[N+]=[N-])COC12
Temperature: 140 °C
Yield: 99.8 %

Procedure:
To a solution of 6-methoxyhexahydrofuro[3,2-b]furan-3-yl methanesulfonate (1.1 g, 4.6 mmol) in anhydrous DMF (25 mL) was added sodium azide (1.66 g, 25.5 mmol). The reaction was heated to 140° C. for 12 h and then diluted with NaHCO3 (sat, 50 mL), and extracted with EtOAc (80 mL×3). The organic layers were washed with H2O (30 mL×5), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a light yellow solid (0.85 g, 99.4%).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:10]=1[NH2:11].Cl[C:18]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20]([OH:22])=[O:21]>CN(C=O)C.[Cu]>[F:8][C:9]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:10]=1[NH:11][C:18]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20]([OH:22])=[O:21]
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Reactant: Nc1ccc(F)cc1F
Agent: [Cu]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1cc(F)c(F)cc1Nc1ccc(F)cc1F
Temperature: 85 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
A suspension of triethyl amine (15 ml, 0.11 mol), 2, 4-difluoroaniline (25 ml, 0.24 mol), copper bronze (2.7 g., 0.04 mol), in hot DMF (25 ml) was treated with a solution of 2-chloro-4,5-difluorobenzoic acid (23 g., 0.12 mol) in 25 ml of DMF and the temperature was maintained at 85° C. for 8 hours. The reaction mixture was allowed to cool to room temperature and was then stirred overnight. The reaction mixture was evaporated in vacuo and the residue was partitioned between ether and aqueous ammonium chloride. The organic phase was washed with 2N HCl and saturated aqueous lithium chloride solution. The ether was dried over sodium sulfate, treated with darco and then filtered and evaporated. The residue was crystallized from hexane-ether to afford 21.6 g (62%) of 2-(2,4-difluorophenylamino)-4,5-difluorobenzoic acid; m.p.: 215°-216° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:19]=[CH:18][C:8]2[NH:9][C:10]([C:12]3[C:16]([NH2:17])=[CH:15][NH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].C(N(C(C)C)CC)(C)C.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>O1CCCC1>[C:29]([NH:17][C:16]1[C:12]([C:10]2[NH:9][C:8]3[CH:18]=[CH:19][C:5]([C:3]([OH:2])=[O:4])=[CH:6][C:7]=3[N:11]=2)=[N:13][NH:14][CH:15]=1)(=[O:33])[CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1ccc2[nH]c(-c3n[nH]cc3N)nc2c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)Nc1c[nH]nc1-c1nc2cc(C(=O)O)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(4-amino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid methyl ester [200 mg, Example 233(k)] in tetrahydrofuran (5 ml) was added diisopropylethylamine (545 μl) and isobutyryl chloride (327 μl) dropwise and the reaction stirred for 30 minutes. The reaction mixture was concentrated in vacuo and the residue was taken up in 1M potassium hydroxide in tetrahydrofuran/methanol (1:3, v/v) (5 ml) and stirred for 1 hour. The reaction mixture was concentrated in vacuo and the residue was taken up in 1M sodium hydroxide in water/methanol (5 ml) and stirred for 1 hour. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water and the layers separated. The aqueous layer was acidified to pH 3-4 with 5% citric acid solution, extracted with ethyl acetate and the organic layer washed with brine. The organic layer was then dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to give 2-(4-isobutyrylamino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (140 mg) as a white solid. LC-MS (METHOD C): RT=2.87 minutes, 313.33 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.C(N(C(C)C)C(C)C)C.[CH3:14][CH:15]([CH3:20])[C:16](=[CH2:19])[CH2:17][OH:18]>C1COCC1>[CH3:1][O:2][CH2:3][O:18][CH2:17][C:16]([CH:15]([CH3:20])[CH3:14])=[CH2:19]
Reactant: COCCl
Reactant: C=C(CO)C(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=C(COCOC)C(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 100.3 %

Procedure:
Chloromethyl methyl ether (98 ml, 1292 mmol) and N-ethyldiisopropylamine (234 ml, 1344 mmol) were added to a solution of 3-methyl-2-methylenebutane-1-ol (61.5 g, 615 mmol) prepared in Reference Example 202 in THF (500 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 22 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in diethyl ether, and the mixture was washed with water and brine, dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 2-methoxymethoxymethyl-3-methyl-1-butene (89 g, quantitative) as a colorless oil.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:24](=[O:25])[N:5]2[CH:6]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])[C:7](=C)[CH2:8][S:9][C@H:4]12.C[OH:27]>>[NH2:2][CH:3]1[C:24](=[O:25])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])=[C:7]([OH:27])[CH2:8][S:9][C@H:4]12
Reactant: CO
Reactant: C=C1CS[C@@H]2C(N)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12

Procedure:
In a further example, p-nitrobenzyl 7-amino-3-methylenecepham-4-carboxylate hydrochloride is dissolved in methanol and ozone is bubbled through the solution at a temperature of about -78° C. Excess ozone is purged from the mixture with nitrogen and the ozonide is decomposed by bubbling sulfur dioxide through the mixture. The reaction mixture is evaporated to dryness and the residue, p-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate is obtained as the hydrochloride salt.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[F:10][C:11]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[C:12]=1[NH2:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:13][C:12]1[C:11]([F:10])=[CH:17][C:16]([F:18])=[CH:15][C:14]=1[F:19])=[O:8]
Reactant: Nc1c(F)cc(F)cc1F
Reactant: O=C(Cl)CCCCCBr
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CCCCCBr)Nc1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
6-Bromohexanoyl chloride (234 mg, 1.1 mmols) was gradualy added dropwise to a chloroform (3 ml) solution of 2,4,6-trifluoroaniline (147 mg, 1.0 mmol) and triethylamine (11 mg, 1.1 mmols) cooling in ice bath, and stirred for 1 hour at room temperature. The reaction mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with 1N-HCl, an aqueous saturated solution of sodium hydrogencarbonate, water, and saturated saline in that order, and dried with anhydrous sodium sulfate, and the solvent was evaporated. Then, the resulting solid was recrystallized from hexan-ether, and 6-bromo-N-(2,4,6-trifluorophenyl)hexan amide 283 mg(yield 87%) was obtained as colorless needle-like crystals. Potassium carbonate (45 mg, 0.33 mmols) and 18-crown-6 (8 mg, 0.03 mmols) were added to DMF (2 ml) solution of the resulting anilide (97 mg, 0.3 mmols) and 2-mercaprbenzoxzole (45 mg, 0.3 mmol), and stirred for 1.5 hours at 80° C. The mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline in that order, and dried with anhydrous sodium sulfate, and the solvent was evaporated. And the resulting crystals were recrystallized from hexane-ether, and colorless needle-like crystals 106 mg (yield: 90%) of the intended product as crystals.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:14]([CH:15]([C:20]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:21]=2[C:22]#N)[C:16]([OH:19])([CH3:18])[CH3:17])[CH:13]=[N:12][CH:11]=1)(C(C)(C)C)(C)C.S(=O)(=O)(O)[OH:30].C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[Cl:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:20]2[C:21]=1[C:22](=[O:30])[O:19][C:16]([CH3:18])([CH3:17])[CH:15]2[N:14]1[C:10]([CH2:9][OH:8])=[CH:11][N:12]=[CH:13]1
Reactant: O=S(=O)(O)O
Reactant: CC(C)(O)C(c1cccc(Cl)c1C#N)n1cncc1CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)OC(=O)c2c(Cl)cccc2C1n1cncc1CO

Procedure:
2-{1-[5-(tert-Butyldimethylsilanyloxymethyl)-imidazol-1-yl]-2-hydroxy-2-methyl-propyl}-6-chloro-benzonitrile (0.188 g, 0.616 mmol), prepared in a similar fashion as described in Example 6c is dissolved in 1,4-dioxane (5 mL). Concentrated sulfuric acid (0.130 mL, 2.46 mmol) and water (0.130 mL) are added and the mixture is stirred at reflux for 16 h. After cooling down, the mixture is basified to pH 10 using solid sodium bicarbonate and is then diluted with water and extracted with ethyl acetate twice. The combined organic phase is dried over Na2SO4 and concentration in vacuo. The residue obtained is purified by silica gel chromatography (dichloromethane-methanol, 9:1) to give 8-chloro-4-(5-hydroxymethyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one; HRMS (ESI) m/z 307.0845 [(M+H)+: Calcd for C15H16N2O3Cl: 307.0849]; 1H NMR (400 MHz, MeOD) δ ppm 1.30 (s, 3 H), 1.56 (s, 3 H), 4.77 (d, J=13.6 Hz, 1 H), 4.83 (d, J=13.6 Hz, 1 H), 5.77 (s, 1 H), 7.02 (s, 1 H), 7.35 (s, 1 H), 7.55 (br. d, J=7.3 Hz, 1 H), 7.68 (dd, J=8.0, 7.3 Hz, 1 H), 7.72 (dd, J=8.0, 1.5 Hz, 1 H).
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=1[CH:9]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Br:6][C:7]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=1[CH:9]=[CH2:1]
Reactant: O=Cc1cc(F)ccc1Br
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cc(F)ccc1Br
Temperature: 0 °C

Procedure:
21.12 g Methyltriphenylphosphonium bromide were suspended in 150 ml tetrahydrofuran and cooled in an ice bath. 21.68 ml n-butyl lithium (2.5 M in n-heptane) were added dropwise and the reaction mixture stirred at 0° C. for thirty minutes. Then 10.0 g commercially available 2-bromo-5-fluorobenzaldehyde were added slowly so that the reaction temperature did not exceed +5° C. After completion of the addition the cooling bath was removed and the reaction mixture stirred at room temperature for one hour. The reaction mixture was diluted by addition of 300 ml ethyl acetate and washed three times with portions of 120 ml brine. The organic phase was dried over MgSO4, the solvent removed in vacuo and the resulting residue purified on silica gel with the eluent heptane=>n-heptane:ethyl acetate=9:1 to obtain 7.9 g 1-Bromo-4-fluoro-2-vinyl-benzene as an oil.
Reaction SMILES: [C:1]([C:4]1[O:8][CH:7]=[N:6][C:5]=1[CH3:9])(=[O:3])[CH3:2].[Li][C:11]1[O:12][CH:13]=[CH:14][CH:15]=1>C(OCC)C>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:1]([C:4]1[O:8][CH:7]=[N:6][C:5]=1[CH3:9])([OH:3])[CH3:2]
Reactant: [Li]c1ccco1
Reactant: CC(=O)c1ocnc1C
Solvent: CCOCC
Product: Cc1ncoc1C(C)(O)c1ccco1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Acetyl-4-methyloxazole (4 g) in dry diethylether was added dropwise to a stirred solution of 2-lithiofuran (1 equivalent) in diethylether at -20° C. The mixture was allowed to warm to room temperature and was then left overnight. Work-up and flash chromatography then gave the title compound as a white solid, m.p. 73°-75° C.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=2[F:31])[CH2:17][O:16][C@H:15]([C:18]([F:21])([F:20])[F:19])[C@H:14]1[CH2:22][OH:23].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:31][C:25]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:24]=1[C@@:13]1([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])[C@H:14]([CH2:22][OH:23])[C@@H:15]([C:18]([F:21])([F:19])[F:20])[O:16][CH2:17]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N[C@@]1(c2cccc(F)c2F)CO[C@H](C(F)(F)F)[C@H]1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2cccc(F)c2F)CO[C@H](C(F)(F)F)[C@H]1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzoyl isothiocyanate (2.0 mL) was added to a solution containing ((2S,3R,4S)-4-amino-4-(2,3-difluorophenyl)-2-(trifluoromethyl)tetrahydrofuran-3-yl)methanol (3.12 g) in DCM (20 mL), and the mixture was stirred at RT for 18 h. Sodium bicarbonate (sat., aq., 50 mL) was then added, the mixture extracted with EtOAc (3×75 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% to 40% EtOAc in hexanes) to obtain the title compound (4.18 g). 1H NMR (400 MHz, CDCl3) δ ppm 3.12 (dd, J=7.6, 4.3 Hz, 1H), 3.18-3.29 (m, 1H), 4.03 (ddd, J=12.3, 7.2, 4.5 Hz, 1H), 4.35-4.49 (m, 1H), 4.59 (d, J=9.9 Hz, 1H), 4.81 (d, J=9.6 Hz, 1H), 7.07-7.23 (m, 2H), 7.49 (t, J=7.2 Hz, 1H), 7.56 (t, J=7.7 Hz, 2H), 7.67 (t, J=7.5 Hz, 1H), 7.88 (d, J=7.1 Hz, 2H), 8.92 (s, 1H), 11.89 (s, 1H)
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[C:12]([F:20])[CH:13]=[CH:14][CH:15]=3)[CH2:10][C:9]=2[C:8]=1[F:21])(=O)[CH2:4][CH3:5].Cl>CO>[CH:3]([C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[C:12]([F:20])[CH:13]=[CH:14][CH:15]=3)[CH2:10][C:9]=2[C:8]=1[F:21])=[CH:4][CH3:5]
Reactant: CCC(=O)c1ccc2c(c1F)Cc1c(F)cccc1-2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC=Cc1ccc2c(c1F)Cc1c(F)cccc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
1.5 g of sodium borohydride was added to a mixture of 20.5 g of 2-propionyl-1,8-difluorofluorene (K-2) and 100 ml of methanol at a temperature of −10° C., and the temperature was gradually raised, and then held at 0° C. for two hours to allow the reaction to proceed. Following completion of the reaction, 30 ml of 1N dilute hydrochloric acid was added to the cooled reaction mixture, and the methanol was then removed by evaporation under reduced pressure. The residue was then extracted into 100 ml of toluene. The organic layer was washed with 100 ml of water. Following drying, 1.0 g of p-toluenesulfonic acid monohydrate was added, and the mixture was refluxed under heat for one hour. The reaction mixture was then cooled to room temperature, 7 ml of a 1N aqueous solution of sodium bicarbonate was added to neutralize the mixture, and the mixture was then washed with 100 ml of water. Following drying, the solvent was removed by evaporation to yield 19.3 g (crude product) of 2-(propen-1-yl)-1,8-difluorofluorene (K-3). This product was used without purification in the subsequent reaction.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:21][C@H:20]([CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[N:8]2[C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]=[CH:11][C:10]=3[N:19]=[C:7]2[CH2:6]1)(=[O:4])=[O:3].C1C=C(Cl)C=C(C(OO)=[O:41])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:1][S:2]([N:5]1[CH2:21][C@H:20]([CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[N:8]2[C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N+:12]([O-:41])=[CH:11][C:10]=3[N:19]=[C:7]2[CH2:6]1)(=[O:3])=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCC[C@H]1CN(S(C)(=O)=O)Cc2nc3cnc4ccccc4c3n21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC[C@H]1CN(S(C)(=O)=O)Cc2nc3c[n+]([O-])c4ccccc4c3n21
Reaction time: 1 h
Yield: 100 %

Procedure:
tert-Butyl 3-[(11S)-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-11-yl]propylcarbamate (6.16 g, 13.4 mmol) was dissolved in 110 mL of CH2Cl2 and treated with MCPBA (4.05 g, 57-86% pure material). After stirring for 1 hour, the reaction mixture was treated with 100 mL of 5% Na2CO3 solution and the layers were separated. The aqueous layer was then extracted with CH2Cl2 (2×50 mL). The combined organic layers were concentrated under reduced pressure to give tert-butyl 3-[(11S)-9-(methylsulfonyl)-5-oxido-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-11-yl]propylcarbamate (6.37 g) as a golden foam.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]=1.[CH2:20]([NH2:25])[CH2:21][CH:22]([CH3:24])[CH3:23]>C(#N)C>[CH3:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][N:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]=[C:3]1[CH2:2][NH:25][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: Cc1ccccc1Cn1c(CCl)nc2ccccc21
Reactant: CC(C)CCN
Solvent: CC#N
Product: Cc1ccccc1Cn1c(CNCCC(C)C)nc2ccccc21
Yield: 92 %

Procedure:
A solution of 5.4 mmole 2-(chloromethyl)-1-[(2-methylphenyl)methyl]benzimidazole in 20 mL of dry Acetonitrile is treated with 10 mL of isoamylamine for 16 hr at room temperature. The solvent is removed in vacuo and the residue is partitioned between 30 mL of ethyl acetate and 10 mL of 1 N NaOH. The ethyl acetate layer is dried over anhydrous Na2SO4 and solvent removed in vacuo to afford 1.6 g 92% ({1-[(2-methylphenyl)methyl]benzimidazol-2-yl}methyl) (3-methylbutyl)amine. 2,4-dimethoxybenzoylchloride 1.5 eq is treated with 1.0 eq of ({1-[(2-methylphenyl)methyl]benzimidazol-2-yl}methyl) (3-methylbutyl)amine in dichloromethane at room temperature for 1 hr. The reaction is quenched with 1 N NaOH and partitioned between dichloromethane and water. The organic layer is dried with Na2SO4 and the solvent removed in vacuo. The residue is chromatographed (SiO2) with ethyl acetate to afford 95% of (2,4-dimethoxyphenyl)-N-({1-[(2-methylphenyl)methyl]benzimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide (Compound 1). Mass Spec M+ 486.