Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[Br:14]N1C(C)(C)C(=O)N(Br)C1=O>ClCCl.CCCCCCC>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:9])([F:10])([F:11])[F:12])=[CH:4][C:3]=1[Br:14]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: Nc1ccc(S(F)(F)(F)(F)F)cc1Br
Temperature: 5 °C
Yield: 173.6 %

Procedure:
4-Aminophenylsulfur pentafluoride (510 g, 2.327 mol) was dissolved in dichloromethane (7 l), the solution was cooled to 5° C. and, while stirring, 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (326 g, 1.14 mol) was introduced in several portions with ice cooling such that the internal temperature was kept at 3-8° C. (about 1 h). Subsequently, the mixture was stirred without external cooling for 1 h and allowed to warm to room temperature. The mixture was filtered through a bed of silica gel (volume about 1 l) and washed with dichloromethane (5.5 l), and the filtrate was concentrated under reduced pressure. About 700 g of a red-brown crystalline mass were obtained and were dissolved in n-heptane (600 ml) at 60° C. and then crystallized in a refrigerator at 4° C. Filtration with suction gave 590 g (85%) of 4-amino-3-bromophenylsulfur pentafluoride as brownish crystals, m.p. 59-59.5° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[N:12]=[C:11]([CH2:13]Br)[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:17]([NH:19][CH:20]([CH:24]([CH3:26])[CH3:25])[C:21]([OH:23])=[O:22])=[O:18]>>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[N:12]=[C:11]([CH2:13][C:20]([NH:19][CH:17]=[O:18])([CH:24]([CH3:26])[CH3:25])[C:21]([OH:23])=[O:22])[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Oc2cccc(CBr)n2)cc1
Reactant: CC(C)C(NC=O)C(=O)O
Product: CC(C)C(Cc1cccc(Oc2ccc(F)cc2)n1)(NC=O)C(=O)O

Procedure:
Following the procedure of Example 1, [6-(4-fluorophenoxy)-2-pyridyl]methyl bromide can be reacted with 2-(N-formylamino)-3-methyl-butanoic acid to give [6-(4-fluorophenoxy)-2-pyridyl]methyl 2-(N-formylamino)-3-methyl-butanoic acid, which is further reacted with methanol, yielding [6-4-fluorophenoxy)-2-pyridyl]methyl 2-amino-3-methylbutanoate.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:9][C:10]1[C:11](=[O:20])[C:12]([CH3:19])=[C:13]([CH3:18])[C:14](=[O:17])[C:15]=1[CH3:16].Cl.C(OCC)(=O)C>C1COCC1>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][C:11]1([OH:20])[C:12]([CH3:19])=[C:13]([CH3:18])[C:14](=[O:17])[C:15]([CH3:16])=[C:10]1[CH3:9])[CH3:8]
Reactant: CC1=C(C)C(=O)C(C)=C(C)C1=O
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)C(C)=C(C)C(=O)C(C)=C1C
Yield: 94 %

Procedure:
Under nitrogen atmosphere, 6 mL of THF was added to 1.22 g (2 mmol, 0.6 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.45 g (3.33 mmol) of 2,3,5,6-tetramethyl-1,4-benzoquinone in 4 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 1 hour. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After cooling, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 0.79 g of the desired product (yield 94%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:5]([C:17]([O:19][CH3:20])=[O:18])=[C:4]([CH:21]([CH3:23])[CH3:22])[N:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[C:5]([C:17]([O:19][CH3:20])=[O:18])=[C:4]([CH:21]([CH3:23])[CH3:22])[N:3]=1
Reactant: COC(=O)c1c(C(C)C)nc(N)c(CO)c1-c1ccc(F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1c(C(C)C)nc(N)c(C=O)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20.7 g (65 mmol) of the compound from Example IV are dissolved in 1.5 1 of dichloromethane, 13.3 g (0.13 mol) of neutral alumina and 28 g (0.13 mol) of pyridinium chlorochromate are added and the mixture is stirred at room temperature for 1 hour.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:24][NH2:25])([OH:23])[C:19]([F:22])([F:21])[F:20])=[O:15].[Br:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:28]=1[C:29](Cl)=[O:30].C(N(C(C)C)CC)(C)C>O1CCCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:24][NH:25][C:29]([C:28]1[C:32]([Cl:36])=[CH:33][CH:34]=[CH:35][C:27]=1[Br:26])=[O:30])([OH:23])[C:19]([F:22])([F:21])[F:20])=[O:15]
Reactant: NCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Reactant: O=C(Cl)c1c(Cl)cccc1Br
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1c(C(=O)NCC(O)(CNC(=O)c2c(Cl)cccc2Br)C(F)(F)F)cnn1-c1ccc(F)cc1
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of 5-amino-N-[2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (250 mg, 0.69 mmol) in tetrahydrofuran (2 ml) was added 2-bromo-6-chlorobenzoyl chloride (192.7 mg, 0.76 mmol) followed by diisopropylethylamine (178 mg, 1.38 mmol). The reaction was left stirring under nitrogen overnight. LC-MS analysis showed the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was redissolved in dichloromethane and washed with 2M hydrochloric acid followed by water. The organic layer was concentrated in vacuo to give the title compound (280 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[CH2:13](O)[CH2:14][CH2:15][OH:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[O:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C1Nc2ccc(Br)cc2C12OCCCO2
Yield: 45.6 %

Procedure:
A mixture of 5-bromoisatin (5.00 g, 22.1 mmol), 1,3 propanediol (4.86 mL, 66.4 mmol, 3 eq) and p-toluenesulfonic acid monohydrate (0.84 g, 4.42 mmol, 0.2 mole %) in benzene (430 mL) was refluxed with a Dean Stark Trap for 5 hr. The mixture was concentrated and washed with sat. aq. NaHCO3 (2×) and brine (1×) and flash chromatographed (Biotage KP silica gel, step gradient 70/30-60/40 Petroleum ether/EtOAc) to give the title compound as a bright yellow solid (2.86 g, 46% ). Anal. Calc'd for C11H10BrNO3: C, 46.50; H, 3.55; N, 4.93. Found: C, 46.82; H, 3.54; N, 4.82. IR: consistent. NMR (300 Mz, DMSO-d6): consistent. MS: (ESI−) m/z 281/283 [M−H], 1 Br pattern observed. m.p.: 202-203° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cl:22][C:23]1(Cl)[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]1(Cl)[O:30][CH2:31][CH2:32][CH2:33]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC.CO>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:33][CH2:32][CH2:31][O:30][C:24]3[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=3[Cl:22])[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: ClCCCOC1(Cl)C(Cl)=CC=CC1(Cl)Cl
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: CCCCO
Product: Fc1ccc(C(c2ccc(F)cc2)C2CCN(CCCOc3c(Cl)cccc3Cl)CC2)cc1
Yield: 27.7 %

Procedure:
A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine (free base 6.90 g, 0.024 mole), 1,3-dichloro-1,2-dichloro-2-(3-chloropropoxy)benzene (5.72 g, 0.024 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at gentle reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g). The reaction was stripped to dryness. The residue was partitioned several times between chloroform and water. The chloroform layer was dried, filtered, and solvent removed to give an oil. The oil was placed in the refrigerator overnight in 50 ml of methanol. A white solid was obtained and dried in vacuo overnight at 80° C. A yield of 3.26 g (27.7%) of white crystalline solid, m.p. 101.5°-103° C. was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.[OH-].[K+].[CH3:11][N:12]([CH2:14][CH2:15]Cl)[CH3:13].Cl>CS(C)=O.O>[Br:8][C:6]1[CH:5]=[CH:4][N:3]([CH2:15][CH2:14][N:12]([CH3:13])[CH3:11])[C:2](=[O:1])[CH:7]=1
Reactant: Oc1cc(Br)ccn1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)CCn1ccc(Br)cc1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
To a solution of 2-hydroxy-4-bromopyridine (0.10 g, 0.57 mmol) in DMSO (1.0 mL) was added KOH (0.13 g, 2.29 mmol) and the resulting reaction mixture was stirred for 10 min at room temperature followed by addition of N,N-dimethylaminoethylchloride.HCl (0.098 g, 0.68 mmol). The reaction mixture was then stirred at 40° C. for 1 h. After the completion of reaction (TLC monitoring), water was added to the reaction and extracted with EtOAc (3×25 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was triturated with ether to obtain the desired product (0.10 g, 72%). MS: 245.10 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH-:15].[O:16]=[C:17]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:30](O)=O)[C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2>C(O)(=O)C>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:5]=[CH:4][C:3]3[N:15]=[C:30]([C:25]4[C:24]5[C:23]6[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=6)[C:17](=[O:16])[C:29]=5[CH:28]=[CH:27][CH:26]=4)[NH:1][C:2]=3[CH:7]=2)[CH2:9][CH2:10]1
Reactant: CN1CCN(c2ccc([NH-])c(N)c2)CC1
Reactant: O=C(O)c1cccc2c1-c1ccccc1C2=O
Solvent: CC(=O)O
Product: CN1CCN(c2ccc3nc(-c4cccc5c4-c4ccccc4C5=O)[nH]c3c2)CC1

Procedure:
The procedure used in Example 68 is followed. In a 250 ml round-bottomed flask under an argon atmosphere, reflux, for 6 hours, a suspension of 4 g of [2-amino-4-(4-methylpiperazin-1-yl)phenyl]amide of 9-oxo-9H-fluorene-4-carboxylic acid, obtained in the previous stage, in 64 ml of acetic acid. After purification by formation of a paste with diisopropyl ether, in this way we obtained 2.5 g of 4-[6-(4-methylpiperazin-1-yl)-1H -benzimidazol-2-yl]-9H-fluoren-9-one, in the form of an orange powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[Br:11]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C>[Br:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][N:6]=1
Reactant: BrBr
Reactant: Clc1ccc2[nH]ncc2c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc2[nH]nc(Br)c2c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A flask was charged with 5-chloro-1H-indazole (4.9 g, 32.11 mmol) and DMF (30 mL). It was then cooled to 0° C., and a solution of bromine (2.4 mL, 46.86 mmol) in DMF (30 mL) was added over several minutes. After addition was complete, the flask was warmed to rt and stirred for 4 hours. Additional bromine (0.89 mL, 16 mmol) was added, and the reaction stirred at room temperature for 20 minutes. The reaction was poured into 600 mL of ice-cold 1% (w/v) Na2S2O3 solution, and the precipitated product was filtered off. The product was redissolved in EtOAc (500 mL), washed with saturated aqueous NaHCO3 then brine, dried over Na2SO4, and concentrated to afford the product. 1H NMR (400 MHz, DMSO-d6) δ 13.60 (br s, 1H), 7.68-7.54 (m, 2H), 7.44 (dd, J=9.0, 1.8 Hz, 1H).
Reaction SMILES: [CH3:1][C@@H:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][CH2:17][C:18]([C:20]2[CH:21]=[CH:22][C:23]3[C:32]4[CH:31]=[C:30]5[CH2:33][CH2:34][CH:35](Br)[C:36](=[O:37])[C:29]5=[CH:28][C:27]=4[O:26][CH2:25][C:24]=3[CH:39]=2)=[O:19])=[O:15])[CH2:4][CH2:3]1.[C:40]([O:44][C:45]([N:47]1[C@@H:51]([CH3:52])[CH2:50][CH2:49][C@H:48]1[C:53]([OH:55])=[O:54])=[O:46])([CH3:43])([CH3:42])[CH3:41].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O.C(Cl)Cl>[CH3:1][C@@H:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][CH2:17][C:18]([C:20]2[CH:21]=[CH:22][C:23]3[C:32]4[CH:31]=[C:30]5[CH2:33][CH2:34][CH:35]([O:55][C:53]([C@@H:48]6[CH2:49][CH2:50][C@H:51]([CH3:52])[N:47]6[C:45]([O:44][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:46])=[O:54])[C:36](=[O:37])[C:29]5=[CH:28][C:27]=4[O:26][CH2:25][C:24]=3[CH:39]=2)=[O:19])=[O:15])[CH2:4][CH2:3]1
Reactant: C[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Reactant: C[C@H]1CC[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCC(Br)C4=O)N1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: C[C@H]1CC[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCC(OC(=O)[C@@H]2CC[C@H](C)N2C(=O)OC(C)(C)C)C4=O)N1C(=O)OC(C)(C)C
Temperature: 40 °C
Yield: 53.1 %

Procedure:
(2S,5S)-2-(2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (700 mg, 1.17 mmol) was treated with a solution of (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (375 mg, 1.64 mmol) in acetone (6 mL) and Cs2CO3 (267 mg, 0.82 mmol). The stirred reaction mixture was heated to 40° C. for 16 h, then cooled to RT and diluted with CH2Cl2 and extracted 3×. The organic phase was washed with brine, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (40% to 100% EtOAc/hexanes) to afford (2S,5S)-2-(2-(9-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carbonyloxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (464 mg, 53%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[NH:16])OCC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][NH2:20]>>[NH2:17][CH2:18][CH2:19][NH:20][C:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[NH:16]
Reactant: CCOC(=N)NC(=O)OCc1ccccc1
Reactant: NCCN
Product: N=C(NCCN)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-benzyloxycarbonyl-O-methyl-isourea (II-OMe) (0.42 g, 2.0 mmol) and 1,2-diaminoethane (Ic) (0.72 g, 12 mmol) was stirred at 40° C. for 3 h and at 25° C. for 1 h. The crystals were collected by filtration. The white crystalline product was washed with toluene (4×1 mL) and dried (vacuum, 30°-35° C., 2 h). The yield of N-(2-aminoethyl)-N'-benzyloxycarbonyl guanidine IIIc was 0.28 g (60% in theory).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][C:22]([O:25][C:26](=[O:38])[NH:27][CH:28]([CH3:37])[C:29](=[O:36])[NH:30][CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)([CH3:24])[CH3:23].C(N(CC)CC)C>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:33]4[CH2:34][CH2:35][CH:31]([NH:30][C:29](=[O:36])[CH:28]([NH:27][C:26]([O:25][C:22]([CH3:24])([CH3:23])[CH3:21])=[O:38])[CH3:37])[CH2:32]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)NC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(NC(=O)OC(C)(C)C)C(=O)NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 61.5 %

Procedure:
A suspension of 1.4 g (50 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1.92 g (7.5 mmol) of [1-methyl-2-oxo-2-[(3-pyrrolidinyl)amino]ethyl]-carbamic acid 1,1-dimethylethyl ester, 1.5 g (15 mmol) of triethylamine and 75 ml of acetonitrile was heated at reflux for five hours. The solvent was removed in vacuo and the residue was partitioned between chloroform/water (250 ml each) and acidified to pH 2.0 at 0° with 6.0M hydrochloric acid. The solid was removed by filtration, washed with water and dried in vacuo to give 2.4 g of the title compound, mp 185°-187°.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[Br:18].Cl[C:29]([O:31][CH3:32])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[F:23][C:22]([F:25])([F:24])[C:20]1[CH:19]=[C:5]([CH:4]=[C:3]([C:2]([F:26])([F:1])[F:27])[CH:21]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[Br:18])[C:29](=[O:30])[O:31][CH3:32]
Reactant: O=[N+]([O-])c1ccc(Br)c(CNCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc([N+](=O)[O-])ccc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [3,5-bis(trifluoromethyl)benzyl](2-bromo-5-nitrobenzyl)amine from Step C (0.47 g, 1.0 mmol) in methylene chloride (20 ml) at room temperature, methyl chloroformate (0.12 ml, 1.54 mmol) and triethylamine (0.29 ml, 2.05 mmol) were added. The solution was stirred at room temperature for 18 h. The solvent was removed under reduced pressure. The title compound was obtained by flash column chromatography using 1:9 EtOAc/hexane as the eluant. 1H NMR (CDCl3, 500 MHz) δ 8.11 (m, 1H), 8.02 (dd, J=9.0, 2.5 Hz, 1H), 7.81 (s, 1H), 7.74 (d, J=9.0 Hz, 1H), 7.70 (m, 1H), 7.65 (m, 1H), 4.67 (m, 4H), 3.89 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>CC(C)=O>[C:29]([O:28][C:26](=[O:27])[CH2:25][O:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
In a 100 mL round bottomed flask benzyl 4-hydroxybenzoate (1.445 g, 6.33 mmol) and potassium carbonate (4.17 g, 30.1 mmol) in acetone (100 ml) were combined. Tert-butyl 2-bromoacetate (0.908 ml, 6.03 mmol) was added dropwise. The solution was stirred at 65° C. overnight. The solution was cooled then, the reaction mixture was filtered through a sintered glass funnel. The filtrate was concentrated to afford pale yellow oil, which was purified via silica gel chromatography (40 g, 30% EtOAc:Heptane) to afford benzyl 4-(2-tert-butoxy-2-oxoethoxy)benzoate (2.06 g, 5.90 mmol, 98% yield) as colorless oil. LC/MS (Table 1, Method a) Rt=4.31 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][NH:8][CH2:9][CH2:10][CH2:11][S:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:22]([S:25][CH2:26][CH:27]([CH3:31])[C:28](Cl)=[O:29])(=[O:24])[CH3:23]>O1CCOCC1>[C:1]([O:5][C:6](=[O:14])[CH2:7][N:8]([C:28](=[O:29])[CH:27]([CH3:31])[CH2:26][S:25][C:22](=[O:24])[CH3:23])[CH2:9][CH2:10][CH2:11][S:12][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSCCCNCC(=O)OC(C)(C)C
Reactant: CC(=O)SCC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CSCCCN(CC(=O)OC(C)(C)C)C(=O)C(C)CSC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.8 %

Procedure:
To a solution of N-(3-methylthiopropyl)glycine t-butyl ester (36.4 g, 0.166 mol) and triethylamine (20.2 g, 0.199 mol) in 300 ml of dioxane was added dropwise 3-acetylthio -2-methylpropanoyl chloride (30.0 g, 0.166 mol). After stirring at room temperature for 16 hours the mixture was filtered and concentrated to yield 52.9 g. Purification by medium pressure liquid chromatography eluting with 20% ethyl acetate in hexane gave 18.0 g (30%) of N-(3-acetylthio-2-methylpropanoyl)-N-(3-methylthiopropyl)glycine t-butyl ester as a colorless oil. Rf =0.19 (20% ethyl acetate in hexane).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:40][O:41][CH3:42])[C:4]([CH3:39])=[C:5]([C:28]([O:30]COC(=O)C(C)(C)C)=[O:29])[CH:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:7]=1[C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:9]>C(OC(C)C)(C)C.O>[CH3:39][C:4]1[N:3]([CH2:40][O:41][CH3:42])[C:2]([CH3:1])=[C:7]([C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:15])([CH3:16])[CH3:17])=[O:9])[C@H:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:5]=1[C:28]([OH:30])=[O:29]
Reactant: COCN1C(C)=C(C(=O)OCOC(=O)C(C)(C)C)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Solvent: CC(C)OC(C)C
Solvent: O
Product: COCN1C(C)=C(C(=O)O)[C@@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.1 %

Procedure:
In 20 ml of isopropyl ether saturated with water was dissolved 590 mg of bis(pivaloyloxymethyl) 1,4-dihydro -2,6-dimethyl-1-methoxymethyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylate obtained in Example 1 or 2, and 200 mg of Lipase PS was added thereto, followed by stirring at room temperature for 72 hours. Any insoluble matter was removed by filtration and washed with dichloromethane. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to obtain 210 mg (yield: 44%) of (R)-1,4-dihydro-2,6-dimethyl-1-methoxymethyl -4-(3-nitrophenyl)-5-pivaloyloxymethoxycarbonyl -3-pyridinecarboxylic acid as a pale yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)CCc1ccc(C(=O)OC)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of methyl 4-(3-methoxy-3-oxopropyl)benzoate (10 g) and sulfuric acid (50 ml) was added dropwise fumed nitric acid (5.7 ml) under ice-cooling, followed by stirring at room temperature for 4 hours. The reaction mixture was poured into ice-water and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue were added methanol and concentrated sulfuric acid, followed by stirring at 105° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added to the residue under ice-cooling. The resulting solid was collected by filtration and washed with a saturated aqueous sodium hydrogen carbonate solution and water to obtain methyl 4-(3-methoxy-3-oxopropyl)-3-nitrobenzoate (12 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:13]1(O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][O:11][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](COc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 13.5 %

Procedure:
Dissolve (R)-(+)-2-(tert-butoxycarbonylamino)-1-propanol (1.75 g, 10 mmol) and phenol (0.95 g, 10 mmol) in anhydrous THF (75 mL). Cool to 0° C., add triphenylphosphine (4.0 g, 15 mmol) and diisopropylazodicarboxylate dropwise and stir at ambient temperature for 18 h. Pour the mixture into water (300 mL), basify to pH 10 with 5N aqueous NaOH, and extract with ethyl ether (3×100 mL). Wash the organic phase with brine, dry over MgSO4, filter and concentrate. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the desired intermediate as an off-white solid (340 mg, 14%).