Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)(O[CH2:13][CH2:14][F:15])(=O)=O>CN(C=O)C.C(OCC)(=O)C>[F:15][CH2:14][CH2:13][NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FCCNc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
In a round bottom flask 4-fluoroaniline (1.3 g, 11.6 mmol, 1.6 mL) 2,6-lutidine (1.24 g, 11.6 mmol) and 2-fluoroethyl tosylate (12; prepared according to Example 2(a)) (2.5 g, 11.6 mmol) were combined in DMF (5 mL) and stirred at 100° C. overnight. The reaction was allowed to cool and then diluted with ethyl acetate (100 mL). This was washed with water (3×40 mL) and the organics were dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (10% B, 100 g, 12 CV, 60 mL/min) to afford 383 mg (20%) of (2-fluoro-ethyl)-(4-fluoro-phenyl)-amine (38) as a yellow oil. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δH 3.30-3.35 (1H, m, NCH2CH2F), 3.40-3.45 (1H, m, NCH2CH2F), 3.90 (1H, s, br, NH), 4.53 (1H, t, J=3 Hz, NCH2CH2F), 4.69 (1H, t, J=3 Hz, NCH2CH2F), 6.51-6.72 (2H, m, 2×NCCH), 6.85-7.05 (2H, m, 2×NCCHCH).
Reaction SMILES: [Si:1]([O:8][CH:9]([C@H:11]1[C:39](=[O:40])[N:13]2[C:14]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:15](S(C3C=CC=CC=3)=O)[C@H:16]([CH3:17])[C@H:12]12)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N+:41]([C:44]1[CH:57]=[CH:56][C:47]([CH2:48][O:49][C:50]([NH:52][CH2:53][CH2:54][SH:55])=[O:51])=[CH:46][CH:45]=1)([O-:43])=[O:42]>>[Si:1]([O:8][C@@H:9]([C@H:11]1[C:39](=[O:40])[N:13]2[C:14]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:15]([S:55][CH2:54][CH2:53][NH:52][C:50]([O:49][CH2:48][C:47]3[CH:56]=[CH:57][C:44]([N+:41]([O-:43])=[O:42])=[CH:45][CH:46]=3)=[O:51])[C@H:16]([CH3:17])[C@H:12]12)[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S(=O)c3ccccc3)[C@H](C)[C@H]12
Reactant: O=C(NCCS)OCc1ccc([N+](=O)[O-])cc1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H](C)[C@H]12

Procedure:
Following a procedure similar to that described in Example 21(b), but using the S-oxide isomer of lower polarity of the 4-nitrobenzyl (1R,5S,6S)-6-[1-t-butyldimethylsilyloxyethyl]-1-methyl-2-phenylsulfinyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 2) and 2-(4-nitrobenzyloxycarbonyl)aminoethylmercaptan as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]([C:11]1[CH:81]=[CH:80][CH:79]=[CH:78][C:12]=1[CH2:13][O:14][C:15]([NH:17][CH2:18][C@H:19]([S:75][S:76][CH3:77])[CH2:20][CH2:21][C@@H:22]([NH:67]C(OC(C)(C)C)=O)[C:23]([O:25][C@H:26]1[C@@H:30]([OH:31])[C@@H:29]([N:32]2[CH:40]=[N:39][C:38]3[C:33]2=[N:34][CH:35]=[N:36][C:37]=3[NH2:41])[O:28][C@H:27]1[CH2:42][O:43][P:44]([O:47][C@H:48]1[CH2:52][C@H:51]([N:53]2[CH:58]=[CH:57][C:56]([NH2:59])=[N:55][C:54]2=[O:60])[O:50][C@@H:49]1[CH2:61][O:62][P:63]([OH:66])([OH:65])=[O:64])([OH:46])=[O:45])=[O:24])=[O:16])=[N+:9]=[N-:10]>ClCCl>[NH2:67][C@H:22]([CH2:21][CH2:20][C@@H:19]([S:75][S:76][CH3:77])[CH2:18][NH:17][C:15]([O:14][CH2:13][C:12]1[CH:78]=[CH:79][CH:80]=[CH:81][C:11]=1[N:8]=[N+:9]=[N-:10])=[O:16])[C:23]([O:25][C@H:26]1[C@@H:30]([OH:31])[C@@H:29]([N:32]2[CH:40]=[N:39][C:38]3[C:33]2=[N:34][CH:35]=[N:36][C:37]=3[NH2:41])[O:28][C@H:27]1[CH2:42][O:43][P:44]([O:47][C@H:48]1[CH2:52][C@H:51]([N:53]2[CH:58]=[CH:57][C:56]([NH2:59])=[N:55][C:54]2=[O:60])[O:50][C@@H:49]1[CH2:61][O:62][P:63]([OH:66])([OH:65])=[O:64])([OH:46])=[O:45])=[O:24]
Reactant: CSS[C@H](CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O)CNC(=O)OCc1ccccc1N=[N+]=[N-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSS[C@H](CC[C@@H](N)C(=O)O[C@H]1[C@@H](O)[C@@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O)CNC(=O)OCc1ccccc1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
A 10% solution of trifluoroacetic acid in dichloromethane (0.1 mL) was added to a solution of (2S,5S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)-5-(methyldisulfanyl)hexanoate (Compound tk17) (2.8 mg, 2.504 μmol) in dichloromethane (0.1 mL), and the mixture was stirred at room temperature for 60 minutes. Following concentrated under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S,5S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-amino-6-((((2-azidobenzyl)oxy) carbonyl)amino)-5-(methyldisulfanyl)hexanoate (Lys(5S-SSMe) (oAcbz)-pdCpA) (Compound tk18) (1.4 mg, 55%).
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:3]=1[CH2:4][N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:22][CH2:23][CH3:24])[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=1.O.[OH-].[Li+]>C1COCC1>[F:1][C:2]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:3]=1[CH2:4][N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:22][CH2:23][CH3:24])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1
Reactant: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(C[C@H](OCC)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution of ethyl(2S)-3-(4-{2-[(2,4-difluorobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (0.047 g, 0.090 mmol) in THF (2.0 mL) was added water (2.0 mL) and lithium hydroxide (0.010 mg, 0.42 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, acidified with 2M HCl, and extracted with ethyl acetate (4×25 mL). The combined organic phase was washed with brine (25 m]L), dried over Na2SO4, and concentrated in vacuo to afford 0.044 g (89%) of a colourless oil.
Reaction SMILES: [CH2:1]([SH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Na].[CH2:15]([CH:17]1[O:19][CH2:18]1)Br>C(O)C.CCOCC>[CH2:1]([S:13][CH2:15][CH:17]([OH:19])[CH2:18][S:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: BrCC1CO1
Reactant: CCCCCCCCCCCCS
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CCCCCCCCCCCCSCC(O)CSCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
26.6 ml Dodecanethiol was added to an ethylate solution of 2.6 g sodium in 100 ml ethanol and the solution was stirred for 1 hour at room temperature. Then 8.5 ml epibromohydrin was added dropwise within 30 min and stirred overnight. The residue was taken up in ether after removing the solvent, washed twice with water and dried. The desired compound crystallized on evaporation of the solution. Yield 28.5 g (62%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:9]2[CH2:11][O:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[CH2:25][NH2:26]>CC#N>[CH:1]1([CH2:7][C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:9]([OH:10])[CH2:11][NH:26][CH2:25][C:24]2[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=[C:22]([O:21][CH3:20])[CH:23]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H]1CO1
Reactant: COc1cc(CN)cc(OC)c1
Solvent: CC#N
Product: COc1cc(CNC[C@@H](O)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)cc(OC)c1
Yield: 60.9 %

Procedure:
To a solution of tert-butyl (S)-2-cyclohexyl-1-((S)-oxiran-2-yl)ethylcarbamate (67.3 mg, 0.25 mmol) in CH3CN (8 mL) was added 3,5-dimethoxybenzylamine (50 mg, 0.3 mmol) and the mixture was heated under reflux overnight. The solvent was removed in vacuo and the residue was purified by the preparative HPLC to give tert-butyl (2S,3R)-1-cyclohexyl-4-(3,5-dimethoxybenzylamino)-3-hydroxybutan-2-ylcarbamate (66.5 mg, 61%). 1H NMR: 0.82 (m, 1H), 0.95 (m, 1H), 1.10-1.48 (m, 6H), 1.42 (s, 9H), 1.65 (m, 4H), 1.80 (m, 1H), 2.67 (m, 2H), 3.46 (m, 1H), 3.64 (m, 1H), 3.72 (d, 2H), 3.79 (s, 6H), 6.35 (m, 1H). MS (E/Z): 437 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[H][H]>C(O)C.O.[Pt]=O>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C(O)C=Cc1ccc(F)cc1Cl
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Solvent: O
Product: O=C(O)CCc1ccc(F)cc1Cl
Yield: 101.4 %

Procedure:
A mixture of 2-chloro-4-fluorocinnamic acid (22.9 g, 0.11 mol) and platinum oxide hydrate (0.5 g, EM Scientific) in 95% ethanol (140 ml) was placed on a Parr hydrogenation apparatus. After the appropriate amount of hydrogen was taken up, the catalyst was filtered and the mixture was concentrated in vacuo to give 22.6 g (98%) of 3-(2-chloro-4-fluorophenyl)propanoic acid as a purple solid. This material was used without further purification.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[CH2:6]([C@@H:13]1[CH2:17][O:16][C:15](=[O:18])[N:14]1[C:19](=[O:26])[CH:20]([CH2:24]I)[CH:21]([CH3:23])[CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>CN(C)C=O>[CH2:6]([C@@H:13]1[CH2:17][O:16][C:15](=[O:18])[N:14]1[C:19](=[O:26])[C@H:20]([CH2:24][S:3][C:1](=[O:4])[CH3:2])[CH:21]([CH3:22])[CH3:23])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)C(CI)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)SC[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
Potassium thioacetate (19 g) was added to a solution of the 4-(R)-benzyl-3-(2-iodomethyl-3-methylbutanoyl)oxazolidin-2-one (56 g) in N,N-dimethylformamide (200 ml), and the mixture was stirred for 3 h at room temperature, then poured into water (600 ml). The mixture was extracted with diethyl ether (2×500 ml) and the organic solvent washed with water and saturated brine, dried (Na2SO4) and evaporated to give the title compound as a pale amber oil (48.6 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C(N(C(C)C)C(C)C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate A1a (2 g, 11.5 mmol) in dichloromethane (0.5M, 23 mL) is treated with ethyldiisopropylamine (3 mL, 17.5 mmol) and the mixture is cooled to 0° C. Methanesulfonyl chloride (0.99 mL, 12.7 mmol) is then added dropwise and the mixture is allowed to stir at room temperature for 6 hours. The mixture is diluted with dichloromethane, washed with 1M HCl, brine, dried over sodium sulfate and concentrated in vacuo to afford tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate A1b as oil that solidifies upon standing: 1H-NMR (400 MHz, CDCl3) δ=5.25-5.19 (m, 1H), 4.30 (ddd, J=10.4, 6.4, 1.2 Hz, 2H), 4.12 (ddd, J=10.4, 4.0, 1.2 Hz, 2H), 3.09 (s, 3H), 1.46 (s, 9H); MS calcd. for C9H18NO5S ([M+H]+): 252.1, found: 252.2. The product is used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[CH2:12]([NH2:18])[CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1>O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH:18][CH2:12][CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: NCC1CCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc(NCC2CCCO2)c(Cl)c1
Temperature: 150 °C

Procedure:
A mixture of 0.3 mol (57.6 g) of 3,4-dichloronitrobenzene and 1 mol (101 g) of tetrahydrofurfurylamine is heated in an oil bath. When the temperature of the reaction medium reaches 110° C., the reaction starts and the temperature rises rapidly to 160° C. and is maintained for a certain time without external heating. When the temperature falls, the reaction medium is heated for 30 minutes in an oil bath at 150° C. and is then poured into 500 ml of ice-cooled water. The expected product initially precipitates in the form of an oil which rapidly crystallises. After it has been filtered off, washed with water, recrystallised and dried in vacuo, the product melts at 70° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH3:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:25]=[C:24]([CH3:26])[S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: Cc1cc2c(NCc3ccc(F)cc3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(4-fluorobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[C:8]([CH3:16])[CH:7]=1>C(O)(=O)C>[F:5][C:6]1[CH:11]=[C:10]([N+:1]([O-:4])=[O:2])[C:9]([NH:12][C:13](=[O:15])[CH3:14])=[C:8]([CH3:16])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(F)cc1C
Solvent: CC(=O)O
Product: CC(=O)Nc1c(C)cc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 87 %

Procedure:
With cooling with ice, fuming nitric acid (25 ml) was dropwise added to an acetic acid (100 ml) solution of N-(4-fluoro-2-methylphenyl)acetamide (I-259) (10.0 g, 59.8 mmol), taking 50 minutes. After the addition, then restoration to room temperature and stirring for 23 hours, the reaction liquid was poured into ice. The precipitated solid was collected by filtration, washed with water, then dried to obtain the entitled compound (11.1 g, 87%) as a pale brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].C(N([CH:39]([CH3:41])[CH3:40])CC)(C)C>CC#N.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH:5]([C:40]3[CH:39]=[CH:41][CH:8]=[CH:7][CH:6]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(C(c3ccccc3)c3ccccc3)C2)c1
Yield: 97.8 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (58 mg, 0.13 mmol) in CH3CN (5 ml) was added α-Bromodiphenyl methane (48.0 mg, 0.19 mmol), and diisopropylethylamine (45 μl, 0.26 mmol). The reaction was microwaved at 130° C. for 10 minutes. The reaction was diluted with EtOAc and washed with brine, sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (39 mg, 49%). Calcd for C39H42F3NO2 (M+H) 613.75, Found 614.4
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[CH2:10][C:9]3([CH2:19][C:18](=[O:20])[C:17]4[C:12](=[CH:13][CH:14]=[C:15](/[CH:21]=[CH:22]/[C:23]([OH:25])=O)[CH:16]=4)[O:11]3)[CH2:8]2)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:42][O:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][O:45]1>C(Cl)Cl>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[CH2:8][C:9]3([CH2:19][C:18](=[O:20])[C:17]4[C:12](=[CH:13][CH:14]=[C:15](/[CH:21]=[CH:22]/[C:23]([NH:42][O:43][CH:44]5[CH2:49][CH2:48][CH2:47][CH2:46][O:45]5)=[O:25])[CH:16]=4)[O:11]3)[CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccc(F)cc3)C1)O2
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccc(F)cc3)C1)O2)NOC1CCCCO1
Yield: 81.1 %

Procedure:
A suspension of (E)-3-[1′-(4-fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (300 mg, 0.74 mmol) in DCM (9 ml) was treated with TEA (0.17 ml, 1.2 mmol) and then with EDC (235 mg, 1.23 mmol), HOBt (166 mg, 1.23 mmol) and NH2OTHP (115 mg, 0.982 mmol) following the procedure described in Example 30, Step B, giving (E)-3-[1′-(4-fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (280 mg) as a light yellow solid.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH3:9][Si:10]([CH3:26])([C:22]([CH3:25])([CH3:24])[CH3:23])[O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.CI>O1CCCC1>[CH3:26][Si:10]([CH3:9])([C:22]([CH3:23])([CH3:25])[CH3:24])[O:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH3:1])[C:19]([OH:21])=[O:20])=[CH:16][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)O)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Into dry tetrahydrofuran (20 ml) at 0° C. under anhydrous conditions was added slowly with stirring lithium diisopropylamide (2 67 g, 25 mmol) and then a solution of 4-(dimethy1-tert-butylsilyloxy)phenylacetic acid (2.66 g, 1.0 mmoles) in tetrahydrofuran (10 ml) was added dropwise. The resultant brown solution was stirred at 20°-25° C. for one hour and at 50° C. for 30 minutes. The solution was then cooled to 0° C. and methyl iodide (3.54 g, 25 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for about 16 hours and then quenched with saturated aqueous ammonium chloride (20 ml) and acidified with 3N hydrochloric acid. The reaction mixture was extracted with diethyl ether (3×100 ml) and the combined extracts washed with saturated aqueous sodium chloride (2×50 ml), dried over magnesium sulfate and the solvent removed in vacuo to afford a tan oil. The oil was chromatographed on a 5× 15 cm column of silica gel eluted with 10 percent isopropanol/hexane to yield the desired product as a solid. m.p. 52°-4° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[N:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:19]([CH3:25])=[N:18][C:13]=4[CH:14]=[N:15][C:16]=3[CH:17]=2)=[CH:2]1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[N:20]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:19]([CH3:25])=[N:18][C:13]=4[C:14]([NH2:38])=[N:15][C:16]=3[CH:17]=2)=[CH:2]1
Reactant: [NH4+]
Reactant: Cc1nc2cnc3cc(OCc4ccoc4)ccc3c2n1CC(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: Cc1nc2c(N)nc3cc(OCc4ccoc4)ccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
7-(Furan-3-ylmethoxy)-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (500 mg) was dissolved in 30 mL of dichloromethane and 3-chloroperoxybenzoic acid (60% pure, 403 mg) was added. The reaction was stirred for 30 minutes at ambient temperature and then 30 mL of aqueous ammonium hydroxide was added. After 10 minutes, p-toluenesulfonyl chloride (268 mg, 1.40 mmol) was added and the reaction was stirred for an additional 15 minutes. The layers were separated and the aqueous fraction was washed with two portions of dichloromethane (20 mL). The organic fractions were combined and washed three times with 20 mL portions of aqueous sodium carbonate. The combined sodium carbonate fractions were extracted with four portions of chloroform (20 mL). All of the organic fractions were combined, dried over magnesium sulfate, and concentrated to yield an orange foam. The crude product was purified using flash column chromatography on silica gel, eluting with a gradient of methanol in chloroform. The clean fractions were combined, concentrated, and the resulting solid was recrystallized from acetonitrile to give 102 mg of 7-(furan-3-ylmethoxy)-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 181.0-183.0.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7](Br)[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3].C([Li])CCC.[C:17]1(=[O:27])[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12>O1CCCC1.[Cl-].[NH4+]>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[C:17]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])=[O:27])[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc(Br)c1
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCOc1cccc(C(=O)c2ccccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
To a solution of 3-(allyloxy)bromobenzene (15.0 g, 70.5 mmol) in tetrahydrofuran (750 mL) at −70° C. was added 1.6M n-butyllithium (44.1 mL, 70.5 mmol). After stirring for 1 hour, a solution of phthalic anhydride (11.4 g, 77.0 mmol) in tetrahydrofuran (100 mL, previously cooled to −70° C.) was added over 1 hour. The mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was diluted with saturated ammonium chloride solution and extracted with diethyl ether. The organic layer was washed three times with 1N sodium hydroxide solution and the combined aqueous layers were back-extracted with a fresh portion of diethyl ether. The aqueous layer was adjusted to pH˜3 with aqueous hydrochloric acid and extracted three times with fresh diethyl ether. The combined organic layers were washed once with water, once with saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo to reveal an off-white solid. Recrystallization from ether/hexane provided 10.3 g (52%) of the title intermediate as a white crystalline material: mp 109° C.; NMR (CDCl3) 8.20 (d, J=8 Hz, 1H), 7.65 (t, J=8 Hz, 1H), 7.60 (t, J=8 Hz, 1H), 7.30-7.45 (m, 3H), 7.28 (d, J=8 Hz, 1H), 7.20 (d, J=8 Hz, 1H), 6.02 (m, 1H), 5.35 (d, J=16 Hz, 1H), 5.30 (d, J=11 Hz, 1H), 4.55 (d, J=6 Hz, 2H); MS-FD m/e 283 (p+1, 27), 282 (p, 100).