Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=3)[CH2:11][CH2:10][N:9]=2)=[CH:4][CH:3]=1.Br>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[CH2:11][CH2:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)CCN=C2c1ccc(Br)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc2c(c1)CCN=C2c1ccc(Br)cc1
Yield: 95.6 %

Procedure:
Cleavage of the methoxy protecting group (analogously to Ex. 14c) from 1-(4-bromo-phenyl)-6-methoxy-3,4-dihydro-isoquinoline (15 g) is effected with 95 ml of acetic acid and 65 ml of 62% aqueous hydrobromide solution at 100° C. and gives 13.7 g of 1-(4-bromo-phenyl)-3,4-dihydro-isoquinolin-6-ol, MS: m/e 301 (M+, 1 Br).
Reaction SMILES: [CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[N:14](C(OC(C)(C)C)=O)[C:13]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=2)[NH:14][C:13]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC(=O)c1c(NCCC(=O)c2ccccc2)c2ccc(C(F)(F)F)cc2n1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1[nH]c2cc(C(F)(F)F)ccc2c1NCCC(=O)c1ccccc1
Yield: 93.6 %

Procedure:
Dissolve 3-[(phenacyl)methylamino]-2-carbethoxy-6-trifluoromethyl-1-(tert-butyloxycarbonyl)-indole (200 mg, 0.407 mmol) from above in methylene chloride. Add trifluoracetic acid and stir overnight at room temperture. Concentrate the reaction in vacuo, dilute with ethyl acetate and rinse with saturated sodium bicarbonate, dry over magnesium sulfate, filter and concentrate in vacuo to yield 3-[(phenacyl)methylamino]-2-carbethoxy-6-trifluoromethylindole as a foam (154 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11]1([CH:17]2[CH2:23][C:22](=O)O[C:19](=[O:20])[CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(C)=O>C1COCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[N:9]3[C:19](=[O:20])[CH2:18][CH:17]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:23][C:22]3=[N:10][C:4]=2[CH:3]=1
Reactant: O=C1CC(c2ccccc2)CC(=O)O1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=C1CC(c2ccccc2)Cc2nc3cc(Cl)c(Cl)cc3n21
Reaction time: 0.5 h
Yield: 18.7 %

Procedure:
The solution of commercial 4,5-dichloro-1,2-phenylenediamine (0.38 g) and 3-phenylglutaric anhydride (0.4 g) in THF (1 ml) was heated shortly and kept at rt for 0.5 h. The solvent was removed in vacuo and the residue redissolved in acetic acid (3 ml). The dark solution was heated to reflux overnight. Then all volatiles were removed in vacuo and the residue was heated with ethanol (5 ml). After reccoling to rt the precipitate was collected by filtration, washed with ethanol, and dried to give a crude (0.39 g). The crude was decolorized in boiling acetone solution with activated carbon and filtered over Celite. Concentration of the filtrate and drying of the residue afforded 7,8-dichloro-3-phenyl-3,4-dihydropyrido[1,2-a]benzimidazol-1(2H)-one (0.13 g) as colourless crystals.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[S:12][C:13]([C:16]3[C:20]([CH3:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[O:18][N:17]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:4]1.C(N(CC)CC)C.[Cl:33][CH2:34][C:35](Cl)=[O:36]>C1COCC1>[Cl:33][CH2:34][C:35]([NH:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[S:12][C:13]([C:16]3[C:20]([CH3:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[O:18][N:17]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:4]1)=[O:36]
Reactant: O=C(Cl)CCl
Reactant: Cc1c(-c2ccc(C(=O)N3CCC[C@H](N)C3)s2)noc1C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@H](NC(=O)CCl)C3)s2)noc1C(F)(F)F
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of ((S)-3-Amino-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone, hydrochloride (Example 26, 79 mg, 0.20 mmol) and triethylamine (69 μL, 0.42 mmol) in THF (3 mL) was treated with chloroacetyl chloride (18 μL, 0.22 mmol), stirred for 1 hr and evaporated to a solid. The solid was triturated and filtered with the aid of water, then air dried to provide the 2-Chloro-N-{(S)-1-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidin-3-yl}-acetamide intermediate as a colorless solid (75 mg, 86%). LC/MS 6.13 min, [M+1]+ 436. The chloroacetyl intermediate (35 mg, 0.08 mmol) was dissolved in acetonitrile (3 mL) containing anhydrous K2CO3, treated with morpholine (14 μL, 0.16 mmol), and stirred for 3 days. The reaction mixture was then evaporated and treated with water to provide an oil which was then triturated with water (3×2 mL), dissolved in EtOAc (4 mL), dried over MgSO4, filtered, and evaporated to afford product as an oil (34 mg, 87%). 1H NMR (CDCl3) 1.62-1.76 (m, 3H), 1.88-1.98 (m, 1H), 2.29 (d, J=1.3, 3H), 2.45-2.48 (m, 4H), 2.93 (s, 2 H), 3.52 (br s, 1H), 3.63-3.67 (m, 4H), 3.72-3.92 (m, 2H), 3.98-4.08 (m, 1H), 7.32 (br s, 1 H), 7.41 (s, 2H). 19F NMR −63.1. LC/MS 4.68 min, [M+1]+487.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10](CC=C)[C:9]=2[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:27][C:28]#[N:29].N1CCOCC1>CN(C=O)C.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>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:18])[N:7]([CH2:27][C:28]#[N:29])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: N#CCCl
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CC#N)c(=O)c2[nH]c(Cl)nc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 26.1 %

Procedure:
To a mixture of 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (200 mg, 0.707 mmol) and Cs2CO3 (254 mg, 0.778 mmol) in anhydrous DMF (5 ml) was added chloroacetonitrile (0.054 ml, 0.85 mmol). The mixture was heated at 50° C. for 18 hours then allowed to cool to rt and degassed under a gentle vacuum then nitrogen introduced. This was repeated twice. Pd(PPh3)4 (82 mg, 0.071 mmol) was added and the mixture degassed once more, before morpholine (0.617 ml, 7.07 mmol) was added and the mixture left to stir for 3 hours at rt. The mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The residue was taken up in MeOH and passed down an amino-propyl SPE (5 g), eluting with MeOH followed by 5-10% AcOH/MeOH. The product fraction was concentrated giving the title compound 52 mg (26%); NMR; δH (400 MHz, d6-DMSO) 0.90 (t, 3H, J=7.5 Hz), 1.26-1.37 (m, 2H), 1.60-1.69 (m, 2H), 3.94 (t, 2H, J=7.5 Hz), 4.87 (s, 2H), 14.72 (br s, 1H); m/z 299.2 [MNH4+].
Reaction SMILES: Cl[S:2][N:3]([CH2:12][CH2:13][CH3:14])[P:4](=[S:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].[CH3:15][NH:16][C:17](=[O:30])[O:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([N:26]([CH3:28])[CH3:27])=[C:21]([CH3:29])[CH:20]=1.[O-][Si]([O-])=O.[Mg+2].C(OCC)C>CN(C)C=O.CCCCCC>[CH2:6]([O:5][P:4]([N:3]([CH2:12][CH2:13][CH3:14])[S:2][CH2:15][NH:16][C:17](=[O:30])[O:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([N:26]([CH3:27])[CH3:28])=[C:21]([CH3:29])[CH:20]=1)([O:8][CH2:9][CH3:10])=[S:11])[CH3:7]
Reactant: CNC(=O)Oc1cc(C)c(N(C)C)c(C)c1
Reactant: CCCN(SCl)P(=S)(OCC)OCC
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCN(SCNC(=O)Oc1cc(C)c(N(C)C)c(C)c1)P(=S)(OCC)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The crude O,O-diethyl N-(chlorothio)-n-propylphosphoramidothioate (prepared in Preparation I) is cooled in an ice-bath and 2.79 gm. (0.013 mole) of 4-(dimethylamino)-3,5-xylyl methylcarbamate dissolved in 20 ml dimethylformamide (with 2 ml triethylamine added) are mixed as a batch. This reaction mixture is stirred at 25° C. for four hours, and then diluted with hexane. The organic solution is washed with water, dried over anhydrous sodium sulfate, and the organic solvents are removed by evaporation under reduced pressure. The residue thus obtained is transferred to a column of "Florisil". The chromatogram is developed first with a solvent mixture consisting of 10 percent diethyl ether in petroleum ether, and finally with 30 percent diethyl ether in petroleum ether. After collecting the later eluate and removing the solvents by evaporation under reduced pressure, there is obtained the desired 4-(dimethylamino)-3,5-xylyl [[(diethoxyphosphinothioyl)-n-propylamino]thio]methylcarbamate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN1CCOCC1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:27]=1[C:28](Cl)=[O:29]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:28](=[O:29])[C:27]3[C:31]([O:35][CH3:36])=[CH:32][CH:33]=[CH:34][C:26]=3[O:25][CH3:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1cccc(OC)c1C(=O)N1CCC(CCO)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 74.5 %

Procedure:
3-(3,4-Dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (2 g, 7.695 mmol) was dissolved in dichloromethane at -78° C. and treated with 4-methylmorpholine (1.8 mL, 16.4 mmol, 2.1 eq.) and 2,6-dimethoxy-benzoyl chloride (1.55 g, 7.73 mmol) in dichloromethane (20 mL). The solution was allowed to warm to 0° C. and stirred for 1.5 hours. The solution was washed with 1N HCl and 5% sodium bicarbonate and the organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (200 g) with a gradient of 50% ethyl acetate in hexane to 6% methanol in dichloromethane to give 2.434 g (75%) of the title compound.
Reaction SMILES: C(OC(NCC1C=C(NC(=O)COC2C=CC([CH:29]([NH:33][C:34]3[CH:35]=[C:36]4[C:41](=[CH:42][CH:43]=3)[C:40]([N:44]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[N:39][CH:38]=[CH:37]4)[C:30]([OH:32])=[O:31])=CC=2)C=CC=1)=O)C1C=CC=CC=1.[CH2:60]([O:67][C:68]([NH:70][CH2:71][C:72]1[CH:73]=[C:74]([NH:83][C:84](=[O:98])[CH2:85][O:86][C:87]2[C:92]([CH3:93])=[CH:91][C:90](B(O)O)=[CH:89][C:88]=2[CH3:97])[CH:75]=[CH:76][C:77]=1[S:78]([CH2:81][CH3:82])(=[O:80])=[O:79])=[O:69])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>>[CH2:60]([O:67][C:68]([NH:70][CH2:71][C:72]1[CH:73]=[C:74]([NH:83][C:84](=[O:98])[CH2:85][O:86][C:87]2[C:92]([CH3:93])=[CH:91][C:90]([CH:29]([NH:33][C:34]3[CH:35]=[C:36]4[C:41](=[CH:42][CH:43]=3)[C:40]([N:44]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:45]([O:47][C:48]([CH3:51])([CH3:49])[CH3:50])=[O:46])=[N:39][CH:38]=[CH:37]4)[C:30]([OH:32])=[O:31])=[CH:89][C:88]=2[CH3:97])[CH:75]=[CH:76][C:77]=1[S:78]([CH2:81][CH3:82])(=[O:80])=[O:79])=[O:69])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)COc2c(C)cc(B(O)O)cc2C)cc1CNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(NC(C(=O)O)c3ccc(OCC(=O)Nc4cccc(CNC(=O)OCc5ccccc5)c4)cc3)ccc12
Product: CCS(=O)(=O)c1ccc(NC(=O)COc2c(C)cc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2C)cc1CNC(=O)OCc1ccccc1
Yield: 82 %

Procedure:
According to the procedure for the preparation of 66D, 79C (150 mg, 0.271 mmol) afforded 205 mg (82%) of 79D as an orange solid. MS (ESI) m/z 926.5 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]([CH2:20][C:21]([OH:23])=[O:22])[O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[Li]CCCC.C(Cl)(=O)C(Cl)=O.O[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C1COCC1.CCCCCC>[N:38]1([CH2:37][CH2:36][O:22][C:21](=[O:23])[CH2:20][CH:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[NH:3][C:2]3=[O:1])[O:12]2)[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: O=C(O)CC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Reactant: OCCN1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(CC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21)OCCN1CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
To a slurry of [3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-yl]-acetic acid (100 mg, 0.32 mmol) in THF (4.0 ml) at room temperature was added 2.5M n-BuLi in hexane (13611), and the reaction was stirred for 10 minutes. After the reaction was cooled to 0° C., oxalyl chloride (163 μl, 0.32 mmol) was added. After stirring for 20 minutes, 4-(2-hydroxyethyl)morpholine (118 μl, 0.976 mmol) was added. The reaction was stirred for 5 minutes at 0° C., and then at room temperature for 20 minutes. The reaction was partitioned between EtOAc and saturated NaHCO3. The EtOAc layer was washed with brine, dried with anhydrous Na2SO4 and rotary evaporated to afford an orange oil. The orange oil was chromatographed through silica gel column, eluted with CHCl3, to give [3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-yl]-acetic acid 2-morpholin-4-yl-ethyl ester as a yellow foam (43 mg, 32%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C@@H:5]([OH:23])/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].C(N[C@H](C(N[C@H](C(N[C@H](C(O)=O)CC1C=CC=CC=1)=O)CC(C)C)=O)CCSC)=O>>[CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([OH:23])/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCCC[C@@H](O)/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Agent: CSCC[C@H](NC=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: CCCCC(O)/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O

Procedure:
16(R)-HETE (0.01-1.0 μM) was preincubated for 10 minutes with the neutrophil suspension (3×106/ml) prior to the addition of formyl-methionyl-leucyl-phenylalanine (fMLP). Samples were then incubated for an additional 10 minutes with 5×10−7M fMLP. All incubations took place at 37° C. Plasma samples for the measurement of LTB4 were collected by centrifugation of the whole blood samples at 1200 rpm for 15 minutes. Samples were stored at 70° C. until analyzed. The plasma was then acidified to pH3 with 1M Hcl. The plasma was then placed on C2 reverse phase columns (Amprep for Amersham Corp., Arlington Heights, Ill.) to extract LTB4. LTB4 was then measured using the Biotrak LTB4 enzyme immunoassay system (Amersham Corp., Arlington Heights, Ill.). All standards and samples were performed in duplicate. Following incubation, all samples were read at 450 nm and the LTB4 concentration in each sample was determined following the generation of a standard curve. LTB4 concentration was expressed as picograms LTB4 per 1000 neutrophils.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:22][OH:23])[NH:5][C:6](=O)[CH2:7][CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:1][O:2][C:3]([CH:4]1[CH2:22][O:23][C:6]([CH2:7][CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:5]1)=[O:24]
Reactant: CCOC(=O)CC(CC(=O)N[C@@H](CO)C(=O)OC)c1ccccc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: CCOC(=O)CC(CC1=NC(C(=O)OC)CO1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
A solution of (±)-N-(4-ethoxycarbonyl-3-phenylbutanoyl) serine methyl ester (723 mg, 2.14 mmole) and Burgess reagent (613 mg, 2.57 mmole) in dry THF (10 mL) was heated at reflux under N2. After 2 hr, the mixture was cooled to RT and concentrated under reduced pressure. The residue was chromatographed on silica gel (50% EtOAc/hexanes) to give the title compound (420 mg, 61%) as a colorless oil: MS (ES) m/e 320 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH2:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:13][C:14]([F:19])([F:18])[C:15](O)=O>>[F:13][C:14]([F:19])([F:18])[C:15]1[NH:12][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1cnc2ccccc2c1N
Product: FC(F)(F)c1nc2cnc3ccccc3c2[nH]1

Procedure:
Using the method of Example 144, 3,4-diaminoquinoline (from Example 39) was reacted with trifluoroacetic acid to provide 2-trifluoromethyl-1H-imidazo[4,5-c]quinoline, m.p. 252°-254° C. Analysis: Calculated for C11H6F3N3 : %C, 55.7; %H, 2.5; %N, 17.7; Found: %C, 55.3; %H, 2.3; %N, 18.2.
Reaction SMILES: Br[CH:2]1[C:11]2[C:6]3=[C:7]([C:12]([C:14](=[O:20])[C:15]([O:17][CH2:18]C)=[O:16])=[CH:13][N:5]3[CH2:4][CH2:3]1)[CH:8]=[CH:9][CH:10]=2>CN(C)C=N.C([O-])(=O)C.[Ag+]>[CH3:18][O:17][C:15](=[O:16])[C:14]([C:12]1[C:7]2=[C:6]3[C:11](=[CH:10][CH:9]=[CH:8]2)[CH:2]([O:17][C:15](=[O:16])[CH3:14])[CH2:3][CH2:4][N:5]3[CH:13]=1)=[O:20]
Reactant: CCOC(=O)C(=O)c1cn2c3c(cccc13)C(Br)CC2
Agent: [Ag+]
Agent: CC(=O)[O-]
Agent: CN(C)C=N
Product: COC(=O)C(=O)c1cn2c3c(cccc13)C(OC(C)=O)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (6-bromo-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)(oxo)acetate (890 mg, 2.76 mmol) in dimethylformamidine (20 mL) at 0° C. was added silver acetate (458 mg, 2.76 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 hr. The mixture was filtered through Celite and rinsed with ethyl acetate (100 mL). The filtrated was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed saturated aqueous sodium chloride solution (50 mL) dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by silica gel chromatography, eluting with a ethyl acetate/hexanes (10-60%) to methyl[6-(acetyloxy)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl](oxo)acetate as a yellow solid (326 mg, 39%). Mp: 165-168° C.; 1H NMR (CDCl3) 400 MHz δ: 8.39 (s, 1H), 8.29 (d, J=7.4 Hz, 1H), 7.31-7.36 (m, 2H), 6.22 (t, J=3.5 Hz, 1H), 4.33-4.36 (m, 2H), 4.41-4.43 (m, 1H), 3.95 (s, 3H), 2.44-2.47 (m, 1H), 2.36-2.39 (m, 1H); LCMS [M+H]: 302.
Reaction SMILES: [OH:1][NH:2][C:3]([CH:5]1[CH2:7][CH2:6]1)=[NH:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[N:19]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:18]([CH2:30][CH2:31][C:32](O)=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>>[CH:5]1([C:3]2[N:4]=[C:32]([CH2:31][CH2:30][CH:18]3[CH2:17][CH2:16][CH:15]([C:12]4[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=4)[N:19]3[S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[O:1][N:2]=2)[CH2:7][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCC(=O)O)CCC2c2ccc(F)cc2)cc1
Reactant: N=C(NO)C1CC1
Product: Cc1ccc(S(=O)(=O)N2C(CCc3nc(C4CC4)no3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, white solid, m.p. 129° C. and MS: m/e=456.4 (M+) was prepared in accordance with the general method of example 13 from N-hydroxy-cyclopropane-carboxamidine and (2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([Br:25])[C:23]=1[OH:24])[C:17]([O:19][CH3:20])=[O:18])(=[O:13])[CH3:12].[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.Cl>C1COCC1.O.C(Cl)Cl>[Br:25][C:22]1[CH:21]=[C:16]([CH:15]=[C:14]([C:11](=[O:13])[CH2:12][C:32]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:33])[C:23]=1[OH:24])[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cc(Br)c(O)c(C(C)=O)c1
Reactant: O=C(Cl)N1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(O)c(C(=O)CC(=O)N2CCOCC2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (1.41 L, 1406 mmol) at −65° C. under nitrogen was added dropwise methyl 3-acetyl-5-bromo-4-hydroxybenzoate (120 g, 439 mmol) in THF (1.2 L). The solution was allowed to warm to 0° C., and maintained at this temperature for 1 hr. The solution was cooled back to −65° C. and morpholine-4-carbonyl chloride (0.055 L, 483 mmol) was added. The mixture was stirred at RT for 2 hrs then cooled to −30° C., DCM (1.5 L) and water (1 L) were added followed by dropwise addition of HCl 6N (500 mL) then HCl2N (300 mL) until pH 7, the aqueous solution was extracted with DCM (3×). The combined extracts were dried over magnesium sulfate and evaporated. The crude product was triturated in MTBE to obtain methyl 3-bromo-4-hydroxy-5-(3-morpholino-3-oxopropanoyl)benzoate (153 g, 90%) as a beige solid. Mass Spectrum: M+H+ 388.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:15])[CH2:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[O:6]1)=[O:4].C1(O)C=CC=CC=1.I[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:30][C:29]=1[CH2:39][CH2:40][CH3:41]>>[CH3:37][C:35]([CH3:36])([CH3:38])[CH2:34][C:31]1[CH:32]=[CH:33][C:28]([O:27][CH2:26][CH2:25][CH2:24][O:14][C:11]2[CH:12]=[CH:13][C:7]3[O:6][C:5]([CH3:15])([C:3]([OH:2])=[O:4])[CH2:9][C:8]=3[CH:10]=2)=[C:29]([CH2:39][CH2:40][CH3:41])[CH:30]=1
Reactant: COC(=O)C1(C)Cc2cc(O)ccc2O1
Reactant: CCCc1cc(CC(C)(C)C)ccc1OCCCI
Solvent: Oc1ccccc1
Product: CCCc1cc(CC(C)(C)C)ccc1OCCCOc1ccc2c(c1)CC(C)(C(=O)O)O2

Procedure:
The title compound was prepared following the general procedure described in Example 1, Step 4, employing the intermediate prepared in Example 1, Step 1 as the phenol and the iodide prepared in Step 2.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]([C:10]2[N:14]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[N:13]=[CH:12][C:11]=2[C:23](O)([CH3:25])[CH3:24])=[C:6]([CH3:27])[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[C:4]1=[O:38])[CH3:2].[N-:39]=[N+]=[N-].[Na+].FC(F)(F)C(O)=O.O>C(Cl)(Cl)Cl.C(OCC)(=O)C.C(O)(=O)C.[Zn]>[NH2:39][C:23]([C:11]1[CH:12]=[N:13][N:14]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[C:10]=1[C:7]1[C:8](=[O:9])[N:3]([CH2:1][CH3:2])[C:4](=[O:38])[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:37])[F:35])[CH:29]=2)[C:6]=1[CH3:27])([CH3:24])[CH3:25]
Reactant: CCn1c(=O)c(-c2c(C(C)(C)O)cnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: [Zn]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: CCn1c(=O)c(-c2c(C(C)(C)N)cnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Yield: 45.2 %

Procedure:
To a solution of 4-(5-(3-ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 288) (114.7 mg) in chloroform (1.0 ml) was added at room temperature sodium azide (28.4 mg) and trifluoroacetic acid (200 μl) and the resulting mixture was stirred at room temperature for sixteen hours. The reaction mixture was diluted with ethyl acetate (30 ml) and the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to afford the residue. To a solution of the obtained residue in acetic acid (1.0 ml) were added at room temperature zinc dust (143.2 mg) and water (200 μl) and the resulting mixture was stirred at room temperature for eight hours. The reaction mixture was diluted with ethyl acetate (30 ml) and the solids were then filtered, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-(4-(2-aminopropane-2-yl)-5-(3-ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (51.8 mg). UPLC/MS 523 (M+H)/0.73 min. (measurement condition 9)