Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)[CH:3]=1.[CH2:18]([NH2:23])[CH:19]([NH2:22])[CH2:20][CH3:21].C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[NH2:22][CH:19]([CH2:20][CH3:21])[CH2:18][NH:23][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)[CH:3]=1
Reactant: Cc1cccc(Nc2cc(Cl)ncc2C#N)n1
Reactant: CCC(N)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCC(N)CNc1cc(Nc2cccc(C)n2)c(C#N)cn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of 6-chloro-4-[(6-methylpyridin-2-yl)amino]pyridine-3-carbonitrile (PrepEx 1.3) (38 mg, 0.16 mmol) in NMP (1 mL) was added butane-1,2-diamine (107 mg, 1.21 mmol) and N,N-diisopropylethylamine (0.163 mL, 0.932 mmol). The reaction mixture was heated to 100° C. After 16 hours, the reaction mixture was allowed to cool to room temperature, filtered, and purified directly via reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to afford 6-[(2-aminobutyl)amino]-4-[(6-methylpyridin-2-yl)amino]pyridine-3-carbonitrile. MS ESI calc'd. for C16H21N6 [M+H]+ 297. found 297.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:32]([F:35])([F:34])[F:33])[C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:32]([F:33])([F:34])[F:35])[C:29]=1[O:30][CH3:31])[C:24]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:25]
Reactant: COc1c(Cl)cc(C(=O)Cl)cc1C(F)(F)F
Reactant: c1ccc2c(c1)NCS2
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1c(Cl)cc(C(=O)N2CSc3ccccc32)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (442 mg) and 37% formalin (0.29 mL) in the same manner as in Example 1 was dissolved in chloroform (8 mL), and triethylamine (0.49 mL) and 3-chloro-4-methoxy-5-trifluoromethylbenzoyl chloride were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (f).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][O:9][C:8]2[CH:17]=[CH:18][C:19]([C:21]3[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[N:25]=3)=[CH:20][C:7]1=2>C(Cl)Cl>[Cl:3][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][O:9][C:8]2[CH:17]=[CH:18][C:19]([C:21]3[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[N:25]=3)=[CH:20][C:7]1=2
Reactant: O=S(Cl)Cl
Reactant: CC1(C)COC(c2ccc3c(c2)C(O)c2ccccc2CO3)=N1
Solvent: ClCCl
Product: CC1(C)COC(c2ccc3c(c2)C(Cl)c2ccccc2CO3)=N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In this process, 1.90 g of 11-hydroxy-2-(4,4-dimethyl-2-oxazoline-2-yl)-6,11-dihydrodibenz[b,e]oxepin is dissolved in 30 ml of methylene chloride and 0.7 ml of thionyl chloride is added thereto under ice-cooling. After stirring the mixture at room temperature for one hour, the solvent is distilled away under reduced pressure to obtain a crude product of 11-chloro-2-(4,4-dimethyl-2-oxazoline-2-yl)-6,11-dihydrodibenz[b,e]oxepin. The crude product as such is dissolved in 10 ml of tetrahydrofuran without purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7]/[C:8]/2=[CH:11]\[C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:18])=O>C1C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7]/[C:8]/2=[CH:11]\[C:12]([Cl:18])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)/C=C1\CCc2ccc(F)cc21
Solvent: c1ccccc1
Product: O=C(Cl)/C=C1\CCc2ccc(F)cc21
Temperature: 25 °C
Yield: 99.9 %

Procedure:
An ice-cold, stirred suspension of (E)-2-(6-fluoro-1-indanylidene)acetic acid (384 mg, 2 mmol) in benzene (10 mL) was treated with oxalyl chloride (761 mg, 6 mmol) and allowed to warm to room temperature during 1.5 h. The resulting yellow solution was concentrated in vacuo to give (E)-2-(6-fluoro-1-indanylidene)acetyl chloride as a pale yellow solid (421 mg, 100%), m.p., 97-99° C.;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19]2[CH2:23][C@H:22]([CH2:24]OS(C)(=O)=O)[O:21][C:20]2=[O:30])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][CH3:17])[C:10](=[O:18])[CH2:9]1.[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C=O)C>[N:31]([CH2:24][C@@H:22]1[O:21][C:20](=[O:30])[N:19]([C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][CH3:17])[C:10](=[O:18])[CH2:9]3)=[C:2]([F:1])[CH:3]=2)[CH2:23]1)=[N+:32]=[N-:33]
Reactant: COCCN1CCN(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN1CCN(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)CC1=O
Temperature: 80 °C
Yield: 88.3 %

Procedure:
(5R)-3-(3-Fluoro-4-{4-(2-methoxyethyl)-3-oxopiperazin-1-yl}phenyl)-5-(methanesulfonyl-oxymethyl)oxazolidin-2-one (990 mg) was dissolved in dry DMF (30 ml), sodium azide (868 mg) was added, and the mixture heated at 80° C. for 4 hours. The mixture was evaporated to dryness, and the residue dissolved in ethyl acetate and washed with three portions of water. The aqueous layer was back-extracted with two portions of ethyl acetate, and the combined organic extracts dried over MgSO4. Evaporation gave (5R)-5-azidomethyl-3-(3-fluoro-4-{4-(2-methoxyethyl)-3-oxopiperazin-1-yl}phenyl)oxazolidin-2-one (770 mg) which was used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:24]3[C:19](=[C:20]([NH:25][C:26](=[O:28])[CH3:27])[N:21]=[CH:22][CH:23]=3)[CH2:18][O:17][C:15]=2[CH:16]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:24]3[C:19](=[C:20]([NH:25][C:26](=[O:28])[CH3:27])[N:21]=[CH:22][CH:23]=3)[CH2:18][O:17][C:15]=2[CH:16]=1
Reactant: CC(=O)Nc1nccc2c1COc1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1nccc2c1COc1cc(OC[C@@H](N)CC(C)C)ccc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.3 %

Procedure:
To a stirred solution of (S)-tert-butyl(1-((4-acetamido-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (150 mg, 0.329 mmol) in CH2Cl2 (10 mL) at room temperature was added TFA (0.025 mL, 0.329 mmol) and the solution was stirred at room temperature for 3 h. The solution was concentrated under reduced pressure and the sample was purified by preparative HPLC (0.1% TFA in water and methanol) yielding (S)-N-(8-((2-amino-4-methylpentyl)oxy)-5H-chromeno[3,4-c]pyridin-4-yl)acetamide (40 mg, 0.113 mmol, 33% yield for three steps) as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 8.34 (d, J=5.3 Hz, 1H), 7.81 (d, J=8.7 Hz, 1H), 7.58 (d, J=5.4 Hz, 1H), 6.77 (m, 1H), 6.63 (d, J=2.4 Hz, 1H), 4.94 (s, 2H), 4.03 (m, 1H), 3.85 (m, 1H), 3.33 (m, 1H), 2.21 (s, 3H), 1.81 (m, 1H), 1.43 (m, 2H), 0.99 (m, 6H); LCMS (ESI) m/e 356.2 [(M+H)+, calcd for C20H26N3O3 356.2]; LC/MS retention time (Method C): tR=1.26 min; HPLC retention time (method A): tR=8.02 min; HPLC retention time (method B): tR=9.08 min.
Reaction SMILES: [P:1]([O:11][CH2:12][C:13]1[C:18]([CH2:19][OH:20])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:21])([O:7][CH2:8][CH:9]=[CH2:10])([O:3][CH2:4][CH:5]=[CH2:6])=[O:2].CC(C)=[O:24].OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.CC(O)C>CC(C)=O.O>[CH2:4]([O:3][P:1]([O:11][CH2:12][C:13]1[C:14]([Cl:21])=[CH:15][CH:16]=[CH:17][C:18]=1[C:19]([OH:24])=[O:20])([O:7][CH2:8][CH:9]=[CH2:10])=[O:2])[CH:5]=[CH2:6]
Reactant: CC(C)=O
Reactant: C=CCOP(=O)(OCC=C)OCc1c(Cl)cccc1CO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: C=CCOP(=O)(OCC=C)OCc1c(Cl)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A solution of diallyl 2-chloro-6-(hydroxymethyl)benzyl phosphate (2.62 g, 7.88 mmol) obtained from Example 27-(3) in acetone (25 ml) was cooled to 0° C., and Jones reagent (a mixture of chromic anhydride (5.34 g) and concentrated sulfuric acid (4.6 ml) diluted with water to 20 ml total volume; 12 ml, ca. 32 mmol) was added thereto. The reaction mixture was stirred at room temperature for 1 hour, and then 2-propanol (1 ml) was added thereto to stop the reaction. The insoluble material was filtered off, and then the filtrate was concentrated under reduced pressure to give an oily residue. The residue was thoroughly dried using a vaccum pump, and then subjected to chromatography on a silica gel (40 g) column (eluent; ethyl acetate:dichloromethane=1:10˜1:1) to afford the title compound (2.065 g, 76% yield) as a pale brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[C:10]=1[CH2:18][OH:19].O[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:23]([CH3:34])[C:22]=1[CH3:35].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[C:10]=1[CH2:18][O:19][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:23]([CH3:34])[C:22]=1[CH3:35]
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: Cc1ccc(-c2snc(C(F)(F)F)c2CO)c(C)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Product: CCOC(=O)CCc1ccc(OCc2c(C(F)(F)F)nsc2-c2ccc(C)cc2C)c(C)c1C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [5-(2,4-dimethylphenyl)-3-(trifluoromethyl)-1,2-thiazol-4-yl]methanol (100 mg, 0.35 mmol, 1.00 equiv), tol (3 mL), ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate (154 mg, 0.69 mmol, 1.99 equiv), ADDP (174 mg, 0.70 mmol, 2.00 equiv), n-Bu3P (140 mg, 0.69 mmol, 1.99 equiv). The resulting solution was stirred overnight at 60° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a TLC plate with ethyl acetate/petroleum ether (1/5). This resulted in 90 mg (crude) of ethyl 3-(4-[[5-(2,4-dimethylphenyl)-3-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-2,3-dimethylphenyl) propanoate as colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([Br:15])[C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].C([O+]([B-](F)(F)F)CC)C.[Cl-].Cl[C:27](Cl)=[N+:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CCOCC>C1(C)C=CC=CC=1>[Br:15][C:12]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]2[C:13]=1[O:14][C:27]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[CH:2][C:1]2=[O:3]
Reactant: COC(=O)c1cc(Br)c(O)c(C(C)=O)c1
Reactant: ClC(Cl)=[N+]1CCOCC1
Agent: CC[O+](CC)[B-](F)(F)F
Agent: [Cl-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
To a stirred solution methyl 3-acetyl-5-bromo-4-hydroxybenzoate (106 g, 388 mmol) in toluene (1 L) was added dropwise (diethyloxonio)trifluoroborate (0.201 L, 1630 mmol), under nitrogen. The resulting solution was left to stir overnight at room temperature, then 4-(dichloromethylene)morpholin-4-ium chloride (143 g, 698 mmol) was added and mixture heated at 90° C. for 12 h. Upon cooling to room temperature, ether (1.5 L) was added and the solid was collected by filtration. This solid was then suspended in MeOH (1 L) and the mixture was heated at 50° C. for 2 h. Upon cooling to room temperature, the solid was collected by filtration then solubilized in DCM (1 L) and washed with water and a saturated solution of sodium bicarbonate. The organic layer was dried over MgSO4, filtered and evaporated to dryness to afford methyl 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylate (68.0 g, 47.6%) as an off-white solid. Mass Spectrum: m/z [M+H]+=368.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[O:12]=[C:13]1[NH:22][CH:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[S:31][CH3:32])[C:20]2[C:19](=[O:33])[CH2:18][CH2:17][CH2:16][C:15]=2[N:14]1[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=1>ClCCl>[O:12]=[C:13]1[NH:22][CH:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[S:31]([CH3:32])=[O:6])[C:20]2[C:19](=[O:33])[CH2:18][CH2:17][CH2:16][C:15]=2[N:14]1[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=1
Reactant: CSc1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Reaction time: 0.17 h

Procedure:
3-chloroperoxybenzoic acid (77%, 111 mg, 0.495 mmol) is added at room temperature to a solution of 4-[2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4,5,6,7,8-octahydro-quinazolin-4-yl]-3-methylsulfanyl-benzonitrile (INTERMEDIATE 6, 340 mg, purity 70%, 0.520 mmol) in dichloromethane (2 mL) and the mixture is stirred for 10 min. The reaction mixture is concentrated under reduced pressure and purified by reversed phase HPLC (X-Bridge C18, gradient of acetonitrile in water, 0.1% NH4OH) yielding the two diasteromers of the title compound.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][C:24](OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].BrC/[CH:43]=[CH:44]\[C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51])[CH2:46][CH3:47].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24]/[CH:43]=[CH:44]\[C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:52][CH3:53])([CH2:54][CH3:55])[CH2:50][CH3:51])[CH2:46][CH3:47])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCC(/C=C\CBr)(CC)O[Si](CC)(CC)CC
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(/C=C\CS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Yield: 59.8 %

Procedure:
Under the same conditions as in Example 3, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthio-pregna-5,7,16-triene (33.0 mg, 0.0568 mmol), (Z)-1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene (91.0 mg, 0.284 mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×1, hexane ethyl acetate=2:1, developed once) to give the title compound as a pale yellow oil (23.8 mg, 60%).
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]1([CH2:14][C@H:15]2[C@H:19]([C:20](OC)=[O:21])[O:18][C:17]([CH3:25])([CH3:24])[N:16]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[Cl-].[NH4+]>CCOCC>[C:20]([C@@H:19]1[O:18][C:17]([CH3:24])([CH3:25])[N:16]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[C@H:15]1[CH2:14][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)(=[O:21])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]c1ccccc1
Reactant: COC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H](C(=O)c2ccccc2)OC1(C)C
Reaction time: 0.5 h

Procedure:
2.36 ml (2 mmol) of a 0.76N solution of phenyllithium in ether are sprayed at -75° into 355 mg (1 mmol) of 3-t-butyl 5-methyl (4S,5R)-4-(cyclohexylmethyl)-2,2-dimethyl-3,5-oxazolidinedicarboxylate in 20 ml of ether and the reaction mixture is stirred at this temperature for 30 minutes, subsequently poured into 50 ml of saturated ammonium chloride solution and extracted three times with 150 ml of ether each time. The three ether extracts are washed in succession with in each case 70 ml of 2N sodium bicarbonate solution and 70 ml of saturated sodium chloride solution, combined, dried over magnesium sulphate, filtered and evaporated. The residual oil (540 mg) is chromatographed on 30 g of silica gel with a 98:2 mixture of toluene and ethyl acetate as the eluting agent, whereby there are obtained 300 mg of t-butyl (4S,5R)-5-benzoyl-4-(cyclohexylmethyl)-2,2-dimethyl-3-oxazolidinecarboxylate as a white solid, MS: 401 (M)+.
Reaction SMILES: [O:1]=[C:2]1[C@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=2)[NH:6][C@@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)[O:3]1.CCO>Cl[Pd]Cl.C1COCC1>[CH3:19][CH2:18][CH:15]([C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH2:8][C@@H:7]([C:2]([OH:3])=[O:1])[NH2:6])[CH2:16][CH3:17]
Reactant: CCC(CC)c1cccc(C[C@@H]2N[C@@H](c3ccccc3)[C@@H](c3ccccc3)OC2=O)c1
Agent: Cl[Pd]Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(CC)c1cccc(C[C@H](N)C(=O)O)c1
Reaction time: 18 h
Yield: 84 %

Procedure:
To a 300 mL Parr bottle were added 0.41 g of PdCl2, 1.36 g of (2R, 3S, 5S)-6-oxo-2,3-diphenyl-5-(3-(3-pentyl)benzyl)morpholine, 50 mL of EtOH, and 30 mL of THF. The mixture was deoxygenated by bubbling nitrogen through for 10 min and was hydrogenated at 45 psi for 18 h. The vessel was purged with nitrogen, catalyst removed by filtration through celite, and the filtrate concentrated in vacuo to a volume of 15 mL. The solution was chilled in an ice bath and triturated with additional of 50 mL of hexane. A fine precipitate slowly formed. After storing at 5° C. overnight, the solid was collected by filtration and dried in vacuo to afford 0.65 g (72%) of 3-(3-pentyl)-L-phenylalanine.HCl as a white powder, m.p. 170° C. (dec).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:8]([CH3:11])=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH3:25])[CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.ClCCl>O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:4]([C:3]=1[CH3:12])[C:5]([C:16]1[C:17]([CH3:25])=[CH:18][C:19]([O:23][CH3:24])=[C:20]([O:21][CH3:22])[C:15]=1[O:14][CH3:13])=[O:7]
Reactant: Cc1ccc(Br)c(C)c1C(=O)O
Reactant: COc1cc(C)cc(OC)c1OC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)c(C(=O)c2c(C)ccc(Br)c2C)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1B (1.3 g, 5.7 mmol), 3,4,5-trimethoxytoluene (1.0 g; 5.7 mmol), P2O5 (3.5 g) and dichloromethane (20 ml) is stirred at room temperature for 16 hours. Subsequently, water (5 ml) and ice are added and dichloromethane is distilled off and the residue is extracted with toluene. The organic phase is washed with water and concentrated. The residue is recrystallized from petrol ethers/toluene. The solid material is collected by vacuum filtration, washed with cold petrol ethers and dried, yielding white crystals, 1.4 g, mp 859° C.
Reaction SMILES: [O-]S([C:5](F)(F)F)(=O)=O.FC1C=CC(B(O)O)=CC=1.[CH:19]1([N:24]2[C:33]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[C:32]3[C:26]([CH2:27][CH2:28][NH:29][CH:30](C)[CH2:31]3)=[N:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([N:24]2[C:33]([C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)=[C:32]3[C:26]([CH2:27][CH:28]([CH3:5])[NH:29][CH2:30][CH2:31]3)=[N:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CC1Cc2c(nn(C3CCCC3)c2-c2ccc(F)cc2)CCN1
Agent: OB(O)c1ccc(F)cc1
Product: CC1Cc2nn(C3CCCC3)c(-c3ccc(F)cc3)c2CCN1

Procedure:
The title compound (160.4 mg) was prepared as in Example 263 from 301 mg of the triflate from Step B and 185 mg of 4-fluorophenylboronic acid. The sequence also produced 2-cyclopentyl-3-(4-fluoro-phenyl)-5-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene. The isomers were separated by SFC chromotagraphy. MS (ESI): exact mass calculated for C19H24FN3, 313.41; found, m/z 314.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.25-7.21 (m, 2H), 7.18-7.12 (m, 2H), 4.22 (m, 1H), 3.24-3.18 (m, 1H), 3.03-2.92 (m, 2H), 2.76-2.67 (m, 2H), 2.60-2.52 (m, 1H), 2.45-2.39 (m, 1H), 2.16-1.82 (m 6H), 1.59-1.47 (m, 2H), 1.25 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([CH2:15][C:16]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]([O:31]C)=[O:30])=[C:25]([O:33][CH3:34])[CH:24]=4)[NH:20]C(=O)N[C:17]3=[O:22])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[OH-:36].[Na+]>>[NH2:20][C:16]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:31])=[O:30])=[C:25]([O:33][CH3:34])[CH:24]=1)([CH2:15][CH:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:17]([OH:36])=[O:22]
Reactant: COC(=O)c1ccc(C2(CC3c4ccccc4Oc4ccccc43)NC(=O)NC2=O)cc1OC
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: COc1cc(C(N)(CC2c3ccccc3Oc3ccccc32)C(=O)O)ccc1C(=O)O

Procedure:
A suspension of 5-(9H-xanthen-9-ylmethyl)-5-(3-methoxy-4-methoxycarbonylphenyl)hydantoin (1.04 g, 2.27 mmol) in aqueous sodium hydroxide (2M, 6.8 ml) was heated at 120° C. in a teflon lined stainless steel sealed tube for 3 days with stirring. After cooling, aqueous hydrochloric acid (5M, 3 ml) was added followed by purification on ion exchange (Dowex50×8-100 resin). The column was eluted sequentially with water, water-tetrahydrofuran (1:1), water and 10% pyridine in water. Fractions collected after the pyridine-water elution were combined, evaporated to dryness, redissolved in water and freeze-dried to give 2-amino-2-(4-carboxy-3-methoxyphenyl)-3-(9H-xanthen-9-yl)propanoic acid as a white powder.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:9]=1[C:10]([C:16](C)=[CH2:17])=[N:11]2)[CH2:2][CH2:3][CH3:4].C[N+]1([O-])CC[O:28]CC1>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH2:1]([O:5][C:6]1[N:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:9]=1[C:10]([C:16](=[O:28])[CH3:17])=[N:11]2)[CH2:2][CH2:3][CH3:4]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=C(C)c1nc2ccnc(OCCCC)c2c2cc(F)ccc12
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1nccc2nc(C(C)=O)c3ccc(F)cc3c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-butoxy-9-fluoro-6-isopropenylbenzo[c]-1,6-naphthyridine (100 mg, 0.320 mmol) in tetrahydrofuran (1.0 ml) and water (0.25 ml) was added 4-methylmorpholine 4-oxide (NMO) (39.6 mg, 0.338 mmol) followed by osmium tetroxide (525 uL of a 4 wt % aqueous solution. The reaction mixture was stirred at room temperature for 1 hr. Additional tetrahydrofuran (1.0 ml) and water (0.25 ml) were added, followed by an additional portion of NMO (39.6 mg, 0.338 mmol). The reaction mixture was partitioned between EtOAc and water. The organic layer was dried over sodium sulfate, filtered, and concentrated to a crude residue that was adsorbed on to silica gel and purified by silica gel chromatography eluting with an EtOAc/hexanes gradient to afford 1-(1-butoxy-9-fluorobenzo[c]-1,6-naphthyridin-6-yl)ethanone. LRMS (ESI) calc'd for (C18H17FN2O2) [M+H]+, 313.1; found 313.1.