Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[C:10]([OH:11])=[C:9]([F:12])[C:8]([C:13]3[CH:22]=[N:21][C:20]4[NH:19][CH2:18][CH2:17][O:16][C:15]=4[CH:14]=3)=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[CH:27][CH:26]=1.CC(C)([O-])C.[K+]>CS(C)=O>[CH:1]1([C:5]2[C:10]([O:11][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[CH:29][CH:30]=3)=[C:9]([F:12])[C:8]([C:13]3[CH:22]=[N:21][C:20]4[NH:19][CH2:18][CH2:17][O:16][C:15]=4[CH:14]=3)=[CH:7][CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: Oc1c(C2CCC2)ccc(-c2cnc3c(c2)OCCN3)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)Cc1ccc(COc2c(C3CCC3)ccc(-c3cnc4c(c3)OCCN4)c2F)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 10.5 %

Procedure:
A solution of 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol (50 mg, 0.17 mmol) and 2-(4-(bromomethyl)phenyl)acetic acid (38 mg, 0.17 mmol) in DMSO (1 mL) was treated with potassium tert-butoxide (38 mg, 0.33 mmol) and stirred for 16 hours at 80° Celsius. The reaction was then cooled to rt, filtered, and the filtrate subjected directly to HPLC purification to give (4-{[6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}phenyl)acetic acid (8 mg, 9%). MS (ESI): mass calcd. for C26H25FN2O4, 448.18; m/z found, 449.2 [M+H]+. 1H NMR (600 MHz, CD3OD) δ 7.72 (s, 1H), 7.60 (s, 1H), 7.40 (d, J=8.1, 2H), 7.31 (d, J=8.1, 2H), 7.19 (d, J=6.0, 2H), 5.04 (s, 2H), 4.38-4.32 (m, 2H), 3.78-3.72 (m, 1H), 3.71-3.67 (m, 2H), 3.63 (s, 2H), 2.29-2.22 (m, 2H), 2.16-2.07 (m, 2H), 2.04-1.97 (m, 1H), 1.84 (t, J=9.6, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[CH:9][N:10](C)C)=[C:4]([C:13]#[N:14])[CH:3]=1.N[C:16]1[C:17]([F:24])=[CH:18][C:19]([CH3:23])=[C:20]([OH:22])[CH:21]=1>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:9][N:10]=[C:13]2[NH:14][C:16]1[C:17]([F:24])=[CH:18][C:19]([CH3:23])=[C:20]([OH:22])[CH:21]=1
Reactant: CN(C)C=Nc1ccc(Br)cc1C#N
Reactant: Cc1cc(F)c(N)cc1O
Solvent: CC(=O)O
Product: Cc1cc(F)c(Nc2ncnc3ccc(Br)cc23)cc1O
Yield: 58 %

Procedure:
5.0 g (19.9 mmol) of N′-(4-bromo-2-cyanophenyl)-N,N-dimethylformamidine and 3.09 g (21.9 mmol) of 5-amino-4-fluoro-2-methylphenol are suspended in 25 ml of acetic acid and heated under reflux for 1 h. The solid obtained after cooling is filtered off and washed with hexane. 4.02 g (58%) of the desired product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[Br:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33]([CH2:35]Cl)[CH:34]=1.O>C(#N)C>[Br:28][C:29]1[CH:34]=[C:33]([CH2:35][N:11]2[C:10](=[O:13])[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:12]2)[CH:32]=[N:31][CH:30]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: ClCc1cncc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: O=c1n(Cc2cncc(Br)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 65 °C
Reaction time: 5 h

Procedure:
171 mg (0.56 mmol) of the compound from Example 5A and 543 mg (1.67 mmol) of cesium carbonate were dissolved in 11 ml of acetonitrile, and 135 mg (0.56 mmol) of 3-bromo-5-(chloromethyl)pyridine hydrochloride were added. The mixture was stirred at 65° C. for 5 h. After cooling to RT, 10 ml of water were added and the mixture was extracted three times with in each case 10 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC [Method 19]. This gave 102 mg (38% of theory) of the target compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:9][NH:10][C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:6][CH2:7][CH3:8])[CH3:2].C1N=CN([C:24](N2C=NC=C2)=[O:25])C=1>C1COCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:9][N:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[NH:17][C:24]1=[O:25])[CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCCC(CNc1ncccc1N)C(=O)OCC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCC(Cn1c(=O)[nH]c2cccnc21)C(=O)OCC
Temperature: 25 °C
Reaction time: 120 h
Yield: 64.4 %

Procedure:
To a stirred solution of 2-[(3-amino-pyridin-2-ylamino)-methyl]-pentanoic acid ethyl ester (70 mg, 0.28 mmol) in THF (10 ml) was added CDI (135 mg, 0.84 mmol). The resulting solution was stirred at room temperature for 5 days after which time the reaction appeared to be complete. Silica gel was added and the mixture was concentrated. The remaining solid was purified via silica gel flash column chromatography (Companion, 12 g silica gel, 30-100% EtOAc/hexanes) to give 50 mg (65%) of the title compound as oil which solidified on standing.
Reaction SMILES: [F:1][C:2]([F:15])([CH:13]=C)[C:3]([CH2:11][CH3:12])([O:6][Si:7]([CH3:10])([CH3:9])[CH3:8])[CH2:4][CH3:5].[O:16]=[O+][O-]>ClCCl.O=O>[F:1][C:2]([F:15])([C:3]([CH2:11][CH3:12])([O:6][Si:7]([CH3:10])([CH3:9])[CH3:8])[CH2:4][CH3:5])[CH:13]=[O:16]
Reactant: C=CC(F)(F)C(CC)(CC)O[Si](C)(C)C
Reactant: O=[O+][O-]
Agent: O=O
Solvent: ClCCl
Product: CCC(CC)(O[Si](C)(C)C)C(F)(F)C=O
Temperature: -78 °C

Procedure:
4,4-difluoro-3-ethyl-3-trimethylsilyloxy-5-hexene (2.00 g, 8.88 mmol) was dissolved in dichloromethane (80 ml), and the solution was cooled to -78° C. A gaseous mixture of O3 in O2 was passed into the solution until it became blue. Nitrogen was bubbled through the solution to remove excess ozone, dimethyl sulfide (3 ml) was added, and the solution was brought slowly to room temperature. Following ozonide decomposition, dichloromethane was added, and the organic layer was washed with water (twice), dried over CaCl2 and concentrated under reduced pressure. Flash chromatography (50 g silica gel; 5% EtOAc in petroleum ether as eluant) to give the title compound as a pale yellow oil, δ 0.14 (s 9H), 0.91 (m, 6H), 1.64 (m, 2H), 1.85 (m, 2H), 9.55 (t, 1H).
Reaction SMILES: Cl.O1CCOCC1.[F:8][CH:9]([F:60])[C:10]([C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][N:54]=2)=[CH:49][CH:48]=1)([OH:46])[CH2:11][C:12]1[N:13](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:14]=[C:15]([CH2:17][C:18]([CH3:26])([CH3:25])[CH:19]([OH:24])[C:20]([F:23])([F:22])[F:21])[N:16]=1.FC(F)C(C1C=CC(C2C=CC(F)=CN=2)=CC=1)(O)CC1N(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=C(CC(C)(C)C(O[Si](C)(C)C)C(F)(F)F)N=1>CO>[F:60][CH:9]([F:8])[C:10]([C:47]1[CH:48]=[CH:49][C:50]([C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][N:54]=2)=[CH:51][CH:52]=1)([OH:46])[CH2:11][C:12]1[NH:13][CH:14]=[C:15]([CH2:17][C:18]([CH3:25])([CH3:26])[CH:19]([OH:24])[C:20]([F:22])([F:23])[F:21])[N:16]=1
Reactant: CC(C)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)(c2ccc(-c3ccc(F)cn3)cc2)C(F)F)n1)C(O)C(F)(F)F
Agent: CC(C)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)(c2ccc(-c3ccc(F)cn3)cc2)C(F)F)n1)C(O[Si](C)(C)C)C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(Cc1c[nH]c(CC(O)(c2ccc(-c3ccc(F)cn3)cc2)C(F)F)n1)C(O)C(F)(F)F
Temperature: 70 °C
Reaction time: 1 h

Procedure:
4M Hydrogen chloride in dioxane (1 mL, 0.25 mmol) was added to a solution of 4-(2-{3,3-difluoro-2-[4-(5-fluoropyridin-2-yl)phenyl]-2-hydroxypropyl}-1-trityl-1H-imidazol-4-yl)-1,1,1-trifluoro-3,3-dimethylbutan-2-ol and 1,1-difluoro-2-[4-(5-fluoropyridin-2-yl)phenyl]-3-(4-{4,4,4-trifluoro-2,2-dimethyl-3-[(trimethylsilyl)oxy]butyl}-1-trityl-1H-imidazol-2-yl)propan-2-ol (from previous step) in methanol (2 mL). After stirring at 70° C. for 1 h, volatiles were removed. The residue was basified with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. Combined extracts were dried (magnesium sulfate) and concentrated Chromatography over silica eluting with 0-60% acetone/methylene chloride afforded the title compound. LCMS: 488 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:19])[NH:14][CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1.I[C:21]1[CH:25]=[CH:24][N:23]([CH3:26])[N:22]=1.CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.CN1CCCC1=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([CH:12]3[C:17]([CH3:18])=[CH:16][CH2:15][N:14]([C:21]4[CH:25]=[CH:24][N:23]([CH3:26])[N:22]=4)[C:13]3=[O:19])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Cc1cc[nH]c(=O)c1N1CCc2nc(N)ncc2C1
Reactant: Cn1ccc(I)n1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN1CCCC1=O
Product: CC1=CCN(c2ccn(C)n2)C(=O)C1N1CCc2nc(N)ncc2C1
Temperature: 70 °C
Reaction time: 17 h
Yield: 51.6 %

Procedure:
A degassed solution of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylpyridin-2(1H)-one (27 mg, 0.100 mmol), 3-iodo-1-methyl-1H-pyrazole (20 mg, 0.097 mmol), N1,N2-dimethylethane-1,2-diamine (5 mg, 0.049 mmol), copper iodide (4 mg, 0.020 mmol), and potassium phosphate (43 mg, 0.197 mmol) 2 mL of N-methylpyrrolidone was heated to 70° C. After allowing the reaction to stir overnight (17 h) at 70° C., the reaction was complete and allowed to cool to room temperature. The reaction was extracted 3×'s with EtOAc (3×5 mL) and 2×'s with NaHCO3 (3×10 mL). The crude organic layers were combined, dried over anhydrous Na2SO4 (s), filtered and then concentrated in vacuo. The crude mixture was then purified using the ISCO flash chromatography system using a 0-100% EtOAc/100-0% Hexane gradient mixture. A second column was done on the impure product using a gradient of MeOH/CHCl3 after which, the appropriate fractions were concentrated, to afford a yellow solid (17 mg, 52%). 1H NMR (DMSO) δ: 8.01 (s, 1H), 7.79 (d, J=6.0, 1H), 6.34 (d, J=6.0, 1H), 6.24 (m, 1H), 6.15 (d, J=7.0 Hz, 2H), 4.00 (br. S, 2H), 3.22 (s, 2H), 2.64(t, j=5.3 Hz, 2H), 2.20 (s, 3H)
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[O:18][CH:19]=2)=[O:14])=[C:8]([Cl:24])[CH:7]=1)C.[OH-].[Na+].Cl>O1CCCC1.CO>[O:18]1[CH:19]=[C:15]([C:13]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:25])=[O:3])=[CH:7][C:8]=2[Cl:24])=[O:14])[C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]1=2
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2coc3ccccc23)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1ccc(NC(=O)c2coc3ccccc23)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
[4-[(Benzo[b]furan-3-ylcarbonyl)amino]-3-chlorophenyl]acetic acid ethyl ester (2.08 g, 5.81 mmol) was dissolved in tetrahydrofuran (15 mL) and methanol (5 mL), and a 1N-aqueous solution of sodium hydroxide (11.60 mL, 11.60 mmol) was added thereto. The mixture was stirred for three hours at room temperature. The reaction liquor was poured onto ice-1N-hydrochloric acid, and precipitated solids were collected by filtration, and dried under reduced pressure, to obtain the title compound (1.70 g, 89%) as a solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:41]=[CH:40][C:20]([CH2:21][O:22]/[N:23]=[C:24](\[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)/[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[CH:19][CH:18]=1.CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22]/[N:23]=[C:24](\[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)/[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:40][CH:41]=1
Reactant: CCOC(=O)CCCC/C(=N/OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/CCCCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (3 ml) was added to a solution of ethyl Z-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoate (120 mg) in tetrahydrofuran (6 ml)-methanol (3 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (3.3 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoic acid (113 mg, yield 99%) as colorless crystals. m.p. 101-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]=O)[CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][OH:19].C(O)(=O)C.[BH4-].[Na+]>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:16][CH2:17][CH2:18][OH:19])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: O=CC1CCCC(c2ccc(Cl)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: OCCNCC1CCCC(c2ccc(Cl)cc2)C1
Temperature: 0 °C

Procedure:
To a solution of C6 (338 mg, 1.52 mmol) in methanol (5 mL) was added 2-aminoethanol (139 mg, 2.28 mmol) followed by acetic acid (89 μL, 1.55 mmol). The reaction was stirred at reflux for 2 hours, then cooled to 0° C. Sodium borohydride (115 mg, 3.04 mmol) was added and the mixture was allowed to warm to room temperature. The reaction was diluted with ethyl acetate, quenched with water, and then extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide the crude title compound as a liquid. Yield: 362 mg, 1.35 mmol, 89%. This was presumed to be a mixture of stereoisomers. LCMS m/z 268.3 (M+1). 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 7.22-7.28 (m, 2H), 7.10-7.16 (m, 2H), 3.63 (dd, J=5.3, 5.1 Hz, 2H), 2.75 (dd, J=5.3, 5.1 Hz, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:19]1[CH2:20][O:21][C:22](=[O:24])[CH:23]=1.C1C(=O)N([Br:32])C(=O)C1>C(Cl)Cl>[Br:32][C:23]1[C:22](=[O:24])[O:21][CH2:20][C:19]=1[N:3]1[CH2:4][CH2:5][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:2]1=[O:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=CC(=O)OC1)C2=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(Br)C(=O)OC1)C2=O

Procedure:
tert-Butyl 1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (I-16, Step A) (784 mg, 2.33 mmol) was dissolved in DCM (20 mL) and was treated with NBS (498 mg, 2.80 mmol) at 25° C. for 12 hours. The reaction mixture was diluted with DCM (20 mL), washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrates were concentrated and the crude product was purified by column chromatography (ISCO 40 g silica gel column), eluting with 50-100% ethyl acetate/hexane gradient to give the title compound.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]1([CH3:16])[O:9][C@H:8]2[O:10][C@H:11]([C@H:13]3[CH2:15][O:14]3)[CH2:12][C@H:7]2[O:6]1.[NH4+].[Cl-]>C1COCC1.[Cu]I>[CH3:4][C:5]1([CH3:16])[O:9][C@H:8]2[O:10][C@H:11]([C@H:13]([OH:14])[CH2:15][CH3:1])[CH2:12][C@H:7]2[O:6]1
Reactant: CC1(C)O[C@H]2O[C@H]([C@H]3CO3)C[C@H]2O1
Reactant: C[Mg]Br
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC[C@@H](O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a suspension of CuI (19.3 g, 107 mmol) in dry THF (2000 mL) under N2 atmosphere was added methyl magnesium bromide (3 M in diethyl ether, 537 mL, 1.61 mol) at −70° C. After being stirred at this temperature for 1 hour, a solution of (3aR,5S,6aR)-2,2-dimethyl-5-[(2R)-oxiran-2-yl]-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxole (compound 6b, 100 g, 537 mmol, dissolved in anhydrous THF 200 mL) was added to reaction mixture dropwise. After being stirred at −70° C. for additional 2 hours, the reaction mixture was poured into saturated NH4Cl solution. The organic layer was separated and the aqueous phase was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:3 EtOAc in petroleum ether) to afford 82 g of (1R)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propan-1-ol (compound 6c) as a slight yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1)[CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[NH2:41][CH:42]1[CH2:45][N:44]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:43]1.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1)[CH2:12][C:13]([NH:41][CH:42]1[CH2:43][N:44]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:45]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CN(C(=O)OCc1ccccc1)c1ccnc2ccc(C(F)(F)F)cc12
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CN(C(=O)OCc2ccccc2)c2ccnc3ccc(C(F)(F)F)cc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(((benzyloxy)carbonyl)(6-(trifluoromethyl)quinolin-4-yl)amino)acetic acid (306 mg, 0.757 mmol, prepared in step F) and EDCI (217 mg, 1.13 mmol) in DCM (10 mL) was stirred until a clear solution resulted. This solution was added to a suspension of tert-butyl 3-aminoazetidine-1-carboxylate (156 mg, 0.908 mmol) and HOBt (116 mg, 0.757 mmol) in DCM (10 mL). The reaction mixture was stirred overnight at ambient temperature and poured onto saturated aqueous sodium bicarbonate, extracting with ethyl acetate. Concentration of the organic layer followed by purification of the residue by flash chromatography (silica gel, 0-20% MeOH/ethyl acetate) afforded the product.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6]([CH:15]=[CH2:16])=[CH:7][N+:8]([O-])=[CH:9]2)([O-:3])=[O:2].P(Cl)(Cl)([Cl:19])=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:19][C:9]1[C:10]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][CH:11]=2)[C:6]([CH:15]=[CH2:16])=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: C=Cc1c[n+]([O-])cc2cccc([N+](=O)[O-])c12
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C=Cc1cnc(Cl)c2cccc([N+](=O)[O-])c12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The 5-nitro-4-vinylisoquinoline N-oxide (27 g) obtained in Step B mentioned above was suspended in chloroform (300 ml), and added dropwise with phosphorus oxychloride (22.3 ml, Wako Pure Chemical Industries) under ice cooling. After the addition, the reaction mixture was warmed to 60° C., and stirred at the same temperature for one hour. The reaction mixture was poured into in ice water, and neutralized with 2 N sodium hydroxide with stirring. The organic layer was separated, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (15 g).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23][CH2:24][CH2:25][CH2:26][C:27]([O:29]C)=[O:28])[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:3]1=[O:35].Cl>O1CCCC1.CO>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]([CH2:31][CH:32]([CH3:33])[CH3:34])[C:3]1=[O:35]
Reactant: COC(=O)CCCSc1c2c(=O)n(C)c(=O)n(CC(C)C)c2cn1Cc1cccc2ccccc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCC(=O)O)n(Cc3cccc4ccccc34)cc21
Reaction time: 1.5 h

Procedure:
The compound of Example 2, methyl 4-[(2,3,4,6-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4dioxo-1H-pyrrolo[3,4-d]-pyrimidin-5-yl)thio]butanoate (400 mg), was dissolved in 3:1:1 tetrahydrofuran/methanol/1M lithium hydroxide and stirred for 1.5 h before being acidified by dropwise addition of concentrated hydrochloric acid (HCl). The mixture was then extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate (MgSO4) and evaporated to dryness in vacuo. The resultant yellow oil was chromatographed (silica), eluting with 200:10:1 dichloromethane/methanol/glacial acetic acid. The resultant red oil was dissolved in toluene and then evaporated, then similarly with trichloromethane to yield a pink foam. The foam was recrystallised from ethyl acetate/hexane to yield 129 mg of the title compound.
Reaction SMILES: CO.[NH2:3][C:4]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:9]=1)=[O:7].[BH4-].[Na+]>C(OC(=O)C)C>[NH2:3][C:4]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:5]=1[CH:6]([OH:7])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)c2cc(Cl)ccc2N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(C(O)c2cc(Cl)ccc2N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a methanol (5 ml) solution of 2-amino-3′-tert-butoxycarbonylamino-5-chlorobenzophenone (0.4 g) was added sodium borohydride (66 mg). The mixture was stirred for one hour at room temperature, to which was added acetic acid ethyl ester (l00.ml). The mixture was washed with water and dried over anhydrous MgSO4. The solvent was then distilled off, and the residue was purified by means of a silica gel column chromatography to afford the object 2-amino-5-chloro-α-(3-tert-butoxycarbonylaminophenyl)benzyl alcohol (0.4 g) as a colorless oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](Cl)[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:9]=[C:8]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=2)[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Nc1ccc(CCO)cc1
Reactant: N#Cc1cc([N+](=O)[O-])c(Cl)cc1Cl
Product: N#Cc1cc([N+](=O)[O-])c(Nc2ccc(CCO)cc2)cc1Cl

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,4-dichloro-5-nitrobenzonitrile (Grivsky, E. M.; Hitchings, G. H. Ind. Chim. Belge., 1974, 39. 490.) and 4-aminophenylethyl alcohol.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([CH2:7][OH:8])[CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>O1CCCC1>[C:12]([O:11][C:9]([NH:1][C@@H:2]([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:7][O:8][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:10])([CH3:14])([CH3:13])[CH3:15]
Reactant: CCOC(=O)CBr
Reactant: CCCC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[C@@H](COCC(=O)OCC)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 55 %

Procedure:
To as stirred solution of Boc-L-Nle-ol (0.50 g, 1.9 mmol) in dry tetrahydrofuran (15 mL), cooled at 0° C. under nitrogen, NaH (0.05 g, 2.1 mmol) was added. The reaction mixture was stirred for 45 min at 0° C., followed by addition of 18-crown-6 (0.25 g, 0.9 mmol) and subsequently a solution of ethyl bromoacetate (0.47 g, 2.8 mmol) in dry tetrahydrofuran (4 mL) was added dropwise at 0° C. The reaction mixture was stirred for 1 h at 0° C. and overnight at room temperature. The organic solvent was evaporated under reduced pressure and the residue was purified by column-chromatography using chloroform as eluent. Yield 55%; Oil; [a]D=−13.9 (c 1CHCl3); 1H NMR (200 MHz, CDCl3) δ 4.85-4.78 (m, 1H), 4.17 (q, J=7.4 Hz, 2H), 4.03 (s, 2H), 3.72-3.58 (m, 1H), 3.56-3.41 (m, 2H), 1.62-1.21 (m, 18H), 0.85 (t, J=6.6 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ 170.3, 155.6, 78.9, 73.3, 68.4, 60.7, 50.3, 31.5, 28.3, 28.1, 22.5, 14.1, 13.9. Anal. Calcd for C15H29NO5: C, 59.38; H, 9.63; N, 4.62. Found: C, 59.16; H, 9.82; N, 4.51.