Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([CH2:30][OH:31])[CH2:3][N:4]1[C:28](=[O:29])[C:7]2=[N:8][N:9]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[CH:26][CH:25]=[N:24]4)=[CH:19][CH:18]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]2=[N:5]1.[H-].[Na+].IC.[CH3:36][OH:37].[CH3:38]N(C)C=O>O>[CH3:36][O:37][CH:2]([CH2:30][O:31][CH3:38])[CH2:3][N:4]1[C:28](=[O:29])[C:7]2=[N:8][N:9]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[CH:26][CH:25]=[N:24]4)=[CH:19][CH:18]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]2=[N:5]1
Reactant: CN(C)C=O
Reactant: O=c1c2nn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1CC(O)CO
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCC(Cn1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)nc-2c1=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-2-(2,3-Dihydroxypropyl)-5-[4-(1H-pyrazol-1-yl)benzyl]-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one [(Example 11), 0.10 g, 0.24 mmol] was dissolved in degassed N,N-dimethylformamide (5 mL), cooled to 0° C. and sparged under nitrogen. The mixture was treated with sodium hydride (21 mg, 0.53 mmol, 2.2 equiv) and after minutes, treated with iodomethane (37 μL, 0.60 mmol, 2.5 equiv). After stirring for 1 hour, the mixture was treated with methanol (2 mL), poured into water (25 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate containing 10% methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.29-8.26 (1H, m), 7.89 (1H, d, J=2.5 Hz), 7.71 (1H, d, J=1.7 Hz), 7.68 (2H, d, J=8.6 Hz), 7.56-7.51 (3H, m), 7.39 (2H, d, J=8.6 Hz), 6.46 (1H, dd, J=2.4, 1.9 Hz), 5.83 (2H, s), 4.21 (2H, d, J=5.8 Hz), 3.92-3.86 (1H, m), 3.64 (1H, dd, J=10.4, 3.7 Hz), 3.55 (1H, dd, J=10.4, 6.0 Hz), 3.52 (3H, s), 3.42 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 445.1976 [(M+H)+; calculated for C24H24N6O3: 445.1983].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[C:7]2([CH3:15])[CH3:14])([O-:3])=[O:2].[I:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[I-:16].[CH2:17]([N+:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([CH3:15])([CH3:14])[C:8]=1[CH3:13])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCI
Reactant: CC1=Nc2ccc([N+](=O)[O-])cc2C1(C)C
Product: CCCC[N+]1=C(C)C(C)(C)c2cc([N+](=O)[O-])ccc21
Product: [I-]

Procedure:
5-Nitro-2,3,3-trimethylindole (250 mg, 1.22 mmol) and iodobutane (10 ml, 16.17 g, 87.87 mmol) were mixed and heated to reflux for 16hrs. The solvent was removed and the impure material stored at−20° C. for use in later reactions.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][C:18](=[O:36])[C@H:19]([CH2:28][C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].N1C=CC=CC=1>ClCCl>[CH3:16][O:17][C:18](=[O:36])[C@@H:19]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:31][CH:30]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.1 %

Procedure:
Trifluoromethanesulfonic anhydride (3.27 ml, 19.47 mmol) was slowly added to a solution of Boc-L-tyrosine methyl ester (5.0 g, 16.93 mmol) and pyridine (4.11 ml, 50.79 mmol) in dichloromethane (145 ml) at 0° C. and the resulting orange solution was stirred at room temperature for 4 h. The reaction was quenched by addition of NaHCO3 solution (150 ml) and the organic layer was separated, washed with saturated aqueous NaHCO3 (2×100 ml) and brine (1×100 ml), and dried (MgSO4). The solvent was concentrated under reduced pressure to yield (S)-2-tert-butoxycarbonylamino-3-(4-trifluoromethanesulfonyloxyphenyl) propionic acid methyl ester (6.52 g, 90%) that was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]=[N:4][S:5]([C:8]1[O:16][C:15]2[CH:14]=[C:13]([CH3:17])[N+:12]([O-])=[CH:11][C:10]=2[CH:9]=1)(=[O:7])=[O:6].Cl.C(=O)([O-])[O-:22].[Na+].[Na+]>C(OC(=O)C)(=O)C>[CH3:1][N:2]([CH3:19])[CH:3]=[N:4][S:5]([C:8]1[O:16][C:15]2[CH:14]=[C:13]([CH2:17][OH:22])[N:12]=[CH:11][C:10]=2[CH:9]=1)(=[O:7])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc2oc(S(=O)(=O)N=CN(C)C)cc2c[n+]1[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CN(C)C=NS(=O)(=O)c1cc2cnc(CO)cc2o1
Temperature: 140 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
A suspension of N,N-dimethyl-N'-[6-methyl-5-oxido-furo[3,2-c]pyridine-2-sulfonyl]formamidine (4.24 g, 15 mmol) (from Example 13, Step B) in acetic anhydride (13 mL), under a nitrogen atmosphere was heated at 140° C. for 20 minutes to give an amber solution. This reaction mixture was cooled to 100° C. and 6% hydrochloric acid (30 mL) was added. After stirring at 100° C. for 4 hours, the reaction mixture was poured into saturated sodium carbonate (~100 mL) carefully. The product was extracted into methylene chloride, dried over anhydrous sodium sulfate, filtered through a charcoal pad and evaporated to dryness. This residue was triturated with diethyl ether/methylene chloride to give the product (2.21 g, 52% yield) which was used as is.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[C:29]1([S:35]([N:38]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40](B(O)O)=[CH:39]2)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([C:40]1[C:41]3[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]([S:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:37])=[O:36])[CH:39]=1)=[N:3][C:4]=2[N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: O=S(=O)(c1ccccc1)n1cc(B(O)O)c2ccccc21
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)nc21

Procedure:
2-(1-((2-Chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol was reacted with 1-(phenylsulfonyl)-1H-indol-3-ylboronic acid via General Procedure B to give intermediate 2-(1-((9-methyl-6-morpholino-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol. The intermediate was suspended in MeOH (3 mL) whereupon 3N KOH (0.3 mL) was added and the reaction mixture was heated at 50° C. for several hours until the protecting group was removed. Reverse phase purification gave 115. MS (Q1) 490.3 (M)+. 1H NMR (400 MHz, DMSO) δ 11.46 (s, 1H), 8.67-8.51 (m, 1H), 8.13 (d, 1H), 7.53-7.25 (m, 2H), 7.20-7.07 (m, 2H), 4.27 (s, 4H), 4.02 (s, 1H), 3.84 (s, 3H), 3.76 (dd, 12.2, 4H), 3.69 (s, 2H), 2.88 (d, 2H), 1.97 (t, 2H), 1.66 (d, 2H), 1.21 (dt, 3H), 1.02 (s, 6H)
Reaction SMILES: [CH2:1]([O:5]C(Cl)=O)[CH:2](C)[CH3:3].[C:9]1([N:15]2[CH2:20][CH2:19][N:18](C(C)C(O)=O)[CH2:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.[CH2:33]([N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[C:41]1[C:49]1[CH:54]=[CH:53][C:52]([NH2:55])=[CH:51][CH:50]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[NH3:15].[CH2:33]([N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[C:41]1[C:49]1[CH:50]=[CH:51][C:52]([NH:55][C:1](=[O:5])[CH2:2][CH2:3][N:18]2[CH2:17][CH2:16][N:15]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:20][CH2:19]2)=[CH:53][CH:54]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C(=O)O)N1CCN(c2ccccc2)CC1
Reactant: Nc1ccc(-c2nc3ccccc3n2Cc2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N
Product: O=C(CCN1CCN(c2ccccc2)CC1)Nc1ccc(-c2nc3ccccc3n2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
i-Butylchloroformate (0.24 mL) is added to 4-phenylpiperazin-1-ylpropanoic acid (0.39 g) and triethylamine (0.28 mL) in dichloromethane (10 mL) at -20° C. under nitrogen. After stirring for 30 minutes, 4-(1-benzyl-1H-benzimidazol-2-yl)phenylamine (Step A) (0.50 g) in dichloromethane (10 mL) is added dropwise at -20° C. and the mixture allowed to warm to room temperature with stirring. The mixture is diluted with dichloromethane (50 mL), washed with 2N sodium carbonate (50 mL), dried over MgSO4, filtered and evaporated to leave a yellow oil. This oil is purified by MPLC on silica gel eluting with 250:8:1 dichloromethane: ethanol: 0.880 aqueous ammonia to give 0.66 g of the title compound as a yellow foam.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=O)=[C:11]3[N:10]=2)[CH2:4][CH2:3]1.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].N1CCCCC1>CCO>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=[C:24]4[S:20][C:21](=[O:26])[NH:22][C:23]4=[O:25])=[C:11]3[N:10]=2)[CH2:4][CH2:3]1
Reactant: O=C1CSC(=O)N1
Reactant: CN1CCCN(c2ccn3ncc(C=O)c3n2)CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: CN1CCCN(c2ccn3ncc(C=C4SC(=O)NC4=O)c3n2)CC1
Temperature: 70 °C

Procedure:
To 5-(4-methyl-1,4-diazepan-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (36 mg, 0.138 mmol) in EtOH was added 2,4-thiazolidinedione (16 mg, 0.138 mmol) and piperidine (14 μL, 0.138 mmol). The mixture was heated at 70° C. and purified by HPLC to yield 5-((5-(4-methyl-1,4-diazepan-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione. LCMS (M+1=359)
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:32])[C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([N:15]2[CH2:20][CH2:19][C@:18]([CH2:28][CH:29]=[CH2:30])([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[O:17][C:16]2=[O:31])[CH3:14])=[CH:9][CH:8]=1)(=O)[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.C1COCC1>CCOC(C)=O>[CH2:28]([C@@:18]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[O:17][C:16](=[O:31])[N:15]([C@H:13]([C:10]2[CH:9]=[CH:8][C:7]([C:6]3[O:32][C:1]([CH3:2])=[N:4][N:5]=3)=[CH:12][CH:11]=2)[CH3:14])[CH2:20][CH2:19]1)[CH:29]=[CH2:30]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(C(=O)NNC(C)=O)cc2)C(=O)O1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3nnc(C)o3)cc2)C(=O)O1
Temperature: 180 °C
Yield: 29.1 %

Procedure:
Crude N′-acetyl-4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzohydrazide (5 mg, 0.0114 mmol) was mixed with Burgess reagent (˜4 mg, excess), dry THF (1 mL) and put into Microwave Oven, heated to 180° C. for 10 min. at 100 W. LC-MS found reaction completed. The mixture was diluted with EtOAc (8 mL), washed with water (2×3 mL), concentrated and purified by prep HPLC to afford (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (1.4 mg, 29%). LC-MS Method 1 tR=1.61, min, m/z=422; 1H NMR (CDCl3) 7.77 (d, 2H), 7.26 (m, 3H), 7.01 (m, 3H), 5.70 (m, 2H), 5.07 (dd, 2H), 2.98 (m, 1H), 2.62 (s, 3H), 1.55 (d, 3H).
Reaction SMILES: C1C2C(=CC=CC=2)C=C[C:2]=1[C:11](=[O:26])[CH2:12][C:13]([O:15][C:16]([CH3:25])([CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH:17]=[CH2:18])=[O:14].CC(O)(CCC=C(C)C)C=C.C=C1OC(=O)C1>>[O:26]=[C:11]([CH3:2])[CH2:12][C:13]([O:15][C:16]([CH3:25])([CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH:17]=[CH2:18])=[O:14]
Reactant: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)c1ccc2ccccc2c1
Agent: C=C1CC(=O)O1
Agent: C=CC(C)(O)CCC=C(C)C
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(C)=O

Procedure:
The pro-accord 3,7-dimethyl-1,6-octadien-3-yl 3-(β-naphthyl)-3-oxo-propionate, which is a β-ketoester pro-accord, is prepared by treating 3,7-dimethyl-1,6-octadien-3-ol (linalool), which is a fragrance raw material according to the present invention, with diketene under suitable conditions to form intermediate 3,7-dimethyl-1,6-octadien-3-yl 3-oxo-butyrate, which is subsequently treated with 2-naphthoyl chloride to yield the pro-accord. 3,7-Dimethyl-1,6-octadien-3-yl 3-(β-naphthyl)-3-oxo-propionate when exposed to suitable conditions (e.g., exposure to nascent moisture) breaks down to release a mixture of linalool and methyl β-naphthyl ketone, both of which are fragrance raw materials as defined herein.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:17]3)=[CH:12][CH:11]=2)O)=[N:4][CH:5]=[CH:6][N:7]=1.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][C:16]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:17]3)=[CH:12][CH:11]=2)[N:30]2[C:26](=[O:36])[C:27]3[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:29]2=[O:31])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: OC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a suspension of (3-chloropyrazin-2-yl)-(2-phenylquinolin-7-yl)-methanol (1.215 g, 3.49 mmol), phthalimide (566 mg, 3.85 mmol), and PS-PPh3 (loading 2.12 mmol/g; 3.29 g, 6.97 mmol) in dry THF (40 mL), cooled by ice/water, is added DIAD (830 μL, 852 mg, 4.22 mmol). The cooling bath is removed and the flask is vortexed at rt for 1 d. More phthalimide (50 mg, 0.34 mmol), PS-PPh3 (300 mg, 0.636 mmol), and DIAD (80 μL, 82 mg, 0.41 mmol) are added, and vortexing is continued for 2 d. The resin is filtered off on a glass frit (porosity M) and washed with CH2Cl2. The combined filtrates and washings are concentrated in vacuo and chromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with CH2Cl2 (1-22)→2% EtOAc in CH2Cl2 (23-38)→5% (39-61)], mixed fractions are combined and chromatographed again [50 g/150 mL cartridge, eluting with CH2Cl2 (1-22)→2% EtOAc in CH2Cl2 (23-33)→3% (34-55)→5% (56-68)] to obtain the title compound as white foam. 1H NMR (CDCl3, 400 MHz) δ 7.14 (s, 1H), 7.43-7.55 (m, 3H), 7.72-7.79 (m, 3H), 7.82-7.90 (m, 4H), 8.09 (s, 1H), 8.09-8.14 (m, 2H), 8.22 (d, J=8.8 Hz, 1H), 8.40 (d, J=2.4 Hz, 1H), 8.51 (d, J=2.4 Hz, 1H). MS (ES+): m/z 476.9/478.9 (100/38) [MH+]. HPLC: tR=3.5 min (MicromassZQ, nonpolar—5 min).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[OH:28][C@H:29]1[CH2:33][CH2:32][NH:31][C@@H:30]1[C:34]([N:36]([CH3:38])[CH3:37])=[O:35]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([N:31]1[CH2:32][CH2:33][C@H:29]([OH:28])[C@H:30]1[C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CN(C)C(=O)[C@H]1NCC[C@@H]1O
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N2CC[C@H](O)[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 4.23 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 17-2 (crude form 15.1 mmol) as starting materials, respectively 2.75 g (Isomer A) and 2.28 g (Isomer B) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N[S:22]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=[O:35])(=[O:24])=[O:23])CC>>[CH3:17][N:15]([CH3:16])[CH2:14][CH2:13][NH:12][C:10](=[O:11])[C@@H:2]([NH:1][S:22]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=[O:35])(=[O:23])=[O:24])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCNS(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Reactant: CN(C)CCNC(=O)[C@@H](N)Cc1ccccc1
Product: CN(C)CCNC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2

Procedure:
The title compound was prepared from L-Phe-NHCH2CH2NMe2 following the procedure for 2,3-Dioxo-2,3-dihydro-1H-indole-5-sulfonic acid propylamide.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][CH2:11][O:12][C:13]([CH2:15][SH:16])=[O:14].CCN(CC)CC>CS(C)=O>[NH2:5][C:4]1[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[S:16][C:15]=1[C:13]([O:12][CH2:11][CH3:10])=[O:14]
Reactant: CCOC(=O)CS
Reactant: N#Cc1ccccc1F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)c1sc2ccccc2c1N
Yield: 70.5 %

Procedure:
2-Fluorobenzonitrile (0.61 g, 5 mmol), ethyl thioglycollate (0.60 g, 5 mmol) and NEt3 (1.52 g, 15 mmol) are stirred in DMSO (5 mL) at 100° C. under N2 for 3 h. The reaction mixture is poured onto ice-water (50 mL), and the solid is collected by suction filtration, rinsed with water, and air dried to give ethyl 3-aminobenzothiophene-2-carboxylate (0.78 g, 70%) as a grey-brown solid. 1H NMR (DMSO) δ8.14 (IH, d, J=7.7 Hz), 7.88 (1H, d, J=8.1 Hz), 7.50 (1H, dt, Jd =1.2 Hz, Jt =7.5 Hz), 7.39 (1H, dt, Jd =1.2 Hz, Jt =7.6 Hz), 7.17 (2H, brs), 4.26 (2H, q, J=7.1 Hz), 1.29 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]1[N:12]=[C:13]([NH2:16])[S:14][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cl:18][CH2:19][C:20](Cl)=[O:21]>CN(C)C=O.C(OCC)(=O)C.O>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]1[N:12]=[C:13]([NH:16][C:20](=[O:21])[CH2:19][Cl:18])[S:14][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1csc(N)n1
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of 2-(2-amino-4-thiazolyl)malonic acid diethyl ester in N,N-dimethylformamide (10 parts) is added monochloroacetyl chloride (1.3 equivalents) under ice cooling. After stirring under ice cooling for 30 minutes and at room temperature for 1 hour, the reaction mixture is diluted with ethyl acetate and water, washed with water, dried, and concentrated in vacuum to give 2-(2-monochloroacetamido-4-thiazolyl)malonic acid diethyl ester. Yield: 99.6%.
Reaction SMILES: [CH:1]1([O:6][CH2:7][C:8](Cl)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:11]([C:14]1[C:15]([NH2:23])=[N:16][N:17]2[CH:22]=[CH:21][CH:20]=[N:19][C:18]=12)([CH3:13])[CH3:12].CO>N1C=CC=CC=1>[CH:1]1([O:6][CH2:7][C:8]([NH:23][C:15]2[C:14]([CH:11]([CH3:13])[CH3:12])=[C:18]3[N:19]=[CH:20][CH:21]=[CH:22][N:17]3[N:16]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1c(N)nn2cccnc12
Reactant: O=C(Cl)COC1CCCC1
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)c1c(NC(=O)COC2CCCC2)nn2cccnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from Example 133C (1.5 mL of solution in CH2Cl2) was added to a solution of the product from Example 112C (86 mg, 0.49 mmol) in pyridine (1.0 mL) in a 4 mL vial. The reaction mixture was stirred at room temperature for 2 h. Methanol (0.5 mL) was added, and the solution was stirred for 30 minutes and then concentrated under vacuum. The residue was purified by flash chromatography (silica gel, eluted with hexanes-EtOAc, 70:30-0:100) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.45 (d, J=7.1 Hz, 6H) 1.57-1.69 (m, 2H) 1.70-1.87 (m, 6H) 3.24 (hept, J=7.1 Hz, 1H) 4.10-4.13 (m, 1H) 4.11-4.12 (m, 2H) 6.72 (dd, J=6.8, 4.1 Hz, 1H) 8.39 (dd, J=4.1, 1.7 Hz, 1H) 8.58 (dd, J=6.8, 1.7 Hz, 1H) 8.60 (s, 1H); MS (ESI) m/z 303 (M+H)+; Anal. Calculated for C16H22N4O2: C, 63.71; H, 7.44; N, 18.20. Found: C, 63.56; H, 7.33; N, 18.53.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][CH:24]([CH2:26][OH:27])[O:23][C:22]2=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][CH:24]([CH2:26][O:27][S:37]([CH3:36])(=[O:39])=[O:38])[O:23][C:22]2=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CC(CO)OC3=O)cc2F)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CC(COS(C)(=O)=O)OC3=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A solution of 375 mg (0.95 mmol) of oxazolidinone 9 and 144 mg (0.20 mL, 1.42 mmol) triethylamine in 3.8 mL dichloromethane at 0° C. was treated dropwise with 130 mg (0.09 mL, 1.14 mmol) of methanesulfonyl chloride followed by stirring at 0° C. for 1 hour. The solution was diluted with 30 mL dichloromethane and was extracted with water (2×25 mL) and with saturated NaHCO3 (25 mL). Drying (Na2 SO4) and concentration in vacuo afforded 440 mg (98%) of mesylate 10 as a white solid, sufficiently pure for use in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[N+:13]([O-])=O.[CH3:17]O>[Ni]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH3:17])[C:5]=1[NH2:13]
Reactant: COC(=O)c1cc(N(C)C)ccc1[N+](=O)[O-]
Reactant: CO
Agent: [Ni]
Product: COC(=O)c1cc(N(C)C)cc(C)c1N
Yield: 98 %

Procedure:
Raney Nickel (80 mg) was added to a suspension of 5-dimethylamino-2-nitro-benzoic acid methyl ester (400 mg, 1.78 mmol) in methanol (20 mL) and hydrogenated under atmospheric pressure at room temperature for 2 hr. The reaction mixture was filtered over celite and the filtrate was concentrated in vacuum to afford methyl 2-amino-5-dimethylamino-benzoic acid methyl ester (340 mg, 98%) as greenish brown liquid.
Reaction SMILES: [C:1](=[O:4])(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[C:9]1([CH3:16])[C:10]([CH3:15])=[CH:11][CH:12]=[CH:13][CH:14]=1>>[NH2:7][C:6]1[N:8]=[C:1]([OH:4])[C:9]2[CH2:16][CH2:15][CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[N:5]=1
Reactant: N=C(N)N
Reactant: Cc1ccccc1C
Reactant: O=C(O)O
Product: Nc1nc(O)c2c(n1)CCCCCC2

Procedure:
A mixture of ethyl-2-cyclooctanone carboxylate (3.5 g) and guanidine carbonate (3.82 g) in xylene (50 ml) was refluxed overnight; after cooling the white solid was collected by filtration, washed with water, and dried to yield 2.0 g of product.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([C:15]#[N:16])([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].CO.O.O.[OH-].[Li+]>O1CCCC1>[Cl:1][C:2]1[C:11]([C:12]([C:15]#[N:16])([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cccc(C(C)(C)C#N)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of methyl 2-chloro-3-(1-cyano-1-methylethyl)benzoate (1.67 g, 7.02 mmol) in tetrahydrofuran (24 mL)/methanol (8 mL)/water (8 mL) was added lithium hydroxide-monohydrate (501 mg, 11.9 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and 6N hydrochloric acid (2.8 mL) was added dropwise to the residue. The precipitate was collected by filtration, and washed with water to give the title compound (1.43 g, 91%) as a white powder.