Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:24])[C@@H:6]([CH3:23])[CH2:7][C@H:8]([NH2:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH3:3].[C:25]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:30]=[CH:29][C:28]([CH2:31][C@@H:32]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:33][C@@H:34]([CH3:38])[C:35]([OH:37])=[O:36])=[CH:27][CH:26]=1.[C:53](Cl)(=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OC(C)C)(=O)C.O.C(N(CC)CC)C>[CH2:2]([O:4][C:5](=[O:24])[C@H:6]([CH3:23])[CH2:7][C@H:8]([NH:22][C:53](=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)[CH3:3].[C:25]1([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:26]=[CH:27][C:28]([CH2:31][C@@H:32]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:44])[CH3:45])=[O:41])[CH2:33][C@@H:34]([CH3:38])[C:35]([OH:37])=[O:36])=[CH:29][CH:30]=1
Reactant: CCOC(=O)[C@@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC(=O)OC(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
10 g (2S,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride (3-a, R1=R2=H, R3=Et) in isopropyl acetate (50 ml) is added to a mixture of pivaloyl chloride (4.1 ml) in isopropyl acetate (50 ml). The mixture is then stirred for 40 min at room temperature. Triethylamine (10.3 ml) in isopropyl acetate (30 ml) is then added over a period of 1 h. The resulting mixture is stirred for 16 h. Citric acid (7.5 g) dissolved in water (30 ml) is added and the phases are separated. The organic phase is washed twice with water (30 ml) and concentrated in vacuo to give (2R,4S)-5-Biphenyl-4-yl-4-(2,2-dimethylpropionylamino)-2-methylpentanoic acid ethyl ester (3-a, R1=Piv, R2=H, R3=Et). 1H NMR (DMSO): 1.05 (9H), 1.09 (3H), 1.15 (3H), 1.54 (1H), 1.78 (1H), 2.48 (1H), 2.72 (2H), 3.97 (1H), 4.00 (2H), 7.15 (1H), 7.25 (2H), 7.34 (1H), 7.45 (2H), 7.55 (2H), 7.62 (2H).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][N+:11]#[C-:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:14]I.[OH-].[Na+].O>ClCCl>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([S:7]([CH:10]([N+:11]#[C-:12])[CH3:14])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: CI
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a solution of toluene-4-sulfonylmethylisocyanide (15 g), methyl iodide (109 g) benzyl trimethyl ammonium chloride (3.5 g) in dichloromethane (300 mL) was added 5 mol/L aqueous sodium hydroxide solution (307 mL) under ice cooling, and this mixture was stirred at same temperature for 2 hours. To this reaction mixture was added water and this mixture was extracted with diethyl ether. This organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (16 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C:10](=[O:14])[C@@H:9]1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([Mg]Cl)[CH:23]=[CH2:24]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@:10]([OH:14])([CH2:24][CH:23]=[CH2:22])[C@@H:9]1[C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OCCN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Reactant: C=CC[Mg]Cl
Solvent: C1CCOC1
Product: C=CC[C@@]1(O)OCCN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(3S)-4-Benzyl-3-(4-fluorophenyl)-2-morpholinone (see International Patent Specification No. WO95/18124) (13.6 g, 47.6 mmol) was dissolved in anhydrous tetrahydrofuran (200 ml) and cooled to below -70° C. under an inert atmosphere. Allyl magnesium chloride (26.2 ml of a 2.0M solution in tetrahydrofuran; 52.4 mmol) was added dropwise over 15 minutes, maintaining the temperature below -70° C. After 30 minutes, the reaction was quenched by the addition of a saturated solution of ammonium chloride and allowed to warm to room temperature. The resulting suspension was extracted with ethyl acetate (3×100 ml), and the combined organic extracts dried (MgSO4) and concentrated in vacuo to yield the title compound in ~3:1 mixture of the lactols as a light yellow oil (15.3 g, 98%), which was used without further purification. MS (ES+) m/z 328 (M+1. 22%), 310 (M-OH, 61), 269 (100).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[C:8]2[CH2:9][C:10]3[S:14][C:13]([SH:15])=[N:12][C:11]=3[C:16]=2[CH:17]=[CH:18][CH:19]=1)C.[Br-].[C:22]1([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[S:15][C:13]2[S:14][C:10]3[CH2:9][C:8]4[C:7]([O:6][CH2:5][C:4]([OH:3])=[O:20])=[CH:19][CH:18]=[CH:17][C:16]=4[C:11]=3[N:12]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)COc1cccc2c1Cc1sc(S)nc1-2
Reactant: c1ccc(Cc2ccccc2)cc1
Agent: [Br-]
Product: O=C(O)COc1cccc2c1Cc1sc(SC(c3ccccc3)c3ccccc3)nc1-2
Yield: 61 %

Procedure:
Using ethyl[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and diphenylmethane bromide, the procedure of Example 21 was otherwise repeated to synthesize the title compound. Yield 61%.
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].[N:7]1[NH:8][N:9]=[N:10][C:11]=1[C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.IC>O1CCCC1.CN(C)C=O>[CH3:1][N:9]1[N:8]=[N:7][C:11]([C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)=[N:10]1
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(-c2nn[nH]n2)c1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nnc(-c2cccc(O)c2)n1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A suspension of cesium carbonate (0.60 g, 1.83 mmol), 3-(2H-tetrazol-5-yl)-phenol (0.30 g, 1.85 mmol) (from Example 25 supra) in tetrahydrofuran-N,N-dimethylformamide (5:2, 17.5 mL) was heated at 70° C. for 3 hours. Iodomethane (0.29 g, 2.04 mmol) (Aldrich) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phase washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography eluting with 40% ethyl acetate in hexanes to give 3-(2-methyl-2H-tetrazol-5-yl)-phenol. (Yield 0.23 g, 70%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:18]=2[OH:24])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[O:24][C:18]3[CH:19]=[CH:20][C:21]([Br:23])=[CH:22][C:17]=3[N:16]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cc(Br)ccc1O)C1CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Brc1ccc2oc(C3CCN(Cc4ccccc4)CC3)nc2c1
Yield: 24.3 %

Procedure:
Intermediate 22 (47.6 g, 0.122 mol) was dissolved in xylene (500 ml) and added p-Toluenesulphonic acid (46 g, 0.24 mol). This mixture was refluxed for 20 h under a dean-stark condenser. Xylene was removed and pH of the residue was adjusted to 9 using aq NaHCO3 solution. Work up (EtOAc/H2O) afforded the crude. Crude was purified by column on 60-120 mesh silicagel using a gradient mixture of EtOAc and Petether (10:90) as eluent to afford the titled compound (11 g) as brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=O)=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].Cl.[NH2:36][OH:37].C([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:12]=[CH:13][C:14]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:18][C:19](=[N:36][OH:37])[C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=[CH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2ccc(-c3ccc(C(=O)O)c(F)c3)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2ccc(-c3ccc(C(=O)O)c(F)c3)cc2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from 3-fluoro-4′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (5.8:1) as a colorless oil, MS (ESI+): m/z=469.1917 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:14]C(=O)OC(C)(C)C)[CH2:9][S:10](=[O:13])(=[O:12])[NH2:11])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[NH2:14][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:9][S:10]([NH2:11])(=[O:12])=[O:13]
Reactant: CC(C)(C)OC(=O)NC(CS(N)(=O)=O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: NC(CS(N)(=O)=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.1 %

Procedure:
Tert-butyl 1-(4-chlorophenyl)-2-sulfamoylethylcarbamate (Intermediate 79) (325 mg, 0.97 mmol) was treated with trifluoroacetic acid (8 mL). The resulting solution was stirred for 15 minutes at room temperature. The mixture was concentrated under reduced pressure and the residue was purified by ion exchange chromatography, using an SCX column. The column was washed with methanol and the desired product was eluted using ammonia in methanol (2M) and pure fractions were evaporated to dryness to afford 2-amino-2-(4-chlorophenyl)ethanesulfonamide (221 mg, 97%) as a near colourless solid.
Reaction SMILES: [C:1]1([C@H:7]([O:33]C(=O)C)[C:8](=[O:32])[N:9]([C:22]2[CH:23]=[N:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>O1CCCC1.O>[OH:33][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([N:9]([C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=1)=[O:32]
Reactant: CC(=O)O[C@H](C(=O)N(CCc1ccc(C(F)(F)F)cc1)c1cnc2ccccc2c1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([C@@H](O)c1ccccc1)N(CCc1ccc(C(F)(F)F)cc1)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 155 mg acetic acid (S)-phenyl-{quinolin-3-yl-[2-(4-trifluoromethyl-phenyl)-ethyl]-carbamoyl}-methyl ester in tetrahydrofuran (6.0 mL) were added 3.0 mL water and 20 mg lithium hydroxide monohydrate. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted 3 times with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethylacetate to provide the title compound. MS(m/e): 451.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:30]([CH3:38])[CH2:31][CH:32]([CH3:37])[CH2:33][CH2:34]C=C)[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([NH:20][C@:21]1([C:26]([O:28][CH3:29])=[O:27])[CH2:23][C@H:22]1[CH:24]=[CH2:25])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:10](=[O:11])[N:12]2[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]2[C:18](=[O:19])[NH:20][C@:21]2([C:26]([O:28][CH3:29])=[O:27])[CH2:23][C@H:22]2[CH:24]=[CH:25][CH2:34][CH2:33][CH:32]([CH3:37])[CH2:31][C@H:30]1[CH3:38])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)OC)C[C@H]1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: COC(=O)[C@@]12C[C@H]1/C=C\CCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2
Solvent: ClCCCl
Product: COC(=O)[C@@]12C[C@H]1C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2
Temperature: 80 °C

Procedure:
A solution of (1R,2S)-methyl 1-((2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate (2.68 g, 5 mmol) in DCE (600 mL) was sparged with nitrogen for 30 min. and then Hoveyda-Grubbs Catalyst 2nd Generation (0.189 g, 0.300 mmol) was added and the reaction heated to 80° C. for 2 hrs. The reaction was concentrated and purified by flash chromatography on silica gel (20-60% Acetone in hexanes) to give 2.1 g of the product (2R,6S,7R,13aS,14aR,16aS,Z)-methyl 6-((tert-butoxycarbonyl)amino)-2-hydroxy-7,9-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate. MS: MS m/z 530.18 (M++23).
Reaction SMILES: [Na].CO[C:4](=O)[CH2:5][CH2:6][S:7][C:8]1[C:17]([C:18](=[O:26])[NH:19][CH2:20][C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:27]([F:30])([F:29])[F:28])[CH:14]=2)[N:9]=1.I[CH2:33][CH2:34]CCC>CO>[CH2:6]([S:7][C:8]1[C:17]([C:18]([NH:19][CH2:20][C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)=[O:26])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:27]([F:30])([F:29])[F:28])[CH:14]=2)[N:9]=1)[CH2:5][CH2:4][CH2:33][CH3:34]
Reactant: CCCCCI
Reactant: COC(=O)CCSc1nc2ccc(C(F)(F)F)cc2cc1C(=O)NCc1cccs1
Agent: [Na]
Solvent: CO
Product: CCCCCSc1nc2ccc(C(F)(F)F)cc2cc1C(=O)NCc1cccs1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
198 mg (8.6 mmol) sodium were added slowly to MeOH (86 ml) and the solution was stirred for 5 min at RT. Then a solution of 455 mg (1.0 mmol) 3-(3-(thiophen-2-ylmethylcarbamoyl)-6-(trifluoromethyl)quinolin-2-ylthio)propanoic acid methyl ester (Example 26) in MeOH (10 ml) was added at RT. The reaction solution was then heated for 30 min at 70° C. Then 396 μl (3.0 mmol) 1-iodopentane were added at RT and the mixture was stirred for 1 h at RT. Then the mixture was concentrated to small volume under vacuum and the residue was taken up with EE. It was washed with water and brine and the organic phase was dried over Na2SO4, filtered and concentrated to small volume under vacuum. 167 mg (0.4 mmol, 38%) 2-(pentylthio)-N-(2-thienylmethyl)-6-(trifluoromethyl)-3-quinoline carboxamide were obtained as residue. MS: m/z 439.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][CH2:13][CH:14]([O:16]C1CCCCO1)[CH3:15].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][CH2:13][CH:14]([OH:16])[CH3:15]
Reactant: CC(COc1c([N+](=O)[O-])ccc(F)c1F)OC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CC(O)COc1c([N+](=O)[O-])ccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6.35 g of 2,3-difluoro-6-nitro{[2-(tetrahydropyran-2-yl)oxypropyl]oxy}benzene (I, Xa=Xb=F, Rc=THP, 60 ml of anhydrous ethanol and 640 mg of pyridinium tosylate was stirred at room temperature overnight and then heated under refluxing for 1 hour. The solvent was removed under reduced pressure. To the residue were added ethyl acetate and 1 N hydrochloric acid. The mixture was shaken, and the organic layer was separated. The organic layer was washed successively with a saturated sodium bicarbonate aqueous solution and water, then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to yield the oily titled compound. This product was used in the following reaction without purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[I:11][C:12]1[CH:13]=[N:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C>N1C=CC=CC=1.ClCCl.[Cu]=O>[I:11][C:12]1[CH:13]=[N:14][N:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:16]=1
Reactant: Ic1cn[nH]c1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1-n1cc(I)cn1
Yield: 76.2 %

Procedure:
A mixture of 1-fluoro-2-nitrobenzene (14.5 g, 0.1 mol), 4-iodopyrazole (20 g, 0.1 mol), potassium carbonate anhydrous (14 g, 0.1 mol) and catalytical amounts of copper(II) oxide in pyridine (35 ml) was heated to reflux for 16 hours. After cooling, the mixture was diluted with dichloromethane (1 litre). Activated charcoal (12 g) was then added and the mixture was heated to reflux for 1 hour. After cooling, it was filtered through celite. The filtrate was evaporated and the remaining oil was purified by silica gel chromatography using ethyl acetate and hexane as eluents, giving 4-iodo-1-(2-nitro-phenyl)-1H-pyrazole (24 g).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[CH3:14][C:15]1([CH3:26])[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[C:18](=[O:24])[CH2:17][C:16]1=[O:25].C(N(CC)CC)C.CC(C)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6]([CH:17]1[C:16](=[O:25])[C:15]([CH3:26])([CH3:14])[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[C:18]1=[O:24])=[O:7])([O-:3])=[O:2]
Reactant: CC1(C)C(=O)CC(=O)C(C)(C)C1=O
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)C(C(=O)c2ccc(Cl)cc2[N+](=O)[O-])C(=O)C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
2-Nitro-4-chlorobenzoyl chloride (2.2 g, 10 mmol) and 4,4,6,6-tetramethyl-1,3,5-cyclohexanetrione (1.8 g, 10 mmol) were dissolved in methylene chloride. Triethylamine was added and the resulting solution stirred at room temperature for 30 minutes. The solution was washed with 1 normal hydrochloric acid (1N HCl), and saturated sodium chloride (brine), dried over anhydrous magnesium sulfate (MgSO4) and concentrated under vacuum. The residue was dissolved in 20 ml acetonitrile. Triethylamine (5 ml, 3.5 equivalents) and acetone cyanohyrdin (0.5 g, 0.6 equivalent) were added and the mixture stirred at room temperature for 4 hours. After dilution with ether, the solution was washed with 1N HCl and extracted with 5% K2CO3. The basic extract was acidified with HCl and extracted with ether. The ether extract was washed with brine, dried over MgSO4 and concentrated under vacuum, yielding 2.2 g of crude product.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:22])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1.CN(C)C=O.[H-].[Na+].[CH2:30](I)[CH2:31][CH2:32][CH3:33]>O>[CH2:30]([N:1]([CH2:4][CH2:5][CH2:10][CH3:9])[C:2]1[N:3]([CH3:22])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1)[CH2:31][CH2:32][CH3:33]
Reactant: Cc1cc(C)c(-c2cn(C)c3nc(N)n(C)c(=O)c23)c(C)c1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCN(CCCC)c1nc2c(c(-c3c(C)cc(C)cc3C)cn2C)c(=O)n1C
Reaction time: 0.5 h
Yield: 122.4 %

Procedure:
To a solution of 2-amino-5-mesityl-3,7-dimethyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (100 mg, 0.34 mmol) and N,N-dimethylformamide (2 ml) was added sodium hydride (60% in oil, 27 mg, 0.66 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of n-BuI (184 mg, 1.00 mmol) and N,N-dimethylformamide (1 ml) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 1 hour, the mixture was diluted with water (20 ml) and extracted with ethyl acetate (50 ml×2). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (4:1) to give 85 mg (62%) of the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]3[CH2:11][CH2:12][NH:13][C:7]3([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:6][N:5]2[CH:21]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]23[NH:13][CH2:12][CH2:11][N:8]2[C:9](=[O:10])[C:4]2[N:5]([CH:21]=[C:2]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)[CH:3]=2)[CH2:6]3)=[CH:15][CH:16]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C1c2cc(Br)cn2CC2(c3ccc(Cl)cc3)NCCN12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: O=C1c2cc(-c3cccnc3)cn2CC2(c3ccc(Cl)cc3)NCCN12
Temperature: 150 °C
Yield: 39.2 %

Procedure:
7-bromo-10a-(4-chlorophenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (50 mg, 0.14 mmol), pyridine-3-boronic acid (18.5 mg, 0.15 mmol), dichlorobis(triphenylphosphine)palladium(II) (1.9 mg, 2.7 μmol) and sodium carbonate (22 mg, 0.21 mmol) were suspended in a mixture of 1,2-dimethoxyethane (1.4 mL), ethanol (200 μL) and water (300 μL). The reaction vessel was flushed with argon, sealed and heated in a microwave reactor at 150° C. for 10 min. After this time water (50 mL) was added and the mixture extracted with CH2Cl2. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to give a crude mixture. This mixture was purified by flash chromatography (Biotage SP4, 12 g cartridge, 0-10% MeOH gradient in CH2Cl2) to give 10a-(4-chlorophenyl)-7-(pyridin-3-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one as a white solid (20 mg, 40% yield). 1H NMR (400 MHz, d6-acetone): δ 3.30-3.31 (m, 1H), 3.33-3.40 (m, 1H), 3.43-3.50 (m, 1H). 3.75 (dt, 1H, J 10.8, 8.0 Hz), 4.46 (d, 1H, J 12.4 Hz), 4.74 (d, 1H, J 12.4 Hz), 7.14 (d, 1H, J 1.8 Hz), 7.23 (d, 1H, J 1.8 Hz), 7.27 (ddd, 1H, J 8.0, 4.8, 0.9 Hz), 7.32-7.36 (m, 2H), 7.40-7.44 (m, 2H), 7.85 (ddd, 1H, J 7.9, 2.4, 1.7 Hz), 8.34 (dd, 1H, J 4.7, 1.6 Hz), 8.75 (dd, 1H, J 2.4, 0.8 Hz).
Reaction SMILES: OC1CN(C([O-])=O)CC=C1.[Si:11]([O:18][CH2:19][CH2:20][C:21]1[C@@H:22]([CH2:35][O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][C@@H:25](O)[CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:63]([O:66][NH:67][S:68]([C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=1[N+:77]([O-:79])=[O:78])(=[O:70])=[O:69])[CH:64]=[CH2:65].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[CH2:63]([O:66][N:67]([C@H:25]1[CH2:24][N:23]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[C@H:22]([CH2:35][O:36][Si:37]([C:40]([CH3:41])([CH3:43])[CH3:42])([CH3:39])[CH3:38])[C:21]([CH2:20][CH2:19][O:18][Si:11]([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:12])[CH3:13])=[CH:26]1)[S:68]([C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=1[N+:77]([O-:79])=[O:78])(=[O:70])=[O:69])[CH:64]=[CH2:65]
Reactant: C=CCONS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C=C(CCO[Si](C)(C)C(C)(C)C)[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C([O-])N1CC=CC(O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCON([C@@H]1C=C(CCO[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a solution of (2S,5S)-tert-butyl 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-((tert-butyldimethylsilyl)oxy)methyl)-5-hydroxy-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 281, 7.33 g, 14.61 mmol) in toluene (100 mL) at room temperature was added triphenylphosphine (4.58 g, 17.53 mmol), N-(allyloxy)-2-nitrobenzenesulfonamide (3.77 g, 14.61 mmol) and diisopropyl azodicarboxylate (3.45 mL, 17.53 mmol). The reaction mixture was stirred overnight at room temperature then concentrated. The resulting oil was triturated with hexane and filtered to remove triphenylphosphine oxide. The filtrate was concentrated onto silica gel. Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded the title compound (7.5 g, 69.2%) as a light yellow oil.