Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:6]([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[O:9][C:8]2([CH3:19])[CH3:18])[CH:5]=[N:4][CH:3]=1.O1C=CC=C1P(C1O[CH:33]=[CH:34][CH:35]=1)C1OC=CC=1.C([Sn](CCCC)(CCCC)C1CC1)CCC>CN1CCCC1=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:34]1([C:2]2[N:6]([CH:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10](=[O:17])[O:9][C:8]3([CH3:19])[CH3:18])[CH:5]=[N:4][CH:3]=2)[CH2:35][CH2:33]1
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1I
Reactant: c1coc(P(c2ccco2)c2ccco2)c1
Agent: [Pd]
Agent: CCCC[Sn](CCCC)(CCCC)C1CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN1CCCC1=O
Product: CC1(C)OC(=O)c2ccccc2C1n1cncc1C1CC1
Temperature: 95 °C

Procedure:
To a flask charged with 4-(5-iodo-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one (350 mg, 0.95 mmol) (Example 2b), tris(dibenzylideneacetone)dipalladium(0) (98 mg, 0.095 mmol) and trifuran-2-yl-phosphane (33 mg, 0.142 mmol) and flushed with N2 is added tributylcyclopropyltin (1.89 g, 5.7 mmol) in degassed N-methylpyrrolidinone (3 mL). The mixture is degassed for 15 min and heated to 95° C. for 25 h. The reaction mixture is quenched with water and extracted with ethyl acetate three times. The organic phase is combined, dried over sodium sulfate, concentrated and the residue is purified by semi-preparative reverse phase HPLC to give 4-(5-cyclopropyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one as white solid; (ESI) m/z 283.2 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 0.69 (s, 1 H), 0.81 (br. s, 1 H), 1.09 (br. s, 2 H), 1.29 (s, 3 H), 1.56 (s, 3 H), 1.94 (br. s, 1 H), 5.78 (s, 1 H), 6.68 (s, 1 H), 7.14 (br. s, 1 H), 7.42 (d, J=7.1 Hz, 1 H), 7.63 (td, J=7.6, 1.3 Hz, 1 H), 7.75 (td, J=7.6, 1.3 Hz, 1 H), 8.21 (dd, J=7.8, 1.3 Hz, 1 H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:14][C@@H:15]([OH:40])[C@@H:16]([NH:28][C:29](=[O:39])[O:30][C@@H:31]3[C@H:38]4[C@H:34]([O:35][CH2:36][CH2:37]4)[O:33][CH2:32]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:54](Cl)(=[O:56])[CH3:55]>C1COCC1.C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:14][C@@H:15]([OH:40])[C@@H:16]([NH:28][C:29](=[O:39])[O:30][C@@H:31]3[C@H:38]4[C@H:34]([O:35][CH2:36][CH2:37]4)[O:33][CH2:32]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][NH:27][C:54](=[O:56])[CH3:55])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCN)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)NCCOc1ccc(C[C@H](NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H](O)CN(CC(C)C)S(=O)(=O)c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Yield: 86 %

Procedure:
A solution of 21 mg (0.033 mmol) of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-[4-(2-aminoethoxy)benzyl]propylcarbamate in 2 mL of 1:1 THF/CH2Cl2 was treated with 9 μL (0.050 mmol) of N,N-diisopropylethylamine followed by 2.6 μL (0.036 mmol) of acetyl chloride. The resulting solution was stirred at RT. After 1.5 hours the solution was concentrated in vacuo and the residue subjected to flash chromatography (SiO2, 95:5 CH2Cl2/MeOH) to afford the desired compound in 86% yield as a white foam. 1H NMR (CDCl3): 7.29 (dd, 1H), 7.16-7.04 (m, 3H), 7.05 (d, 1H), 6.76 (d, 2H), 6.05 (s, 2H), 5.91 (br s, 1H), 5.01 (d, 1H), 5.05-4.89 (m, 2H), 3.94 (m, 3H), 3.80 (m, 3H), 3.72-3.51 (m, 5H), 3.08 (dd, 1H), 3.01-2.83 (m, 4H), 2.74 (m, 2H), 1.97 (s, 3H), 1.86-1.45 (m, 3H), 0.90 (d, 3H), 0.84 (d, 3H). MS(ESI): 678(M+H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[C:22]1([CH2:28][CH2:29][CH:30]=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1CCCCC1>C(O)C>[C:22]1([CH2:28][CH2:29][CH:30]=[C:18]2[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]3[N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=3)[C:19]2=[O:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=CCCc1ccccc1
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1SC(=CCCc2ccccc2)C(=O)N1CCCCSc1cccc2nccn12

Procedure:
To a solution of 1.61 g (5.0 mmol) of 3-[4-(imidazo-[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 1.34 g (10 mmol) of 3-phenylpropionaldehyde in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=1/4) to yield 2.27 g (quant, brown oily substance) of the desired product.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.[N:15]1C2C(=CC=C3C=2N=CC=C3)C=C[CH:16]=1.C([Cu])#N>CC(N(C)C)=O>[N+:12]([C:5]1[CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]([C:16]#[N:15])=[N:3][CH:4]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc(Br)c(C(F)(F)F)c1
Reactant: c1cnc2c(c1)ccc1cccnc12
Agent: N#C[Cu]
Solvent: CC(=O)N(C)C
Product: N#Cc1ncc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 160 °C
Reaction time: 0.67 h
Yield: 67 %

Procedure:
The crude 2-bromo-5-nitro-3-(trifluoromethyl)pyridine 21 is dissolved in dimethylacetamide (DMA) and phenanthroline (0.2 equivalents) is added. The mixture is heated to 160° C. and CuCN (2 equivalents) is added. The mixture is stirred for 40 minutes. Chromatography is performed to produce the 5-nitro-3-(trifluoromethyl)pyridine-2-carbonitrile 22 in a yield of 67%.
Reaction SMILES: [F:1][C:2]([P:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])(=[O:10])[OH:9])([F:7])[C:3]([F:6])([F:5])[F:4].[CH3:18][N:19]([C:21]([N:24]([CH3:26])[CH3:25])(Cl)[Cl:22])[CH3:20]>>[F:7][C:2]([P:8]([C:11]([F:16])([F:17])[C:12]([F:15])([F:14])[F:13])(=[O:9])[O-:10])([F:1])[C:3]([F:6])([F:5])[F:4].[CH3:18][N:19]([C+:21]([N:24]([CH3:26])[CH3:25])[Cl:22])[CH3:20]
Reactant: O=P(O)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: CN(C)C(Cl)(Cl)N(C)C
Product: CN(C)[C+](Cl)N(C)C
Product: O=P([O-])(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F

Procedure:
5.88 g (19.47 mmol) of bis(pentafluoroethyl)phosphinic acid are added to 3.33 g (19.47 mmol) of bis(dimethylamino)dichloromethane. The hydrogen chloride formed is removed in a stream of nitrogen. The reaction mixture is stirred at room temperature for 30 minutes, and the residue is dried under reduced pressure at 7 Pa and an oil-bath temperature of 60° C. over the course of 3 hours, giving 8.48 g of bis(dimethylamino)chlorocarbenium bis(pentafluoroethyl)phosphinate as a liquid, corresponding to a yield of 99.7%.
Reaction SMILES: OCO[CH2:4][C:5]([O:7][CH3:8])=[O:6].[NH:9]([CH2:16][C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1>[C:5]([CH:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH:17]2[N:18]1[CH2:19][CH2:20][CH2:21]2)([O:7][CH3:8])=[O:6]
Reactant: c1ccc(NC[C@@H]2CCCN2)cc1
Reactant: COC(=O)COCO
Solvent: c1ccccc1
Product: COC(=O)C1N(c2ccccc2)CC2CCCN21
Yield: 98.8 %

Procedure:
In 10 ml of benzene, were dissolved 683 mg of methyl hydroxymethoxyacetate and 1.00 g of (S)-2-(anilinomethyl)pyrrolidine. The resulting solution was refluxed for 30 minutes while removing the water by azeotropic distillation. On removing the solvent by distillation in vacuo, there were obtained 1.38 g of 2-carbomethoxy-3-phenyl-1,3-diazabicyclo[3,3,0]octane, a derivative of glyoxylic acid. NMR peaks: δ(ppm)=1.5-2.3 (4H, multiplet), 2.3-4.1 (5H, multiplet), 3.5 (3H, singlet), 4.6 (1H, singlet), 6.2-7.1 (5H, multiplet). After having been purified by alumina column chromatography and short-path distillation, the substance showed the following results of elementary analysis:
Reaction SMILES: [F:1][CH:2]([C:14]([F:17])([F:16])[F:15])[C:3]([O:5]C(CCCCC)C=C)=[O:4].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N([CH2:35][CH3:36])CC)C.[CH3:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>ClCCl>[F:1][C:2]([C:14]([F:15])([F:16])[F:17])([CH2:37][CH:38]=[CH:39][CH2:40][CH2:41][CH2:42][CH2:35][CH3:36])[C:3]([OH:5])=[O:4]
Reactant: CCCCCC
Reactant: CCN(CC)CC
Reactant: C=CC(CCCCC)OC(=O)C(F)C(F)(F)F
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCC=CCC(F)(C(=O)O)C(F)(F)F
Temperature: 25 °C
Reaction time: 120 h
Yield: 88 %

Procedure:
In 150 ml of dichloromethane was dissolved 42 g (0.16 mol) of the 1-octen-3-yl 2,3,3,3-tetrafluoropropionate as obtained in Reference Example 2, and the resulting solution was cooled with ice under a nitrogen atmosphere. Thereto were added 40 ml (0.2 mol) of trimethylsilyl triflate and 29 ml (0.2 mol) of triethylamine, and the resulting mixture was stirred at room temperature for 120 hours. Then, the reaction mixture was diluted with hexane, and then subjected to extraction with a 7.5% aqueous solution of sodium hydroxide. The resulting aqueous extract was acidified with concentrated hydrochloric acid, and then extracted again with dichloromethane. The resulting extract was dried with magnesium sulfate, and the solvent was removed under reduced pressure, thereby obtaining 37 g of (+)-2-fluoro-2-(trifluoromethyl)-4-decenoic acid in a yield of 88%.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5].[O:33]1[CH2:36][C:35](=O)[CH2:34]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.C(OCC)(=O)C>[Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=2)[C:20]([F:23])([F:21])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH:35]2[CH2:36][O:33][CH2:34]2)[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C1COC1
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NC1CCN(C2COC2)CC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
A solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.2 g, 0.35 mmol), oxetan-3-one (0.027 g, 0.38 mmol) and acetic acid (0.01 mL) in MeOH (5.0 mL) was stirred at ambient temperature for 30 min. After that NaBH3CN (0.022 g, 0.35 mmol) was added at 0° C. slowly lot wise over the period of 10 min and the reaction was stirred for 8 h at ambient temperature. The solvent was removed under reduced pressure to obtain a residue which was diluted with ethyl acetate and washed with saturated NaHCO3 solution and brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a residue, which was triturated with diethyl ether/pentane to afford the title compound as an off-white solid (0.05 g, 23%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[C:51]3[O:50][C:49]([NH2:52])=[N:48][C:47]=3[C:46]([O:53][CH3:54])=[CH:45][CH:44]=2)=[CH:39][CH:38]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([NH:52][C:49]1[O:50][C:51]2[C:43]([C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)=[CH:44][CH:45]=[C:46]([O:53][CH3:54])[C:47]=2[N:48]=1)=[O:8]
Reactant: O=C(O)c1ccnc(CCl)c1
Reactant: COc1ccc(-c2ccc(F)cc2)c2oc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(F)cc2)c2oc(NC(=O)c3ccnc(CCl)c3)nc12

Procedure:
From 2-chloromethyl-isonicotinic acid, HATU and N-diethylisopropylamine in THF, then treatment with 7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl-amine in dioxane and DMF. ES-MS m/e (%): 414 (M{37Cl}+H+, 30), 412 (M{35Cl}+H+, 100).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:17](C1C=C(C=CC=1)C(O)=O)[C:18]1[CH:23]=C[CH:21]=[CH:20][CH:19]=1>[OH-].[Na+]>[C:18]([C:19]1[O:12][C:11]([C:10]2[CH:14]=[CH:15][CH:16]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)=[N:13][C:20]=1[CH3:21])(=[O:17])[CH3:23]
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Reactant: NC(=O)c1cccc(Oc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1oc(-c2cccc(Oc3ccccc3)c2)nc1C
Temperature: 180 °C
Reaction time: 23 h
Yield: 94 %

Procedure:
A mixture of 3-phenoxybenzamide (2.13 g, 10 mmol), 3-phenoxybenzoic acid (4.28 g, 20 mmol), and 3-chloropenta-2,4-dione (0.44 g, 3.3 mmol) was heated to 180° C. under stirring for 23 h. The hot mixture was poured into 1N aqueous sodium hydroxide (100 ml), and extracted with diethyl ether (100+2×50 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate (50 ml) and brine (50 ml), dried over magnesium sulfate, and evaporated to dryness. Purification by silica gel column chromatography (135 g, 16.7% ethyl acetate in n-hexane) afforded the titled compound as solids in 94% yield: 1H NMR (CDCl3) δ7.88-7.83 (1H, m), 7.77-7.53 (1H, m), 7.49-7.34 (3H, m), 7.18-7.12 (2H, m), 7.07-7.00 (2H, m), 2.55 (3H, s), 2.54 (3 H, s).
Reaction SMILES: O.[CH3:2][C:3]1[C:7]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[C:13]([N+:18]([O-])=O)[CH:14]=[N:15]3)=[CH:10][C:9]=2[O:29][CH3:30])=[C:6]([CH3:31])[O:5][N:4]=1.[H][H]>[Pd].C(OCC)(=O)C.C(O)C>[CH3:2][C:3]1[C:7]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[C:13]([NH2:18])[CH:14]=[N:15]3)=[CH:10][C:9]=2[O:29][CH3:30])=[C:6]([CH3:31])[O:5][N:4]=1
Reactant: COc1cc2c(NCc3ccccn3)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COc1cc2c(NCc3ccccn3)c(N)cnc2cc1-c1c(C)noc1C
Yield: 88.6 %

Procedure:
10% palladium on carbon, 50% water paste, (300 mg, 20% wt) was added to a solution of 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-nitro-N-(2-pyridinylmethyl)-4-quinolinamine (1.5 g, 3.70 mmol) in ethyl acetate (90 ml) and ethanol (10 ml). The reaction mixture was stirred in an atmosphere of hydrogen for 3 h. The reaction mixture was filtered through Celite™. The solvent was evaporated from the filtrate. The residue was chromatographed [5% methanol/DCM] to give the title compound as a brown oil (1.23 g, 3.28 mmol, 89% yield). LCMS (formate) Rt 0.63 min, MH+ 376
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[CH2:4][CH:3]1[NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16].C([SiH](CC)CC)C>ClCCCl.O>[CH3:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH2:4][CH:3]([NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])[CH2:2]2
Reactant: CCOC(=O)NC1Cc2ccc(C)cc2C1O
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)NC1Cc2ccc(C)cc2C1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
With stirring at room temperature, the compound (3.30 g, 13.9 mmol) obtained in step C, triethylsilane (4.4 ml, (27.8 mmol) and boron trifluoride-diethyl ether complex (3.4 ml, 27.8 mmol) dissolved in 1,2-dichloroethane (20 ml) were added to 1,2-dichloroethane (90 ml), and the mixture was stirred at 83° C. for 1 hr. After cooling to room temperature, the reaction mixture was diluted with water, and extracted with dichloromethane. The organic layer was washed with diluted aqueous sodium hydroxide solution, diluted hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to give the title compound (2.76 g, yield 91%) as a pale-yellow solid.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=O)[CH2:11][C@H:10]2[CH2:15][C:16]([OH:18])=[O:17])=[O:8])=[CH:3][CH:2]=1.[CH3:25][O:26][NH3+:27].[Cl-].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:27][O:26][CH3:25])[CH2:11][C@H:10]2[CH2:15][C:16]([OH:18])=[O:17])=[O:8])=[CH:5][CH:6]=1
Reactant: CO[NH3+]
Reactant: O=C(O)C[C@@H]1CC(=O)CN1C(=O)c1ccc(-c2ccccc2)cc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CON=C1C[C@@H](CC(=O)O)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 48.7 %

Procedure:
A solution of [(2S)-1-(biphenyl-4-ylcarbonyl)-4-oxopyrrolidin-2-yl]acetic acid (Intermediate 5, 1.50 g, 6.64 mmol), hydroxylamine methyl ether hydrochloride (0.58 g, 6.96 mmol) and triethylamine (1.62 ml, 11.60 mmol) in chloroforme (30 ml) was stirred at RT for 2 days Solvent was removed under reduced pressure and the residue was taken up in ethyl acetate. Organic phase was washed twice with a solution of citric acid 10% and once with brine. Organic phase was then dried on MgSO4, filtered, and concentrated to give [(2S,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl]acetic acid as a cream solid (1.14 g). Yield: 45%. HLPC purity: 92%
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[CH2:16][C:17]([C:19]1[C:20]([CH:33]([CH3:35])[CH3:34])=[C:21]([O:28][S:29](=[O:32])(=[O:31])[NH2:30])[C:22]([CH:25]([CH3:27])[CH3:26])=[CH:23][CH:24]=1)=[O:18])[CH3:3].[CH:36](C1C=CC=C(C(C)C)C=1OS(N=C=O)(=O)=O)([CH3:38])[CH3:37].C(C1C=C(C(C)C)C=C(C(C)C)C=1OS(N=C=O)(=O)=O)(C)C>>[CH3:3][CH:2]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:11])[CH3:12])[CH:7]=[C:6]([CH:13]([CH3:14])[CH3:15])[C:5]=1[CH2:16][C:17]([C:19]1[C:20]([CH:33]([CH3:35])[CH3:34])=[C:21]([O:28][S:29](=[O:31])(=[O:32])[NH2:30])[C:22]([CH:25]([CH3:27])[CH3:26])=[CH:23][C:24]=1[CH:36]([CH3:38])[CH3:37])=[O:18])[CH3:1]
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)c2ccc(C(C)C)c(OS(N)(=O)=O)c2C(C)C)c(C(C)C)c1
Reactant: CC(C)c1cccc(C(C)C)c1OS(=O)(=O)N=C=O
Agent: CC(C)c1cc(C(C)C)c(OS(=O)(=O)N=C=O)c(C(C)C)c1
Product: CC(C)c1cc(C(C)C)c(CC(=O)c2c(C(C)C)cc(C(C)C)c(OS(N)(=O)=O)c2C(C)C)c(C(C)C)c1

Procedure:
This compound was prepared in the same manner as the title compound of Example 5, except that 2,6-diisopropylphenoxy sulfonyl isocyanate was replaced with 2,4,6-triisopropylphenoxy sulfonyl isocyanate, mp 178°-180° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH2:8])[O:4][N:3]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[S:14](Cl)(=[O:16])=[O:15].[OH-].[Na+]>>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:14]([C:10]2[O:9][CH:13]=[CH:12][CH:11]=2)(=[O:16])=[O:15])[O:4][N:3]=1
Reactant: O=S(=O)(Cl)c1ccco1
Reactant: Cc1noc(N)c1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1noc(NS(=O)(=O)c2ccco2)c1C

Procedure:
N-(3,4-dimethyl-5-isoxazolyl)furan-2-sulfonamide was prepared as described in Example 34B from 3,4-dimethyl-5-amino isoxazole (0.122 g, 1.0 mmol), furan-2-sulfonyl chloride (0.50 g, 3.0 mmol) and NaOH (64 mg). Flash chromatography (50% ethyl acetate/hexanes) yielded 70 mg of a yellow solid. Recrystallization from CHCl3/hexanes produced an off-white solid (46 mg, 29% yield), m.p 107-110° C.
Reaction SMILES: [OH-].[Na+].[CH2:3](OCC)C.CN(N=O)C(N[N+]([O-])=O)=N.[OH:18][C@H:19]([CH2:23][C:24]1[CH:32]=[C:31]([CH3:33])[C:30]2[C:26](=[CH:27][N:28]([CH2:34][O:35][CH3:36])[N:29]=2)[CH:25]=1)[C:20]([OH:22])=[O:21]>ClCCl>[OH:18][C@H:19]([CH2:23][C:24]1[CH:32]=[C:31]([CH3:33])[C:30]2[C:26](=[CH:27][N:28]([CH2:34][O:35][CH3:36])[N:29]=2)[CH:25]=1)[C:20]([O:22][CH3:3])=[O:21]
Reactant: CCOCC
Reactant: COCn1cc2cc(C[C@@H](O)C(=O)O)cc(C)c2n1
Agent: CN(N=O)C(=N)N[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COCn1cc2cc(C[C@@H](O)C(=O)OC)cc(C)c2n1
Reaction time: 0.25 h

Procedure:
To a heterogeneous mixture of 5 M sodium hydroxide (20 mL) and diethyl ether (60 mL) at 0° C. was added N-methyl-N′-nitro-N-nitrosoguanidine (1.17 g, 7.95 mmol) in small portions with swirling (no stirbar). After addition was complete, the mixture was allowed to stand at 0° C. for 15 min with occasional swirling. The ethereal was transferred in portions to a suspension of (R)-2-hydroxy-3-(2-(methoxymethyl)-7-methyl-2H-indazol-5-yl)propanoic acid (1.40 g, 5.30 mmol) in dichloromethane (20 mL) until the solid had all dissolved and a yellow color persisted. The reaction was allowed to rest at room temperature for ca. 5 min. before bubbling nitrogen through the solution to remove unreacted diazomethane. The reaction was concentrated and purified by column chromatography (50%→75% ethyl acetate/hexanes) to give 1.47 g (100%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 1.60 (bs, 1H), 2.58 (s, 3H), 2.95 (dd, J=13.9, 7.0, 1H), 3.14 (dd, J=13.9, 4.0, 1H), 3.36 (s, 3H), 3.76 (s, 3H), 4.46 (bm, 1H), 5.65 (s, 2H), 6.90 (s, 1H), 7.31 (s, 1H), 7.99 (s, 1H). Mass spec.: 279.11 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH:12]3[CH2:21][CH2:20][C:15]4([O:19][CH2:18][CH2:17][O:16]4)[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:10]2[C:3]3[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([CH:12]3[CH2:21][CH2:20][C:15]4([O:19][CH2:18][CH2:17][O:16]4)[CH2:14][CH2:13]3)[CH:9]=2)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: Clc1ncnc2c1c(I)cn2C1CCC2(CC1)OCCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Clc1ncnc2c1c(-c1ccc(OCc3ccccc3)cc1)cn2C1CCC2(CC1)OCCO2
Temperature: 80 °C
Reaction time: 5 h
Yield: 60.5 %

Procedure:
A mixture of 4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 7.15 mmol) in ethylene glycol dimethyl ether (100 mL) was treated with 4-(benzyloxy)phenylboronic acid (1.79 g, 7.87 mmol), tetrakis(triphenylphosphine)palladium (0.496 g, 0.429 mmol), and a solution of sodium carbonate (1.83 g, 17.16 mmol) in water (50 mL). A precipitate formed after 20 minutes. Reaction was stirred for 5 hours at 80° C. under a nitrogen atmosphere. The mixture was allowed to cool to room temperature and the organic solvent was removed under reduced pressure. The product was partitioned between the aqueous sodium carbonate layer and ethyl acetate. The aqueous layer was further extracted with ethyl acetate three times. The organic layers were combined, washed with water and brine, dried over magnesium sulfate, and partially concentrated until a precipitate formed. The solid was filtered, washed with ethyl acetate, and dried under a high vacuum. Yielded 2.06 g (61%) of 5-[4-(benzyloxy)phenyl]-4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidine. 1H NMR (DMSO-d6, 400 MHz) δ 8.64(s, 1H), 7.88(s, 1H), 7.52-7.33(m, 7H), 7.08-7.05(d, 2H, J=12 Hz), 5.15(s, 2H), 4.82-4.78 (m, 1H), 3.95-3.89(m, 4H), 2.21-2.13(m, 2H), 1.98-1.96(m, 2H), 1.85-1.75(m, 4H); Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 8.356 min.