Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[N:2]1[C:11]2[NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH2:3]1.[CH3:12][N:13](C=O)C>C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.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>[C:12]([N:2]1[C:11]2[NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH2:3]1)#[N:13]
Reactant: CN(C)C=O
Reactant: BrN1CC=CC2=C1NCCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: N#CN1CC=CC2=C1NCCC2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 0.8914 g (4.18 mmol) 33 in 20 mL DMF was added 0.2949 g (2.51 mmol) zinc cyanide and 0.4825 g (0.42 mmol) tetrakis(triphenylphosphine)palladium(0). After 17 h at 100° C., the reaction mixture was cooled to room temperature, diluted with 120 mL toluene and washed 60 mL 2N NH40H. The aqueous layer was extracted with 60 mL toluene. The combined organic layers were washed with 60 mL brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (50×80 mm silica gel, 5% (10% NH4OH:MeOH):CH2Cl2) yielded 0.7609 g of 34 and triphenylphosphine oxide. This material was partitioned between 50 mL ethyl ether and 50 mL 1M HCl. The aqueous layer was brought to pH 12 with 50% aqueous NaOH and extracted with 3×100 mL CH2Cl2. The combined CH2Cl2 layers were washed with 100 mL brine, dried over Na2SO4, filtered and concentrated in vacuo to give 34. 1H NMR (CDCl3, 400 MHz) δ 8.276 (s, 1H, ArH); 8.037 (s, 1H, ArH); 3.487-3.452 (m, 2H, CH2); 2.729 (t, 2H, J=6.22 Hz, CH2); 2.001-1.942 (m, 2H, CH2); MS (Electrospray): n/z 159.9 (M+H).
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOC1.[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:21][NH:22][C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1.[CH3:41][C:42]1[O:43][CH:44]=[CH:45][C:46]=1[S:47](Cl)(=[O:49])=[O:48]>O1CCCC1.O>[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[CH:21][N:22]([S:47]([C:46]2[CH:45]=[CH:44][O:43][C:42]=2[CH3:41])(=[O:49])=[O:48])[C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: Cc1occc1S(=O)(=O)Cl
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1occc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)c(F)c1-c1cccnc1F
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a suspension of sodium hydride (60% in oil, 34 mg) in tetrahydrofuran (4 mL) were added dropwise 15-crown-5 (0.17 mL), a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (210 mg) in tetrahydrofuran (1 mL) and 2-methylfuran-3-sulfonyl chloride (176 mg) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:3) and basic silica gel column chromatography (eluent: hexane-ethyl acetate=17:3→1:1) to give the title compound as a pale-yellow oil (yield 187 mg, 61%).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]>ClCCl.CO.O=[Mn]=O>[CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(CO)cn3)nc2n1C1CCCC1
Agent: O=[Mn]=O
Solvent: CO
Solvent: ClCCl
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Temperature: 38 °C
Reaction time: 12 h
Yield: 85.1 %

Procedure:
7-Cyclopentyl-2-(5-hydroxymethyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (4.49 g, 11.8 mmol) is dissolved in dichloromethane (175 ml) and methanol (75 ml). Activated MnO2 85% (51.1 g, 503 mmol) is added in 4 portions over period of 48 h with continual stirring. After a further 16 hours the mixture is filtered. The filtrate is heated to 38° C. and more MnO2 (24 g, 236 mmol) is added as 2 batches over 5 hours. After stirring for a further 12 hours, the mixture is cooled and filtered. Concentration in vacuo gave a solid which is triturated with MeOH (10 ml) to give 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (3.8 g, 85%). MS (ESI) m/z 379.2 (M+H)+ (method B).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14].C(Cl)(Cl)Cl.S(=O)(=O)(O)O.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C1(C)C=CC=CC=1>[C:24]([NH:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14])(=[O:26])[CH3:25]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1Cl
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(Cl)c(F)c(NC(C)=O)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 50 mL three-neck round-bottomed flask was charged the methyl 4-amino-3,6-dichloro-5-fluoropicolinate (12.1 mmol), toluene (50 mL), and CHCl3 (15 mL). To this suspension was added dropwise a premixed solution of sulfuric acid (0.05 mmol) and acetic anhydride (24.2 mmol), in toluene (5 mL). The reaction mixture was then heated, under a N2 stream, to 55-60° C. and the reaction was monitored by TLC. Once the reaction was deemed complete the heating mantle was removed and the reaction solution was cooled to ambient temperature. The mixture was then added dropwise to a mixture of saturated aqueous NaHCO3/toluene/CHCl3 (180 mL, 3/10/5), stirred for 20 min, and the layers separated using a reparatory funnel. To the organic layer was added silica gel (14.8 g) and the solvent was removed using a rotary evaporator. The crude product on silica was then purified using a Combi-Flash silica gel purification system using ethyl acetate and hexane as eluents. The purity of the product was analyzed by HPLC: mp=183-186° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.5 (s, 1H, NH), 3.93 (s, 3H), 2.17 (s, 3H); 13C NMR (100.6 MHz, DMSO-d6) δ 167.9, 162.8, 151.7, 149.0, 142.8 (d, JF-C=24 Hz), 136.2 (d, JF-C=80 Hz), 134.7 (d, JF-C=56 Hz), 126.6, 53.2, 22.5; 19F NMR (376.5 MHz, DMSO-d6) δ −114.5; MS Calcd. for C9H7Cl2FN2O3: 280.0. Found: 281 (MH+), 245, 180.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:9]([CH2:12][CH2:13][CH3:14])[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(O)[O-].[Na+].[C-:27]#[N:28].[Na+].C(OCC)(=O)C>CO.O.C(OCC)(=O)C.CCCCCC>[CH2:15]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([CH2:12][CH2:13][CH3:14])[C@H:10]([OH:11])[C:27]#[N:28])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCC[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC[C@@H]([C@H](O)C#N)N(Cc1ccccc1)Cc1ccccc1
Temperature: 2.5 °C
Reaction time: 14 h
Yield: 68.6 %

Procedure:
To a solution of (S)-2-(dibenzylamino)pentanal (125 g; 0.444 mol) in methanol (375 mL) at 0-5° C. was added a previously cooled (0-5° C.) aqueous solution of sodium bisulfite (69.39 g, 0.667 mol; 150 mole %) in water (530 mL). The reaction mixture was stirred at 0-5° C. for 14 hours. A solution of sodium cyanide (32.02 g; 0.667 mol; 150 mol %) in water (402 mL), followed by ethyl acetate (1.25 L) was added to the above reaction mixture at 0° C. Stirring was continued at ambient temperature for 5 hours, monitoring progress of the reaction by TLC analysis (ethyl acetate/hexane, 1:9). Once the reaction was complete, the ethyl acetate layer was separated, washed with water (2×750 mL) and dried over sodium sulfate. The organic extract was concentrated under reduced pressure, washed with hexanes (200 mL), to provide 94 g of crude product as an off-white solid.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)=[C:6]([CH:28]([CH3:30])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)=[C:6]([CH:28]([CH3:30])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1cccc(/C=C/c2c(C(C)C)nc(C(C)C)c(CO)c2-c2ccc(F)cc2)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cccc(CCc2c(C(C)C)nc(C(C)C)c(CO)c2-c2ccc(F)cc2)c1

Procedure:
The title compound was prepared 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[2-(E)-(3-methylphenyl)ethenyl]pyridine (Example 41) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.18 (d, J=7 Hz, 4 H), 7.10 (m, 1 H), 6.97 (m, 1 H), 6.65 (m, 2 H), 4.36 (s, 2 H), 3.44 (sept, J =6.6 Hz, 1 H), 3.35 (d, J=6.6 Hz, 1 H), 2.57 (m, 4 H), 2.28 (s, 3 H), 1.35 (d, J=6.6 Hz, 6 H), 1.34 (d, J=6.6 Hz, 6 H), 1.20 (m, 1 H). FAB-MS: calculated for (C27H32FNO) 405, found 406 (M+H). Anal. Calcd for C27H32FNO: C, 79.96; H, 7.95; N, 3.45. Found: C, 79.30; H, 8.10; N, 3.36. mp 148-150° C. Rf=0.3 (20% ethyl acetate/hexane).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][N:5]2[CH3:13].[N+:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:22]=[C:21]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH2:6][N:5]3[CH3:13])[CH:20]=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CN1CC(=O)Nc2ccc(Br)cc21
Product: CN1CC(=O)Nc2ccc(-c3cccc([N+](=O)[O-])c3)cc21

Procedure:
Prepared according to the procedure for Example 5 from 6-bromo-4-methyl-3,4-dihydro-1H-quinoxalin-2-one (4.8 g, 20 mmol), and 3-nitrophenylboronic acid (4.8 g, 30 mmol). A red powder (0.95 g, 16%): mp 237-243° C. 1H-NMR (DMSO-d6) δ 2.88 (s, 3H), 6.9 (d, J=7.9 Hz, 1H), 7.01 (d, J=2 Hz, 1H), 7.11 (dd, J=7.9, 2.0 Hz, 1H), 7.7 (t, J=7.9 Hz, 1H), 8.1 (m, 2H), 8.37 (t, J=0.7 Hz), MS (ESI) m/z 283(M)+.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.Br[CH2:36][C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH:21]([N:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:10](=[O:11])[CH2:9][N:8]1[C:2](=[O:1])[CH:3]([CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39][CH:38]=2)[C:4](=[O:34])[N:5]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:6]2[CH:27]=[CH:26][CH:25]=[CH:24][C:7]1=2)([CH3:23])[CH3:22]
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reactant: BrCc1cccc2ccccc12
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3cccc4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.17 h
Yield: 97.6 %

Procedure:
To a stirring solution of 300 mg (0.66 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 10 mL DMF at 0° C. is added dropwise over 5 min 1.45 mL (0.72 mmol, 1.1 equiv) of a 0.5M solution of KN(TMS)2 in toluene. The resulting solution is stirred 10 min, then a solution of 160 mg (0.72 mmol, 1.1 equiv) of 1-bromomethylnaphthalene in 3 mL DMF is added. The resulting solution is stirred 2 h at RT and then quenched with 5 mL of H2O. The reaction mixture is then poured into 50 mL of Et2O and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification of the material by silica gel MPLC on an Si60 column using hexane/EtOAc 2/1 as eluent followed by lyophilization in acetonitrile/H2O afforded 385 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ8.01 (d, 1H, J=8.0), 7.80 (d, 1H, J=7.4), 7.69 (d, 1H, J=8.0), 7.50-6.94 (m, 16H), 6.84 (dd, 1H, J=1.5, 8.3), 5.04 (m, 1H), 4.36 (d, 1H, J=16.4), 4.17 (d, 1H, J=16.4), 3.92 (m, 2H), 3.85 (s, 3H), 3.82 (m, 1H), 1.09 (t, 6H, J=7.1); low resolution MS (FAB)m/e 598 (MH+), 597 (M+), 433.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:11]1[S:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][C:17]=2[NH:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25]([CH3:30])=[CH:24]3)[CH:12]=1>>[CH3:30][C:25]1[NH:26][C:27]2[C:23]([CH:24]=1)=[CH:22][C:21]([NH:20][C:17]1[CH:16]=[CH:15][N:14]=[C:13]3[CH:12]=[C:11]([C:5]4[S:6][C:2]([CH3:1])=[CH:3][CH:4]=4)[S:19][C:18]=13)=[CH:29][CH:28]=2
Reactant: Cc1ccc(B(O)O)s1
Reactant: Cc1cc2cc(Nc3ccnc4cc(Br)sc34)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5ccc(C)s5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 5-methylthiophene-2-boronic acid and (2-bromothieno[3,2-b]pyridin-7-yl)-(2-methyl-1H-indol-5-yl)-amine by the procedure analogous to example 2 above. 1H NMR (400 MHz, CD3OD) δ8.03 (d, 1H), 7.29 (m, 3H), 7.15 (s, 1H), 6.99 (m, 1H), 6.83 (d, 1H), 6.54 (d, 1H), 6.10 (s, 1H), 2.41 (s, 3H), 2.22 (s, 3H); RP18-HPLC RT: 6.08 minutes; API MS: 376 (M+1).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:12][C@H:11]([CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])[C:10]1=[N:41][OH:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:49][C:50](OC(C)=O)=[O:51]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:50]([O:42][N:41]=[C:10]1[C@@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:12][C@@H:11]1[CH2:32][P:33](=[O:40])([O:34][CH2:35][CH3:36])[O:37][CH2:38][CH3:39])(=[O:51])[CH3:49]
Reactant: CC(=O)OC(C)=O
Reactant: CCOP(=O)(C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)C1=NO)OCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOP(=O)(C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)C1=NOC(C)=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
To a solution of diethyl (((2S,4R,5S,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-(hydroxyimino)tetrahydro-2H-pyran-2-yl)methyl)phosphonate (2.0 g, 3.35 mmol, 1.0 equiv) in dry DCM (40 mL) was added catalytic DMAP, pyridine (2.1 mL, 26.8 mmol, 8.0 equiv) and Ac2O (1.26 mL, 13.4 mmol, 4.0 equiv) slowly. The mixture was stirred at room temperature for 16 hours and then the concentrated in vacuo. The product thus obtained was then purified by silica gel chromatography, eluting with MeOH:acetone:chloroform:petroleum ether (0.5:0.5:1:8), to give diethyl (((2 S,4R,5 S,6R)-3-(acetoxyimino)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)phosphonate as a colorless oil (1.5 g, 70%). 1H NMR (400 MHz, CDCl3) δ 7.32 (dddd, J=21.0, 10.3, 8.1, 6.0 Hz, 13H), 7.20 (ddq, J=8.2, 5.4, 3.0 Hz, 2H), 5.48-5.38 (m, 1H), 4.90 (d, J=11.6 Hz, 1H), 4.72 (d, J=11.5 Hz, 1H), 4.62-4.44 (m, 5H), 4.18-4.02 (m, 4H), 3.95-3.83 (m, 2H), 3.63 (qd, J=10.1, 4.8 Hz, 2H), 2.61-2.46 (m, 1H), 2.26-2.15 (m, 4H), 1.32 (td, J=7.1, 1.9 Hz, 6H). MS ESI (M+1) 639.8; calc for C34H42NO9P 639.3.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:30])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:29])[CH:18]=2)[CH:13]=1.C(N(CC)C(C)C)(C)C.[C:40]1([CH2:46][S:47](Cl)(=[O:49])=[O:48])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:30])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([CH:23]2[CH2:24][CH2:25][N:26]([S:47]([CH2:46][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)(=[O:49])=[O:48])[CH2:27][CH2:28]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:29])[CH:18]=2)[CH:13]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)Cc3ccccc3)CC2)c1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
To a 0° C. solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 102 mg, 0.237 mmol) and N,N-diisopropylethylamine (124 μL, 0.711 mmol) in methylene chloride (6.0 mL) was added α-toluenesulfonyl chloride (90.4 mg, 0.474 mmol). After stirring for ˜10 minutes at 0° C., the light yellow reaction mixture was allowed to warm to room temperature and then stirred for 4 hours at room temperature under nitrogen. During this time, some solvent had evaporated. The reaction mixture was diluted with water (˜25 mL) and extracted with methylene chloride (3×25 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, concentrated, and purified by silica gel chromatography (eluting with 33% ethyl acetate/hexanes) to give [6-fluoro-3-methyl-4-(1-phenylmethanesulfonyl-piperidin-4-yl)-naphthalen-2-yl]-acetic acid methyl ester (88 mg, 79%). MS cald. for C26H29FNO4S [(M+H)+]: 470, obsd. 470.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2.[N:17]1[N:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]2=[CH:19][C:18]=1[CH2:26][C:27](O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([N:13]([CH2:14][CH2:15][CH3:16])[CH2:27][CH2:26][C:18]1[CH:19]=[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]3[N:17]=1)[CH2:9][CH2:8]2
Reactant: CCCNC1CCc2cccc(OC)c2C1
Reactant: O=C(O)Cc1cc2ccccn2n1
Product: CCCN(CCc1cc2ccccn2n1)C1CCc2cccc(OC)c2C1

Procedure:
Synthesis works according to the preparation of A4-1 or A4-4 when using N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R═OMe) and 2-pyrazolo[1,5-a]pyridinyl acetic acid (A3-12: R═OMe, Cy=2-pyrazolo[1,5-a]pyridinyl) (synthesis according to literature: Awano, K. Chem Pharm Bull 1992, Vol 40, p 631; Löber, S Bioorg Med Chem Lett 2002, Vol 12, p 2377) and subsequent reaction according to the synthesis of A5-1.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[O:24][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:31][OH:32])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.[CH3:46][C:47]1[O:51][C:50]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[N:49][C:48]=1[CH2:58][O:59][C:60]1[CH:65]=[CH:64][C:63](O)=[CH:62][CH:61]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Si:1]([O:18][CH2:19][C:20]1[O:24][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:22][C:21]=1[CH2:31][O:32][C:63]1[CH:62]=[CH:61][C:60]([O:59][CH2:58][C:48]2[N:49]=[C:50]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:51][C:47]=2[CH3:46])=[CH:65][CH:64]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(O)cc1
Reactant: CC(C)(C)[Si](OCc1oc(-c2ccccc2)nc1CO)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(OCc2nc(-c3ccccc3)oc2CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Reaction time: 15 h
Yield: 81.9 %

Procedure:
To a mixture of [5-(tert-butyldiphenylsilyloxymethyl)-2-phenyl-1,3-oxazol-4-yl]methanol (1.11 g), tributylphosphine (1.01 g), 4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenol (0.70 g) and tetrahydrofuran (80 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.26 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 5-(tert-butyldiphenylsilyloxymethyl)-4-[[4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy]methyl]-2-phenyl-1,3-oxazole as an oil (1.44 g, yield 81%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:20]=[CH:19][C:18]3[N:17]([CH3:21])[C:16]4[CH2:22][CH:23]5[NH:27][CH:26]([C:15]=4[C:14]=3[C:13]=2C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[F:35][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]2[CH2:22][CH:23]4[NH:27][CH:26]([C:15]3=2)[CH2:25][CH2:24]4)(=[O:10])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cccc(C(F)(F)F)c4)ccc31)C1CCC(C2)N1
Solvent: O=C(O)C(F)(F)F
Product: Cn1c2c(c3cc(S(=O)(=O)c4cccc(C(F)(F)F)c4)ccc31)C1CCC(C2)N1
Yield: 95 %

Procedure:
The product of step A was subjected to Boc-deprotection with TFA following the procedure of Example 28, step B. The crude material was purified by flash column chromatography (SiO2, 9:1 dichloromethane/methanol) to give 2-(3-trifluoromethylphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole trifluoroacetate (130 mg, 95%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 8.20 (s, 1H), 8.10-8.14 (m, 2H), 7.57-7.78 (m, 3H), 7.33 (d, J=8.7 Hz 1H), 4.89 (d, J=4.5 Hz, 1H), 4.30-4.34 (m, 1H), 3.60 (s, 3H), 3.40 (dd, J=12.0, 4.5 Hz, 1H), 2.65 (d, J=16.8 Hz, 1H), 2.30-2.39 (m, 2H), 2.08-2.16 (m, 1H), 1.66-1.72 (m, 1H).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13]([OH:16])(=O)=[O:14])[CH:8]=1.P(Cl)(Cl)([Cl:19])=O>>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13]([Cl:19])(=[O:16])=[O:14])[CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1cccnc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1cccnc1
Temperature: 130 °C
Yield: 35.9 %

Procedure:
Phosphorus pentachloride (3.0 g, 14.6 mmol) was added to a solution of 3-pyridinesulfonic acid (1.5 g, 9.42 mmol) dissolved in phosphoryl trichloride (2.45 g, 16.0 mmol) and the mixture heated to 130° C. for 3 h under argon. The mixture was concentrated in vacuo, the residue was quenched over ice and extracted with ether. The organic phase was washed with a saturated sodium bicarbonate solution and concentrated in vacuo to give the crude title compound (0.6 g, 36%) which was used immediately without purification.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]1[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=1)[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.Br[CH2:16][C:17]1[N:22]=[C:21]([N:23]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:33])[CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C>[CH3:14][N:13]1[C:9]([C:3](=[N:2][O:1][CH2:16][C:17]2[N:22]=[C:21]([N:23]3[C:24](=[O:33])[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:31]3=[O:32])[CH:20]=[CH:19][CH:18]=2)[C:4]2[S:5][CH:6]=[CH:7][CH:8]=2)=[CH:10][N:11]=[CH:12]1
Reactant: Cn1cncc1C(=NO)c1cccs1
Reactant: O=C1c2ccccc2C(=O)N1c1cccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: Cn1cncc1C(=NOCc1cccc(N2C(=O)c3ccccc3C2=O)n1)c1cccs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.1 %

Procedure:
To a solution of N-hydroxy-1-(1-methyl-1H-imidazol-5-yl)-1-(2-thienyl)methanimine (4.10 g, 19.8 mmol) and 2-[6-(bromomethyl)pyridin-2-yl]-1H-isoindole-1,3(2H)-dione (6.89 g, 21.7 mmol) in acetonitrile (100 mL) were added cesium carbonate (13.5 g, 41.4 mmol) and potassium iodide (328 mg, 1.98 mmol). After stirring at room temperature for 24 h, the reaction mixture was filtered, the insolubles washed with ethyl acetate, and the combined filtrates concentrated in vacuo. Purification on silica gel afforded 2-{6-[({[(1-methyl-1H-imidazol-5-yl)(2-thienyl)methylene]amino}oxy)methyl]pyridin-2-yl}-1H-isoindole-1,3(2H)-dione [7.91 g, yield 86%; HPLC/MS: m/z=444 (M+H); log P(HCOOH)=1.66].