Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C@@H:6]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[CH2:9][N:8]([CH2:21][CH3:22])[C:7]1=[O:23])#[N:2].Cl.Cl.[O:33]=[C:34]1[NH:42][C:37]2=[N:38][CH:39]=[CH:40][CH:41]=[C:36]2[N:35]1[CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.C(N(CC)C(C)C)(C)C>C(O)CCCC>[C:1]([N:3]=[C:4]([N:46]1[CH2:45][CH2:44][CH:43]([N:35]2[C:36]3[C:37](=[N:38][CH:39]=[CH:40][CH:41]=3)[NH:42][C:34]2=[O:33])[CH2:48][CH2:47]1)[NH:5][C@@H:6]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[CH2:9][N:8]([CH2:21][CH3:22])[C:7]1=[O:23])#[N:2]
Reactant: CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=NC#N)Oc2ccccc2)C1=O
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: CCCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=NC#N)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)C1=O
Yield: 4.6 %

Procedure:
A solution of phenyl N′-cyano-N-[(3R,6S)-6-(2,3-difluorophenyl)-1-ethyl-2-oxoazepan-3-yl]imidocarbamate (166 mg, 0.402 mmol) and 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride (116 mg, 0.402 mmol), in 1-pentanol (10 mL) was treated with N,N-diisopropylethylamine (52 mg, 0.402 mmol). This mixture was heated to reflux for 24 h. Concentration and purification by silica gel chromatography (0%→10% methanol/dichloromethane) followed by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (10 mg). MS 537.5 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:38]=[CH:37][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:36])[C:21]([CH3:35])([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)C1C=CC=CC=1>O1CCCC1.[Pd]>[OH:29][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH3:35])([CH2:30][CH2:31][CH:32]([CH3:33])[CH3:34])[C:20](=[O:36])[C:19]=1[C:14]1[NH:13][C:12]2[CH:37]=[CH:38][C:9]([OH:8])=[CH:10][C:11]=2[S:16](=[O:17])(=[O:18])[N:15]=1
Reactant: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)=C(O)c2ccccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 98.8 %

Procedure:
A solution of Example 28G (1.68 g, 3.17 mmol) in tetrahydrofuran (40 mL) was treated with 10% palladium on carbon (0.168 g, 10% weight) and stirred at 25° C. under a hydrogen balloon for 72 hours. The vessel was purged with nitrogen gas and the mixture was filtered through celite. The filtrate was concentrated in vacuo to give the title compound (1.38 g, 99%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.43 (m, 1 H) 0.74 (m, 7 H) 1.32 (m, 1 H) 1.58 (m, 3 H) 2.15 (m, 2 H) 7.17 (m, 2 H) 7.57 (m, 2 H) 7.76 (m, 2 H) 8.16 (m, 1 H) 10.40 (m, 1 H) 13.66 (m, 1 H). MS (ESI−) m/z 439 (M−H)−.
Reaction SMILES: C([NH:9][C:10](=[S:36])[NH:11][C:12]1[N:17]=[C:16]2[N:18]([CH2:30][CH3:31])[C:19]([C:21]([N:23]([CH:27]3[CH2:29][CH2:28]3)[CH:24]3[CH2:26][CH2:25]3)=[O:22])=[CH:20][C:15]2=[C:14]2[N:32]([CH3:35])[CH:33]=[N:34][C:13]=12)(=O)C1C=CC=CC=1.[OH-].[Na+]>CCO>[CH:27]1([N:23]([CH:24]2[CH2:25][CH2:26]2)[C:21]([C:19]2[N:18]([CH2:30][CH3:31])[C:16]3=[N:17][C:12]([NH:11][C:10]([NH2:9])=[S:36])=[C:13]4[N:34]=[CH:33][N:32]([CH3:35])[C:14]4=[C:15]3[CH:20]=2)=[O:22])[CH2:28][CH2:29]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(=S)NC(=O)c3ccccc3)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(N)=S)nc21
Temperature: 25 °C
Yield: 82.1 %

Procedure:
4-(3-Benzoylthioureido)-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 2A, 306 mg, 0.61 mmol) and 1N NaOH (10 ml, 10.00 mmol) in 10 ml EtOH were heated at 60° C. for 1 h. The reaction was cooled to room temperature and concentrated. The remaining aqueous solution was extracted (3×) with ethyl acetate. The organic phase was dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography (dichloromethane/methanol 0-4%) gave N,N-dicyclopropyl-6-ethyl-1-methyl-4-thioureido-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide as a yellow solid (199 mg, 82% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:36]=[CH:37][C:38]2[O:42][CH2:41][CH2:40][C:39]=2[CH:43]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[O:42]1[C:38]2[CH:37]=[CH:36][C:35]([C:2]3[CH:3]=[CH:4][C:5]4[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]5[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]6[CH2:30][CH2:29][O:28][CH2:27][CH2:26]6)=[CH:21][CH:22]=5)=[O:15])=[CH:7][C:6]=4[CH:32]=3)=[CH:43][C:39]=2[CH2:40][CH2:41]1
Reactant: [O-]B([O-])Oc1ccc2c(c1)CCO2
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc5c(c4)CCO5)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 2,3-dihydrobenzofuran-5-yl borate (104 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 6 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:3) to give crystals, which were recrystallized from ethanol to give pale yellow crystals of 7-(2,3-dihydrobenzofuran-5-yl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 56) (246 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[C:20](=[O:29])[CH:19]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCOCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[C:20](=[O:29])[CH:19]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(O)cc1
Reactant: O=C1C=C(OCCCCCCO)c2ccccc2C1=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: N#Cc1ccc(OCCCCCCOC2=CC(=O)C(=O)c3ccccc32)cc1
Temperature: 10 °C
Reaction time: 10 h
Yield: 62.4 %

Procedure:
A mixture of 4-hydroxybenzonitrile (87 mg, 0.73 mmol), naphthoquinone 4 (200 mg, 0.73 mmol), PPh3 (191 mg, 0.73 mmol) in dioxane (10 mL) was cooled to 10° C. and treated with DEAD (140 mg, 0.80 mmol). The reaction mixture was stirred for 10 h,, concentrated in vacuo and purified by chromatography (5% EtOAc in benzene) to afford 11 as a yellow solid (171 mg, 53%), 1H NMR (CDCl3) 8.13 (dd, J=7.3, 1.4 Hz, 1H), 8.86 (dd, J=7.7, 1.1 Hz, 1H), 7.67 (dt, J=7.5, 1.5 Hz 1H), 7.60 (dt, J=7.5, 1.5 Hz, 1H), 7.57 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.9 Hz, 2H), 5.96 (s, 1H), 4.17 (t, J=6.4 Hz, 2H), 4.03 (t, J=6.3 Hz, 2H), 1.80-2.05 (m, 4H), 1.58-1.68 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:5][CH:4]=[C:3]1[C:21]([O:23]CC)=[O:22].[OH-].[Na+]>CO>[O:1]=[C:2]1[NH:7][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)=[CH:11][CH:10]=2)=[N:5][CH:4]=[C:3]1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1cnc(Nc2ccc(N3CCCCC3)cc2)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc(Nc2ccc(N3CCCCC3)cc2)[nH]c1=O
Temperature: 40 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
A mixture of ethyl 6-oxo-2-((4-(piperidin-1-yl)phenyl)amino)-1,6-dihydropyrimidine-5-carboxylate (100 mg, 0.298 mmol), sodium hydroxide (1M, aq), and methanol was stirred at 70° C. for 2 hours and for 40° C. overnight. The reaction mixture was filtered to remove the solid precipitate to verify product. Recombined the filtrate and precipitate to concentrate by adding 3 mL dioxane and heated to 103° C. for 4 hours with an additional 1 mL of NaOH added. The reaction mixture was then heated at 40° C. overnight. After the overnight heating, the reaction mixture was cooled and the solvent removed. The reaction mixture was diluted with water, and the pH was adjusted to about 3.0. The reaction mixture was filtered to obtain the end product. 1H-NMR confirmed the product (55 mg, 60% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH2:12][CH3:13])[N:6]=[CH:7]2.[I-].CS[C:17]1[S:18][CH2:19][CH:20]2[CH2:28][C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N+:21]=12>>[CH2:12]([C:5]1[N:6]=[CH:7][C:8]2[C:3]([CH:4]=1)=[C:2]([N:1]=[C:17]1[N:21]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[CH2:28][CH:20]3[CH2:19][S:18]1)[CH:11]=[CH:10][CH:9]=2)[CH3:13]
Reactant: CSC1=[N+]2c3ccccc3CC2CS1
Reactant: CCc1cc2c(N)cccc2cn1
Agent: [I-]
Product: CCc1cc2c(N=C3SCC4Cc5ccccc5N34)cccc2cn1
Yield: 70.6 %

Procedure:
Following the procedure of Example 1 but starting with 5-amino-3-ethylisoquinoline (3.3 g) and (RS)-3-methylthio-9,9a-dihydrothiazolo[3,4-a]indolium iodide (6.3 g), (RS)-3-[(3-ethylisoquinol-5-yl)imino]-9,9a-dihydrothiazolo[3,4-a]indole (4.4 g) is obtained, after recrystallisation from ethanol (40 cc), in the form of white crystals melting at 142° C.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:12]([CH2:13][OH:14])=[C:11]([Cl:15])[N:10]=[C:9]2[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:5][CH:4]=1)#N.[H-].C([Al+]CC(C)C)C(C)C.[OH-:32].[Na+]>C1C=CC=CC=1>[CH:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:12]([CH2:13][OH:14])=[C:11]([Cl:15])[N:10]=[C:9]2[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:5][CH:4]=1)=[O:32]
Reactant: [OH-]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(C#N)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 5.05 g of 1-(4-cyanobenzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole in 350 mL of benzene at 25° was added dropwise 22.8 mL of diisobutylaluminum hydride (0.15M in toluene). The mixture was warmed to 45° and stirred for 16 hours. After cooling, the reaction mixture was poured in ice-cold 20% aqueous sulfuric acid. This solution was allowed to warm to 25° and then stirred for 2 hours. The solution was colled to 0°, neutralized using aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 0-20% ethyl acetate/benzene) provided 3.60 g of 1-(4-formyl-benzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole; NMR (200 MHz, CDCl3) δ9.96 (s, 1H); 7.47 (A2M2, 4H); 5.26 (s, 2H); 4.42 (s, 2H); 2.54 (t, 2H); 1.64 (quint., 2H); 1.32 (sext., 2H); 0.86 (t, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[CH:7]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]([CH3:14])[CH:8]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][C:4]([O:13][C:12]1[CH:11]=[CH:10][C:9]([CH3:14])=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(Cl)CCCl
Reactant: Cc1ccc(O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(OC(=O)CCCl)cc1
Reaction time: 24 h
Yield: 54.6 %

Procedure:
3-Chloropropionyl chloride (12.5 ml, 0.131 mol) was added for three minutes to a solution of p-cresol (12.90 g, 0.119 mol) in pyridine (9.5 ml, 0.12 mol) and CH2Cl2 (53 ml) at 0° C. After stirring the reaction mixture for one day at 0° C. to room temperature, solvent was removed by rotary evaporation. The concentrate was treated with brine (50 ml) and 0.5 M citric acid (150 ml) and extracted with EtOAc (3×100 ml). The organic extracts were washed with 100 ml; 1 N HCl, H2O, cold 0.1 N NaOH, H2O and brine. After solvent removal, the residue was purified by silica gel flash column chromatography eluting with 7.5% EtOAc/hexane to give 12.90 g (55%) of 19 as a colorless liquid: NMR δ 2.34 (s, 3H), 3.03 (t, 2H, J=7), 3.86 (t, 2H, J=7), 6.95-7.01 (m, 2H), 7.17 (d, 2H, J=8).
Reaction SMILES: C([O:8][C:9]1[C:10]([C:38]([NH:40][CH2:41][C:42]([O:44]CC2C=CC=CC=2)=[O:43])=[O:39])=[N:11][C:12]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([CH:35]([OH:37])[CH3:36])=[CH:31][N:30]=4)=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[N:13][C:14]=1[CH3:15])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[C:10]([C:38]([NH:40][CH2:41][C:42]([OH:44])=[O:43])=[O:39])=[N:11][C:12]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([CH:35]([OH:37])[CH3:36])=[CH:31][N:30]=4)=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[N:13][C:14]=1[CH3:15]
Reactant: Cc1nc(CC2CCN(c3ccc(-c4ccc(C(C)O)cn4)cc3)CC2)nc(C(=O)NCC(=O)OCc2ccccc2)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1nc(CC2CCN(c3ccc(-c4ccc(C(C)O)cn4)cc3)CC2)nc(C(=O)NCC(=O)O)c1O
Temperature: 25 °C
Reaction time: 9 h
Yield: 55.6 %

Procedure:
Benzyl [({5-(benzyloxy)-2-[(1-{4-[5-(1-hydroxyethyl)pyridin-2-yl]phenyl}piperidin-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.10 g, 0.16 mmol) was dissolved in ethyl acetate (30 mL), and 10% palladium-activated carbon (0.25 g) was added, followed by stirring at room temperature for 9 hours under a hydrogen atmosphere. After the reaction solution was filtered with celite, the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: ethyl acetate/methanol), and a fraction corresponding to the Rf value=0.10 (ethyl acetate/methanol=4/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.045 g, 0.089 mmol) as a yellow solid (yield 56%).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[OH:8][NH:9][CH2:10][CH2:11][CH2:12][P:13](=[O:16])([OH:15])[OH:14]>C(O)=O>[CH:5]([N:9]([CH2:10][CH2:11][CH2:12][P:13](=[O:14])([OH:16])[OH:15])[OH:8])=[O:7]
Reactant: O=P(O)(O)CCCNO
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CN(O)CCCP(=O)(O)O
Reaction time: 0.17 h

Procedure:
Formic acid (20 ml.) was added dropwise to acetic anhydride (40 ml.) at 0°-5° C. in the course of 15 minutes with stirring. After stirring was continued at the same temperature for 10 minutes and then at 45°-50° C. for 15 minutes, the mixture was cooled down to 0°-5° C. To this cooled mixture was added dropwise a solution of 3-(N-hydroxyamino)propylphosphonic acid (32.8 g.) in formic acid (60 ml.) at the same temperature in the course of 20 minutes, stirred for additional 45 minutes at ambient temperature, and then the resultant mixture was concentrated under reduced pressure. The residue was dissolved in ethanol (300 ml.), treated with activated charcoal (6 g.) and then filtered. The filtrate was diluted with ethanol (200 ml.) and treated with 28% aqueous ammonia (28 ml.) with stirring under ice-cooling to give an oily precipitate. The precipitate was separated by decantation and dissolved in water (120 ml.). The aqueous solution was treated with activated charcoal (4 g.), and filtered. To the aqueous filtrate was added ethanol (800 ml.) at 80° C. and allowed to stand overnight at ambient temperature to give crystalline monoammonium salt of 3-(N-formyl-N-hydroxyamino)propylphosphonic acid (30.55 g.), mp 158°-160.5° C. (dec.) The same monoammonium salt (4.35 g.) was recovered additionally from the mother liquor, by concentrating it to about 100ml under reduced pressure mixing with ethanol (300 ml.) and allowing to stand at ambient temperature for 2 hours.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6]/[CH:7]=[CH:8]/[C@H:9]([CH3:19])[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C.C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CO>[CH3:19][C@H:9]([CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)/[CH:8]=[CH:7]/[CH2:6][CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)CC/C=C/[C@H](C)CCCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](/C=C/CCCO)CCCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (-)-(R)-6-methyl-9-phenyl-(E)-4-nonenoic acid ethyl ester, prepared by the procedure described in J. Org. Chem., 59(8), 2253 (1994), (1.0 g, 3.8 mmol) and 7.9 mL of anhydrous THF was added dropwise to a 0° C. suspension of LAH (0.03 g, 7.9 mmol) and 7.9 mL of anhydrous THF. The reaction mixture was stirred for 2 hours at 0° C. and for 1 hour at room temperature. After cooling again to 0° C., 1.2 mL of MeOH was added slowly. The mixture was stirred for 0.25 hours at room temperature, then concentrated in vacuo. Saturated aqueous Rochelle's salt was added, and the mixture was extracted with isopropyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound (0.84 g) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.095 (d, 3H), 1.21-1.38 (m, 3H), 1.51-1.70 (m, 4H), 2.02-2.15 (m, 3H), 2.58 (t, 2H), 3.65 (q, 2H), 5.23-5.45 (m, 2H), 7.18 (m, 3H), 7.28 (m, 2H). MS (DCl/NH3) m/e 250 (M+NH4)+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C@H:10]1[CH2:9][C@@H:8]([C:6]2[O:7][NH:29][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccccc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccccc1F
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluorobenzyl)piperidine-1-carboxylate (1.95 g, 5.34 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. Sodium hydroxide (0.213 g, 5.34 mmol) dissolved in water (2.000 mL) was added dropwise and the colourless solution continued to stir at −40° C. for 30 min. Hydroxylamine (50% by weight in water, 0.327 mL, 5.34 mmol) was added dropwise. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (25 mL, 150.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and MTBE/water added. The phases were separated and the organic phase dried over Na2SO4 and evaporated to yield a slightly yellow foam. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using two injections with a gradient of 15-75% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(2-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.09 g, 61%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.80-2.17 (m, 4H), 2.72-2.87 (m, 2H), 2.91-3.02 (m, 1H), 3.12-3.24 (m, 1H), 3.52 (s, 3H), 3.95-4.05 (m, 1H), 4.29-4.40 (m, 1H), 5.72 (s, 1H), 6.94-7.12 (m, 3H), 7.12-7.20 (m, 1H). MS m/z 335 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](I)=[CH:11][C:10]([NH2:14])=[N:9]1.[F:15][C:16]1[CH:17]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:19]=[C:20]([CH2:22][O:23][C@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])[CH:21]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:18]2[CH:19]=[C:20]([CH2:22][O:23][C@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])[CH:21]=[C:16]([F:15])[CH:17]=2)=[CH:11][C:10]([NH2:14])=[N:9]1
Reactant: C[C@@H](OCc1cc(F)cc(B2OC(C)(C)C(C)(C)O2)c1)C(F)(F)F
Reactant: Nc1cc(I)n(-c2ccccc2F)n1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: C[C@@H](OCc1cc(F)cc(-c2cc(N)nn2-c2ccccc2F)c1)C(F)(F)F
Temperature: 105 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(2-fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine (38 mg) in 1,4-dioxane (0.4 ml) were sequentially added 2-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (52 mg) prepared according to the same procedures as Preparation 15, palladium (II) acetate (3 mg), tricyclohexylphosphine (7 mg), 2M aqueous solution of potassium carbonate (0.2 ml) at room temperature, and the mixture was stirred at 105° C. for 4 hours. After removing the aqueous layer of this reaction mixture, the organic layer was filtered through silica gel (5 g), and subjected to elution with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel thin-layer chromatography (eluent: n-hexane/ethyl acetate 1/1) to give the titled compound.
Reaction SMILES: [CH2:1]([N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1)[CH:2]=[CH2:3].[CH3:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=1)=[O:24]>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[CH2:1][CH2:2][CH2:3][C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:23](=[O:24])[CH3:22])=[CH:27][CH:28]=2)=[CH:6][C:7]=1[C:13]([F:14])([F:15])[F:16])#[N:10]
Reactant: CC(=O)Nc1ccc(Br)cc1
Reactant: C=CCN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Product: CC(=O)Nc1ccc(CCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized according to Example 84B from 4-[2-propen-1-yl(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-bromoacetanilide: MS (APCI) m/z 444 (M+1).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([S:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)=[C:18]([NH2:20])[CH:19]=1>>[CH3:12][C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:20][C:18]3[CH:19]=[C:14]([CH3:13])[CH:15]=[CH:16][C:17]=3[S:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:24][CH:23]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1
Reactant: Cc1ccc(Sc2ccc(Oc3ccccc3)cc2)c(N)c1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc(Sc2ccc(Oc3ccccc3)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (50 mg, 0.28 mmol) was reacted with the product from Example 70a (86 mg, 0.28 mmol) for 24 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (64 mg, 50%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.37 (s, 3H), 2.73-2.79 (m, 3H), 6.30 (d, J=6.99 Hz, 1H), 6.78-6.87 (m, 2H), 6.97 (d, J=7.72 Hz, 2H), 7.17-7.24 (m, 1H), 7.24-7.28 (m, 2H), 7.32-7.36 (m, 3H), 7.37-7.46 (m, 2H), 7.79 (d, J=8.82 Hz, 1H), 8.42 (d, J=7.35 Hz, 1H), 8.96 (d, J=8.46 Hz, 1H), 11.00 (s, 1H); MS (ESI+) m/z 450 (M+H)+, (ESI−) m/z 448 (M−H)−.