Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH:11]=O.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]1=[S:23].[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>CO.[Pd]>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][NH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]1=[S:23]
Reactant: O=CC1CCc2ccccc2O1
Reactant: NCCCN1CCCNC1=S
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CO
Product: S=C1NCCCN1CCCNCC1CCc2ccccc2O1
Reaction time: 48 h
Yield: 7 %

Procedure:
A mixture of 3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (0.015 mol) and 1-(3-aminopropyl)tetrahydro-2(1H)-pyrimidinethione (0.01 mol) in methanol (150 ml) was hydrogenated for 2 days at room temperature (atmospheric pressure) with palladium on activated carbon (2 g) as a catalyst. After uptake of H2 (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 95/5). The pure fractions were collected and the solvent was evaporated. The residue (0.3 g) was dissolved in ethanol (30 ml) and converted into the ethanedioic acid salt (1:1) with ethanedioic acid (0.3 g; 0.0124 mol). The precipitate was filtered off and dried (vacuum), yielding 0.3 g (7%) of (±)-1-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]propyl]tetrahydro-2(1H)-pyrimidinethione ethanedioate(1:1); mp. 217.6° C. (comp. 14).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[N:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([N:31]5[CH:35]=[N:34][N:33]=[N:32]5)[CH:26]=4)[CH2:23][C:22](=[O:37])[NH:21][C:9]=3[CH:10]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2cnnn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3cnnn3)c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1

Procedure:
Prepared from {4′-fluoro-3-[3-oxo-3-(3-tetrazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K56) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (54 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17]CC=C)=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[N:10]2[CH3:33])=[C:5]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:4]=1)#[N:2].N1CCOCC1>C1COCC1.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:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)[C:11](=[O:32])[N:10]2[CH3:33])=[C:5]([S:34]([CH3:37])(=[O:35])=[O:36])[CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)[C@@H]1c1ccc(C#N)cc1S(C)(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CC1=C(C(=O)O)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
The reaction was carried out under argon. Allyl (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (157 mg, 0.294 mmol) and morpholine (1.5 eq., 38 mg, 0.441 mmol) were initially charged in dry THF (5 ml) at RT. The reaction mixture was degassed repeatedly (evacuation followed by venting with argon). Under protective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 17 mg, 0.015 mmol) was added, and the reaction mixture was stirred at RT for 16 h (HPLC control). The mixture was then concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a solid (120 mg, 83% of theory).
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[C:13]3[NH:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH:10]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24].[C:28]1([C:34]#[CH:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCOCC1.[Cu](I)I.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:19]=[C:14]1[C:13]2[NH:20][CH:21]=[CH:22][C:12]=2[C:11]2[CH:10]=[C:9]([C:35]#[C:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:18]=[CH:17][C:16]=2[NH:15]1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]
Reactant: O=c1[nH]c2ccc(I)cc2c2cc[nH]c12
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: CCC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccc(C#Cc3ccccc3)cc2c2cc[nH]c12
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 93.3 %

Procedure:
20 mg (0.11 mmol) of copper iodide, 28 mg (0.27 mmol) of triethylamine and 14 mg (0.02 mmol) of dichlorobis(triphenylphosphine)-palladium (II) are added to a suspension of 80 mg (0.21 mmol) of 8-iodo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 2.4 ml of anhydrous dioxan, then this mixture is degassed under argon. After 15 minutes, 32 mg (0.31 mmol) of phenylacetylene is added, then the mixture is heated at 100° C. for 3 hours. The raw reaction product is filtered on celite, the filtrate is evaporated to dryness and the residue is purified by chromatography on silica (eluent cyclohexane/ethyl acetate) to give 70 mg (93%) of 4-oxo-8-phenylethynyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a yellow solid.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH:28]1([CH2:32][C:33](O)=[O:34])[CH2:31][CH2:30][CH2:29]1>>[CH:28]1([CH2:32][C:33]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:8]4[C:7]5[CH2:6][CH2:5][O:4][C:12]=5[CH:11]=[CH:10][N:9]=4)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:34])[CH2:31][CH2:30][CH2:29]1
Reactant: O=C(O)CC1CCC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(CC1CCC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (81 mg, 76%), MS (ISP) m/z=427.5 [(M+H)+], mp 193° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and cyclobutane-acetic acid.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[F:29][C:30]1[CH:38]=[C:37]2[C:33]([CH2:34][N:35]([CH:40]([CH3:42])[CH3:41])[C:36]2=[O:39])=[CH:32][C:31]=1B(O)O>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][C:30]=3[F:29])[C:36](=[O:39])[N:35]([CH:40]([CH3:42])[CH3:41])[CH2:34]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Reactant: CC(C)N1Cc2cc(B(O)O)c(F)cc2C1=O
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4cc5c(cc4F)C(=O)N(C(C)C)C5)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and (6-fluoro-2-isopropyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)boronic acid. LCMS (M+H)+=483.1.
Reaction SMILES: BrC1C=CC([C:8]2[CH:21]=[CH:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11][C:10]=3[CH:9]=2)=CC=1.C1(B(O)O)C2C=CC3C(=CC=CC=3)C=2C=CC=1.[Br:39][C:40]1[CH:41]=[C:42](I)[CH:43]=[CH:44][CH:45]=1>>[Br:39][C:40]1[CH:45]=[C:44]([C:10]2[CH:11]=[CH:12][C:21]3[CH:20]=[CH:19][C:18]4[C:17]([C:8]=3[CH:9]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:43]=[CH:42][CH:41]=1
Reactant: Brc1cccc(I)c1
Reactant: Brc1ccc(-c2ccc3c(ccc4ccccc43)c2)cc1
Agent: OB(O)c1cccc2c1ccc1ccccc12
Product: Brc1cccc(-c2ccc3ccc4ccccc4c3c2)c1

Procedure:
Synthesis was performed in the same manner as in the synthesis of 2-(4-bromophenyl)phenanthrene except that: phenanthrene-1-boronic acid was used instead of phenanthrene-2-boronic acid; and 3-bromoiodobenzene was used instead of 4-bromoiodobenzene.
Reaction SMILES: C([C:3]1[N:7]([C:8]2[CH:13]=[C:12]([S:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[N:6]=[C:5]([O:22][C:23]([F:32])([F:31])[CH:24]([F:30])[O:25][C:26]([F:29])([F:28])[F:27])[CH:4]=1)=O.C([O-])(=O)C.[Na+].[Cl-].[OH:39][NH3+:40].[CH3:41]O>>[F:21][C:9]1[CH:10]=[C:11]([CH3:20])[C:12]([S:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:13][C:8]=1[N:7]1[C:3](=[N:40][OH:39])[C:4](=[CH2:41])[C:5]([O:22][C:23]([F:31])([F:32])[CH:24]([F:30])[O:25][C:26]([F:27])([F:28])[F:29])=[N:6]1
Reactant: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)OC(F)(F)F)cc2C=O)cc1SCC(F)(F)F
Reactant: [NH3+]O
Reactant: CO
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Product: C=C1C(OC(F)(F)C(F)OC(F)(F)F)=NN(c2cc(SCC(F)(F)F)c(C)cc2F)C1=NO

Procedure:
Then, 0.43 g of 5-formyl-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole was dissolved in 15 mL of methanol, and 110 mg of sodium acetate and 90 mg of hydroxylammonium chloride were added, followed by stirring under reflux with heating for 2 hours. Then, the solvent was distilled off under reduced pressure, extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:3) to obtain 0.29g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-(hydroxyimino)methylene-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole (1H-NMR (CDCL3/TMS δ (ppm) value) 6: (majar) 2.55 (3H, s), 3.38 (2H, q), 6.05 (1H, dt), 6.54 (1H, s), 7.15 (1H, d), 7.61 (1H, d), 7.71 (1H, brs), 7.83 (1H, d)).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[C:12](O)(=O)[CH3:13].[CH2:16](O)[CH3:17]>C1COCC1>[CH:17]1([CH2:12][CH2:13][N:1]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4](=[O:5])[C:2]2=[O:3])[CH2:16][CH2:7][CH2:6][CH2:4][CH2:2]1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CCO
Reactant: CC(=O)O
Solvent: C1CCOC1
Product: O=C1C(=O)N(CCC2CCCCC2)c2ccccc21
Yield: 83 %

Procedure:
A solution of 1-(2-Cyclohexyl-ethyl)-isatine (180 mg, 0.70 mmol) previously obtained (see isatine 2 in table 5) and Benzenesulfonyl hydrazide (120 mg, 0.70 mmol) in a solution of acetic acid, ethanol and THF (20%, 40%, 40%) is stirred at room temperature for 12 h. After concentration, a yellow precipitate is filtered and washed with ethanol to afford a desired product. M=239 mg, Yield: 83%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:31])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([CH3:26])[N:20]=3)=[CH:15][C:14]=2[O:29][CH3:30])[N:10]=1.[Cl-].[S:33]1[CH:37]=[C:36]([CH2:38][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:35]=[CH:34]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:31])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:38]\[C:36]4[N:35]=[CH:34][S:33][CH:37]=4)=[CH:22][N:21]([CH3:26])[N:20]=3)=[CH:15][C:14]=2[O:29][CH3:30])[N:10]=1
Reactant: COc1cc(COc2nn(C)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: c1ccc([P+](Cc2cscn2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(C)cc2/C=C\c2cscn2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 26.9 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-methyl-1H-pyrazole-4-carbaldehyde (0.50 g), [(1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (0.95 g), potassium carbonate (0.33 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 15 hrs, and further stirred at 50° C. for 3 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1 to 3:1, v/v) to give 2-(2-furyl)-4-({2-methoxy-4-[({1-methyl-4-[(Z)-2-(1,3-thiazol-4-yl)ethenyl]-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole as colorless crystals (0.16 g, yield 26%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 97-98° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C@H:13]1[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:23][N:24]4[CH2:29][CH2:28][CH:27]([O:30][CH3:31])[CH2:26][CH2:25]4)[CH:19]=3)[CH2:14]1)[CH2:6][CH2:5]2.[O:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[CH2:37]OS(C)(=O)=O>>[CH3:31][O:30][CH:27]1[CH2:26][CH2:25][N:24]([CH2:23][C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@@H:13]([N:7]2[CH2:6][CH2:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:37][C@@H:33]5[CH2:34][CH2:35][CH2:36][O:32]5)[CH:3]=4)[C:8]2=[O:12])[CH2:22][CH2:21]3)[CH2:29][CH2:28]1
Reactant: CS(=O)(=O)OC[C@@H]1CCCO1
Reactant: COC1CCN(Cc2ccc3c(c2)CC[C@H](N2CCc4cc(O)ccc4C2=O)C3)CC1
Product: COC1CCN(Cc2ccc3c(c2)CC[C@H](N2CCc4cc(OC[C@@H]5CCCO5)ccc4C2=O)C3)CC1

Procedure:
According to method F, 6-hydroxy-2-[(S)-6-(4-methoxypiperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-3,4-dihydro-2H-isoquinolin-1-one was alkylated with methanesulfonic acid (S)-1-(tetrahydrofuran-2-yl)methyl ester. The product was thus obtained with the molecular weight of 504.68 (C31H40N2O4); MS (ESI): 505 (M+H+).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3](=O)[CH2:4][CH3:5].Cl.[NH2:10][OH:11].[OH-].[Na+]>O>[F:1][C:2]([F:8])([F:7])/[C:3](=[N:10]/[OH:11])/[CH2:4][CH3:5]
Reactant: NO
Reactant: CCC(=O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC/C(=N\O)C(F)(F)F
Temperature: 25 °C
Yield: 44.4 %

Procedure:
To a solution of 1,1,1-trifluorobutan-2-one (5.0 g, 39.9 mmol) and hydroxylamine hydrochloride (3.22 g, 46.3 mmol) in water (28 mL) was added a solution of sodium hydroxide (1.84 g, 46.0 mmol) in water (14 mL), then the mixture was brought to reflux for 4 hr. After cooling to room temperature, the mixture was extracted with dichloromethane (3×50 mL) and the combined organic layers were washed with water, brine, then dried over anhydrous sodium sulfate. Filtration and concentration then distillation using a 10 cm Vigreux column (b.p. 123-124° C.) afforded (E)-1,1,1-trifluorobutan-2-one oxime (2.50 g, 44.5% yield) as a clear liquid. 1H NMR (400 MHz, CDCl3): 9.18 (br s, 1H), 2.52 (q, 2H), 1.21 (t, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][CH:4]=1)#[CH:2].I[C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:14][C:13]3[C:15]([CH:10]=2)=[CH:16][CH:17]=[CH:18][CH:12]=3)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C#Cc1ccc(C=C)cc1
Reactant: Nc1ccccc1I
Product: C=Cc1ccc(-c2cc3ccccc3[nH]2)cc1
Yield: 72 %

Procedure:
The general procedure was used to convert 1-Ethynyl-4-vinyl-benzene and 2-iodoaniline to the title product. Purification by flash chromatography gave the analytically pure product as a white solid, 72% yield. 1H NMR (300 MHz, CDCl3) δ 8.31 (s, br, 1H), 7.64-7.61 (d, J=8.29, 3H), 7.49-7.46 (d, J=8.29, 2H), 7.40-7.38 (d, J=8.10, 1H), 7.22-7.16 (dt, J=6.97, 1H), 7.14-7.09 (dt, J=7.91, 1H), 6.84 (s, 1H), 6.78-6.69 (dd, J=10.73, 1H), 5.82-5.76 (dd, J=17.70, 1H), 5.30-5.26 (dd, J=10.73, 1H). Anal. Calcd. for C16H13N: C, 87.64; H, 5.98; N, 6.39.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[CH:26][CH:27]=5)[C:22]([CH2:39][C:40]([O:42]C)=[O:41])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O1CCCC1>CO>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:26][CH:27]=5)[C:22]([CH2:39][C:40]([OH:42])=[O:41])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCCOc1ccc2c(c1)c(CC(=O)OC)cn2Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(CC(=O)O)c5cc(OCCCCC(=O)O)ccc54)ccc3o2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.6 %

Procedure:
A mixture of methyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(4-ethoxycarbonylbutoxy)indole-3-acetate (0.2 g) and 1N-sodium hydroxide (1.66 ml) in a mixed solvent of tetrahydrofuran (2 ml) and methanol (1 ml) was stirred at room temperature for 4 hours. After removal of solvents, the aqueous solution was acidified with diluted hydrochloric acid. The resulting precipitates were collected by filtration and washed with water to give 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(4-carboxybutoxy)indole-3-acetic acid (0.15 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:28]=CC)=[C:20]([NH:23][C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:32].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH:28]=[O:32])=[C:20]([NH:23][C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC=Cc1c(NC(=O)OC)ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)Nc1ccc2c(c1C=O)OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of {(2R)-7-[(methoxycarbonyl)amino]-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (5.12 g, 11.8 mmole) in tetrahydrofuran (400 mL) was added 2.42 mL of 4% aqueous osmium tetroxide (0.39 mmole). After 0.5 hour, sodium periodate (12.6 g, 59.1 mmole) in water (100 mL) was added dropwise over a period of 1 hour. The heterogeneous solution was stirred under nitrogen at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuum to yield the (R)-enantiomer of the title compound as a light beige solid (4.80 g, 97%).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.F[C:23](F)(F)[C:24]([OH:26])=O>C([O-])([O-])=O.[K+].[K+]>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:17]4[N:18]=[CH:19][C:7]([N:6]5[CH2:10][CH2:23][C:24](=[O:26])[CH2:2][CH2:1]5)=[CH:8][CH:16]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ncc2c3ccnc(F)c3n(C3CCCC3)c2n1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 170.8 %

Procedure:
Compound 245 (200 mg, 0.41 mmol) was dissolved in a solution of water (0.150 mL, 8.33 mmol) in trifluoroacetic acid (3.00 mL, 38.9 mmol). The solution was stirred at room temperature for 2 hours and then poured into aqueous K2CO3 (10%, 30 mL). This was extracted with dichloromethane+10% methanol (3×30 mL), and the combined organics were dried (MgSO4) and evaporated to give a yellow solid. Silica gel chromatography (gradient elution hexanes+2.5% TEA/50-100% ethyl acetate+2.5% TEA) afforded compound 305 as a yellow solid (156 mg, 86%).
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[N:6]=[CH:5][C:4]([C:3]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:9][CH:8]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[N:19][CH:20]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cn3)noc2C)nc1
Product: Cc1onc(-c2ccc(Cl)cn2)c1COc1ccc(C(=O)N2CCOCC2)cn1
Yield: 15 %

Procedure:
As described for example 301, [6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (108 mg, 0.3 mmol) was converted, using morpholine instead of 4-aminotetrahydropyran to the title compound (18 mg, 15%) which was obtained as a white solid. MS: m/e=415.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:23])[CH2:4]1.[O:24]1[C:33]2[CH:32]=[C:31]([CH:34]=O)[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1.S([O-])([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)Cl>[O:24]1[C:33]2[CH:32]=[C:31]([CH2:34][NH:1][CH2:2][C@@H:3]3[O:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][N:11]4[C:20]5[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=5)[CH:14]=[CH:13][C:12]4=[O:23])[CH2:4]3)[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: COc1cnc2ccc(=O)n(CCN3CCO[C@@H](CN)C3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CCO[C@@H](CNCc4cc5c(cn4)OCCO5)C3)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
To a solution of 1-{2-[(2S)-2-(aminomethyl)-4-morpholinyl]ethyl}-7-(methyloxy)-1,5-naphthyridin-2(1H)-one (0.100 g, 0.314 mmol) in 1:1 (MeOH/CH2Cl2) (25 mL) were added 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde) (for a synthesis see WO2004/058144 Example 2(c) or WO03/087098, Example 19(d)) (0.052 g, 0.314 mmol) and sodium sulphate (0.100 g) and the resulting solution stirred for 18 hours at ambient temperature. Na(OAc)3BH (0.200 g, 0.942 mmol) was added and the solution stirred an additional 2 h. The reaction mixture was concentrated onto silica gel and chromatographed to yield a colorless oil and further purified by HPLC(CH3CN/H2O) to yield the title compound as a white powder (0.049 g, 33%).