Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][C:10]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][C:10]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]([O:14][C:23](=[O:25])[CH3:24])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C1CCc2cc(C(=O)c3ccccc3)c(O)cc21
Product: COC(=O)C1CCc2cc(C(=O)c3ccccc3)c(OC(C)=O)cc21

Procedure:
A solution of 10 g of 5-benzoyl-6-hydroxy-indane-1-carboxylic acid methyl ester in 100 ml of acetic anhydride is heated to the reflux temperature for 4 hours under anhydrous conditions. It is then evaporated to dryness in vacuo. The evaporation residue is mixed with 200 ml of toluene and evaporated in vacuo. Distillation of the evaporation residue in a high vacuum gives, in the fraction boiling at 195°-200° C/0.06 /mm Hg, 5-benzoyl-6-acetoxy-indane-1-carboxylic acid methyl ester in the form of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19](O)(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].Cl.[CH3:39][O:40][NH2:41]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:41][O:40][CH3:39])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:26][CH2:27][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:29][CH2:30]1)=[O:24]
Reactant: CON
Reactant: O=C(c1cnc2c(S(=O)(=O)O)cnn2c1Nc1cc(Cl)ccc1Cl)N1CCC(c2ccc(F)cc2)CC1
Agent: Cl
Product: CONS(=O)(=O)c1cnn2c(Nc3cc(Cl)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 43.1 %

Procedure:
Using 7-(2,5-dichlorophenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonic acid (0.15 g, 0.27 mmol) obtained in step 1 and O-methylhydroxylamine hydrochloride (0.089 g, 1.06 mmol) instead of tert-butylamine, and in the same manner as in Example 1 step 3, the title compound (0.069 g, 44%) was obtained.
Reaction SMILES: C([O:4][C:5]1[CH:21]=[CH:20][C:8]([CH:9]=[CH:10][C:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]2)=[O:12])=[CH:7][C:6]=1[O:22][CH3:23])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][C:5]1[CH:21]=[CH:20][C:8]([CH:9]=[CH:10][C:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]2)=[O:12])=[CH:7][C:6]=1[O:22][CH3:23]
Reactant: COc1cc(C=CC(=O)N2CCC(C)CC2)ccc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc(C=CC(=O)N2CCC(C)CC2)ccc1O
Yield: 75.4 %

Procedure:
Using 5.2 g of 1-(4-acetoxy-3-methoxycinnamoyl)-4-methylpiperidine (Example 55), 70 ml of methanol, and 5 g of potassium carbonate, a reaction similar to that conducted in Example 54 was carried out. As a result, 3.4 g of 1-(4-hydroxy-3-methoxycinnamoyl)-4-methylpiperidine (a compound of the present invention) was obtained as a yellow oil, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[CH3:25][S:26]([C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](O)=[O:32])(=[O:28])=[O:27]>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:11][CH:12]=1)[NH:5][C:31]([C:30]1[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=1[S:26]([CH3:25])(=[O:28])=[O:27])=[O:32]
Reactant: CS(=O)(=O)c1ccccc1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccccc1S(C)(=O)=O
Yield: 99 %

Procedure:
4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[(2-methylsulfonylphenyl)carbonyl]-L-phenylalanine methyl ester was prepared in 99% yield from 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester and 2-methylsulfonylbenzoic acid using the general procedure described in example, LR MS: 548 (M+).
Reaction SMILES: [CH2:1]([Sn:5]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:28][CH2:29][CH2:30][CH3:31])[C:6]1[CH:27]=[CH:26][C:9]([C:10]([O:12][Sn](CCCC)(CCCC)CCCC)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C1(N=C=NC2CCCCC2)CCCCC1.O[N:52]1[C:56](=[O:57])[CH2:55][CH2:54][C:53]1=[O:58]>C1COCC1.CC(O)=O>[CH3:35][CH2:34][CH2:33][CH2:32][Sn:5]([C:6]1[CH:27]=[CH:26][C:9]([C:10]([O:12][N:52]2[C:56](=[O:57])[CH2:55][CH2:54][C:53]2=[O:58])=[O:11])=[CH:8][CH:7]=1)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1O
Reactant: CCCC[Sn](CCCC)(CCCC)OC(=O)c1ccc([Sn](CCCC)(CCCC)CCCC)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.2 %

Procedure:
To a solution of 1.29 g (1.84 mmol) of tri-n-butylstannyl 4-(tri-n-butylstannyl)benzoate in 18.4 mL of anhydrous THF was added 417 mg (2.02 mmol) of dicyclohexylcarbodiimide (Sigma) and 212 mg (1.84 mmol) of N-hydroxysuccinimide (Sigma, and the mixture was stirred for 15 hours at room temperature. To the mixture was then added three drops of HOAc. The solids were removed by filtration, and the mixture was concentrated. Purification by silica gel chromatography (25% EtOAc/hexane) yielded 731 mg (78%) of N-succinimidyl 4-(tri-n-butylstannyl)benzoate: 1H NMR (CDCl3)δ 0.50-2.20 (m, 27H), 2.90 (s, 4H), 7.65 (d, J=8 Hz, 2H), 8.06 (d, J=8 Hz, 2H). IR (neat) 1780, 1750, 1190, 1055, 980 cm-1.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]3[S:19][C:12]4[N:13]=[CH:14][N:15]=[C:16](SC)[C:11]=4[CH:10]=3)=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[NH3:26].[NH4+].[Cl-]>O1CCOCC1.C(Cl)Cl.O>[CH:1]1([N:4]2[C:8]([C:9]3[S:19][C:12]4[N:13]=[CH:14][N:15]=[C:16]([NH2:26])[C:11]=4[CH:10]=3)=[C:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CSc1ncnc2sc(-c3c(-c4ccccc4)ncn3C3CC3)cc12
Reactant: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1ncnc2sc(-c3c(-c4ccccc4)ncn3C3CC3)cc12
Yield: 35 %

Procedure:
6-(1-cyclopropyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno[2,3-d]pyrimidine (Intermediate 71) (25 mg), NH3 (aq. conc) and NH4Cl (sat. aq.) in dioxane (2 mL) were heated under microwave conditions (CEM explorer, 170° C., 4 hours). The reaction mixture was diluted with DCM and water. The aqueous layer was extracted with DCM and then the combined organics were concentrated. The crude product was purified by flash chromatography on silica eluting with Hex:EtOAc (1:1 to 100% EtOAc, then MeOH:EtOAc 95:5) to afford the title compound as a solid (8 mg, 35%);
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:48]1([C@H:54]([NH2:56])[CH3:55])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CC(N(C)C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:56][C@@H:54]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH3:55])=[O:6]
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1Cl
Reactant: C[C@@H](N)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: C[C@@H](NC(=O)c1ccc(-c2ccncc2)cc1Cl)c1ccccc1
Reaction time: 8 h
Yield: 70.74 %

Procedure:
A 20-ml scintillation vial was charged with a solution of 2-chloro-4-(pyridin-4-yl)benzoic acid in DMA (20.0 mg, 0.085 mmol, 1.0 eq), a solution of HATU in DMA (39.06 mg, 0.103 mmol, 1.20 eq), and triethylamine (28.83 μL, 0.205 mmol, 2.40 eq). The mixture was briefly shaken and a solution of (R)-1-phenylethanamine (14.52 mg, 0.1198 mmol, 1.40 eq) in DMA was added. The mixture was left to shake at room temperature overnight. The mixture was then concentrated in vacuo and dissolved in 1.4 ml of DMSO/methanol (1:1 v/v) and submitted for reverse phase purification to afford (R)-2-chloro-N-(1-phenylethyl)-4-(pyridin-4-yl)benzamide (27.30 mg, 70.74% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.S(Cl)([Cl:12])(=O)=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][Cl:12])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: ClSc1ccc(Cl)cc1
Temperature: 10 °C

Procedure:
A solution of 4-chlorothiophenol, 1 (20.15 g, 0.139 mol) in 170 mL of anhydrous carbon tetrachloride was placed in a 0.5 L 3-neck round bottom flask equipped with a magnetic stirrer, thermocouple, addition funnel, nitrogen line, heating mantle, condenser and caustic scrubber to absorb acidic gases (SO2 and HCl). A catalytic amount of pyridine (3 mL) was added to the solution, and the flask's content was chilled to ˜10° C. Sulfuryl chloride (55.2 g, 0.409 mol) was slowly added to the solution of 1, and the reaction mixture was gently refluxed for 3 hours. The resulting red solution was cooled to room temperature, quickly filtered through glass wool, and concentrated by rotary evaporation to yield 23 g of 4-chlorobenzene sulfenyl chloride, 2 as a viscous red oil. This crude material was used immediately for preparation of 4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:22][C:23](=[O:26])[CH2:24]Br)([CH3:21])([CH3:20])[CH3:19].C(OCC)C>CN(C=O)C.O>[C:8]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:11][CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26])(=[O:10])[CH3:9]
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(5-chloro-2-hydroxyphenyl)-ethanone (2 g), potassium carbonate (1.62 g) and tert-butylbromoacetate (1.73 ml) in DMF (5 ml) was stirred at ambient temperature for 16 h. Diethyl ether and water were added and the organic layer separated, it was washed with water, aqueous potassium carbonate solution, brine, dried (Na2SO4) and the solvent removed in vacuo to give the sub-title compound (2.84 g).
Reaction SMILES: C(O)(=O)C.C([O:7][C:8](=O)/[C:9](=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]2)=[C:25]([O:35][CH3:36])[CH:24]=1)/[CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)C.[OH-].[Na+].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][N:13]1[CH2:12][CH2:11][CH2:10]/[C:9](=[CH:22]\[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]3)=[C:25]([O:35][CH3:36])[CH:24]=2)/[C:8]1=[O:7]
Reactant: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCCNCc1cccc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(/C=C2\CCCN(Cc3cccc(F)c3)C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Yield: 28.9 %

Procedure:
An acetic acid (3 mL) solution of (E)-5-(3-fluorobenzylamino)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid ethyl ester (81 mg) was heated to reflux overnight. After cooling the reaction solution to 0° C., it was neutralized with 1N sodium hydroxide solution, and then a saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate=1:5→ethyl acetate), and 21 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [N:1]1([C:10]2[S:14][C:13]([C:15]([O:17]C)=O)=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])[CH:11]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[NH3:31]>CO>[N:1]1([C:10]2[S:14][C:13]([C:15]([NH2:31])=[O:17])=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:28])([F:29])[F:30])[CH:11]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccccc1C(F)(F)F
Reactant: N
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example 1, 195 mg of methyl 5-(1H-imidazo[4,5-c]pyridin-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate (compound B1a) and 36 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[N:20][NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[C:13](=[O:19])[NH:14]3)=[CH:4][CH:3]=1>[Pd].CO.C1COCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[N:20][NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[C:13](=[O:19])[NH:14]3)=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3cccc(C=Cc4ccc(O)cc4)c32)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3cccc(CCc4ccc(O)cc4)c32)cc1
Reaction time: 1 h
Yield: 9.3 %

Procedure:
A mixture of 0.028 g (0.64 mmol) of 4-(N′-{4-[2-(4-hydroxyphenyl)-vinyl]-2-oxo-1,2-dihydro-indol-3-ylidene}-hydrazino)-benzenesulfonamide (Z isomer) and 0.015 g of 10% palladium on charcoal in 60 mL of MeOH:THF (4:1) was subjected to hydrogenation on a Parr apparatus at 50 psi for 1 h. The mixture was filtered through celite, and the filtrate was concentrated to give 0.026 g (93%) of the title compound as a yellow solid: 1H NMR (DMSO-d6): δ 2.82 (t, J=8.0 Hz, 2H), 3.23 (t, J=8.0 Hz, 2H), 6.69 (d, J=8.4 Hz, 2H), 6.78 (d, J=7.7 Hz, 1H), 6.89 (d, J=7.7 Hz, 1H), 7.07 (d, J=8.4 Hz, 2H), 7.18 (t, J=7.7 Hz, 1H), 7.26 (s, 2H), 7.45 (d, J=8.8 Hz, 2H), 7.71 (d, J=8.8 Hz, 2H), 9.20 (bs, 1H), 11.12 (s, 1H), 13.02 (s, 1H); APCI-MS m/z 435 (M−1)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4]([CH:5]=[C:6](Br)Br)[C@H:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C([Li])CCC.Cl[C:23]([O:25][CH3:26])=[O:24].P(O)(O)([O-])=O.[Na+]>C1CCCCC1.O1CCCC1>[CH3:1][C:2]1([CH3:16])[C@@H:4]([C:5]#[C:6][C:23]([O:25][CH3:26])=[O:24])[C@H:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C=C(Br)Br)C1(C)C
Agent: O=P([O-])(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)C#C[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
55 g of tert-butyl(1R,cis)2,2-dimethyl-3-(2,2-dibromovinyl)-cyclopropane-carboxylate were introduced into 550 cm3 of tetrahydrofuran and the mixture was cooled to -70° C. 132 cm3 of a 20% solution of butyllithium in cyclohexane were added over 40 minutes to the mixture which was stirred for 30 minutes at -65° C. 12.5 cm3 of methyl chloroformate were then added thereto and after 2 hours reaction at -70° C., the temperature was allowed to rise again to -20° C. The mixture was poured into an aqueous solution of monosodium phosphate and the mixture was extracted with ether. The organic phase was washed, dried and evaporated to dryness under reduced pressure. 38.3 g of the residue were chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate mixture to obtain 17.2 g of tert.-butyl(1R,cis)2,2-dimethyl-3-[2-(methoxy carbonyl)-ethynyl]-cyclopropane-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][NH:19][C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-].[K+].[I:24]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[I:24][C:21]1[C:15]2[C:16](=[N:17][CH:18]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:14]=2)[NH:19][CH:20]=1
Reactant: COc1cc(-c2cnc3[nH]ccc3n2)cc(OC)c1OC
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-c2cnc3[nH]cc(I)c3n2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.8 %

Procedure:
To a 0° C. mixture of 2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (2.4 g, 8.4 mmol) in dimethylformamide (30 ml) was added KOH (2 g, 36 mmol). After 20 min, iodine (3.2 g, 13 mmol) was added portionwise over 10 min and the reaction mixture was stirred for 4 h and poured into 0° C. saturated aqueous sodium thiosulfate (˜300 mL). Ice cold water (˜100 mL) was added and the resultant precipitate was collected, washed with water and dried in vacuo at 60° C. to afford 3.1 g (89%) of 7-iodo-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine as a brown solid. MP 230-232° C., M+H=412.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].C>C(OCC)(=O)C>[C:1]([O:4][CH2:5][CH:6]1[O:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc(C(=O)O)o1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1CCC(C(=O)O)O1
Yield: 71.2 %

Procedure:
A solution of 5-acetoxymethylfuran-2-carboxylic acid (5.00g) in ethyl acetate (250ml) was stirred with decolourising charcoal (5.0g) for 10mins. The mixture was filtered through Kieselguhr and the residue was washed with ethyl acetate (30ml). The combined filtrates were hydrogenated over 5% rhodium on carbon (2.5g) until hydrogen uptake ceased. The mixture was filtered through Kieselguhr and the residue was washed with ethyl acetate (30ml). The combined filtrates were evaporated to give the title acid as an oil (3.64g); vmax (Film) 3700-2800 and 1742cm-1 ; δH [(CD3)2CO]1.4-2.5 and 2.00 (7H, m+s), 3.9-4.55 (4H, m) and 7.52 (1H, br s). [Mass spectrum: M+ (188), MH+ (189)].
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][CH2:4][CH:3]1[CH2:13][C:14]([OH:16])=O.C(C(Cl)=O)C.[NH2:22][OH:23]>>[OH:23][NH:22][C:14](=[O:16])[CH2:13][CH:3]1[C:2](=[O:1])[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)CC1CCc2ccccc2NC1=O
Reactant: NO
Agent: CCC(=O)Cl
Product: O=C(CC1CCc2ccccc2NC1=O)NO

Procedure:
The (2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-acetic acid is treated with EtCOCl and freshly prepared NH2OH by following a similar procedure described in example 1 to provide the title compound N-hydroxy-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-acetamide which is purified by preparative LC/MS. 1H NMR (400 MHz, MeOD) δ 7.28 (m, 2H), 7.17(dt, 1H, J=1.2 Hz, J=8.0 Hz), 7.04 (dd, 1H, J=1.2 Hz, J 8.0 Hz), 2.90 (m, 2H), 2.72 (m, 1H), 2.55 (m, 1H), 2.28 (m, 1H), 2.15 (m, 1H), 1.97 (m, 1H). MS: (ES+): 235.3 [M+1].
Reaction SMILES: CN(C(ON1N=[N:16][C:11]2[CH:12]=[CH:13][CH:14]=[N:15]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43](OC)=[O:44])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH:27]=1.CCN(C(C)C)C(C)C.NCCCCNC(=O)OC(C)(C)C.FC(F)(F)C(O)=O>CN(C=O)C.C(Cl)Cl>[NH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:16][C:43]([C:40]1[S:39][C:35]2[N:36]=[CH:37][N:38]=[C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][C:28]=3[O:47][CH:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)[C:34]=2[C:41]=1[CH3:42])=[O:44]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Agent: CC(C)(C)OC(=O)NCCCCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1c(C(=O)NCCCCN)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
HATU (0.073 g, 0.193 mmol) was added into a mixture of methyl 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.07 g, 0.175 mmol) and Hünig's base (30 μL, 0.175 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. tert-Butyl 4-aminobutylcarbamate (0.164 g, 0.875 mmol) was added, the coolant removed and the reaction stirred at ambient temperature overnight. The product was recrystallised from EtOAc to yield colourless solid. The solid was dissolved in DCM (2.0 mL), treated with trifluoroacetic acid (0.50 mL) and the reaction stirred at ambient temperature for 2 hours. The reaction mixture was applied to an SCX cartridge and eluted with MeOH (30 mL) followed by ammonia in MeOH. Evaporation of appropriate fractions gave the product as a colourless solid (0.024 g, 29%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][Br:9])[CH:5]=[CH:4][N:3]=1.[Cl:10]C1C=C(C)N=CN=1>>[Br:9][CH2:8][C:6]1[CH:5]=[C:4]([Cl:10])[N:3]=[CH:2][N:7]=1
Reactant: BrCc1ccnc(Br)n1
Reactant: Cc1cc(Cl)ncn1
Product: Clc1cc(CBr)ncn1

Procedure:
Prepared according to the same procedure as 2-bromo-4-(bromomethyl)pyrimidine, starting with 4-chloro-6-methylpyrimidine. 1H NMR (500 MHz, DMSO-d6) δ 9.07 (s, 1H), 7.91 (d, J=0.9 Hz, 1H), 4.66 (s, 2H), Mass spec.: 208.9 (MH)+.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:17])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].[CH3:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([CH3:25])[NH:20]1>C(O)C>[CH3:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([CH3:25])[N:20]1[CH2:2][CH:3]([OH:17])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: CC1CCCC(C)N1
Reactant: COCCOc1ccccc1OCC(O)CCl
Solvent: CCO
Product: COCCOc1ccccc1OCC(O)CN1C(C)CCCC1C
Yield: 74.3 %

Procedure:
A mixture of 5.2 g of 1-chloro-3-[2-(2-methoxyethoxy)phenoxy]-2-propanol, 4.6 g of 2,6-dimethylpiperidine and 50 ml of ethanol is refluxed for 16 hours. The ethanol is removed, and ether is added to the residue. The insoluble matter is filtered off, and the filtrate is extracted with two 80 ml portions of 10% hydrochloric acid. The aqueous layer is made alkaline with sodium hydroxide, and the separated oil is extracted twice with ether. The ether layer is dried over anhydrous potassium carbonate, and the ether is removed to give 5.0 g of 1-(2,6-dimethylpiperidino)-3-[2-(2-methoxyethoxy)phenoxy]-2-propanol, melting at 92°-94°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([O:10]C)=[O:9].CO.O.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1Cl
Temperature: 50 °C
Yield: 81 %

Procedure:
Methyl 3-chloro-4′-nitrobiphenyl-4-carboxylate (0.50 g, 1.4 mmol) was suspended in THF (6 mL), MeOH (6 mL) and water (3 mL), and NaOH (0.27 g, 6.9 mmol) was added. The reaction mixture was heated at 50° C. for 3 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure and acidified with 2N HCl. The resulting solid was collected by filtration and dried in a 40° C. vacuum oven, yielding 0.315 g (83%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.81-8.10 (m, 5H), 8.21-8.38 (m, 2H).