Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([NH:20][C:21]2[CH:31]=[CH:30][C:24]([C:25](OCC)=[O:26])=[CH:23][N:22]=2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CO.O>O1CCCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([NH:20][C:21]2[N:22]=[CH:23][C:24]([CH2:25][OH:26])=[CH:30][CH:31]=2)[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1ccc(N[C@@H]2CCCN(Cc3ccccc3)C2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: OCc1ccc(N[C@@H]2CCCN(Cc3ccccc3)C2)nc1
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To a suspension of lithium aluminum hydride (70 mg, 1.8 mmol) in tetrahydrofuran (2 mL) was added a solution of ethyl 6-{[(3R)-1-benzyl-3-piperidinyl]amino}nicotinate (250 mg, 0.74 mmol) in tetrahydrofuran (5 mL) dropwise at 0° C. under nitrogen and the mixture was stirred at same temperature for 3 hrs. To the reaction mixture was added methanol and water dropwise at 0° C. and the mixture was stirred for 1 h. The precipitate was removed by vacuum filtration and the filtrate was evaporated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give (6-{[(3R)-1-benzyl-3-piperidinyl]amino}-3-pyridinyl)methanol (219 mg, 100%) as an oil.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O1CCCC1.[Na].[CH2:24]([O:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30]Br)[CH3:25]>C(O)C>[CH2:24]([O:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][S:17][C:14]1[CH:13]=[CH:12][C:11]([C:1]23[CH2:8][CH:7]4[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]4)[CH2:10]2)[CH2:2]3)=[CH:16][CH:15]=1)[CH3:25]
Reactant: CCOC(=O)CCCBr
Reactant: Sc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCCSc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 50 °C

Procedure:
A solution of 5 g of the crude 4-(1-adamantyl)-thiophenol obtained above, in 25 ml of absolute ethanol and 25 ml of absolute tetrahydrofurane is added dropwise to a solution of 500 mg of sodium in 20 ml of absolute ethanol whilst stirring in a dry nitrogen atmosphere, and 2.9 ml of 4-bromobutyric acid ethyl ester are then added under the same conditions. After completion of the addition, the mixture is heated to 50° C for 14 hours. It is then evaporated to dryness in vacuo and the evaporation residue is partitioned between 3 times 100 ml of methylene chloride and 100 ml of 2 N hydrochloric acid. The organic phases are washed until neutral, dried over sodium sulphate and evaporated in vacuo. Chromatography of the evaporation residue on 240 g of silica gel, with benzene as the eluant, yields chromatographically pure 4-[4-(1-adamantyl)-phenylthio]-butyric acid ethyl ester in the form of a yellow-brown oil (IR spectrum: C=0 band at 1,740 cm-1 (in CH2Cl2)).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1NCCCCC1c1cccc(O)c1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCCCCC1c1cccc(OCc2ccccc2)c1
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
A solution of 3-(3-hydroxyphenyl)hexahydro-2H-azepin-2-one (2.05 g) in dry DMF was added dropwise to a suspension of sodium hydride (0.3 g). After 30 minutes at ambient temperature, benzyl chloride (1.3 g) was added. The mixture was stirred for a further 2 hours and then cooled, and treated with water. The resulting solution was extracted several times with toluene, and the combined toluene layers washed thoroughly with water. The solvent was evaporated to give an oil that crystallised from ethyl acetate to give the title compound as a white solid (1.4 g) m.p. 119°-122° C.
Reaction SMILES: C[C:2]1[C:6]([CH3:8])([CH3:7])[CH:5]([CH2:9][C:10]([OH:12])=[O:11])[CH2:4][CH:3]=1.[C:13]1(C)C=CC(S(O)(=O)=O)=C[CH:14]=1.[CH2:24](O)C>CCCCCCC>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][CH:5]1[CH2:4][C:3]([CH3:24])=[CH:2][C:6]1([CH3:7])[CH3:8])[CH3:14]
Reactant: CCO
Reactant: CC1=CCC(CC(=O)O)C1(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCC
Product: CCOC(=O)CC1CC(C)=CC1(C)C
Temperature: 71 °C

Procedure:
A solution containing a mixture (99 g) of γ-campholenic acid (56%) and α-campholenic acid (43%), p-toluenesulfonic acid (2 g), ethanol (750 ml) and heptane (750 ml) was kept at reflux (71° C.) for 16 hours, while the condensate was perculated through a layer of molecular sieves (3 Å) (100 g). The solvent was then removed, the residue taken up in CH2Cl2 (1 liter) and the solution extracted with ice cold 5% aqueous sodium hydroxide (1 liter) and water (2×500 ml). Concentration of the dried CH2Cl2 solution gave a crude oil (115 g), which was distilled through a 9" glass packed column to give 95 g of a colorless liquid; bp 73°-75° C. @ 1.5 mm Hg; analysis: (CW 20M fused silica column, 120°-190° C.; 5° C./min.) 60% ethyl γ-campholenate and 40% ethyl α-campholenate; odor: fruity, berry; flavor: sweet, fruity, berry.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[CH2:10][C@@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:22])[CH2:10][C@@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][N:32]1[CH2:31][CH2:30][CH:29]([O:28][C:27]2[CH:35]=[CH:36][C:24]([F:23])=[CH:25][CH:26]=2)[CH2:34][CH2:33]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CI)CC(=O)OCc1ccccc1
Reactant: Fc1ccc(OC2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)CN1CCC(Oc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Triphenylphosphine bound to cross-linked polystyrene resin (2.16 g, mol/g, 6.47 mmol) is suspended in dry DCM (50 ml) at ambient temperature under a nitrogen atmosphere. Iodine (1.64 g, 6.47 mmol) is added and the reaction mixture stirred for 15 minutes. Imidazole (0.50 g, 7.35 mmol) is then added and the reaction mixture is stirred for a further 15 minutes. A solution of (R)-3-.tert.-butoxycarbonylamino-4-hydroxy-butyric acid benzyl ester (prepared as described by D. Gani et al J. Chem. Soc. Perkin Trans. 1, 2513–2525, 1997 (0.909 g, 2.94 mmol) in dry DCM (10 ml) is added and the reaction mixture is stirred at reflux for 1 hour. The polymer is removed by filtration, and the filtrate is first washed with aqueous 5% sodium thiosulphate solution and then water. The organic phase is dried over MgSO4 and evaporated to yield (R)-3-tert-butoxycarbonylamino-4-iodo-butyric acid benzyl ester as a crude oil. A solution of (R)-3-tert-butoxycarbonylamino-4-iodo-butyric acid benzyl ester (1.017 g, 2.43 mmol) and 4-(4-fluoro-phenoxy)-piperidine (0.569 g, 2.916 mmol) in DMF (25 ml) is treated with triethylamine (0.406 ml, 2.916 mmol). The reaction mixture is stirred at ambient temperature for 60 hours, and then partitioned between ethylacetate and water. The ethylacetate phase is dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with 2:1 hexane/ethylacetate) to afford (R)-3-tert-butoxycarbonylamino-4-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-butyric acid benzyl ester. [MH]+ 487.1.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11](=[O:15])[C:12]([O-:14])=O.[K+].[CH3:17][C@@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:19]1>>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:24]([N:20]1[CH2:21][CH2:22][N:23]([C:12](=[O:14])[C:11]([C:7]2[C:6]3[C:10](=[C:2]([Br:1])[N:3]=[CH:4][CH:5]=3)[NH:9][CH:8]=2)=[O:15])[C@@H:18]([CH3:17])[CH2:19]1)=[O:31]
Reactant: O=C([O-])C(=O)c1c[nH]c2c(Br)nccc12
Reactant: C[C@H]1CN(C(=O)c2ccccn2)CCN1
Agent: [K+]
Product: C[C@H]1CN(C(=O)c2ccccn2)CCN1C(=O)C(=O)c1c[nH]c2c(Br)nccc12

Procedure:
Precursor 5n, (S)-1-picolinoyl-3-methyl-4-[(7-bromo-6-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a starting from Potassium (7-bromo-6-azaindol-3-yl)oxoacetate, Precursor 4g, and (S)-3-methyl-1-picolinoyl-piperazine. 1H NMR (500 MHz, CDCl3) δ 8.63-7.36 (m, 7H), 5.02-3.06 (m, 7H), 1.42-1.26 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[Cl:10][CH2:11][C:12](=O)[CH2:13][C:14]([O:16][CH3:17])=[O:15]>C1COCC1>[ClH:10].[Br:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]2[N:4]([CH:11]=[C:12]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[N:9]=2)[CH:5]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: Nc1ncc(Br)cc1Br
Solvent: C1CCOC1
Product: COC(=O)Cc1cn2cc(Br)cc(Br)c2n1
Product: Cl
Yield: 29.6 %

Procedure:
A mixture of 3,5-dibromopyridin-2-amine (9.03 g, 35.8 mmol) and methyl 4-chloro-3-oxobutanoate (2.0 g, 13 mmol) in THF (50 mL) was heated at reflux 48 hrs. The solid was filtered and dried to give methyl 2-(6,8-dibromoimidazo[1,2-a]pyridin-2-yl)acetate hydrochloride (1.48 g, 36% yield). LCMS B: 1.54 min (RT); (M+H)+=347.07 (75%), 349.07 (100%), 351.04 (75%). 1H NMR, 400 MHz, CDCl3: δ 9.01 (d, 1.4 Hz, 1 H), 8.38 (s, 1 H), 8.07 (d, 1.4 Hz, 1 H), 4.25 (s, 2 H), 3.40 (s, 3 H).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][O:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@@H:12]1/[CH:17]=[CH:18]/[CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])C.[OH-].[Li+].Cl>CO.C1COCC1.O>[OH:25][CH:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])/[CH:18]=[CH:17]/[C@H:12]1[CH2:13][CH2:14][C:15](=[O:16])[N:11]1[CH2:10]/[CH:9]=[CH:8]\[CH2:7][O:6][CH2:5][C:4]([OH:26])=[O:3]
Reactant: CCCCCC(O)/C=C/[C@H]1CCC(=O)N1C/C=C\COCC(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCC(O)/C=C/[C@H]1CCC(=O)N1C/C=C\COCC(=O)O
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of {(Z)-4-[(R)-2-((E)-3-hydroxy-oct-1-enyl)-5-oxo-pyrrolidin-1-yl]-but-2-enyloxy}-acetic acid ethyl ester (0.22 g, 0.6 mmol) in a mixture of 5 mL of methanol and 5 mL THF at room temperature under a nitrogen atmosphere was added an aqueous solution of lithium hydroxide (0.1 g, 2.4 mmol) in 3 mL of water. The reaction was stirred at 45° C. overnight, cooled to room temperature and treated with aqueous hydrochloric acid (1 M) until acidic. The residue was diluted with water (10 mL) and extracted with ethyl acetate. The organic solution was dried (brine, Na2SO4) and evaporated to yield {(Z)-4-[(R)-2-((E)-3-hydroxy-oct-1-enyl)-5-oxo-pyrrolidin-1-yl]-but-2-enyloxy}-acetic acid; ESMS m/Z M+, 339.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:10])[NH:6][CH2:7][C:8]#[N:9])[CH:2]=[CH2:3].[OH-:11].[Na+].S(O)(O)(=O)=O.[NH2:18]O.Cl>CO.O>[CH2:1]([O:4][C:5](=[O:10])[NH:6][CH2:7][C:8](=[NH:18])[NH:9][OH:11])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)NCC#N
Reactant: NO
Reactant: [OH-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CCOC(=O)NCC(=N)NO
Temperature: 20 °C
Reaction time: 16 h
Yield: 132 %

Procedure:
To a solution of 140 g of cyanomethyl-carbamic acid allyl ester in 1 l of methanol were added over 15 min a solution of 40.0 g of sodium hydroxide and 82.1 g of hydroxylamine sulfate in 200 ml of water, the reaction mixture being cooled in an ice-bath. The mixture was stirred at 20° C. for 16 h and then, the pH of the suspension was adjusted to 7.0 by the addition of concentrated hydrochloric acid. The solids were removed by filtration and the mother liquor was evaporated in vacuo. The solid residue was recrystallized from ethyl acetate to yield 143.1 g of N-hydroxycarbamimidoylmethyl-carbamic acid allyl ester as white crystals, m.p. 91°-92° C.
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:6]=[O:7].[CH2:8]=[CH:9][CH:10]=[CH2:11]>CN(C=O)C.N1CCCC1.C(O)(=O)CC>[CH:3]([C:2]1([CH:1]=[O:5])[CH2:6][CH2:11][CH:10]=[CH:9][CH2:8]1)=[CH2:4].[CH:3]([CH:2]1[CH2:1][CH2:11][C:10]([CH:6]=[O:7])=[CH:9][CH2:8]1)=[CH2:4]
Reactant: C=O
Reactant: C=CC=C
Reactant: C/C=C/C=O
Solvent: CN(C)C=O
Solvent: C1CCNC1
Solvent: CCC(=O)O
Product: C=CC1(C=O)CC=CCC1
Product: C=CC1CC=C(C=O)CC1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 93 %

Procedure:
The 500 mL flask was charged with crotonaldehyde (210.3 g, 3 mol), formaldehyde (270.0 g, 3.24 mol, 36% aqueous solution) and DMF (50 g, 0.68 mol). A cooled mixture of pyrrolidine (5.33 g, 0.075 mol) and propionic acid (5.56 g, 0.075 mol) was added with stirring during 5 minutes. This combined mixture was then slowly pumped with stirring into a heated (100° C.) autoclave that had been charged with a solution of 1,3-butadiene (570.4 g, 5 mol) in DMF (250 g, 3.42 mol). (Careful: a cold autoclave has to be charged with a cooled solution of butadiene in DMF, boiling point of butadiene: −4.5° C.). At this temperature, the internal pressure was 12.0 bar. During the first 3 h of this addition, the internal pressure slowly rose to 14.5 bar, while the temperature was kept at 100° C. The pressure then slowly dropped to 11.0 bar until the addition was finished after 4.5 hours. The reaction mixture was stirred at 100° C. for another 2 hours. After that time (the pressure was less than 8.1 bar) the reaction mixture was cooled to room temperature (by means of an internal cooling device) upon which the internal pressure dropped to less than 2 bar. The mixture was transferred to a 2.0 L separation funnel and diluted with hexane (620 g) and water (300 g) (Careful: excessive butadiene evaporates during this operation: use well ventilated hood). The upper layer was separated and washed successively with aq. acetic acid (50 ml) and water (50 ml) and then with sat. aq. sodium bicarbonate solution. The organic phase was dried with MgSO4, filtered and concentrated under reduced pressure to furnish the crude product as a yellow oil (254 g) which was then distilled in vacuo over a 10 cm-Vigreux column (b.p. 47-72° C., 0.1 mbar), to yield 1-vinylcyclohex-3-ene carbaldehyde and 4-vinylcyclohex-1-ene carbaldehyde (189.9 g, 46.5%) in a ratio of about 2:1. The compounds may be separated by distillation or chromatography on silica gel under conditions known to the skilled person.
Reaction SMILES: CN(C)C=O.[O:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[C:17]([NH2:25])=[N:16]2)[CH2:8][CH2:7]1.Br.Br[CH2:28][CH2:29][CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[O:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[C:17]([NH:25][CH2:28][CH2:29][CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[N:16]2)[CH2:8][CH2:7]1
Reactant: Nc1nn(CCCN2CCOCC2)c2ccc(Cl)cc12
Reactant: CCN(CC)CCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nn(CCCN2CCOCC2)c2ccc(Cl)cc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 59.1 %

Procedure:
To 60 ml of anhydrous N,N-dimethylformamide were added 9.63 g of the 1-(3-morpholinopropyl)-3-amino-5-chloroindazole, 8.98 g of 3-bromopropyldiethylamine hydrobromide and 7.89 g of anhydrous potassium carbonate, and the mixture was stirred for 12 hours at 80° C. After cooling, the mixture was added with 80 ml of water and extracted with diethyl ether. The diethyl ether layer was extracted three times with 2N hydrochloric acid, and the hydrochloric acid layer was washed with diethyl ether. The pH of the layer was adjusted to at least 11 with potassium carbonate, and the alkali layer was extracted three times with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography (alumina: 200 g) using chloroform as the developing solvent to give 7.87 g of 1-(3-morpholinopropyl)-3-(3-diethylaminopropylamino)-5-chloroindazole having the following analytical values in a yield of 59%.
Reaction SMILES: N1(/[C:6](/[CH3:13])=[CH:7]\[C:8]([O:10][CH2:11][CH3:12])=[O:9])CCCC1.[N+:14]([CH2:17][CH3:18])([O-:16])=O.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[C:8]([C:7]1[C:17]([CH3:18])=[N:14][O:16][C:6]=1[CH3:13])([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC[N+](=O)[O-]
Reactant: CCOC(=O)/C=C(/C)N1CCCC1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)noc1C
Reaction time: 8 h

Procedure:
A solution of the ethyl β-pyrrolidinocrotonate (427 g. = 2.33 moles), 190 ml. (182 g., 2.43 mole) of nitroethane and 1300 ml. of triethylamine in 1200 ml. of anhydrous chloroform was cooled in an ice bath under nitrogen. A solution of 235 ml. (393 g. = 2.56 mole) of phosphorous oxychloride in 400 ml. of chloroform was added at such a rate that the temperature did not rise above 15°. During the addition, which took place over a three-hour period, a viscous orange precipitate formed. This suspension was then stirred under nitrogen overnight. As much solvent as possible was removed at reduced pressure and the resulting red-brown paste was diluted with water and extracted with ether. The ether solutions were washed sequentially with water, 3N hydrochloric acid, water, 5 percent sodium hydroxide solution and water, and were dried over anhydrous sodium sulfate. Solvent removal at reduced pressure gave a dark oil which was distilled through a short Vigreux column to give 4-carboethoxy-3,5-dimethyl-isoxazole as a slightly cloudy, colorless liquid of b.p. 100° /11mm.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])=[O:7])=[N:15][CH:16]=1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ccc(Br)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Br)cn1)c1ccccc1[N+](=O)[O-]
Yield: 77.9 %

Procedure:
A solution of 2-nitrobenzoyl chloride (3.70 g, 20 mmol, 1.0 equiv), 2-amino-5-bromopyridine (3.50 g, 1.0 equiv), pyridine (10 mL) in 25 mL of methylene chloride was stirred overnight. The volatile was evaporated, flash chromatography on silica gel gave N-(5-bromo-2-pyridinyl)-(2-nitro)phenylcarboxamide (5.02 g, 77%). MS found for C12H9BrN3O3 (M+H)+: 322. Step 2: A solution of N-(5-bromo-2-pyridinyl)-(2-nitro)phenylcarboxamide (1.0 g, 3.1 mmol, 1.0 equiv) in 30 mL of EtOAc was treated with SnCl2.2H2O (2.80 g, 4 equiv) at reflux for 4 h. The volatile was evaporated and the residue was redissolved in EtOAc, washed with saturated aqueous NaHCO3 and 1N NaOH. The organic layer was dried over MgSO4, filtered and evaporated to N-(5-bromo-2-pyridinyl)-(2-amino)phenylcarboxamide (0.89 g, 98%). MS found for C12H11BrN3O (M+H)+: 292. Step 3: A mixture of N-(5-bromo-2-pyridinyl)-(2-amino)phenylcarboxamide (292 mg, 1 mmol, 1.0 equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoyl chloride (349 mg, 1 equiv), pyridine (3 mL) in 10 mL of dichloromethane was stirred at rt overnight, washed with H2O. The organic layer was dried over MgSO4, filtered, evaporated and refluxed in 2 mL of trifluoroacetic acid for 30 min. TFA was then evaporated and HPLC (C18 reversed phase) eluting with 0.5% TFA in H2O/CH3CN gave N-(5-bromo-2-pyridinyl)-(2-4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenylcarboxamide (470 mg, 85%). MS found for C25H20BrN4O4S (M+H)+: 551.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:28](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:28])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 161, step 1, 5-[(R)-3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless solid, MS (ESI+): m/z=410.2 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][O:18][C@H:17]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=3)=[O:29])=[C:23]([F:39])[CH:22]=2)[CH2:16]1)=O)(C)(C)C.[OH-].[Na+]>O.C(#N)C>[C:37]([C:33]1[CH:32]=[C:31]([NH:30][C:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([C@H:17]3[O:18][CH2:19][CH2:20][NH:15][CH2:16]3)=[CH:22][C:23]=2[F:39])=[O:29])[CH:36]=[CH:35][CH:34]=1)#[N:38]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(NC(=O)Nc3cccc(C#N)c3)c(F)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: N#Cc1cccc(NC(=O)Nc2ccc([C@@H]3CNCCO3)cc2F)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
To a stirred solution of trifluoroacetic acid (216 μl) in water (4.5 ml) was added a solution of (R)-2-{4-[3-(3-cyano-phenyl)-ureido]-3-fluoro-phenyl}-morpholine-4-carboxylic acid tert-butyl ester (85 mg) in acetonitrile (2 ml). The reaction mixture was then capped and the mixture was shaken at 80° C. for 3 h. The reaction mixture was then cooled to room temperature and poured into 1 M aq. NaOH and the resulting mixture was extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis); gradient: heptane/EtOAc/MeOH) to afford 1-(3-cyano-phenyl)-3-((R)-2-fluoro-4-morpholin-2-yl-phenyl)-urea (45 mg, 61%) as a white solid. MS (ISP): 341.1 ([M+H]+).
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[OH2:14].C([O-])(=O)C.[Na+].Cl.[NH2:21]O>CO>[CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[CH:4]=[C:5]([C:9](=[N:21][OH:14])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: O
Reactant: CC(=O)c1cccc([Si](C)(C)C)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=NO)c1cccc([Si](C)(C)C)c1
Temperature: 25 °C

Procedure:
To a solution of the title compound of Step C (8.9 g) in methanol (120 mL)/water (50 mL) was added sodium acetate (7.5 g) followed by the addition of hydroxylamine hydrochloride (3.8 g). The mixture was heated at reflux overnight, cooled to room temperature, and concentrated to an oil. The oil was mixed with water and extracted three times with methylene chloride. The combined organic phases were dried (MgSO4), concentrated, and chromatographed on silica gel with 8% ethyl acetate/hexane to afford the title compound of Step D as an oil. 1H NMR (CDCl3): δ 8.8 (br s,1H), 7.77 (s,1H), 7.5 (m,2H), 7.37 (t,1H), 2.31 (s,3H), 0.27 (s,8H).