Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(COC)OC.COP([CH2:15][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=O)OC.[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O)([O:25][CH3:26])=[O:24]>C(O)(=O)C>[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1/[CH:35]=[CH:15]/[C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([O:25][CH3:26])=[O:24]
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Reactant: COC(=O)CCCCCCc1ccccc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COCCOC
Product: CCCCCC(=O)/C=C/c1ccccc1CCCCCCC(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1.25 g. of this benzyl alcohol in 75 ml. of chloroform is added to a slurry of 12.5 g. of activated manganese dioxide in 75 ml. of chloroform. The mixture is stirred for one hour, filtered and the solvent is evaporated to leave 2-(6-carbomethoxyhexyl)benzaldehyde as a clear oil. To a slurry of 260 ml. of a dispersion of sodium hydride in mineral oil in 40 ml. of dimethoxyethane is added a solution of 1.31 g. of dimethyl(2-oxoheptyl)phosphonate in 25 ml. of dimethoxyethane. The slurry is stirred for one hour, cooled to 0° C. and 1.22 g. of the benzaldehyde in 20 ml. of dimethoxyethane is added. The mixture is stirred at 0° for 30 minutes and at room temperature for three hours. It is then neutralized with acetic acid and the solvent removed in vacuo. The residue is chromatographed on silica gel to yield 1-(6-carbomethoxyhexyl)-2-(3-oxo-trans-1-octenyl)benzene as a pale yellow oil.
Reaction SMILES: [O:1]=[C:2]1[C:6]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[CH:5]2[CH2:19][CH:20]=[CH:21][CH:22]=[C:4]2[O:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(Cl)[Cl:30]>C1COCC1>[ClH:30].[CH3:18][N:16]([CH3:17])[CH2:15][CH2:14][C:6]([C:5]1[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=1[OH:3])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[CH2:2][OH:1]
Reactant: Cc1ccccc1C1(CCN(C)C)C(=O)OC2=CC=CCC21
Reactant: ClCCl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(CO)(CCN(C)C)c1ccccc1O
Product: Cl
Reaction time: 1 h

Procedure:
A solution of 2-[2-oxo-3-(2-tolyl)-3-dihydrobenzofuranyl]-N,N-dimethylethylamine (90 g, 305 mmol) in anhydrous THF (400 ml) was added to a suspension of LiAlH4 (11.4 g, 300 mmol) in THF (850 ml) at 0°. This mixture was stirred 1 hour, quenched with saturated NH4Cl (200 ml) and the organic phase decanted. The solids were washed with EtOAc (3×300 ml) and decanted. The organic solutions were combined and evaporated in vacuo to give an oil which solidified on cooling. The crude residue was dissolved in CH2Cl2 (500 ml), washed with dilute NH4Cl until the pH became 8, and dried over Na2SO4. A solution of the diolamine (8.4 g) in CH2Cl2 (60 ml) was added dropwise to an ethereal/HCl solution (1200 ml). Filtration of the precipitated salt gave 8.6 g of a solid, which was recrystallized from MeCN (800 ml) to yield 6.7 g (71%) of crystals, m.p. 205°-207°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[N:12][C:11]=2[CH2:10][CH2:9]1.ClCCl>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)Cl.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[N:12][C:11]=2[CH:10]=[CH:9]1
Reactant: Cc1ccccc1N1CCc2nnc3c(C)cccc3c21
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ccccc1-n1ccc2nnc3c(C)cccc3c21

Procedure:
To a refluxing slurry of 10% Pd/C (0.4 g) in diphenyl ether (20 ml) was added 1-(2-methylphenyl)-6-methyl-2,3-dihydropyrrolo [3,2-c]cinnoline (1.25 g, 0.0045 mol). After 0.5 hour at reflux temperature the reaction mixture was cooled, diluted with chloroform and the catalyst was filtered off over hyflo. The product was isolated by column chromatography using dichloromethane (11) then chloroform. The oil obtained was crystallized from ethyl acetate, 0.42 g, m.p. 105-106°.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([NH2:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH2:4][C@H:5]([NH2:13])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [N-]=[N+]=NC[C@H](N)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: NC[C@H](N)Cc1ccccc1
Yield: 103.3 %

Procedure:
A sample of the compound from step 3d (1.2 g, 6.8 mmole) was hydrogenated (4 atm) in ethanol over 1.2 g of 10% Pd/C for 21.5 hours at room temperature. The mixture was filtered to remove the catalyst, and the solvent was removed to afford the title compound (1.055 g). MS m/z (M+H)+: 151, MS m/z (M+NH4)+: 168.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:11][CH:10]=[N:9][N:8]=2)=[CH:3][CH:2]=1.[Li]CCCC.[N:17]#N.CCOCC.[C:24]([C:31](N)([CH2:34][CH3:35])[CH:32]=[O:33])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:24]([C@@H:31]([CH2:34][CH3:35])[C:32]([NH2:17])([C:10]1[O:11][C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[N:8][N:9]=1)[OH:33])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: c1cc(-c2nnco2)ccn1
Reactant: N#N
Reactant: CCC(N)(C=O)C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC[C@H](C(=O)OC(C)(C)C)C(N)(O)c1nnc(-c2ccncc2)o1
Temperature: -45 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the 5-pyridin-4-yl-[1.3.4]oxadiazole (11.5 g, 78.2 mmol) in THF (300 mL) was added HMPA (5 ML) and n-BuLi (1.6 M solution in 48.9 mL of hexane) dropwise under N2 at −78° C. After 1 h, MgBr.Et2O (20.2 g, 78.2 mmol) was added and the reaction mixture was allowed to warm to −45° C. for 1 h before being treated with 2-Boc-amino-butyraldehyde (9.7 g, 50.8 mmol) in THF (50 mL). The reaction mixture was stirred for 1 h, quenched with saturated NH4Cl, and extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4 and concentrated. The residue was purified with silica gel column chromatography to yield 2(S)-Boc-amino-1-(5-pyridin-4-yl-[1.3.4]oxadiazol-2-yl)-butan-1-ol (3.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[C:17]([F:24])=[CH:18][C:19]([F:23])=[C:20]([CH:22]=1)[NH2:21].[F:25][C:26]([C:29]1[CH:33]=[C:32]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[O:31][N:30]=1)([CH3:28])[CH3:27].C(N(C(C)C)CC)(C)C>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[C:17]([F:24])=[CH:18][C:19]([F:23])=[C:20]([NH:21][C:35]([NH:34][C:32]2[O:31][N:30]=[C:29]([C:26]([F:25])([CH3:27])[CH3:28])[CH:33]=2)=[O:36])[CH:22]=1
Reactant: COc1cc2ncnc(Oc3cc(N)c(F)cc3F)c2cc1OC
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccccc2)on1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cc(NC(=O)Nc4cc(C(C)(C)F)no4)c(F)cc3F)c2cc1OC
Yield: 31 %

Procedure:
To a stirred solution of 5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluoroaniline (100 mg, 0.3 mmoles) from the previous step and phenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate described in Example 42A (96 mg, 0.32 mmoles) in anhydrous DMF (10 mL), was added 4-(dimethylamino)pyridine (20 mg, 0.16 mmoles) and diisopropylethylamine (80 μL, 0.45 mmoles) and the reaction heated to 70 C overnight. The reaction was then concentrated to an oil and purified by silica gel chromatography eluting with a gradient of ethyl acetate/dichloromethane, 3-80%, to afford 1-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluorophenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea (46.33 mg, 31% yield) as a white solid. 1H (300 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.92 (s, 1H), 8.57 (s, 1H), 8.13 (m, 1H), 7.67 (m, 1H), 7.57 (s, 1H), 7.41 (s, 1H), 6.12 (s, 1H), 3.98 (s, 6H), 1.65 (d, J=21 Hz, 6H); LCMS (ESI) m/z (M+H)+504.
Reaction SMILES: C([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)(O)=O.[N+:12]([CH2:15][CH3:16])([O-])=O.C([O-])(=O)C.[NH4+].CCCCCC.CCOC(C)=O>C(O)(=O)C>[NH2:12][CH:15]([CH2:7][C:6]1[CH:5]=[CH:4][CH:11]=[CH:10][CH:9]=1)[CH3:16]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(N)Cc1ccccc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 161.5 %

Procedure:
To a solution of 1.902 q (12.68 mmol) of 3-carboxybenzaldehyde in 10 mL of glacial acetic acid, was added 2.848 mL (2.970 g, 38.04mmol) of nitroethane and 1.080 g (13.95 mmol) of ammonium acetate. The solution was then heated with stirring under nitrogen in a 110° C. oil bath. Then, all of the solid went into solution near 60° C. and the mixture turned a deep yellow color. After 3 hours, thin layer chromatography with 3:1 hexane/EtOAc indicated that no starting material remained. The reaction mixture was cooled to room temperature, and then partitioned between water and methylene chloride, with acidification to about pH2 with 6 M HCl. The organic layer was washed with 6 M HCl, then dried with magnesium sulfate. The solvents were then removed with a rotary evaporator, yielding 2.768 g (98%) of crude material, which was carried on without further purification because of the difficulty of chromatographing the very polar carboxylic acid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:9](=[O:11])C)[S:7][CH:8]=1)([CH3:3])[CH3:2].[OH-:12].[Na+]>O1CCOCC1.Cl[O-].[Na+]>[CH:1]([C:4]1[CH:5]=[C:6]([C:9]([OH:11])=[O:12])[S:7][CH:8]=1)([CH3:2])[CH3:3]
Reactant: CC(=O)c1cc(C(C)C)cs1
Reactant: [OH-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1COCCO1
Product: CC(C)c1csc(C(=O)O)c1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
A solution of 1-(4-isopropylthiophen-2-yl)ethanone (example 74, step a) (1 g) in 1,4-dioxane (10 mL) was cautiously added to a solution of sodium hydroxide (1.19 g) in aqueous sodium hypochlorite (8%, 50 mL) at 60° C. The resulting mixture was heated to 75° C. and stirred for 1 h. The reaction was allowed to cool and the aqueous phase washed with DCM (50 mL). The aqueous phase was treated with aqueous sodium bisulphite solution (10%, 20 mL) and carefully acidified with concentrated hydrochloric acid. The resulting mixture was extracted with DCM (3×50 mL). The combined organic solutions were dried over sodium sulphate, filtered and evaporated to give a yellow oil. Purification was by preparative HPLC (Sunfire™, Gradient: 5-95% acetonitrile in 0.2% aqueous TFA). The fractions containing product were combined, evaporated and dried under high vacuum to give the subtitled compound as a white solid. Yield 0.5 g.
Reaction SMILES: OC[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH3:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[CH3:22])[CH:17]=O.S(=O)(=O)(O)O.[CH3:28][C:29]1[CH:30]=[C:31]([CH:45]=[CH:46][C:47]=1[CH3:48])[CH:32]=[C:33]([C@@H:35]([C@H:37]([C@@H:39]([C@@H:41]([CH2:43][OH:44])[OH:42])[OH:40])[OH:38])[OH:36])[OH:34]>>[CH3:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[CH3:22])[CH:17]=[C:43]([OH:44])[C@@H:41]([OH:42])[C@@H:39]([OH:40])[C@H:37]([OH:38])[C@@H:35]([OH:36])[C:33](=[CH:32][C:31]1[CH:45]=[CH:46][C:47]([CH3:48])=[C:29]([CH3:28])[CH:30]=1)[OH:34]
Reactant: Cc1ccc(C=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)cc1C
Reactant: Cc1ccc(C=O)cc1C
Agent: O=S(=O)(O)O
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Product: Cc1ccc(C=C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=Cc2ccc(C)c(C)c2)cc1C
Temperature: 21 °C
Reaction time: 6 h
Yield: 0.5 %

Procedure:
A 500 ml four-necked flask was charged with a 70 wt % aqueous solution of 143 g (0.55 mole) of D-sorbitol, 73.7 g (0.55 mole) of 3,4-dimethylbenzaldehyde and 12 g of 50 wt % sulfuric acid. The air inside the system was replaced with nitrogen gas. The contents of the flask were stirred at a temperature of 21° C. for 6 hours. The obtained reaction mixture was analyzed by GC. It was found that mono(3,4-dimethylbenzylidene)-D-sorbitol was produced in a yield of 70% and 0.5% or less of bis(3,4-dimethylbenzylidene)-D-sorbitol was also produced.
Reaction SMILES: O=O.[CH2:3]=[CH:4][CH3:5].[C:6]([OH:9])(=[O:8])[CH3:7]>>[CH2:3]([OH:8])[CH:4]=[CH2:5].[C:6]([O:9][CH2:3][CH:4]=[CH2:5])(=[O:8])[CH3:7]
Reactant: CC(=O)O
Reactant: C=CC
Agent: O=O
Product: C=CCO
Product: C=CCOC(C)=O

Procedure:
FIG. 2 shows a process further including a step of producing an aqueous 70% by mass allyl alcohol solution by hydrolyzing allyl acetate produced using a hydrolysis reactor 24. When allyl acetate produced by reacting oxygen, acetic acid and propylene is subsequently hydrolyzed to produce allyl alcohol, allyl acetate separated and distilled by the first distillation column 9 shown in FIG. 1 may be fed to the hydrolysis reactor. In the example of FIG. 2, a reaction mixed liquid (a bottom liquid 14 of a gas-liquid separator column) is fed through a middle tank 7 to a hydrolysis reactor 24 without separating and purifying allyl acetate. In FIG. 2, 26 denotes a second distillation column, and a reaction liquid 25 from the hydrolysis reactor 24 is distilled and separated into a bottom liquid of a second distillation column, and a top liquid 27 of a second distillation column. A bottom liquid of a second distillation column contains an acetic acid (comprising the unreacted acetic acid and acetic acid produced by hydrolysis), water and the other high-boiling point components. A top liquid 27 of a second distillation column is a mixture of allyl alcohol, allyl acetate and water.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCCCCCCOCc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCCCCOCc1ccccc1)C(=O)OCC
Reaction time: 2 h
Yield: 68.2 %

Procedure:
To sodium metal (1.32 g, 0.0573 mol) dissolved in dry ethanol (150 ml) under argon at room temperature was added diethyl malonate (14.13 g, 0.088 mol) over a period of 10 minutes and the solution left for 2 hours. B1 (10.0 g 0.044 mol) was then added dropwise over 2 hours and this solution heated at reflux overnight. Excess salts were quenched by the addition of 50 ml of water and the total solvent volume reduced to 50-100 ml. Diethyl ether (100 ml) and water (50 ml) were added and the aqueous layer extracted 3 times with diethyl ether. The organic fractions were combined, dried (K2CO3), and the solvent removed to yield the crude product as a yellow oil. Distillation of the oil (0.5 mBar, 220° C.) gave the title compound (10.52 g, 68%) as a colourless viscous oil. δH (CDCl3) 1.32 (6H, t, Me), 1.43 (6H, br s, (CH2)3CH2CH), 1.69 (2H, p, CH2CH2O), 1.99 (2H, q, CH2CH), 3.39 (1H, t, CH), 3.53 (2H, t, CH2OCH2Ph), 4.25, 4.28 (4H, 2×q, OCH2Me), 4.57 (2H, s, CH2Ph), 7.3-7.4 (5H, m, Ph). δC (CDCl3) 13.9 (2 C, Me), 25.7 (1 C, CH2(CH2)2CH), 27.1 (1 C, CH2(CH2)2O), 28.5 (1 C, CH2CH2CH), 28.9 (1 C, CH2CH2O), 29.5 (1 C, CH2CH), 51.8 (CHCO2Et), 61.0 (2C, OCH2Me), 70.1, 72.7 (2C, CH2OCH2), 127.3 (1C, CH(CH)2C), 127.4 (2C, CGC), 128.1 (2C, CHCHC), 138.5 (1C, CCH2O) 169.3 (2C, CO2).
Reaction SMILES: [OH-:1].[Na+].[OH:3][C:4]1[CH2:9][CH:8]([C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[C:12]([CH2:18][C:19]#[N:20])[C:11]=2[CH3:21])[CH2:7][C:6](=[O:22])[C:5]=1[C:23](=[O:26])[CH2:24][CH3:25]>C1(C)C=CC=CC=1>[OH:3][C:4]1[CH2:9][CH:8]([C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[C:12]([CH2:18][C:19](=[O:1])[NH2:20])[C:11]=2[CH3:21])[CH2:7][C:6](=[O:22])[C:5]=1[C:23](=[O:26])[CH2:24][CH3:25]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(CC#N)c2C)CC1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(CC(N)=O)c2C)CC1=O
Yield: 40 %

Procedure:
Sodium hydroxide solution (10%, 4 ml) was added to a solution of 3-hydroxy-2-propionyl-5-(3-cyanomethyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (1.5 g, 4.6 mmol) in toluene (10 ml) and the mixture was refluxed for 2 h. After cooling the toluene was separated and the aqueous layer acidified and extracted with ethylacetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. Chromatography on silica gel (elution with an increasing gradient of ethylacetate in methylene chloride) gave 3-hydroxy-2-propionyl-5-(3-carbamoylmethyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one as a pale solid (0.6 g, 40%). Proton magnetic resonance spectrum (CDCl3 ; 67 in ppm): 1.25 (3H,t,J6.5 Hz); 2.24 (3H,s); 2.28 (3H,s); 2.32 (3H,s); 2.2-4.2 (7H,m); 3.60 (2H,s); 5.3 (1H,brs); 6.0 (1H,brs); 6.85 (1H,s); 18.10 (1H,s). Infrared spectrum (CHCl3): ν max 1670 b cm-1. Also recovered from the chromatography was a sodium bicarbonate soluble fraction identified as 2-[3-(4-propionyl-5-hydroxycyclohex-3-one-4-enyl)-2,4,6-trimethylpheny]acetic acid (0.25 g, 17%) a colourless solid. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 1.2 (3H, t,J6.5 Hz); 2.13 (3H,s); 2.2 (3H,s); 2.26 (3H, s); 2.3-4.1 (7H,m); 3.50; (2H,s); 6.75 (1H,s). Infrared spectrum: ν max (NUjol) 3300-2500 b, 1680-1630 b cm-1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[F:10][C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:12]=1[NH2:13]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:13][C:12]2[C:14]([O:18][CH3:19])=[CH:15][CH:16]=[CH:17][C:11]=2[F:10])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COc1cccc(F)c1N
Product: COc1cccc(F)c1Nc1nc(Cl)ncc1Cl

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(2-fluoro-6-methoxy-phenyl)-amine was prepared from 2,4,5-Trichloro-pyrimidine and 2-Fluoro-6-methoxyaniline in an analogous manner to Example 1230a. Title product was obtained as an off white solid (3.80 g, 62%). MP=133-135. LCMS 289.03 (M+H), HPLC purity=94%, 1H-NMR (DMSO-d6, 400 MHz) δ 9.24 (s, 1H), 8.35 (s, 1H), 7.39-7.35 (m, 1H), 7.00-6.91 (m, 2H), 3.80 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:10]=1[C:11](Cl)=[O:12].[CH3:20][N:21]([CH3:29])[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCOCC1>[CH2:27]([O:26][C:24](=[O:25])[C:23](=[CH:22][N:21]([CH3:29])[CH3:20])[C:11](=[O:12])[C:10]1[CH:14]=[C:15]([F:19])[C:16]([F:18])=[CH:17][C:9]=1[F:8])[CH3:28]
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Reactant: CCOC(=O)C=CN(C)C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (2.09 mL, 15 mmol) was added with stirring to a solution of 2,4,5-trifluorobenzoyl chloride (1.95 g, 10 mmol) and ethyl 3-dimethylaminoacrylate 20 (1.43 g, 10 mmol) in 1,4-dioxane (20 mL). The mixture was stirred at r.t. overnight, and solvent was removed under vacuum. The residue was dissolved in ethyl ether (100 mL) and hexanes (20 mL), and the resulting mixture was washed with water (2×100 mL), 2% aq. citric acid (2×100 mL), brine (100 mL), 2.5% aq. NaHCO3 (2×100 mL), and brine (100 mL). The organic layer was dried (MgSO4), and the solvents removed under vacuum to provide ethyl-2-(dimethylamino)methylene-2-(2,4,5-trifluorobenzoyl)acetate 21 as a light orange oil (Yield 2.55 g (85%). MS (m/z): 302 [M+H]+. Rt 4.9 min.). A solution of Compound 21 (0.301 g, 1.0 mmol) and 5-(S)-acetamidomethyl-3-(4-amino-3-fluorophenyl)-oxazolidine-2-one (0.267 g, 1.0 mmol) in EtOH (9 mL) was agitated at 40° C. for 16 h. The solvent was removed under vacuum, and the resulting residue dissolved in ethyl ether (75 mL). The ether solution was washed with 3% aq. citric acid (2×40 mL), brine (40 mL), and dried (MgSO4). The solvent was removed under vacuum to afford Compound 22 as a thick light-orange oil. Yield 0.50 g (90%). MS (m/z): 524 [M+H]+. Rt 5.5 min.
Reaction SMILES: N[C@@H]1CCCCN(CC2CC2)C1=O.[CH:14]1([CH2:17][N:18]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]([NH:25][C:26](=[O:32])OC(C)(C)C)[C:19]2=[O:33])[CH2:16][CH2:15]1.C(O)(C(F)(F)F)=O.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.C(N(C(C)C)CC)(C)C.[Cl:63][C:64]1[CH:73]=[C:72]2[C:67]([C:68]([N:75]3[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]3)=[CH:69][C:70]([NH2:74])=[N:71]2)=[CH:66][CH:65]=1>>[NH2:74][C:70]1[CH:69]=[C:68]([N:75]2[CH2:76][CH2:77][N:78]([C:26]([NH:25][C@H:20]3[CH2:21][CH2:22][CH2:23][CH2:24][N:18]([CH2:17][CH:14]4[CH2:15][CH2:16]4)[C:19]3=[O:33])=[O:32])[CH2:79][CH2:80]2)[C:67]2[C:72](=[CH:73][C:64]([Cl:63])=[CH:65][CH:66]=2)[N:71]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCN(CC2CC2)C1=O
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Agent: N[C@@H]1CCCCN(CC2CC2)C1=O
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(CC4CC4)C3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 78, (3R)-3-amino-1-(cyclopropylmethyl)hexahydro-2H-azepin-2-one by de-protection of [(3S)-1-(cyclopropylmethyl)hexahydro-2-oxo-1H-azepin-3-yl]-carbamic acid, 1,1-dimethylethyl ester with TFA, p-nitrophenyl chloroformate, diisopropylethyl amine, and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product. LC-MS: 471 (M++1). 1H NMR (CDCl3) δ 7.65 (d, 1H), 7.55 (s, 1H), 7.10 (d, 1H), 6.22 (d, 1H), 6.05 (s, 1H), 4.85 (s, 2H), 4.50 (m, 1H), 3.60 (m, 4H), 3.50 (m, 1H), 3.40 (m, 1H), 3.30 (m, 1H), 3.20 (m, 1H), 3.06 (m, 4H), 2.05 (m, 1H), 1.70–1.90 (m, 3H), 1.40 (m, 2H), 0.90 (m, 1H), 0.45 (m, 2H), 0.20 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2cccc([N+](=O)[O-])c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-3′-nitroacetophenone.
Reaction SMILES: C([O-])(=[O:3])C.[Na+].[Cl:6][C:7]1[CH:8]=[C:9]([NH:25][C:26](=[O:30])[C:27]([OH:29])=[O:28])[CH:10]=[C:11]([Cl:24])[C:12]=1[O:13][C:14]1[N:15]=[N:16][C:17](Cl)=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=1>C(O)(=O)C>[Cl:6][C:7]1[CH:8]=[C:9]([NH:25][C:26](=[O:30])[C:27]([OH:29])=[O:28])[CH:10]=[C:11]([Cl:24])[C:12]=1[O:13][C:14]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[C:17](=[O:3])[NH:16][N:15]=1
Reactant: CC(=O)[O-]
Reactant: CC(C)c1cc(Oc2c(Cl)cc(NC(=O)C(=O)O)cc2Cl)nnc1Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1cc(Oc2c(Cl)cc(NC(=O)C(=O)O)cc2Cl)n[nH]c1=O
Temperature: 100 °C
Yield: 56.1 %

Procedure:
A mixture of glacial acetic acid (55 mL), sodium acetate (1.2 g, 14.7 mmol) and N-[3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-oxalamic acid (28) (1.7 g, 4.2 mmol) was heated to 100° C. for 24 h. The reaction mixture was cooled to room temperature and was concentrated under vacuum. The resulting solid was diluted with water (50 mL). The mixture was made acidic to pH=3 by the addition of glacial acetic acid. The solids were filtered and rinsed well with water and dried on the funnel. The solid was slurried in 1:1:2 isopropyl acetate: methyl tert-butyl ether: hexanes (3 mL) and then was heated to reflux. The mixture was cooled and filtered. A slight amount of impurity was detected by TLC. The solid was slurried in isopropyl acetate (10 mL) and filtered. The resulting pure solid was dried under high vacuum for 24 h and then dried in a vacuum oven at 80° C. for 24 h to afford N-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-oxalamic acid (29) (0.91 g, 56%) as a white solid; EI(+)-HRMS m/z calcd for C15H13Cl2N3O5 (M+H) 386.0305, found 386.0308. Molecular Weight=386.1940; Exact Mass=385.0232