Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH:5]([CH2:8]O)[CH2:4]1)[CH3:2].[BrH:10].C(=O)([O-])[O-].[Na+].[Na+]>>[Br:10][CH2:8][CH:5]1[CH2:6][CH2:7][N:3]([CH2:1][CH3:2])[CH2:4]1
Reactant: CCN1CCC(CO)C1
Reactant: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCN1CCC(CBr)C1

Procedure:
A mixture of 5.0 g. (0.0388 mol.) of N-ethyl-3-hydroxymethylpyrrolidine and 50 ml. of 48% hydrogen bromide was refluxed for 17 hours. The reaction mixture was cooled, made basic by addition of solid sodium carbonate and extracted twice with methylene chloride. The combined extracts were dried (MgSO4) and evaporated to dryness to give 3-bromomethyl-N-ethylpyrrolidine.
Reaction SMILES: [CH2:1](O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:20]([N:22]([CH2:48][CH3:49])[C:23](=[O:47])[C:24]1[CH:29]=[CH:28][C:27]([CH:30]([C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:46]=2[N:45]=[CH:44][CH:43]=[CH:42]3)[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1)[CH3:21].[OH-].[Na+]>C(Cl)Cl>[CH2:48]([N:22]([CH2:20][CH3:21])[C:23](=[O:47])[C:24]1[CH:29]=[CH:28][C:27]([CH:30]([N:31]2[CH2:32][CH2:33][N:34]([CH2:1][C:2]3[O:6][CH:5]=[CH:4][CH:3]=3)[CH2:35][CH2:36]2)[C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:46]=2[N:45]=[CH:44][CH:43]=[CH:42]3)=[CH:26][CH:25]=1)[CH3:49]
Reactant: OCc1ccco1
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc3cccnc23)N2CCNCC2)cc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C(c2cccc3cccnc23)N2CCN(Cc3ccco3)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
To a 0° C. solution of furfurylalcohol (0.19 ml; 2.24 mmol) and triethylamine (0.52 ml; 3.73 mmol) in methylene chloride (4 ml) was added methanesulfonyl chloride (0.17 ml; 2.24 mmol). The mixture was stirred 1 hour at 0° C., then compound 1 (300 mg; 0.75 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight, then heated to 45° C. and stirred for 1½ hours. The reaction mixture was allowed to cool to room temperature and NaOH 2N was added untill pH was basic. The mixture was extracted with methylene chloride (3×). The combined methylene chloride extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by reverse phase using 10%-25% CH3CN/H2O (TFA as the buffer) gave 197 mg of desired product (TFA salt).
Reaction SMILES: [C:1]1([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:8][CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:10]#[CH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(BC(C(C)C)C)(C(C)C)C.[Br-:41]>>[Br:41]/[CH:11]=[CH:10]/[CH:9]([O:8][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: C#CC(CCCCCC)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Br-]
Agent: CC(C)C(C)BC(C)C(C)C
Product: CCCCCCC(/C=C/Br)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Treatment of 3-triphenylmethoxy-1-nonyne (Example 128) with disiamylborane and the bromide by the procedure described in Example 1173 is productive of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].Br[C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[OH:1][C:2]1[CH:7]=[C:6]([O:8][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH3:20])[CH3:19])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc(C(C)=O)c(O)c1

Procedure:
This compound was synthesized from 2′,4′-dihydroxyacetophenone and ethyl bromoisobutyrate (1 eq) according to general method 4 described earlier. It was purified by chromatography on silica gel (elution: cyclohexane/ethyl acetate 9:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:11]=[CH:12][C:3]=2[O:2][CH3:1])=[O:19])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc2ccccc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc2ccccc2c1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.9 %

Procedure:
A solution of 2-methoxynaphthalene (20.0 g, 120 mmol) and 4-fluorobenzoyl chloride (15 ml, 126 mmol) in methylene chloride (200 ml) was cooled in an ice bath under nitrogen and aluminum chloride (18.5 g, 129 mmol, 1.1 equiv.) was added portionwise over 10 minutes. The reaction mixture was stirred at room temperature for 3 h and then poured into 2N HCl (500 ml). The product was extracted into methylene chloride, and washed with brine, and dried over sodium sulfate. The organic layer was concentrated in vacuo to give 34.6 g of 1-(4-fluoro-benzoyl)-2-methoxynaphthalene as a solid (97% yield) which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][CH3:16])[CH:8]=2)[C:3]=1[OH:17].[CH3:18][O:19][CH2:20]Cl.C(N(C(C)C)CC)(C)C>C1COCC1>[Br:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][CH3:16])[CH:8]=2)[C:3]=1[O:17][CH2:18][O:19][CH3:20]
Reactant: CCCc1cc2cc(OC)ccc2c(O)c1Br
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCc1cc2cc(OC)ccc2c(OCOC)c1Br
Yield: 92 %

Procedure:
2-Bromo-6-(methyloxy)-3-propyl-1-naphthalenol (94) (0.62 g, 2.10 mmol) was treated with chloromethyl methyl ether in the presence of diisopropylethylamine in THF to give 0.66 g (92%) of the title compound (95) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.02 (t, J=7.3 Hz, 3H), 1.65-1.75 (m, 2H), 2.84 (t, J=7.7 Hz, 2H), 3.72 (s, 3H), 3.90 (s, 3H), 5.23 (s, 2H), 7.04 (d, J=2.6 Hz, 1H), 7.12 (dd, J1=9.3 Hz, J2=2.5 Hz, 1H), 7.38 (s, 1H), 8.03 (d, J=9.1 Hz, 1H). LCMS (ESI): m/z 361 (M+Na)+, m/z 337 (M−H)−.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17]O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:44]1(=[O:54])[NH:48][C:47](=[O:49])[C:46]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:45]12.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:48]3[C:44](=[O:54])[C:45]4[C:46](=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:47]3=[O:49])[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 20 °C

Procedure:
135.0 g (417. mmol) 4-(1-diphenylmethyl-piperidin-4-yl)-butan-1-ol, 109.5 g (417 mmol) triphenylphosphine and 61.3 g (417 mmol) phthalimide are suspended in THF. Thereafter, 2.6 g (417 mmol) azodicarboxylic acid diethyl ester are added dropwise within two and a half hours under protective atmosphere and light cooling (ca. 15-25° C.). After an additional hour, the solvent is removed under vacuum and the residue is crystallized three times from acetic acid ethyl ester (1000 ml, 1200 ml and 1100 ml). Colorless crystals with an MP of 150-152° C.; yield 103 g (54.5 %).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6]([OH:8])=O)[CH3:2].O1CCCC1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH2:20][NH2:21].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6]([NH:21][CH2:20][C:19]1[CH:18]=[C:17]([F:16])[CH:24]=[C:23]([F:25])[CH:22]=1)=[O:8])[CH3:2]
Reactant: NCc1cc(F)cc(F)c1
Reactant: CCOC(=O)C(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C(=O)NCc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
To a solution of 2.92 g (20 mmol) methyl-malonic acid monoethyl ester in 100 ml of tetrahydrofuran 2.86 g (20 mmol) of 3,5-difluorobenzylamine, 3.83 g (20 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 2.70 g (20 mmol) of 1-hydroxybenzotrizole hydrate and 2.58 g (20 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. After concentration in vacuo 0.5 N HCl (50 ml) was added and the mixture was extracted with dichloromethane (three times 50 ml). The combined organic layers were extracted with 0.5 N aqueous NaHCO3 solution, dried (MgSO4) and evaporated on the rotary evaporator. The residue was purified by flash chromatography (hexane/ethyl acetate=3:1) to yield 4.29 g (79%) of the tide compound as white crystalline solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][O:27][C:28]1[N:33]=[C:32](B(O)O)[CH:31]=[CH:30][CH:29]=1>CCCCCCC.CCOC(C)=O>[CH3:26][O:27][C:28]1[N:33]=[C:32]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I
Reactant: COc1cccc(B(O)O)n1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1cccc(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1

Procedure:
The title compound was prepared in analogy to example 72, from N-(4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide and 6-methoxypyridin-2-ylboronic acid (CAS RN 372963-51-4) and using a gradient of n-heptane:EtOAc (100:0 to 60:40) for the chromatographic purification. The product was purified a second time by preparative HPLC (Phenomenex Gemini® column) eluting with a gradient of acetonitrile:water (50:50 to 95:5). Colorless oil (17%). MS (ESI): m/z=456.114 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH:19]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)[C:14](OCC)=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:30](OCC)(=O)C.C(O)C>C1C=CC=CC=1.C(O)(=O)C>[CH3:30][C:14]([C:13]1[CH:12]=[C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=1)=[O:15]
Reactant: CCOC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1

Procedure:
5.0 g of 50% sodium hydride suspension and a few ml of benzene were introduced in a 500 ml three-necked flask, supplied with a stirrer, reflux condenser and dropping funnel. 18.1 g of ethyl 3,5-dibenzyloxybenzoate in 150 ml of dry benzene were added. The reaction mixture was stirred and heated on an oil bath (90°-100°C.), and 4.5 g of ethyl acetate in 25 ml of dry benzene were slowly added and then heated and stirred for 7 hours. The reaction mixture was cooled. A few ml of ethanol were added and the whole was then poured into 150 ml of 50% acetic acid solution. The acidic water phase was extracted with ether. The ether phase was washed with water, sodium bicarbonate solution and water, and then dried with magnesium sulphate. After evaporation an oil was recovered. This oil was treated with 80 ml of dioxane, 16 ml of water and 8 ml of concentrated hydrochloric acid and the mixture was heated on an oil bath at 130°-140°C. for 15 hours. After evaporation, ether was added and the ether phase washed with water, 2-N sodium hydroxide solution and water. The ether phase was then evaporated and the residue was dissolved in hot ethanol and 200 ml of 1-N sodium hydroxide solution was added. The mixture was refluxed for 5 hours in order to hydrolyze remaining ethyl 3,5-dibenzyloxybenzoate. The ethanol was evaporated and the water phase extracted with ether. The ether phase was washed with water, dried with magnesium sulphate and evaporated. The remaining oil crystallized from petroleum ether (B.p. 80°-110°C.). M.p. 61.5°-62.0°C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][C:7]([C:9]2[N:10]=[C:11]([SH:14])[S:12][CH:13]=2)=[CH:6][CH2:5][N:4]1[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[OH:1][CH2:2][C@@H:3]1[CH2:8][C:7]([C:9]2[N:10]=[C:11]([S:14][CH2:27][C:26]3[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[S:12][CH:13]=2)=[CH:6][CH2:5][N:4]1[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16]
Reactant: C=CCOC(=O)N1CC=C(c2csc(S)n2)C[C@H]1CO
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCOC(=O)N1CC=C(c2csc(SCc3ccc(OC)cc3)n2)C[C@H]1CO
Reaction time: 3 h
Yield: 49.5 %

Procedure:
To a solution of allyl (2S)-2-(hydroxymethyl)-4-(2-mercapto-1,3-thiazol-4-yl)-3,6-dihydro-1(2 H)-pyridinecarboxylate (218 mg, 0.7 mmol) in THF (3 ml) were added at 0–5° C. 4-methoxybenzyl chloride (95 ml, 0.70 mmol) and triethylamine (98 ml, 0.7 mmol). The mixture was stirred for 3 hours and then at room temperature for 45 minutes. To the solution were added an aqueous sodium hydrogen carbonate solution and ethy acetate. The mixture was separated with a separating funnel. The organic layer was washed with a saturated aqueous sodium solution, dried over magnesium sulfate and the organic layer was removed in vacuo. The residue was purified with preparative TLC to give allyl (2S)-2-(hydroxymethyl)-4-{2-[(4-methoxybenzyl)sulfanyl]-1,3-thiazol-4-yl}-3,6-dihydro-1(2 H)-pyridinecarboxylate (150 mg, 50%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:29])[C:13](=[N:26][C:27]#[N:28])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([C:24]#[N:25])([CH3:23])[CH3:22])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[S:38]([NH:41][C:42]1[C:43]([O:57][CH3:58])=[N:44][CH:45]=[C:46](B2OC(C)(C)C(C)(C)O2)[CH:47]=1)(=[O:40])=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[C:27]([N:26]=[C:13]1[N:12]([CH3:29])[C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:2]([C:46]4[CH:47]=[C:42]([NH:41][S:38]([C:32]5[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=5[F:30])(=[O:40])=[O:39])[C:43]([O:57][CH3:58])=[N:44][CH:45]=4)=[CH:3][C:4]=3[C:5]=2[N:14]1[C:15]1[CH:16]=[CH:17][C:18]([C:21]([C:24]#[N:25])([CH3:22])[CH3:23])=[CH:19][CH:20]=1)#[N:28]
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(F)cc1F
Reactant: Cn1c(=NC#N)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(Br)ccc3ncc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncc(-c2ccc3ncc4c(c3c2)n(-c2ccc(C(C)(C)C#N)cc2)c(=NC#N)n4C)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 111 °C

Procedure:
To the stirred solution N-(8-bromo-1-(4-(2-cyanopropan-2-yl)phenyl)-3-methyl-1H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (0.211 mmol) in dry DMF (5 ml) was added 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (0.390 mmol) followed by catalyst palladium dichlorobis triphenylphosphine (0.021 mmol). Saturated solution of sodium carbonate (0.780 mmol) was added to it and the resulting solution was heated to 111° C. for 8 minutes in microwave. Solvent was removed and the crude material was extracted in EtOAc, washed with brine several times and dried over anhydrous Na2SO4. The solvent was evaporated and the crude solid was purified (silica gel column, CHCl3/MeOH as eluent) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.[CH3:33][O:34][CH2:35][C:36](O)=[O:37].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[CH3:33][O:34][CH2:35][C:36]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)=[O:37]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Reactant: COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 0.25 g, 0.57 mmol), methoxyacetic acid (0.15 ml, 1.96 mmol), 4-dimethylaminopyridine (0.02 g, 0.16 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.25 g, 1.30 mmol) were combined in DMF (4 ml). The suspension was allowed to stir for one hour at room temperature resulting in a clear solution. The mixture was then diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The residue obtained upon filtration and evaporation was purified via chromatography (silica gel, 0.5 to 5% methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with diethyl ether yielded the title compound as a white solid (0.25 g), melting point: 170° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.C[Si](C)(C)O[NH:32][CH2:33][CH3:34].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-:74])C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([NH:32][CH2:33][CH2:34][OH:74])[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: CC(C)(C)[O-]
Reactant: CCNO[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: OCCNc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 120 °C
Reaction time: 0.1 h
Yield: 20.4 %

Procedure:
A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (300 mg, 0.72 mmol), Pd(OAc)2 (20 mg, 0.1 mmol), Trimethylsilanyloxy-ethylamine (190 mg, 1.44 mmol), X-phos (70 mg, 0.144 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 120° C. for 6 min under the irradition of microwave. The mixture was filtered over celite. The filtrate was concentrated to dryness and purified by pre-HPLC to afford 64.8 mg of 188. (yield=21%). 1H NMR (CDCl3, 400 MHz): δ8.02 (s, 1H), 7.51-7.45 (m, 1H), 7.08-7.00 (m, 4H), 6.24-6.22 (d, J=8.8 Hz, 1H), 4.17-4.15 (m, 2H), 3.76-3.74 (m, 2H), 3.45-3.42 (m, 2H), 3.06-3.04 (m, 2H). LC-MS (ESI): m/z=442 [M+H]+
Reaction SMILES: [OH:1][N:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1([CH3:14])[CH3:13].[CH3:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:17]=1[C:18](Cl)=[O:19]>>[CH3:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:17]=1[C:18]([O:1][N:2]1[C:3]([CH3:14])([CH3:13])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]1([CH3:12])[CH3:11])=[O:19]
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: CC1(C)c2ccccc2C(C)(C)N1O
Product: Cc1cc(C)c(C(=O)ON2C(C)(C)c3ccccc3C2(C)C)c(C)c1
Yield: 92 %

Procedure:
Using this hydroxylamine compound and 2,4,6-trimethylbenzoyl chloride in a procedure otherwise similar to that for preparing the compound 101 gives a 92% yield of the compound 104 which is obtained in the form of colourless crystals; melting point: 181-183° C. (dichloromethane/methanol).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=1)[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[N:12]=1)=[O:6].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.O>CN1CCCC1=O>[C:14]1([CH3:21])[CH:15]=[C:16]([CH3:20])[CH:17]=[C:18]([CH3:19])[C:13]=1[C:11]1[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:22]=[CH:23][N:24]=[C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:3]=2)[S:9][CH:10]=1
Reactant: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(Cl)c3)n2)c(C)c1
Reactant: C1COCCN1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(N4CCOCC4)c3)n2)c(C)c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 64.3 %

Procedure:
A mixture of 2-chloro-N-(4-mesitylthiazol-2-yl)isonicotinamide (500.0 mg, 1.4 mmol, 1.0 equiv) and morpholine (1.5 mL, 16.8 mmol, 12 equiv) in methylpyrrolidone (15.0 mL) was stirred at 150° C. for 16 h. The mixture was poured into icy H2O (20.0 mL), and the resultant solids were filtered to provide N-(4-mesitylthiazol-2-yl)-2-morpholinoisonicotinamide (358.6 mg, 0.90 mmol) as yellow solids in 63% yield: 1H NMR (DMSO-d6, 500 MHz) δ 8.30 (d, J=5.1 Hz, 2 H), 7.50 (s, 1 H), 7.22 (d, J=5.1 Hz, 2 H), 7.10 (s, 1H), 6.92 (s, 2 H), 3.70-3.73 (m, 4 H), 3.53-3.55 (m, 4 H), 2.26 (s, 3 H), 2.05 (s, 6H); ESI-MS: m/z 409.3 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][CH2:8][O:9][C:10](/[CH:12]=[CH:13]/[CH2:14]P(OCC)(OCC)=O)=[O:11].[CH3:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=O.Cl>O1CCCC1.O>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([C:24]([CH3:23])=[CH:14][CH:13]=[CH:12][C:10]([O:9][CH2:8][CH3:7])=[O:11])=[CH:27][CH:28]=1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Reactant: COc1ccc(C(C)=O)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=CC=C(C)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.6 %

Procedure:
A stirred solution of 25.3 grams (0.230 mole) of potassium tert.-butoxide in 250 mL of tetrahydrofuran was cooled to 0 ° C., and a solution of 56.5 grams (0.230 mole) triethyl 4-phosphonocrotonate in 50 mL of tetrahydrofuran was added dropwise while maintaining the reaction mixture temperature at about 0°-10 ° C. The complete addition required about 30 minutes. The reaction mixture was then stirred for one hour at 0°-5° C., and then 26.6 grams (0.180 mole) of 4-methoxyacetophenone was added in one portion. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature as it stirred for about 18 hours. After this time the reaction mixture was made acidic with an aqueous 2N hydrochloric acid solution and diluted with about 200 mL of water. The mixture was extracted with two 250 mL portions of diethyl ether. The combined extracts were washed with one 250 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was taken up in 150 grams of silica gel, and the solvent was removed under reduced pressure. The silica gel mixture was placed on top of a column of silica gel, and the mixture was eluted with 10% ethyl acetate in petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 6.9 grams of ethyl 5-(4-methoxyphenyl)-2,4-hexadienoate. The NMR spectrum was consistent with the proposed structure. This reaction was repeated several times.