Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH2:27])=[O:26])=[CH:20][CH:19]=1.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.C(O)(=O)C>[Cl:16][C:12]1[CH:11]=[C:10]([C:4]2[N:3]=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([NH2:27])=[O:26])=[CH:22][CH:23]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: NC(=O)Cc1ccc(N)cc1
Reactant: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCc1cc(Nc2ccc(CC(N)=O)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 108 °C
Yield: 62.4 %

Procedure:
A mixture of 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.150 g, 0.59 mmol) and 2-(4-aminophenyl)acetamide (0.107 g, 0.71 mmol) and 4M HCl in dioxane (2 drops) in acetic acid (3 mL) was heated for 2 h at 108° C. After this time, the mixture was cooled to rt, neutralized with saturated NaHCO3, extracted with EtOAc, dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with methylene chloride and methanol to afford the title compound (0.135 g, 62%) as a white solid. MW=366.84. 1H NMR (DMSO-d6, 500 MHz) δ 9.57 (s, 1H), 8.33-8.29 (m, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.58-7.54 (m, 2H), 7.43 (br s, 1H), 7.27 (d, J=8.5 Hz, 2H), 6.86 (br s, 1H), 6.59 (s, 1H), 3.35 (s, 2H), 2.67 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H); ESI MS m/z 367 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][CH2:4][CH:5]([C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=1)[NH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[OH-].[Na+]>CO.O1CCCC1>[F:29][C:2]([F:1])([F:28])[CH2:3][CH2:4][CH:5]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:26][CH:27]=1)[NH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CCOC(=O)c1ccc(C(CCC(F)(F)F)Nc2cnc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(CCC(F)(F)F)Nc2cnc3ccccc3c2)cc1
Reaction time: 17 h

Procedure:
To a solution of ethyl (+/−)-4-(4,4,4-trifluoro-1-(quinolin-3-ylamino)butyl)benzoate (95 mg, 0.24 mmol) in methanol (1.2 mL) and tetrahydrofuran (1.2 mL) was added 1 N aq sodium hydroxide (1.2 mL, 1.2 mmol). After 17 hours, the solution was concentrated under reduced pressure to remove methanol and tetrahydrofuran. The mixture was then acidified to pH 5 with 1 N aq hydrochloric acid and diluted with sat. aq sodium chloride (20 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure to give (+/−)-4-(4,4,4-trifluoro-1-(quinolin-3-ylamino)butyl)benzoic acid. 1HNMR (400 MHz, CD3OD) δ 8.50 (br. s, 1 H), 8.02 (d, J=8.2 Hz, 2 H), 7.80-7.73 (m, 1 H), 7.57 (d, J=8.2 Hz, 2 H), 7.53-7.47 (m, 1 H), 7.40-7.32 (m, 2 H), 6.95 (d, J=2.5 Hz, 1 H), 4.73-4.64 (m, 1 H), 2.55-2.39 (m, 1 H), 2.39-2.22 (m, 1 H), 2.22-2.04 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[N:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:50][CH3:51])=[C:22]([C:24]2[C:33]3[C:28](=[CH:29][C:30]([S:34](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:36])=[O:35])=[CH:31][CH:32]=3)[C:27](=[O:49])[NH:26][N:25]=2)[CH:23]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:50][CH3:51])=[C:22]([C:24]2[C:33]3[C:28](=[CH:29][C:30]([S:34]([N:7]([C:5]4[S:6][C:2]([F:1])=[CH:3][N:4]=4)[CH2:8][C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=4)(=[O:36])=[O:35])=[CH:31][CH:32]=3)[C:27](=[O:49])[NH:26][N:25]=2)[CH:23]=1
Reactant: COc1ccc(CNc2ncc(F)s2)cc1
Reactant: COc1ccc(Cl)cc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncc(F)s2)S(=O)(=O)c2ccc3c(-c4cc(Cl)ccc4OC)n[nH]c(=O)c3c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.9 %

Procedure:
A vial was charged with 5-fluoro-N-(4-methoxybenzyl)thiazol-2-amine (67.1 mg, 0.282 mmol), perfluorophenyl 1-(5-chloro-2-methoxyphenyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonate (100 mg, 0.188 mmol), and THF (938 μl). The resulting solution was cooled to 0° C. for 10 min. Then lithium bis(trimethylsilyl)amide (1M in THF) (413 μl, 0.413 mmol) was added drop wise. LCMS after 15 min showed incomplete conversion of SM. Additional LHMDS (400 μL, 1M in THF) was added. After 15 min, TLC showed complete conversion of PFP-sulfonate to a lower spot. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 70% EtOAc in heptane, to provide 1-(5-chloro-2-methoxyphenyl)-N-(5-fluorothiazol-2-yl)-N-(4-methoxybenzyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonamide (65 mg, 59.0% yield) as a brown solid. m/z (ESI) 587.0 (M+H)+, 609.0 (M+Na)+. 1-(5-Chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(5-fluorothiazol-2-yl)-4-oxo-3,4-dihydrophthalazine-6-sulfonamide (65 mg, 0.105 mmol) was dissolved in DCM (1053 μl, 0.105 mmol) and then TFA (40.6 μl, 0.527 mmol) was added. After 30 min at rt, LCMS showed a complete conversion of SM to product. Purification was done with 0.1% NH4OH in ACN and water as mobile phase to afford impure product. The product was purified further by RPLC on the acidic Gilson. Fractions containing the product were combined and washed with sat. NaHCO3. The product was extracted with DCM. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated to afford 1-(5-chloro-2-methoxyphenyl)-N-(5-fluorothiazol-2-yl)-4-oxo-3,4-dihydrophthalazine-6-sulfonamide (1.3 mg, 2.64% yield) as off-white solid. m/z (ESI) 467.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1[Cl:7].[CH3:12][N:13]1[C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:7][C:6]1[O:5][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[C:17]1[N:13]([CH3:12])[N:14]=[CH:15][CH:16]=1
Reactant: COC(=O)c1cc(Br)c(Cl)o1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)c(Cl)o1
Yield: 55.1 %

Procedure:
A solution of methyl 4-bromo-5-chloro-2-furancarboxylate (1.1 g, 4.59 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.05 g, 5.05 mmol)[prepared according to Preparation 7], potassium carbonate (3.17 g, 22.97 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.117 g, 0.23 mmol) in 1,4-dioxane (19.14 ml) and water (3.83 ml) was stirred at 80° C. in a sealed tube for 1 h. The reaction mixture was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 4-25% EtOAc in hexanes) yielding methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (800 mg, 2.53 mmol, 55% yield) as a yellow oil: LCMS m/e ES 240, 242 (M, M+2)+.
Reaction SMILES: [Br:1][CH:2]1[CH:10]2[CH2:11]C3[CH:5]4[C:9]2([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])C=C[CH:6]4[O:21]C13.C[N+]1([O-])CC[O:26]CC1.S([O-])([O-])=O.[Na+].[Na+].[CH2:36]1[CH2:40][O:39][CH2:38][CH2:37]1>[Os](=O)(=O)(=O)=O.O>[Br:1][CH:2]1[CH:10]2[CH2:11][CH:36]3[CH:37]4[C:9]2([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:5]([OH:26])[CH:6]([OH:21])[CH:38]4[O:39][CH:40]13
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)(C)[Si](C)(C)OCC12C=CC3OC4C(Br)C1CC4C32
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC12C(O)C(O)C3OC4C(Br)C1CC4C32
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of (+)-9-bromo-2-(t-butyldimethylsilyloxymethyl)-5,8-epoxytricyclo[5.2.1.02,6]dec-3-ene (3a′) (283 mg, 0.762 mmol) in a mixed solvent of THF (15 ml) and water (5 ml) was cooled to 0° C. and stirred. To the solution were added 4-methylmorpholine N-oxide (155 mg, 1.14 mmol) and a 0.197 M-THF solution of osmium tetraoxide (1.5 ml, 0.3 mmol). Subsequently, the mixture was allowed to warm up to room temperature and stirred overnight. A 10% aqueous solution of sodium sulfite (15 ml) was added and the mixture was filtered through Celite. The filtered product was washed thoroughly with water, THF and diethyl ether. The combined washings and filtrate were diluted with diethyl ether (80 ml). The organic layer was washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, respectively, and dried over magnesium sulfate. Subsequently, the solvent was distilled off under reduced pressure to obtain the residue. Silica gel column chromatography (eluting solvent: n-hexane/diethyl ether=2/1) of the residue afforded (+)-9-bromo-2-(t-butyldimethylsilyloxymethyl)-3,4-dihydroxy-5,8-epoxytricyclo[5.2.1.02,6]decane (4a′) (246 mg, 0.607 mmol, 80% yield), with the following data:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][Br:30])=[CH:27][CH:26]=1>>[Br-:30].[C:1]([C:4]1[CH:5]=[N+:6]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=2)[CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2]
Reactant: Fc1ccc(CBr)cc1
Reactant: COc1ccc2c(c1)CCC(Cc1ccncc1C(C)=O)C2=O
Product: COc1ccc2c(c1)CCC(Cc1cc[n+](Cc3ccc(F)cc3)cc1C(C)=O)C2=O
Product: [Br-]

Procedure:
The title compound 129 is prepared according to the procedure reported in Example 38.1 with compound 103 (110 mg, 0.36 mmol) and 4-fluorobenzyl bromide (76 μL, 0.61 mmol) as reactants. White solid. (Yield 149 mg, 83%).
Reaction SMILES: [Cl:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][CH:11]=2)[C@@H:5]([CH2:18][CH2:19][C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C@H:4]([OH:28])[CH2:3]1.C(=O)(O)[O-].[K+].Br.Br[CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40].C(#N)C>O.CCOC(C)=O>[Cl:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]([O:17][CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])=[O:16])=[CH:12][CH:11]=2)[C@@H:5]([CH2:18][CH2:19][C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C@H:4]([OH:28])[CH2:3]1
Reactant: O=C(O)c1ccc(CCC[C@@H]2[C@@H](CCc3cc(Cl)cc(Cl)c3)[C@H](O)C[C@H]2Cl)s1
Reactant: CCN(CC)CCBr
Agent: Br
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(CC)CCOC(=O)c1ccc(CCC[C@@H]2[C@@H](CCc3cc(Cl)cc(Cl)c3)[C@H](O)C[C@H]2Cl)s1
Temperature: 65 °C
Reaction time: 48 h
Yield: 39.9 %

Procedure:
A mixture of 5-(3-((1R,2R,3R,5R)-5-chloro-2-(3,5-dichlorophenethyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylic acid (212 mg, 0.46 mmol), potassium bicarbonate (212 mg, 2.1 mmol), 2-bromo-N,N-diethylethanamine hydrobromide (132 mg, 0.51 mmol) and acetonitrile (1.5 mL) was heated at 65° C. After 2 d at 65° C., the mixture was cooled to room temperature and diluted with water (50 mL) and EtOAc (100 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified on 40 g silica (CH2Cl2→20% MeOH/CH2Cl2, gradient) to afford a mixture of the desired ester and the starting acid. Fractions containing the desired ester were combined and concentrated. The residue was taken up in EtOAc (100 mL) and washed with saturated aqueous NaHCO3 (50 mL). The aqueous phase was extracted with EtOAc (50 mL) and the combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified on 80 g silica (CH2Cl2→15% MeOH/CH2Cl2, gradient) to afford 103 mg (40%) of 2-(diethylamino)ethyl 5-(3-((1R,2R,3R,5R)-5-chloro-2-(3,5-dichlorophenethyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylate
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([O:16][CH3:17])[C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([O:16][CH3:17])[C:4]=1[C:5]([Cl:20])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(F)(F)F)cc(OC)c1C(=O)O
Solvent: Cc1ccccc1
Product: COc1cc(C(F)(F)F)cc(OC)c1C(=O)Cl
Temperature: 85 °C
Yield: 98.9 %

Procedure:
To a suspension of 14.47 g (57.84 mmol) 2,6-dimethoxy-4-trifluoromethyl-benzoic acid in 160 ml toluene containing four drops DMF under nitrogen at room temperature, was added 42 ml (578.4 mmol) thionyl chloride. The mixture was heated in an 85° C. oil bath for 3 hours. The solvent was removed in vacuo to provide 15.37 g (yield: 98.9%) of the title compound as an off-white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6](F)[CH:5]=1.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([OH:22])[CH:21]=1)[CH:17]=[O:18].Cl>CN(C=O)C.O>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([O:13][C:14]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:16]([CH:17]=[O:18])[CH:15]=2)[CH:5]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: O=Cc1cc(O)cc(O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Cl)cc1Oc1cc(O)cc(C=O)c1
Temperature: 80 °C
Yield: 23.1 %

Procedure:
Sodium hydride (502 mg, 60% in mineral oil) was added portionwise to 4-chloro-2-fluorobenzonitrile (2.04 g) and 3,5-dihydroxybenzaldehyde (1.81 g) in DMF and the solution heated to 80° C. for 16 h. The cooled solution was diluted with water, acidified with concentrated hydrochloric acid, extracted twice with ethyl acetate, the extracts dried over sodium sulphate and evaporated. Purification by chromatography gave the sub-title compound as a white solid (0.83 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9][CH2:10][CH2:11][CH2:12]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:12][CH2:11][CH2:10][Br:9]
Reactant: BrCCCBr
Reactant: Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Fc1ccccc1OCCCBr
Reaction time: 24 h
Yield: 26.2 %

Procedure:
To a solution of 2-fluorophenol (0.040 mL, 0.448 mmol) in acetonitrile (4 mL) was added 1,3-dibromopropane (0.450 mL, 4.43 mmol) followed by Cs2CO3 (0.232 g, 0.713 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (4 mL) and extracted with DCM (8 mL). The organic layer was dried through a phase separator and concentrated under vacuum. The residue was taken up in DMSO and purified by preparatory HPLC (without TFA) to give the title compound (0.0274 g, 26.2%). EI-MS Rt (2.24 min).
Reaction SMILES: C(OC(CO[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:14]1(=[O:15])[NH:10][C:11](=[O:20])[C:12]2=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]12
Reactant: CC(C)(C)OC(=O)CON1C(=O)c2ccccc2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C

Procedure:
To a solution of 2.77 g of N-(t-butoxy carbonylmethoxy) phthalimide (Compound (13)) in 10 ml of anhydrous methylene chloride was added dropwise 1.37 g of trifluoro acetic acid, and the mixture was followed by stirring at room temperature over night. After the reaction was completed, the resultant was filtrated to give 520 mg of N-(corboxy methoxy) phthalimide (Compound (11)) in the form of white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C:4]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)[CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1>C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:32][C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)[CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: COC(=O)C(=Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
(+)-1,2-bis((2S,5S)-2,5-Diethylphospholano)benzene (cyclooctadiene) rhodium(I)trifluoromethanesulfonate (0.22 g) was dissolved in 2 mL of DCM and added to a solution of 2-tert-butoxycarbonylamino-3-{(S)-2-[3-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]-dioxin-6-yl}-acrylic acid methyl ester (1.8 g) in 20 mL EtOAc. The mixture was then degassed and flushed with hydrogen and stirred under hydrogen atmosphere (balloon) for 1 hour. The solvent was then evaporated and the residue was purified by silica gel flash chromatography (DCM to 5% EtOAC in DCM) to get pure product 1.7 g. 1H NMR (400 MHz, CDCl3): 7.55 (d, 1H), 7.46 (d, 1H), 7.24-7.37 (m, 2H), 7.00-7.06 (m, 2H), 6.92-6.97 (m, 1H), 6.90 (d, 1H), 6.70 (d, 1H), 6.61-6.70 (m, 1H), 5.08 (m, 1H), 5.03 (d, 2H), 4.99 (d, 1H), 4.50-4.60 (m, 1H) 4.34 (m, 1H), 3.98 (m, 1H) 3.74 (s, 3H), 2.80-3.20 (m, 2H), 1.44 (s, 9H). LCMS (m/z): 589.
Reaction SMILES: [CH3:1][C:2]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].O>N1C=CC=CC=1>[CH3:1][C:2]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:3][CH2:4][CH2:5][O:6][S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: CC(C)(CCCO)[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCC(C)(C)[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-methyl-4-nitro-1-pentanol (7 gm) in pyridine (40 ml) was cooled in an ice bath and treated with tosyl chloride (19 gm) added in portions over 20 mins. When the addition was complete the mixture was stirred at room temperature for 1 hr. Water (20 ml) was then added and the mixture stirred for 15 mins. The mixture was poured into water and extracted twice with ethyl acetate. The ethyl acetate solution was washed successively with water, citric acid solution, water, sodium bicarbonate solution, water and brine. The solution was dried over magnesium sulphate and evaporated. The product was obtained by crystallisation from ether: 60/80 petroleum ether. Yield 8.18 gm.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].S(Cl)(Cl)=O.[NH:16]1[CH2:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:16]2[CH2:19][CH2:18][CH2:17]2)=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: C1CNC1
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)N2CCC2)ccc1Br

Procedure:
From 4-bromo-3-methylbenzoic acid (400 mg), thionyl chloride (0.5 ml) and azetidine (1 g).
Reaction SMILES: Cl.[CH2:2]([O:5][C:6](=[O:16])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:8])[CH2:3][CH3:4].C(N(CC)CC)C.[Cl:24][C:25]1=[C:26]([Cl:32])[C:27]([O:29][C:30]1=O)=[O:28]>O1CCCC1.C(O)(=O)C>[Cl:24][C:25]1[C:30](=[O:29])[N:8]([C@@H:7]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:6]([O:5][CH2:2][CH2:3][CH3:4])=[O:16])[C:27](=[O:28])[C:26]=1[Cl:32]
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: CCCOC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCOC(=O)[C@H](Cc1ccccc1)N1C(=O)C(Cl)=C(Cl)C1=O

Procedure:
The hydrochloride thus obtained (1.0 g) was dissolved in 25 ml of tetrahydrofuran and allowed to react with 1.2 ml of triethylamine at room temperature for 30 minutes, the precipitated crystals were separated by filtration, and the filtrate concentrated under a reduced pressure to give a colorless oily product. This oily product and 700 mg of dichloromaleic anhydride were dissolved in 6 ml of acetic acid and refluxed for 3 hours, and after completion of the reaction, the reaction mixture was concentrated under a reduced pressure, the residue was dissolved in ethyl acetate, washed with water, and dried over magnesium sulfate, followed by evaporation of the solvent. The residue obtained was purified by silica gel chromatography (eluant: n-hexane-ethyl acetate=9/1) to give 1.41 g of the desired compound as a colorless oily product (yield: 97%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[CH2:23]([O:25][P:26]([C:31]([C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1)([F:33])[F:32])(=[O:30])[O:27][CH2:28][CH3:29])[CH3:24]>>[CH2:23]([O:25][P:26]([C:31]([F:33])([F:32])[C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11](=[O:12])[NH:13][CH3:14])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=2)=[CH:36][CH:35]=1)(=[O:30])[O:27][CH2:28][CH3:29])[CH3:24]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(N)cc1
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)cc1
Yield: 6 %

Procedure:
The title product was prepared according to the procedure for Example 102 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 104A, 40.0 mg, 0.12 mmol) and diethyl[(4-aminophenyl)(difluoro)methyl]-phosphonate (Compound 188A, 40.5 mg, 0.15 mmol). The crude product was purified by silica gel chromatography (5% 7 N NH3 in MeOH in DCM) to afford the desired product as a white solid (4.1 mg, yield: 6%). 1H NMR (CD3OD, 400 MHz): δ=1.32 (t, J=7.2 Hz, 6H), 2.90 (s, 3H), 4.14-4.25 (m, 4H), 7.22 (t, J=8.4 Hz, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.51 (dt, J=1.2, 7.2 Hz, 1H), 7.66 (dd, J=1.2, 7.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 2), 8.39 (s, 1H), 8.47 (d, J=8.4 Hz, 1H). MS (ES+): m/z 574.12 [MH+]. HPLC: tR=4.13 min (OpenLynx, polar—5 min).
Reaction SMILES: ClCCC1OC=[N:6]C=1C.[N+:10]([CH:13]=[C:14]([NH:27][CH3:28])[NH:15][CH2:16][CH2:17][S:18][CH2:19][CH2:20][C:21]1[O:25][CH:24]=[N:23][C:22]=1C)([O-:12])=[O:11].NC1OC(CCCl)=CN=1>>[N+:10]([CH:13]=[C:14]([NH:27][CH3:28])[NH:15][CH2:16][CH2:17][S:18][CH2:19][CH2:20][C:21]1[O:25][C:24]([NH2:6])=[N:23][CH:22]=1)([O-:12])=[O:11]
Reactant: Cc1ncoc1CCCl
Reactant: CNC(=C[N+](=O)[O-])NCCSCCc1ocnc1C
Agent: Nc1ncc(CCCl)o1
Product: CNC(=C[N+](=O)[O-])NCCSCCc1cnc(N)o1

Procedure:
Using 5-(2-chloroethyl)-4-methyloxazole as starting material in the procedure of Example 21 the product is 1-nitro-2-methylamino-2-[2-(2-(4-methyl-5-oxazolyl)ethyl)thioethylamino]-ethylene. Also, using 2-amino-5-(2-chloroethyl)oxazole (prepared by reacting 2-amino-5-(2-hydroxyethyl)oxazole with thionyl chloride) in the procedure of Example 21 gives 1-nitro-2-methylamino-2-[2-(2-(2-amino-5-oxazolyl)ethyl)thioethylamino]ethylene.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.O>[CH2:15]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#Cc1ccccc1CCCO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1CCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(3-hydroxypropyl)benzonitrile (Example 323c, 3.83 g) in DMF (40 mL) under nitrogen was treated with 60% Sodium hydride (1.140 g) and stirred at room temperature for 1 h before adding benzyl bromide (2.83 mL). The resulting solution was stirred at 20° C. for 60 h. The reaction mixture was diluted with water (200 mL), and extracted with ethyl acetate (200 mL). The organic was dried (MgSO4), filtered and evaporated. The residue was purified (SiO2 chromatography eluting with 30% diethyl ether in isohexane). Pure fractions were evaporated to dryness to afford the subtitle compound as an oil (2.3 g).