Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([OH:29])=O)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH2:44][NH2:45])[CH2:38][CH2:37]2)=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([NH:45][CH2:44][CH2:43][CH2:42][N:39]3[CH2:40][CH2:41][N:36]([C:33]4[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=4)[CH2:37][CH2:38]3)=[O:29])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NCCCN1CCN(c2ccncc2)CC1
Reactant: O=C(O)CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Product: O=C(CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1)NCCCN1CCN(c2ccncc2)CC1

Procedure:
The title compound was prepared from [5-(3,4-dichloro-benzenesulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetic acid (Example 2c) and 3-(4-pyridin-4-yl-piperazin-1-yl)-propylamine (Reference Example 8) according to the method described in Example 1e. MS (EI) 651.2 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[CH3:12][N:13](C=O)C>O.[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:8]1[C:9]2[C:4](=[CH:3][C:2]([C:12]#[N:13])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Brc1ccc2cnccc2c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1ccc2cnccc2c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Under N2, a mixture of 6-bromoisoquinoline (400 mg, 1.9 mmol), Zn(CN)2 (446 mg, 3.8 mmol) and Pd(PPh3)4 (40 mg) in DMF (20 mL) was stirred at 100° C. for 1 hour. Cooled the mixture to room temperature and dissolved in water. Followed standard aqueous/EtOAc workup and purified by column chromatography (PE:EtOAc=10:1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N+:12]([O-])[CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(OC(=O)C)(=[O:19])C>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[O:19])[NH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc(-c2ccc[n+]([O-])c2)cc1
Product: O=c1[nH]cccc1-c1ccc([N+](=O)[O-])cc1

Procedure:
3-(4-Nitrophenyl)pyridine-1-oxide (P2, 2.5 g, 11.6 mmol) was stirred at reflux in acetic anhydride (25 mL) for 18 hours, then allowed to cool. The reaction mixture was concentrated and concentrated hydrochloric acid (25 mL) was added. The solution was stirred at reflux for 4 hours, then allowed to cool. The reaction mixture was poured onto ice/water and filtration followed by drying under high vacuum afforded the title compound as a solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:31]2([CH3:32])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:33])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:26])[CH2:18][CH2:19][C@@H:20]([F:25])[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:34][C:35](=[O:37])[CH3:36])[CH2:6]1)(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+].[Br:43]N1C(C)(C)C(=O)N(Br)C1=O>CCCCCC>[C:1]([O:4][C@@H:5]1[C@@:31]2([CH3:32])[C:9](=[CH:10][CH:11]([Br:43])[C@@H:12]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:33])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:26])[CH2:18][CH2:19][C@@H:20]([F:25])[C:21]([OH:24])([CH3:22])[CH3:23])[CH2:8][C@@H:7]([O:34][C:35](=[O:37])[CH3:36])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CC[C@@H](F)C(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Product: CC(=O)O[C@@H]1CC2=CC(Br)[C@H]3[C@@H]4CC[C@H]([C@H](C)CC[C@@H](F)C(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Temperature: 80 °C

Procedure:
A mixture of 0.520 g. (0.0010 mole) of [1α,3β,24R]-24-fluorocholest-5-en-1,3,25-triol 1,3-diacetate, 0.45 g. of sodium bicarbonate, 0.192 g. (0.00066 mole) of 1,3-dibromo-5,5-dimethylhydantoin and 25 ml. of hexane was heated at reflux (80° C.) for 1 hr and cooled. The mixture was filtered and the solids were triturated with hexane and filtered. The filtrates were evaporated to dryness to yield [1α,3β,7ξ,24R]-7-bromo-24-fluorocholest-5-en-1,3,25-triol 1,3-diacetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[CH:5][N:4]=1.CCN(C(C)C)C(C)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.Cl.Cl.[F:40][C:41]1[C:42]([C@H:47]([C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[NH2:48])=[N:43][CH:44]=[CH:45][CH:46]=1>C1(C)C=CC=CC=1>[F:40][C:41]1[C:42]([C@H:47]([C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:57])([F:58])[F:56])=[CH:51][CH:50]=2)[NH:48][C:9]([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=2)=[O:11])=[N:43][CH:44]=[CH:45][CH:46]=1
Reactant: COc1ncc(C(=O)O)cn1
Reactant: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1F
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COc1ncc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2F)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methoxypyrimidine-5-carboxylic acid (80 mg, 0.519 mmol), DIPEA (0.25 mL, 1.435 mmol) in toluene (3 mL) was added DPPA (0.19 mL, 0.882 mmol). The reaction was stirred at 80° C. for 2 hours. (S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamine dihydrochloride (167 mg, 0.487 mmol) was then added as a solid in one portion. After 24 hours, the reaction was concentrated in vacuo and the residue was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with 0% to 80% EtOAc in hexane, to provide the title compound as an off-white solid. 1H NMR (DMSO-d6, 400 MHz) δ ppm 9.02 (d, J=4.7 Hz, 1H), 8.97 (d, J=8.6 Hz, 1H), 8.30 (d, J=7.8 Hz, 1H), 7.63-7.77 (m, 3H), 7.54 (d, J=8.2 Hz, 2H), 7.39 (s, 1H), 7.01 (s, 1H), 6.66 (d, J=8.6 Hz, 1H), 3.93 (s, 3H) MS (ESI pos. ion) m/z: 407.0 (M+H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]1[C:27]([CH2:28][OH:29])=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([Br:36])[CH:24]=2)[C:19]1=[O:37])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C1COCC1.O>[CH2:11]([N:18]1[C:27]([CH:28]=[O:29])=[C:26]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([Br:36])[CH:24]=2)[C:19]1=[O:37])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=c1c2ccc(Br)cc2c(-c2ccccc2)c(CO)n1Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.6 %

Procedure:
Under a nitrogen stream, to a solution of oxalyl chloride (0.54 ml) in THF (28 ml) was added dropwise a solution of DMSO (0.58 ml) in THF (5 ml) at −70° C. or below and the mixture was stirred for 10 min. A solution of 2-benzyl-6-bromo-3-hydroxymethyl-4-phenyl-2H-isoquinolin-1-one (1.30 g) in THF (7 ml) was added dropwise at −70° C. or below and the mixture was stirred at −60° C. to −50° C. for 1 hr. To the reaction mixture was added dropwise triethylamine (3.1 ml) at 50° C. or below and the mixture was allowed to warm to room temperature and stirred for 30 min. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethyl acetate-hexane to give the title compound (810 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:25]2[CH2:30][CH2:29][C:28]([CH3:32])([CH3:31])[CH2:27][CH2:26]2)=[CH:8][C:9]=1[N:10]([CH:20]([CH2:23][OH:24])[CH2:21][OH:22])[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH2:33]=O>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:25]2[CH2:26][CH2:27][C:28]([CH3:31])([CH3:32])[CH2:29][CH2:30]2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:23][O:24][CH2:33][O:22][CH2:21]1)[C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])=[O:4]
Reactant: C=O
Reactant: COC(=O)c1sc(C2CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C(CO)CO
Product: COC(=O)c1sc(C2CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1COCOC1

Procedure:
5-(4,4-Dimethyl-cyclohexyl)-3-[[1,3]dioxan-5-yl-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester was prepared from 5-(4,4-dimethyl-cyclohexyl)-3-[(2-hydroxy-1-hydroxymethyl-ethyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester using paraformaldehyde following a procedure described earlier (example 38, step IV).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li])CCC.[C:15](=O)=[O:16].C([Li])(C)(C)C.CN(C)C=O>C1COCC1.C(OCC)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:15]=[O:16]
Reactant: O=C=O
Reactant: c1ccc2[nH]ccc2c1
Agent: [Li]C(C)(C)C
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: O=Cc1cc2ccccc2[nH]1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
Indole (74) (1.00 g, 8.54 mmol) was dissolved in 50 mL of dry THF. The resulting solution was cooled at −78° C. A solution of 2.5 M of n-butyllithium (3.80 mL, 9.39 mmol) was slowly added to the THF solution and was stirred for 30 min. Carbon dioxide was passed through the reaction mixture over 10 min. The resulting solution was allowed to warm to room temperature. The excess of carbon dioxide was removed under reduced pressure while the solution was concentrated to 25 mL. 50 mL of dry THF was added to the concentrated solution, which was cooled again to −78° C. A solution of 1.7 M of tert-butyllithium (5.00 mL, 8.54 mmol) was slowly added to the THF solution, which was stirred at −78° C. for 1 hour. Anhydrous N,N-dimethylformamide (0.83 mL, 8.5 mmol) was added to the solution. The resulting mixture was warmed to room temperature over a period of 1.5 hours. Water (10 mL) was added and the mixture was stirred for 15 min. Diethyl ether was added. The organic layer was washed with brine (3×). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The solid was purified over silica gel using 80/20 hexanes/ethyl acetate as eluent to give Compound 75, (0.7129 g, 58%). 1H NMR (500 MHz, CDCl3): d (ppm), 9.88 (s, 1H); 7.77 (d, 1H, J=8.1 Hz); 7.48 (d, 1H, J=8.3 Hz); 7.41 (t, 1H, J=7.0 Hz); 7.3 (s, 1H); 7.20 (t, 1H, J=7.4 Hz). 13C NMR (500 MHz, CDCl3): δ (ppm), 182.89; 138.80; 136.87; 128.25; 124.37; 122.20; 115.60; 113.28.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([N+:11]([O-])=O)=[C:4]([CH:14]([CH3:16])[CH3:15])[CH:3]=1.C(N(CC)CC)C>O1CCCC1.[Pd]>[CH:8]([C:6]1[C:5]([NH2:11])=[C:4]([CH:14]([CH3:16])[CH3:15])[CH:3]=[CH:2][N:7]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1cc(Cl)nc(C(C)C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)c1ccnc(C(C)C)c1N

Procedure:
5.0 g of 6-chloro-2,4-diisopropyl-3-nitropyridine are dissolved in 100 ml of tetrahydrofuran and, after the addition of 2.75 g of triethylamine and 7.5 g of 5% palladium/carbon catalyst, hydrogenated under normal pressure at from +20° C. to +25° C. The reaction mixture is filtered over diatomaceous earth and the filtrate is concentrated. The residue is purified by column chromatography on silica gel (eluant: ethyl acetate/hexane 1:3). 2,4-Diisopropyl-3-aminopyridine is obtained in the form of a waxlike solid, m.p. 35°-39° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>C(#N)C>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: BrCc1ccccn1
Reactant: C1CCNC1
Solvent: CC#N
Product: c1ccc(CN2CCCC2)nc1

Procedure:
To 20.0 g (0.124 mole) of 1-(2-picolyl)pyrrolidine, obtained via the alkylation of 2-bromomethylpyridine with pyrrolidine, in 100 ml acetonitrile was added one equivalent of cyanomethyl benzenesulfonate in 50 ml acetonitrile maintaining the temperature at about 25°. After the addition was complete, the reaction was stirred at room temperature for 18 hours. The acetonitrile was removed under reduced pressure and tetrahydrofuran was added. The crystalline product was collected by filtration and washed with tetrahydrofuran and ether. After air drying, the yield of colorless crystals was 38.5 g (86%), m.p. 118.5°-120°.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[C:7](=[O:14])[C:8]3[CH:13]=[N:12][CH:11]=[CH:10][C:9]=3[CH:2]12.CCN(C(C)C)C(C)C.[Br:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Br:24][C:25]1[CH:30]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:28]=[CH:27][C:26]=1[S:35]([N:6]1[CH2:5][CH2:4][N:3]2[C:7](=[O:14])[C:8]3[CH:13]=[N:12][CH:11]=[CH:10][C:9]=3[CH:2]2[CH2:1]1)(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Br
Reactant: O=C1c2cnccc2C2CNCCN12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2cnccc2C2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3Br)CCN12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 1,3,4,10b-tetrahydropyrido[4′,3′:3,4]pyrrolo[1,2-a]pyrazin-6(2H)-one (may be prepared as in Intermediate 22, 90 mg) in dichloromethane (15 mL) was added DIPEA (0.415 mL). This was cooled in an ice bath and to this was added 2-bromo-4-(trifluoromethyl)benzenesulfonyl chloride (162 mg). The mixture was stirred at room temperature overnight. The reaction mixture was washed with aqueous saturated sodium bicarbonate solution in a hydrophobic frit and then re-extracted with DCM. The combined organic phases were evaporated to give the title compound as a yellow oil which was used in the next reaction (263 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][OH:9]
Reactant: O=Cc1ccncc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccncc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 3-chloro-4-pyridinecarboxaldehyde (43.80g, 0.310mol) in ethanol (200 ml) was cooled in an ice bath and treated with powdered sodium borohydride (5.85 g, 0.155 mol) added in portions over approximately 2 min. The resulting solution was removed from the ice bath and stirred at ambient temperature. After 1 hr the solution was recooled in an ice bath and treated with acetone (22 ml) to decompose excess borohydride. The solution was again removed from the ice bath and stirred at ambient temperature. After 30 min the reaction solution was evaporated under vacuum to a viscous oil.
Reaction SMILES: C1(C)C=CC(S([NH:10][N:11]=[CH:12][C:13](Cl)=[O:14])(=O)=O)=CC=1.[F:17][C:18]1[CH:19]=[C:20]([NH:29][C:30](=[O:35])[O:31][CH:32]([CH3:34])[CH3:33])[CH:21]=[C:22]([F:28])[C:23]=1/[CH:24]=[CH:25]/[CH2:26][OH:27].CN(C)C1C=CC=CC=1.C(N(CC)CC)C>ClCCl>[N+:11](=[CH:12][C:13]([O:27][CH2:26]/[CH:25]=[CH:24]/[C:23]1[C:18]([F:17])=[CH:19][C:20]([NH:29][C:30]([O:31][CH:32]([CH3:33])[CH3:34])=[O:35])=[CH:21][C:22]=1[F:28])=[O:14])=[N-:10]
Reactant: Cc1ccc(S(=O)(=O)NN=CC(=O)Cl)cc1
Reactant: CC(C)OC(=O)Nc1cc(F)c(/C=C/CO)c(F)c1
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)Nc1cc(F)c(/C=C/COC(=O)C=[N+]=[N-])c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Glyoxylic acid chloride p-toluenesulfonylhydrazone (4.64 g, 17.8 mmol) was added to a suspension of isopropyl 3,5-difluoro-4-[(1E)-3-hydroxyprop-1-enyl]phenylcarbamate (2.68 g, 9.89 mmol) in dichloromethane (66 mL). The mixture was cooled to 0° C. and treated with N,N-dimethylaniline (2.26 mL, 17.8 mmol). After 30 minutes, triethylamine (6.89 mL, 49.5 mmol) was added and the mixture stirred 30 minutes at 0° C. and 15 minutes at room temperature. The reaction mixture was then concentrated to ca. 15 mL and 50 mL of water added. The mixture was extracted with two portions of diethyl ether and the combined organic solutions washed with saturated NaHCO3, brine, and dried (MgSO4), filtered and concentrated. Purification by column chromatography (0-25% ethyl acetate-hexane) provided the title compound a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]([CH3:25])=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]([CH3:25])=[C:12]([CH2:14][O:15][C:16]3[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=3)[N:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc(COc3cccc([N+](=O)[O-])c3)c(C)o2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc(COc3cccc(N)c3)c(C)o2)cc1
Temperature: 25 °C
Yield: 6.8 %

Procedure:
A solution of 6.0 g (0.18 mol) of 2-(4-methoxyphenyl)-5-methyl-4-[(3-nitrophenoxy)methyl]oxazole and 20.0 g (0.09 mol) of stannous chloride dihydrate in 150 ml of ethanol is heated to 70° C. for 20 hours. The solution is allowed to cool to room temperature and poured into 2 L of ice water. The mixture is made alkaline by the addition of solid sodium bicarbonate and extracted twice with 500 ml of ethyl acetate. The combined ethyl acetate solution is washed with 500 ml of brine, dried over anhydrous magenesium sulfate and concentrated in vacuo to obtain a residue. Recrystallization from ether/hexane gives 3.8 g (69%) of crystals, m.p. 132°-134° C. The product is used without further purification in subsequent reactions.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22]C(=O)C)[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][CH2:10][CH2:9]1.[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.C(#N)C.[OH-].[NH4+]>CC(O)C>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH2:22])[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][CH2:10][CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCNC(=O)CC3)c(F)c2)C(=O)O1
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(C)O
Product: NC[C@H]1CN(c2ccc(N3CCNC(=O)CC3)c(F)c2)C(=O)O1
Temperature: 47.5 °C
Reaction time: 18 h

Procedure:
An ice cold, stirred mixture of the product of Example 2, Step 1 (0.22 g, 0.50 mmol) in tetrahydrofuran (THF; 15 mL), under nitrogen, is treated dropwise during 2 minutes, with a lM solution of tetrabutylammonium fluoride in THF (1.5 mL). The mixture is kept in the ice bath for 10 minutes and at ambient temperature (24° C.) for 1 hour 25 minutes, diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and concentrated. Chromatography of the residue on silica gel with mixtures of 25 methanol-methylene chloride containing 3-6% methanol gave 0.15 g of the alcohol, a compound of formula 9 (Scheme 1) where R is hydrogen: MS(ES) m/z 324 (M+H+). A stirred suspension of the alcohol (0.15 g, 0.46 mmol) in methylene chloride (15 mL) and THF (8 mL), under nitrogen, is treated with triethylamine (0.5 mL, 1.4 mmol) and then portionwise during 1 minute at ambient temperature, with 0.14 g (0.56 mmol) of m-nitrobenzenesulfonyl chloride. The mixture is stirred for 90 minutes, mixed with additional methylene chloride (10 mL) to give a solution and kept at ambient temperature for 1 hour. It is then kept for several days at -11° C., diluted with methylene chloride, washed with saturated sodium bicarbonate, water and brine, dried (Na2SO4) and concentrated to give 0.21 g of the m-nitrobenzenesulfonate, a compound of formula 10 (Scheme 1). A stirred mixture of the m-nitrobenzenesulfonate (0.21 g, 0.44 mmol), acetonitrile (10 mL), 2-propanol (10 mL) and 29% ammonium hydroxide (10 mL) is warmed at 45-50° C. under a Dry Ice-acetone condenser for 4.5 hours and kept at ambient temperature for 18 hours. Additional ammonium hydroxide (5 mL) is added and the mixture is warmed at 45-50° C. for 4.5 hours, kept at ambient temperature for 1 hour, treated with 5 mL of ammonium hydroxide and kept at ambient temperature for 18 hours. It is then concentrated to give a yellow solid which is chromatographed on silica gel with mixtures of methanol-methylene chloride containing 5-7.5% methanol followed by 8% methanol-0.2% ammonium hydroxide-methylene chloride to give the titled product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[C:3]=1[CH3:10].C([Mg]Cl)(C)C.[C:16](=[O:18])=[O:17]>O1CCCC1>[F:9][C:4]1[C:3]([CH3:10])=[C:2]([CH:7]=[CH:6][C:5]=1[F:8])[C:16]([OH:18])=[O:17]
Reactant: Cc1c(Br)ccc(F)c1F
Reactant: O=C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)ccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The acid was synthesised as reported in US 2005/0054733A1 and described below 1-bromo-3,4-difluoro-2-methylbenzene (I67) (8.07 g, 39.0 mmol) was cooled to 0° C. in tetrahydrofuran (THF) (40 mL). Isopropylmagnesium chloride (29.2 mL, 58.5 mmol) was added dropwise and the solution stirred at room temperature overnight. The solution was cooled to 0° C. and gassed slowly with Carbon dioxide (excess) for 1 hour. The cooling was removed and gassing continues for 4 hours before allowing the solution to stand at room temperature overnight. Water (10 ml) was added and the solvents removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and 2N Hydrochloric acid (25 mL). The aqueous phase was extracted with ethyl acetate (5×50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to a crude solid that was recrystalised from cyclohexane to afford product in 4.68 g.
Reaction SMILES: C([Li])CCC.[I:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[C:15]([O:18][CH2:19][CH3:20])(=[O:17])[CH3:16]>O1CCCC1.CCCCCC>[CH2:19]([O:18][C:15](=[O:17])[CH:16]=[CH:11][C:10]1[CH:13]=[CH:14][C:7]([I:6])=[CH:8][CH:9]=1)[CH3:20]
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc(I)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A stirred, cooled (−78° C.) solution of triethylphosphonoacetate (11.1 mL, 56 mmol) in anhydrous tetrahydrofuran (100 mL) was treated with a 1.6M solution of n-butyl lithium in hexanes (27 mL, 43.75 mmol). After 10 min, the reaction mixture was cannulated into a cooled (−78° C.) solution of 4-iodo-benzaldehyde (6.5 g, 28 mmol) in tetrahydrofuran (20 mL). The reaction mixture was allowed to warm to 0° C. over 1 h. It was quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford an oil that was subjected to flash column chromatography over silica gel (230-400 mesh) using 6-8% ethyl acetate in hexane as the eluent to afford the title compound (2.7 g pure, 3.2 g ˜95% pure, 69%).