Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:9]=[C:10]([C:14]2[CH:15]=[C:16]3[C:21](=[N:22][CH:23]=2)[N:20]([C:24]([NH2:26])=[O:25])[CH2:19][CH2:18][CH2:17]3)[CH:11]=[N:12][CH:13]=1)(C)(C)C.N1C=CC=CC=1.C([O-])(O)=O.[Na+].O>C1COCC1.CCOC(C)=O>[OH:6][CH2:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:15]=[C:16]3[C:21](=[N:22][CH:23]=2)[N:20]([C:24]([NH2:26])=[O:25])[CH2:19][CH2:18][CH2:17]3)[CH:11]=[N:12][CH:13]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: NC(=O)N1CCCc2cc(-c3cncc(CO)c3)cnc21
Reaction time: 2 h
Yield: 91.4 %

Procedure:
6-[5-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (40 mg, 0.10 mmol) is dissolved in 2.0 mL of THF and HF pyridine (0.04 mL) is added. The mixture is stirred for 2 hrs and saturated aqueous NaHCO3 solution (5 mL) is added along with water (10 mL) and EtOAc (25 mL). The mixture is stirred for 10 min and the aqueous layer is separated, extracted with EtOAc (2×10 mL). The organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 26 mg of the titled product.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[C:34]([C:37]1[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[O:40][CH:41]=1)(=[O:36])[CH3:35]>O1CCCC1>[Br:1][CH2:35][C:34]([C:37]1[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[O:40][CH:41]=1)=[O:36]
Reactant: [Br-]
Reactant: CC(=O)c1coc2ccccc12
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1coc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 27.4 %

Procedure:
A solution of phenyltrimethylammonium tribromide (2.47 g) in tetrahydrofuran (20 ml) was added dropwise at ambient temperature under nitrogen over 5 minutes to a stirred solution of 3-acetylbenzo[b]furan (1 g) in tetrahydrofuran (20 ml), then the mixture was stirred at ambient temperature for a further 1.5 hours, filtered, and the solvent removed in vacuo. The residue was triturated with ether, and the resulting solid was collected by filtration and dried in vacuo at ambient temperature to give 3-(2-bromoacetyl)benzo[b]furan as an off-white solid (0.25 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH3:15].[Cl-].[NH4+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH3:15])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2cc[nH]c2c1
Reactant: CC(Cl)c1ccccn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(c1ccccn1)n1ccc2ncc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
To an ice-cooled suspension of 6-bromo-1H-pyrrolo[3,2-b]pyridine (7.0 g, 35 mmol) in N,N-dimethylformamide (100 mL) was slowly added a solution of sodium hydride (2.12 g, 88.28 mmol, 60% in mineral oil) in N,N-dimethylformamide (20 mL). After 30 min at 0° C., a solution of 2-(1-chloroethyl)pyridine (5.0 g, 35 mmol) in N,N-dimethylformamide (20 mL) was slowly added. The mixture was then warmed to room temperature. After 16 h, saturated aqueous ammonium chloride solution (20 mL) was slowly added to the reaction mixture, and the resulting solution was concentrated in vacuo. The resulting residue was purified by flash column chromatography (10→30% ethyl acetate in petroleum ether) to afford 6-bromo-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[3,2-b]pyridine (6.0 g, 56% yield). 1H NMR (400 MHz, Chloroform-d) δ 8.61 (d, J=4.4 Hz, 1 H), 8.47 (d, J=2.0 Hz, 1 H), 7.70 (s, 1 H), 7.62-7.57 (m, 2 H), 7.21-7.18 (m, 1 H), 6.81-6.76 (m, 2 H), 5.66-5.61 (m, 1 H), 2.00 (d, J=7.2 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([NH2:20])[CH2:16][CH2:15]3)=[O:13])[C:6]=2[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][N:17]([NH:20][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:21]=1
Reactant: CCOC(=O)Cl
Reactant: NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33.7 %

Procedure:
A mixture of 5-chloro-3-[(4-amino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone (0.85 g), anhydrous potassium carbonate (430 mg), dichloromethane (40 ml), dioxane (10 ml) and ethyl chloroformate (339 mg) was stirred for 1.5 hours at room temperature. The insoluble materials were filtered off and the filtrate was concentrated under reduced pressure. The residue was recrystallized from a mixture of chloroform and dioxane to give colorless crystals of 5-chloro-3-[(4-ethoxycarbonylamino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone (0.35 g).
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl.[Cl:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1.N1C=CC(CCCO)=CC=1>>[ClH:28].[N:35]1[CH:36]=[CH:37][C:32]([CH2:31][CH2:30][CH2:29][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]4[CH:24]=[CH:25][S:26][C:20]=4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])=[CH:33][CH:34]=1
Reactant: ClCCCc1ccncc1
Reactant: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(O)cc12
Agent: Cl
Agent: OCCCc1ccncc1
Product: ON=c1cc(-c2cc3sccc3cn2)oc2ccc(OCCCc3ccncc3)cc12

Procedure:
6-(3-Pyridin-4-yl-propoxy)-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one oxime, hydrochloride was prepared in 7% overall yield using the method described in example 127, starting from 6-hydroxy-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl oxime (example 127A) and 4-(3-Chloro-propyl)-pyridine hydrochloride, prepared from 4-pyridine propanol (U.S. Pat. No. 6,362,336).
Reaction SMILES: C(Cl)Cl.[C:4](OC(=O)C)(=[O:6])[CH3:5].[OH:11][C:12]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>N1C=CC=CC=1>[C:4]([O:11][C:12]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:6])[CH3:5]
Reactant: O=C(O)c1cc(N2CCCCC2)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(N2CCCCC2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methylene chloride (9.0 mL), pyridine (0.82 mL), and acetic anhydride (0.46 mL) were sequentially added to the obtained 2-hydroxy-5-(piperidin-1-yl)benzoic acid (0.90 g), followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and a 10% aqueous solution of citric acid and ethyl acetate were added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, and the resulting mixture was washed with water and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration to obtain 0.55 g of 2-acetoxy-5-(piperidin-1-yl)benzoic acid as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[Br:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28](=[O:31])[CH2:29]Br>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:29]=1[C:28](=[O:31])[C:27]1[CH:32]=[CH:33][CH:34]=[C:25]([Br:24])[CH:26]=1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: O=C(CBr)c1cccc(Br)c1
Product: COC(=O)Cc1c(C(=O)c2cccc(Br)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans 4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 3-bromophenacyl bromide.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[F:16][C:17]([F:24])([F:23])[C:18](OCC)=[O:19].Cl>C1COCC1>[F:16][C:17]([F:24])([F:23])[C:18]([C:15]1[C:10]([F:9])=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:19]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Fc1ccccn1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1cccnc1F)C(F)(F)F
Temperature: -78 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
Lithium diisopropylamide (8.2 mL, 14.8 mmol, 1.8M in heptane) was added to THF (20 mL) cooled to −78° C. in a dry ice/acetone bath. 2-Fluoropyridine (1.07 mL, 12.4 mmol) was added dropwise, and the resulting mixture was stirred at −78° C. for 3 hours. Ethyl trifluoroacetate (2.06 mL, 17.2 mmol) was added to the suspension dropwise. The reaction mixture was allowed to slowly warm to room temperature. After 1 hour, the mixture was poured into 1M hydrochloric acid (35 mL) and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over magnesium sulfate, filtered, and evaporated to yield the hydrate of 2,2,2-trifluoro-1-(2-fluoropyridin-3-yl)ethanone (1.9 g, 90%) as a semisolid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCC1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH:12]1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCN(C(=O)OCc2ccccc2)C1
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: O=C1CCCN(C(=O)OCc2ccccc2)C1Cc1ccccc1
Temperature: 25 °C
Yield: 6.3 %

Procedure:
A stirring solution of N-(benzyloxycarbonyl)-3-piperidone (1000 mg, 4.25 mmol) and pyrrolidine (454 mg, 6.38 mmol, Aldrich) in dry toluene (10 mL) in a round bottom flask fitted with a Dean-Stark trap was refluxed for 4 h. The reaction was conc. in vacuo to a orange oil. The oil was dissolved in dry acetonitrile (10 mL) and then benzyl bromide (800 mg, 4.68 mmol, Aldrich) was added. The reaction was heated to reflux for 16 h and then cooled to room temperature. The reaction was quenched by the addition of 1M HCl (50 mL) and then extracted with EtOAc (4×40 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and conc. in vacuo to an oil. The oil was purified by flash chromatography (SiO2, 7–20% EtOAc in hexanes) to yield 86 mg of the product as a white solid. MS (ESI) 324 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4](Cl)[N:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([NH2:41])[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[CH:28][CH:27]=1>C1COCC1>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([CH:32]([NH:41][C:4]2[N:3]=[C:2]([Cl:1])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])[C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[CH:38][CH:37]=1
Reactant: COc1ccc(C(N)c2ccc(OC)cc2)cc1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: C1CCOC1
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(c4ccc(OC)cc4)c4ccc(OC)cc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 50 °C

Procedure:
To a solution of N-[(1S,2R,3S,4R)-4-(2,6-dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide (Intermediate J7) (2.6 g, 7.22 mmol) in dry THF (26 ml) is added C,C-Bis-(4-methoxy-phenyl)-methylamine (Intermediate Y) (3.5 g, 14.44 mmol). The mixture is heated at 50° C. for 12 hours and then concentrated in vacuo. The residue is dissolved in chloroform and washed sequentially with 1.5N HCl, water and saturated aqueous brine solution. The organic phase is dried over anhydrous sodium sulphate and concentrated in vacuo. The crude product is purified by chromatography on silica (60-120 mesh) eluting with 2% methanol in chloroform to afford the title product. LC-MS (0.1% formic acid, acetonitrile): (MH+ 567)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:11]=[CH:10][NH:9][C:5]2=[N+:6]([O-])[CH:7]=1.C(=O)([O-])O.[Na+].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[CH:11][C:4]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cc(F)cc2cc[nH]c21
Agent: O=C([O-])O
Agent: [Na+]
Product: Fc1cnc2[nH]ccc2c1Cl

Procedure:
A solution of 1.7 g of 5-fluoro-1H-pyrrolo[2,3-b]pyridine-7-oxide in 10 cm3 of phosphorus oxychloride is maintained at the reflux point of the POCl3 for 8 hours. After distilling off the POCl3 under vacuum, the residue is treated with 50 g of ice, and the pH of the solution obtained is brought in the region of 8-9 by addition of sodium hydrogen carbonate. The aqueous phase is extracted with five times 80 cm3 of ethyl acetate. The combined organic phases are then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). 1.3 g of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine are thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [N:1]1([NH:7][C:8](=[O:34])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([C:19]3[CH:28]=[CH:27][C:26]4[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=4[CH:20]=3)=[O:18])=[CH:11][C:10]=2[OH:33])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C(O)C>[N:1]1([NH:7][C:8](=[O:34])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]([OH:18])[C:19]3[CH:28]=[CH:27][C:26]4[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:31])([CH3:32])[C:21]=4[CH:20]=3)=[CH:11][C:10]=2[OH:33])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)COc3ccc(C(=O)NN4CCOCC4)c(O)c3)ccc21
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(C(O)COc3ccc(C(=O)NN4CCOCC4)c(O)c3)ccc21
Yield: 75.4 %

Procedure:
Starting from 5.5 g (12 mmol) of N-morpholinyl-2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzamide in a manner analogous to Example 10 and by recrystallisation in 10 volume of ethanol, 4.24 g (77%) of the expected product of melting point 153° C. are collected.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:9][CH:8]=1)C)=[O:4].F[C:22](F)(F)C(NC1C=CC(I)=C(C)C=1)=O>>[F:20][C:2]([F:1])([F:19])[C:3]([NH:5][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][OH:18])=[C:11]([CH3:22])[CH:12]=1)=[O:4]
Reactant: CN(C(=O)C(F)(F)F)c1ccc(C#CCCCO)cc1
Reactant: Cc1cc(NC(=O)C(F)(F)F)ccc1I
Product: Cc1cc(NC(=O)C(F)(F)F)ccc1C#CCCCO

Procedure:
The title compound was synthesized in a manner analogous to that described in Intermediate 36, using Intermediate 35 in place of Intermediate 33. ES/MS calcd. for C14H14F3NO2 285.1. Found m/z=286 (M+H)+.
Reaction SMILES: [C:1]([CH:5]([O:7][C:8]([C:11]([O:17][C:18]([C:21](C(O[Na])=O)([F:23])[F:22])([F:20])[F:19])([C:13]([F:16])([F:15])[F:14])[F:12])([F:10])[F:9])[F:6])([F:4])([F:3])[F:2].C(=O)=O>COCCOCCOCCOCCOC>[C:1]([CH:5]([O:7][C:8]([C:11]([O:17][C:18]([CH:21]([F:22])[F:23])([F:20])[F:19])([C:13]([F:14])([F:15])[F:16])[F:12])([F:10])[F:9])[F:6])([F:4])([F:3])[F:2]
Reactant: O=C(O[Na])C(F)(F)C(F)(F)OC(F)(C(F)(F)F)C(F)(F)OC(F)C(F)(F)F
Agent: COCCOCCOCCOCCOC
Agent: O=C=O
Product: FC(OC(F)(F)C(F)(OC(F)(F)C(F)F)C(F)(F)F)C(F)(F)F
Yield: 30.9 %

Procedure:
36.2 g (0.08 mol) of CF3CFHOCF2CF(CF3)OCF2CF2CO2Na and 80 mL of tetraglyme were stirred and heated in a 200 mL 3-neck flask fitted with a thermometer, stirrer and distillation column topped by a Dry Ice-cooled trap and nitrogen bubbler. The salt largely dissolved and reaction was noted in the temperature range 180° to 195°. 17.9 g of colorless distillate was obtained. Gas chromatography and IR analysis confirmed the presence of ##STR1## (6.0 g, 28% yield), that is, the compound of formula 2 wherein X is F, X1 is H and n is 1, and CF3CFHOCF2CF(CF3)OCF2CF2H (9.5 g, 31% yield).
Reaction SMILES: [Br:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=O)=[C:4]([N:13]2[CH2:18][CH:17]([CH3:19])[O:16][CH:15]([CH3:20])[CH2:14]2)[CH:3]=1.[NH:21]1[C:28](=[O:29])[CH2:27][C:25](=[O:26])[NH:24][C:22]1=[O:23]>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:6][C:27]3([CH:14]4[CH:15]([CH3:20])[O:16][CH:17]([CH3:19])[CH2:18][N:13]42)[C:25](=[O:26])[NH:24][C:22](=[O:23])[NH:21][C:28]3=[O:29])=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: CC1CN(c2cc(Br)c([N+](=O)[O-])cc2C=O)CC(C)O1
Solvent: CC(C)O
Product: CC1CN2c3cc(Br)c([N+](=O)[O-])cc3CC3(C(=O)NC(=O)NC3=O)C2C(C)O1
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 39.2 %

Procedure:
A mixture of 4-bromo-2-(2,6-dimethylmorpholin-4-yl)-5-nitrobenzaldehyde (from Step 2) (989 mg, 2.88 mmol) and barbituric acid (369 mg, 2.88 mmol) in isopropanol (15 mL) is sealed in a 20 mL scintillation vial and shaken at 85° C. for 2.5 hours. The product is adsorbed onto silica gel and purified by silica gel chromatography using a gradient from 20% EtOAc in CH2Cl2 to 25% EtOAc in CH2Cl2 as eluent. Product is isolated and dried (20 Torr, 100° C.) to give 512 mg of yellow solid. 1H NMR (DMSO-d6) δ 11.90, 11.62, 7.79, 7.36, 4.32, 3.87, 3.47-3.63, 2.94, 2.81, 1.15, 0.94.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.CCCCCC.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.[Cl-].[NH4+]>C1COCC1.CCOCC>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: c1ccoc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Fc1ccc(Cc2ccco2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
To a 0° C. solution of furan (13.6 g, 0.20 mol) in a mixture of anhydrous ether (230 mL) and anhydrous THF (70 mL) under nitrogen was added a 2.5M solution of n-butyllithium in hexane (54.0 mL, 0.134 mol). The mixture was stirred at 0° C. for 1.5 hours and then transferred by cannula to a stirred -78° C. solution of 4-fluorobenzyl bromide (23.6 g, 0.125 mol) and tetrakis-(triphenylphosphine)palladium (O) (1.25 g, 0.001 mol) in anhydrous THF (200 mL). The transfer was made under nitrogen over a period of 30-40 minutes. The reaction mixture was stirred at ambient temperature overnight, saturated aqueous solution of ammonium chloride was added and the mixture extracted with ether. The ether layer was dried (MgSO4), concentrated in vacuo and the residue distilled at reduced pressure to give 2-(4-fluorophenylmethyl)furan as a colorless oil (17.89 g, 81% ). b.p. 57°-62° C. at 0.5-0.7 mm-Hg.
Reaction SMILES: C(N[C:5]1[C:6]([Cl:34])=[C:7]([NH:24][C:25](=[O:33])[C@:26]([OH:32])([CH3:31])[C:27]([F:30])([F:29])[F:28])[CH:8]=[CH:9][C:10]=1[S:11]([C:14]1C=CC(NCCO)=C[CH:15]=1)(=O)=O)(=O)C.C[O-].[Na+].C([I:40])C.CCOC(C)=O>C1COCC1>[CH2:14]([S:11][C:10]1[CH:9]=[CH:8][C:7]([NH:24][C:25](=[O:33])[C@:26]([OH:32])([CH3:31])[C:27]([F:30])([F:29])[F:28])=[C:6]([Cl:34])[C:5]=1[I:40])[CH3:15]
Reactant: CC(=O)Nc1c(S(=O)(=O)c2ccc(NCCO)cc2)ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c1Cl
Reactant: CCI
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCSc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1I
Temperature: 25 °C

Procedure:
To a stirred solution of (R)-N-[4-mercapto-3-iodo-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 29) (5.85 g) in anhydrous THF (40 ml) under argon was added sodium methoxide (0.44 g) followed by ethyl iodide (0.65 ml) and the mixture was heated under reflux for 1 hour and allowed to cool to ambient temperature. EtOAc (200 ml) was added, the organic phase was washed with brine (100 ml) and dried. Volatile material was removed by evaporation and the residue was purified by flash column chromatography eluting with 5-30% EtOAc/isohexane to give the title compound (2.08 g) as a pale yellow solid. NMR (CDCl3) 1.36 (t, 3H), 1.75 (s, 3H), 2.92-2.99 (q, 2H), 7.15 (d, 1H), 8.34 (d, 1H), 8.89 (s, 1H); m/z: 452.
Reaction SMILES: [ClH:1].[CH3:2][C:3]([N+:9]([O-])=O)([CH2:6][NH:7][CH3:8])[CH2:4][OH:5]>CO.[Ni].O>[ClH:1].[NH2:9][C:3]([CH3:2])([CH2:6][NH:7][CH3:8])[CH2:4][OH:5]
Reactant: CNCC(C)(CO)[N+](=O)[O-]
Agent: [Ni]
Agent: Cl
Solvent: O
Solvent: CO
Product: CNCC(C)(N)CO
Reaction time: 48 h
Yield: 163.6 %

Procedure:
To a solution of 2-methyl-3-(methylamino)-2-nitropropan-1-ol hydrochloride (5.4 g) in methanol (32 ml) was added a slurry of Raney Nickel in H2O (1.5 ml). The vessel was pressurized with H2 (450 psi) and the suspension stirred for 48 h. The mixture was filtered through Celite and concentrated in vacuo to give a crude liquid (7.4 g, >100%), which was used directly in the next step without purification. 1H NMR (400 MHz, CDCl3) δ 1.01 (s, 3H), 2.26 (s, 3H), 2.99 (s, 2H), 3.41-3.44 (d, J=11.6, 1 H), 3.48-3.51 (d, J=11.6 Hz, 1H). LRMS (ESI/APCI) m/z 145 [M+H]+.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[F:6][C:7]1[CH:8]=[C:9]([C:15](=O)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].O>C(O)C.C1(C)C=CC=CC=1>[F:6][C:7]1[CH:8]=[C:9]([C:15](=[N:2][OH:3])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: COc1ccc(C(=O)Cc2ccccc2)cc1F
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C(Cc2ccccc2)=NO)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Hydroxylamine hydrochloride (3.7 g, 53.2 mmol) and potassium hydroxide (2.98 g, 53.2 mmol) were suspended in absolute ethanol (25 mL) and stirred for 30 minutes. To this, a suspension of 1-(3-fluoro-4-methoxyphenyl)-2-phenyl-ethan-1-one from Step 1 (10.0 g, 40.9 mmol) in toluene (150 mL) was added in one portion. The yellow suspension was warmed to reflux for 16 hours, then the suspension was cooled to room temperature. Water (100 mL) was added, and the resulting solution was extracted with ethyl acetate (2×100 mL). The combined organic solution was washed with brine (100 mL), dried over magnesium sulfate and filtered. The resulting solution was evaporated under reduced pressure to yield a crude residue. The residue was crystallized from boiling ethanol/water to yield, upon filtration and drying 1-(3-fluoro-4-methoxyphenyl)-2 phenyl-ethan-1-one oxime as ivory-colored crystals (10.0 g, 94%): 1H NMR (CDCl3 /300 MHz) δ 7.42 (dd, J=12.69, 2.01, 1H), 7.36-7.19 (m, 6H), 6.89 (dd, J=8.66, 8.46 HZ, 1H), 4.16 (s, 2H), 3.88 (s, 3H). 19F NMR (CDCl3 /282.2 MHz): 135.517 (m).
Reaction SMILES: [N:1]([C:4](=[CH:10][C:11]1[C:12]2[N:13]([C:17]([Br:21])=[C:18]([CH3:20])[N:19]=2)[CH:14]=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-].[K+].[Br-]>>[Br:21][CH:17]1[N:13]2[CH:14]=[CH:15][C:16]3[C:11]([CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:1]=3)=[C:12]2[N:19]=[C:18]1[CH3:20]
Reactant: CCOC(=O)C(=Cc1cccn2c(Br)c(C)nc12)N=[N+]=[N-]
Agent: [Br-]
Agent: [K+]
Product: CCOC(=O)c1cc2c3n(ccc-2n1)C(Br)C(C)=N3

Procedure:
From 6k (yield: 98%); mp 224-226° C.; IR (KBr) 3288, 1685, 1258, 1188 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.40 (t, 3H, J=7 Hz), 2.46 (s, 3H), 4.41 (q, 2H, J=7 Hz), 6.99 (d, 1H, J=7 Hz), 7.62 (s, 1H), 7.84 (d, 1H, J=7 Hz), 10.27 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ 13.4, 14.3, 61.3, 93.2, 101.3, 107.4, 114.3, 121.7, 126.8, 132.8, 139.0, 141.4, 161.6; MS m/z 323 (M++2, 50), 321 (M+, 49), 277 (100), 275 (97), 168 (24). Anal. Calcd for C13H12BrN3O2: C, 48.47; H, 3.75; N, 13.04. Found: C, 48.15; H, 3.88; N, 12.97.