Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[CH2:33][NH2:34])=[CH:22][CH:23]=3)[CH:18]=[N:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](C1C=CC([O:44][C:45](=O)[NH:46][C:47]2[O:51][N:50]=[C:49]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:48]=2)=CC=1)([O-])=O>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[CH2:33][NH:34][C:45]([NH:46][C:47]4[O:51][N:50]=[C:49]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:48]=4)=[O:44])=[CH:22][CH:23]=3)[CH:18]=[N:17]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Reactant: CC(C)(C)OC(=O)N1CCN(CCn2ncc3cc(Oc4ccc(F)cc4CN)ccc32)CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CCn2ncc3cc(Oc4ccc(F)cc4CNC(=O)Nc4cc(C(C)(C)C)no4)ccc32)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.3 %

Procedure:
A solution of 4-{2-[5-(2-aminomethyl-4-fluorophenoxy)-indazol-1-yl]-ethyl}-piperazine-1-carboxylic acid tert-butyl ester (0.050 g, 0.107 mmol) dissolved in dichloromethane (2 mL) was treated with (3-tert-butyl-isoxazol-5-yl)-carbamic acid 4-nitrophenyl ester (0.081 g, 0.266 mmol) and stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate (60 mL), washed with 1N NaOH (5 mL), water (2×10 mL), brine, dried over MgSO4, and concentrated under reduced pressure. The residue was chromatographed eluting with acetone/hexanes (2:3, then 1:1) to afford 0.056 g of product (83% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:5]2.C([Li])CCC.C([O:27][B:28](OC(C)C)[O:29]C(C)C)(C)C.Cl>CCCCCC.C1COCC1>[CH2:11]([CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([B:28]([OH:29])[OH:27])[CH:3]=2)[CH2:7]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCCCCC1Cc2ccc(Br)cc2C1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCC1Cc2ccc(B(O)O)cc2C1
Temperature: -70 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
In a 200 ml-reaction vessel, 3.16 g (1.02×10-2M) of 5-bromo-2-n-octylindan and 45 ml of dry THF were placed. To the mixture, 1.5M-solution of n-butyllithium in 7.2 ml of hexane was added dropwise in 20 minutes at -70° C. under argon atmosphere, followed by stirring for 2 hours at -70° C. To the above mixture, a solution of 4.14 g (2.20×10-2M) of triisopropylborate in 9 ml of dry THF was added dropwise in 20 minutes below -70° C., followed by stirring for 1 hour at the same temperature, gradual restoration to room temperature and further stirring for 20 hours. After the reaction, 15 ml of 10%-HCl aqueous solution was added dropwise to the reaction mixture to be decomposed under cooling, followed by extraction with ether. The ether layer was washed with water and dried with anhydrous sodium sulfate, followed by distilling-off of the solvent and purification by silica gel column chromatography to obtain 1.96 g of 2-octylindan-5-boronic acid (Yield: 70%).
Reaction SMILES: Cl.C(OC([N:9]([CH2:16][C:17]1[CH:42]=[CH:41][C:20]([CH2:21][NH:22][C:23]2[C:33]3[CH2:32][CH2:31][N:30](C(=O)C(F)(F)F)[CH2:29][CH2:28][C:27]=3[CH:26]=[CH:25][C:24]=2[Cl:40])=[CH:19][CH:18]=1)[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=O)(C)(C)C.O.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[Cl:40][C:24]1[CH:25]=[CH:26][C:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH2:32][C:33]=2[C:23]=1[NH:22][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1)C1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1ccc2c(c1NCc1ccc(CNC3CCCCC3)cc1)CCNCC2
Reaction time: 1 h
Yield: 85.4 %

Procedure:
Bubble hydrogen chloride into a solution of 6-{-4-[N-(tert-butoxycarbonyl)-N-(cyclohexyl)-aminomethyl]-benzylamino}-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (355 mg, 0.6 mmol) in EtOAc (5 mL) at room temperature. Stir the mixture for 1 h, and concentrate in vacuo. Dissolve the residue in methanol (5 mL) and add water (2 mL) and K2CO3 (1 g, 7.2 mmol). Stir the mixture at room temperature overnight. Concentrate the mixture in vacuo and partition the residue between water (20 mL) and DCM (20 mL). Extract the aqueous phase with DCM (2×20 mL). Dry the combined organic extracts over Na2SO4, filter, and concentrate in vacuo. Purify by reverse phase chromatography [Phenomonex C18(2) column (5×25 cm) eluting with a gradient of water:acetonitrile (0.1% TFA in each) 9:1 through 2:3 over 50 min, 118 mL/min]. Concentrate pure fractions and apply to a SCX column (3.5 g) eluting with methanol and 3N ammonia in methanol to obtain 7-chloro-6-{4-[N-(cyclohexyl)-aminomethyl]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (204 mg, 86%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:19])=[C:12]([CH2:17][NH2:18])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br-].[CH:21]1([Zn+])[CH2:23][CH2:22]1>C1COCC1.CCOC(C)=O.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>[Cl:16][C:15]1[CH:14]=[CH:13][C:12]([CH2:17][NH2:18])=[C:11]([F:19])[C:10]=1[O:9][C:4]1[CH:3]=[C:2]([CH:21]2[CH2:23][CH2:22]2)[CH:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: [Zn+]C1CC1
Reactant: NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NCc1ccc(Cl)c(Oc2cc(Cl)cc(C3CC3)c2)c1F
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a solution of ({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (0.460 g, 1.260 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.029 g, 0.025 mmol) in THF (10 ml) was added cyclopropylzinc bromide (0.5 M solution in THF) (6.30 ml, 3.15 mmol) and the reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give ({4-chloro-3-[(3-chloro-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)amine (0.281 g, 0.861 mmol, 68% yield). 1H NMR (400 MHz, METHANOL-d4) d ppm 7.20-7.44 (m, 3H), 6.76 (s, 1H), 6.54 (s, 1H), 3.86 (s, 2H), 1.74-2.05 (m, 1H), 0.83-1.08 (m, 2H), 0.40-0.76 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)([CH:4]1[S:8][CH2:7][CH2:6][S:5]1)[CH3:3].[CH3:17][O:18]C(Cl)Cl.O>ClCl.C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:2]([CH:4]2[S:5][CH2:6][CH2:7][S:8]2)([CH3:1])[CH3:3])=[CH:10][C:11]=1[CH:17]=[O:18]
Reactant: COc1ccc(C(C)(C)C2SCCS2)cc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: ClCl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(C)(C)C2SCCS2)cc1C=O
Temperature: -60 °C
Reaction time: 0.05 h
Yield: 30.5 %

Procedure:
To a stirred solution of Compound 80 (0.254 g, 1 mmol) in dry CH2 Cl2 (5 ml) was added a solution of TiCl4 in CH2Cl2 (1M, 3 ml) with cooling (-60° C.). After 3 min., to this was added dichloromethyl methyl ether (0.46 g, 4 mmol) dropwise. The reaction mixture was stirred at same temperature for 1 hr. The mixture was poured into water and stirred at room temperature for 15 min. The organic layer was separated and the aqueous layer was extracted with Et2O (50 ml×2). The combined solution was washed with brine, dried (MgSO4) and concentrated in vacuo to give crude product. The crude product was purified by a column chromatography to give Compound 81 (86 mg) as an oil
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:11].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:24](O)=[O:25]>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:24]=[O:25])=[CH:10][C:5]=2[O:4][C:3]1=[O:11]
Reactant: Cn1c(=O)oc2ccccc21
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: Cn1c(=O)oc2cc(C=O)ccc21
Reaction time: 0.5 h
Yield: 45 %

Procedure:
3-Methyl-3H-benzooxazol-2-one (2.00 g, 13.42 mmol) and hexamethylenetetramine (3.76 g, 26.84 mmol) were dissolved in trifluoroacetic acid (20 mL) and heated at reflux for 20 hours. The volatiles were removed in vacuo and the residue was treated with ice water (60 mL). The resultant mixture was stirred for 30 minutes and then made basic with sodium carbonate. The solid was isolated by filtration and washed with water then dried under vacuum. The solid was purified by column chromatography on silica gel eluting with an ethyl acetate and hexane solvent gradient. This provided the desired product as a white solid (1.07 g, 45%).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:12]=[C:11]2[C:7]([NH:8][CH:9]=[N:10]2)=[C:6]([NH2:13])[N:5]=1.[CH3:14][O:15][CH2:16][CH2:17][OH:18]>>[CH3:14][O:15][CH2:16][CH2:17][O:18][C:4]1[N:12]=[C:11]2[C:7]([NH:8][CH:9]=[N:10]2)=[C:6]([NH2:13])[N:5]=1
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Product: COCCOc1nc(N)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a flask with 150 ml 2-methoxyethanol, was added NaH (13 g, 60% dispersion in mineral oil). The mixture was allowed to stir at room temperature for 10 min. Then 6-amino-2-chloroadenine (Compound (1)) (25 g, 0.15 mol) was added. The reaction was refluxed for 2 days while monitoring by LC/MS. Additional NaH (5 g, 60% dispersion in mineral oil) was added and refluxing was continued for another day. After the starting material was consumed, the reaction mixture was cooled to rt (“room temperature”) and the solvent was removed under vacuum. Water was added, and the mixture was neutralized with acetic acid until a solid precipitated. The solid Compound (15) was collected and dried under high vacuum. 1H NMR (DMSO-d6) δ 3.28 (s, 3H), δ 3.61 (t, 2H), δ 4.28 (t, 2H), δ 7.08 (bs, 2H), δ 7.88 (s, 1H), δ 145 (bs, 1H); MS: 210.0 (M+H)+, 208.1 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[O:6][C@@H:7]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1.[CH3:39]I>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[O:6][C@@H:7]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([N:22]([CH3:39])[C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1
Reactant: CI
Reactant: COc1ccc(O[C@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)cc1OC
Product: COc1ccc(O[C@H](CCN2CCC(c3cccc(N(C)C(=O)C(C)C)c3)CC2)c2ccccc2)cc1OC

Procedure:
Prepared by Procedure T and Scheme AD using N-(3-{1-[(3R)-3-(3,4-dimethoxyphenoxy)-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and methyl iodide: ESMS m/e: 531.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:18][C:17]3[C:12](=[N:13][C:14](SC)=[N:15][CH:16]=3)[N:11]([CH3:21])[C:10]2=[O:22])[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(C=CC=1)C(OO)=O.[NH3:34].O1CCOCC1>C(Cl)Cl>[NH2:34][C:14]1[N:13]=[C:12]2[N:11]([CH3:21])[C:10](=[O:22])[N:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH2:1])[CH:3]=3)[CH2:18][C:17]2=[CH:16][N:15]=1
Reactant: N
Reactant: CSc1ncc2c(n1)N(C)C(=O)N(c1ccc(F)c(N)c1)C2
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1C(=O)N(c2ccc(F)c(N)c2)Cc2cnc(N)nc21
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of Example A1 (400 mg, 1.3 mmol) in CH2Cl2 (5 mL) was added 3-chloroperoxybenzoic acid (mCPBA) (430 mg, 2.5 mmol) in one portion. After stirring for 2 h, the reaction mixture was quenched with aq NaHCO3 and aq NaHSO3. The organic layer was separated and was washed with brine, dried Na2SO4) and concentrated in vacuo. The crude product was dissolved in DMSO (2 mL) and was treated with a solution of ammonia in dioxane (2 M, 30 ml, 60 mmol). The mixture stirred overnight at RT. The reaction was concentrated under reduced pressure and the residue was purified by silica gel chromatography to provide 7-amino-3-(3-amino-4-fluorophenyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (276 mg, 77% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 7.88 (s, 1 H), 6.96 (dd, J=8.4, 6.6 Hz, 1 H), 6.68 (dd, J=6.3, 2.1 Hz, 1 H), 6.52 (br s, 2 H), 6.44 (m, 1 H), 5.18 (s, 2 H), 4.48 (s, 2 H), 3.19 (s, 3 H); MS (ESI) m/z: 289.2. (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=O)=[CH:4][CH:3]=1.Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][NH2:29]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])[N:29]=[C:10]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)C1CCOCC1)c1ccc(Cl)cc1
Reactant: COc1ccccc1NN
Agent: Cl
Solvent: CCO
Product: COc1ccccc1-n1nc(C2CCOCC2)cc1-c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
A solution of 1-(4-chlorophenyl)ethanone (2.0 g, 12.9 mmol) in anhydrous THF was cooled in a dry ice acetone bath and treated with sodium hexamethyldisilazid (14.2 mL, 1M in THF, 14.2 mmol). The resulting solution was stirred for 1 h at −78° C. and a solution of tetrahydro-pyran-4-carbonyl chloride (1.92 g, 12.9 mmol) in THF was slowly added. The resulting solution was stirred for 30 min at −78° C., allowed to warm up to room temperature and stirred for 5 h. The reaction was quenched by adding 6N HCl and extracted with EtOAc (×3). The organic fractions were combined and washed with sat. NaCl, dried over Na2SO4 and evaporated under vacuum. The resulting residue was purified by silica column chromatography to give 2 g (58%) of 1-(4-chlorophenyl)-3-(tetrahydro-2H-pyran-4-yl)propane-1,3-dione. 1-(4-chlorophenyl)-3-(tetrahydro-2H-pyran-4-yl)propane-1,3-dione 1 g (3.75 mmol) was taken in absolute ethanol (20 mL) and TEA (1.4 mL, 10 mmol) was added slowly. This solution was stirred for 20 min and added drop-wise to a solution of (2-methoxyphenyl)hydrazine hydrochloride (0.7 g, 4.0 mmol) in ethanol (20 mL). This solution was heated to 60° C. and stirred for 5 h. Ethanol was removed under vacuum and the residue was taken in EtOAc and washed with water, and sat. NaCl. The solution was dried over Na2SO4 and evaporated. The residue was purified by silica column chromatography to give 5-(4-chlorophenyl)-1-(2-methoxyphenyl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1.[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:18][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:16])([F:17])[F:1])=[CH:9][CH:8]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)Cc1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)c1ccc(OC(F)(F)F)cc1
Yield: 103.2 %

Procedure:
A mixture of ethyl 2-(4-(trifluoromethoxy)phenyl)acetate (1.99 g, 8.00 mmol), N-bromosuccinimide (NBS) (1.57 g, 8.80 mmol) and 2,2′-azobis(2-methylpropionitrile) (AIBN) (66 mg, 0.400 mmol) in carbon tetrachloride (10 ml) was heated under reflux for 5 hours. The reaction mixture was concentrated in vacuo, diluted with diethyl ether (200 ml), washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to give ethyl 2-bromo-2-(4-(trifluoromethoxy)phenyl)acetate (65) (2.70 g, quantitative yield) as yellow oil.
Reaction SMILES: [CH3:1][C@@:2]1(O)[C@H:9]([CH3:10])[O:8][C@@H:5]([O:6][CH3:7])[CH2:4][C@@H:3]1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14].S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH2:1]=[C:2]1[C@H:9]([CH3:10])[O:8][C@@H:5]([O:6][CH3:7])[CH2:4][C@@H:3]1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14]
Reactant: CO[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@](C)(O)[C@H](C)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: C=C1[C@@H](NC(=O)C(F)(F)F)C[C@H](OC)O[C@H]1C

Procedure:
The starting material for the preparation of the intermediates III-A and III-B is methyl 2,3,6-trideoxy-4-C-methyl-3-trifluoroacetamido-α-L-lyxo hexopyranoside (VII), a known compound described in British patent application No. 2034707. Treatment of this compound (VII) in anhydrous benzene with thionyl chloride, followed by aqueous sodium bicarbonate gives methyl 2,3,4,6-tetradeoxy-4-C-methylene-3-trifluoroacetamido-α-L-threohexopyranoside (VIII). Catalytic hydrogenation of compound VIII proceeds stereoselectively giving methyl 2,3,4,6-tetradeoxy-4-C-methyl-3-trifluoroacetamido-α-L-arabino-hexopyranoside (XI). Mild acid hydrolysis of compounds VIII and XI gives the corresponding hexopyranoses IX and XII which by treatment with trifluoroacetic anhydride are transformed into the corresponding 1-0-trifluoroacetates X and XIII. Treatment of these intermediates with dry hydrogen chloride in anhydrous diethyl ether leads to the 1-chloroderivatives III-A and III-B, respectively. The foregoing sequence of transformations is shown in the scheme below: ##STR3## For the preparation of the 1-chloroderivative III-C, the key intermediate XVI is obtained by either of two different routes. Oxidation of compound VIII with meta-chloroperbenzoic acid in 1,2-dichloroethane gives compound XVI, which may alternatively be obtained by treatment with diazomethane of methyl 2,3,6-trideoxy-3-trifluoroacetamido-α-L-threo-hexopyranosid-4-ulose (XV), a known compound described in U.S. Pat. No. 4,039,663, as shown below: ##STR4## Azidolysis of methyl 2,3,6-trideoxy-4-C-hydroxymethyl-4,4'-anhydro-3-trifluoroacetamido-α-L-lyxo-hexopyranoside (XVI) gives the azido compound XVII. Catalytic hydrogenation thereof, followed by N-trifluoroacetylation affords compound XVIII, which on mild acid hydrolysis gives XIX. Subsequent 0-trifluoroacetylation thereof, followed by treatment with dry hydrogen chloride in anhydrous diethyl ether gives the 1-chloroderivative III-C.
Reaction SMILES: [C:1]1(C=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13](O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>N1C=CC=CC=1>[C:9]1([C:14](=[CH2:13])[C:15]([OH:17])=[O:16])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc2ccccc12
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: C=C(C(=O)O)c1cccc2ccccc12
Temperature: 25 °C

Procedure:
1-Naphthyl acrylic acid was prepared by reaction of 1-naphthaldehyde and malonic acid. 1-Naphthaldehyde (46.8 g.), malonic acid (60.0 g.), pyridine (120 ml.), and piperidine (3 ml.) were charged into a 500 ml. round bottom flask and refluxed on a water bath for 4 hours. The reaction solution was cooled to room temperature and poured onto a mixture of 175 ml. concentrated hydrochloric acid and 300 g. of crushed ice. A white precipitate formed and the slurry was stirred until all the ice had melted. The precipitate was separated from the slurry by filtration and washed with one portion of 10% hydrochloric acid (75 ml.) and two portions of deionized water (each 75 ml.). The 1-naphthyl acrylic acid precipitate was fully dewatered by continued application of suction on the filter, and then vacuum dried at 40°C. for 24 hours.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([C:6]([NH:9][C:10]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O:22][CH2:23][C:24]1[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=1)=[O:11])([CH3:8])[CH3:7])#[N:5].C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)(=O)C>[OH:3][NH:2][C:4]([C:6]([NH:9][C:10]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O:22][CH2:23][C:24]1[CH:25]=[N:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=1)=[O:11])([CH3:8])[CH3:7])=[NH:5]
Reactant: NO
Reactant: CC(C)(C#N)NC(=O)c1ccc2ccccc2c1OCc1ccc(C(F)(F)F)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(NC(=O)c1ccc2ccccc2c1OCc1ccc(C(F)(F)F)nc1)C(=N)NO
Temperature: 25 °C
Yield: 10.3 %

Procedure:
0.16 g hydroxylamine hydrochloride was added to a room temperature solution of 0.28 g 1-(6-trifluoromethyl-pyridin-3-yl-methoxy)-naphthalene-2-carboxylic acid (cyano-dimethyl-methyl)-amide and 0.50 g potassium carbonate in 5 ml 95% ethanol, and the resulting mixture was heated at reflux for 24 h. The reaction mixture was cooled to room temperature, diluted with 100 ml ethyl acetate, and was washed twice with 100 ml sat. sodium hydrogen carbonate solution and 100 ml brine. The combined organic layers were dried over sodium sulphate, and concentrated in vacuo to give an orange oil. Purification of the residue by RP-HPLC afforded 0.031 g of 1-(6-trifluoromethyl-pyridin-3-yl-methoxy)-naphthalene-2-carboxylic acid [1-(N-hydroxycarbamimidoyl)-1-methyl-ethyl]-amide as a colorless foam.
Reaction SMILES: [OH-].[CH2:2]([N+:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1C=C[C:34]2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)[O:39][C:37](=[O:38])[C:35]=2C=1.C(O)(=O)C=C>CO>[C:37]([O-:39])(=[O:38])[CH:35]=[CH2:34].[CH2:24]([N+:9]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: C=CC(=O)O
Agent: CCCCCCC[N+](CCCCCCC)(CCCCCCC)CCCCCCC
Agent: [OH-]
Solvent: CO
Product: C=CC(=O)[O-]

Procedure:
The AgOH is resuspended in 400 ml of methanol. Purified tetraalkylammonium iodide (0.1 moles or 53.77 g) (Aldrich Chemical Co., Milwaukee, WI) is dissolved separately in 100 ml. of methanol and is added to the AgOH suspension. Almost immediately, the AgOH develops a greenish cast. The mixture is stirred for an hour and then filtered through a sintered-glass funnel. The filtrate now contains 0.1 moles of tetraheptylammonium hydroxide. A small amount of phenolphthalein is added, turning the solution red indicating that the solution is basic. Acrylic acid is added until the red color disappears. The methanol is removed by evaporation in a rotary flash evaporator leaving tetraheptylammonium acrylate. The resulting tetraheptylammonium acrylate was found to be electrically conductive.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[C:8](=[O:21])[C:9]2[C:14]([C:15](=[O:19])[C:16]=1[O:17][CH3:18])=[C:13]([NH2:20])[CH:12]=[CH:11][CH:10]=2.N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:5][O:6][C:7]1[C:8](=[O:21])[C:9]2[C:14]([C:15](=[O:19])[C:16]=1[O:17][CH3:18])=[C:13]([NH:20][C:1](=[O:3])[CH3:2])[CH:12]=[CH:11][CH:10]=2
Reactant: CC(=O)Cl
Reactant: COC1=C(OC)C(=O)c2c(N)cccc2C1=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC1=C(OC)C(=O)c2c(NC(C)=O)cccc2C1=O
Temperature: 0 °C

Procedure:
Acetyl chloride (1.5 ml, 20 mmol) is added dropwise, over 10 min, to an ice water cooled, stirred suspension of 12a from Example 5 (466 mg, 2 mmol) in chloroform (15 ml) containing pyridine (1.6 ml, 20 mmol). After a total reaction time of 30 min, the mixture is diluted with chloroform (50 ml) and then washed with water (2×25 ml). The chloroform phase is dried over MgSO4, concentrated to dryness and the residue recrystallized from iso-propanol affording 498 mg (85%) of 12b R1 =R2 =OCH3, with mp 162°-163°.