Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([O:9]C)=O)[CH2:4][CH2:3]1.[H-].[Na+].[CH3:13]I.[BH4-].[Na+]>O1CCCC1.CO>[OH:9][CH2:7][C@H:5]1[N:6]([CH3:13])[C:2](=[O:1])[CH2:3][CH2:4]1
Reactant: CI
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN1C(=O)CC[C@H]1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
To a solution of (S)-methyl 5-oxo-pyrrolidine-2-carboxylate (Aldrich, 2.86 g, 20 mmol) in tetrahydrofuran (50 mL) at 0° C. was added in portions 60% oil dispersion NaH (720 mg, 30 mmol). Methyl iodide (1.88 mL, 30 mmol) was added and the mixture was allowed to warm to ambient temperature and stirred for 16 h. The mixture was concentrated under reduced pressure and residue was partitioned between water and ethyl acetate. The organic layer was washed with water, brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was redissolved in anhydrous tetrahydrofuran (50 mL), sodium borohydride (946 mg, 25 mmol) was added followed by dropwise addition (˜20 min) of methanol (20 mL) at 50° C. The reaction mixture was stirred for an additional 1 h at a range from 45° C. to 50° C., then cooled to room temperature and concentrated under reduced pressure. Citric acid (10%) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, ethyl acetate-ethanol 4:1) to afford 1.3 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 1.77 (m 1H), 1.95 (m, 1H), 2.18 (m, 2H), 2.69 (s, 3H), 3.43 (m, 2H), 3.55 (m, 1H), 4.77 (t, J=6 Hz, 1H); MS (DCI/NH3) m/z 130 (M+H)+, 147 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:17][CH3:18].[Cl:19][C:20]1[N:25]=[C:24](Cl)[C:23]([Cl:27])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:19][C:20]1[N:25]=[C:24]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]3)=[CH:4][C:3]=2[O:17][CH3:18])[C:23]([Cl:27])=[CH:22][N:21]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COc1cc(N2CCN(C(C)=O)CC2)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(C)=O)CC2)ccc1Nc1nc(Cl)ncc1Cl
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1-(4-(4-amino-3-methoxyphenyl)piperazin-1-yl)ethanone (150 mg) prepared in Preparation Example 1, 2,4,5-trichloropyrimidine (120 mg) and potassium carbonate (120 mg) were dissolved in dimethylformamide (2 ml), and stirred at 80° C. overnight. The dimethylformamide of the mixture was removed under reduced pressure and added with water to form a solid. The solid was filtered to obtain a target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[O:9])=[CH:4][C:3]=1[N+:20]([O-])=O.O.O.[Sn](Cl)Cl>C(O)(=O)C>[NH2:20][C:3]1[CH:4]=[C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[O:9])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(N)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccccc1C(=O)c1ccc(N)c(N)c1
Temperature: 75 °C
Reaction time: 7 h
Yield: 36.7 %

Procedure:
Methyl 2-[(4-amino-3-nitrophenyl)carbonyl]benzoate (0.74 g, 2.47 mmol) was dissolved in acetic acid (9 mL) at 45° C. and tin (II) chloride dihydrate (2.22 g, 9.84 mmol) was added. The mixture was stirred at 75° C. for 7 h and then was concentrated in vacuo. The residue was transferred to an Erlenmeyer flask using a little ethyl acetate and diluted with ether (20 mL). The mixture was stirred while cooling in an ice-water bath and sodium hydroxide (50% solution in water) (6 mL) was added dropwise. The solid which formed was removed by filtration and was washed with hot ethyl acetate. The combined filtrate was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford methyl 2-[(3,4-diaminophenyl)carbonyl]benzoate as a yellow solid (0.245 g, 0.907 mmol, 37% yield). 1H NMR (400 MHz, d6-DMSO): 7.87 (dd, 1H), 7.65 (td, 1H), 7.57 (td, 1H), 7.32 (dd, 1H), 6.93 (d, 1H), 6.66 (dd, 1H), 6.44 (d, 1H), 5.49 (s, 2H), 4.69 (s, 2H), 3.57 (s, 3H); MS (EI) for C15H14N2O3: 293 (MNa+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:12]1([C:18]2[O:22][N:21]=[CH:20][C:19]=2[CH2:23][CH2:24][C:25](O)=[O:26])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:25](=[O:26])[CH2:24][CH2:23][C:19]3[CH:20]=[N:21][O:22][C:18]=3[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Reactant: Nc1ccc2ncccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCc1cnoc1-c1ccccc1)Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A mixture of 6-aminoquinoline (0.38 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (0.56 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.46 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.60 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(6-quinolyl)-3-(5-phenyl-4-isoxazolyl)propionamide (0.79 g, yield 89%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 170–171° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][CH2:12][CH3:13])[C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[C:20]([O:23][CH2:24][C:25](Cl)=[O:26])(=[O:22])[CH3:21]>C(Cl)Cl>[C:20]([O:23][CH2:24][C:25]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][CH2:12][CH3:13])[C:3]=1[C:4]([NH2:6])=[O:5])=[O:26])(=[O:22])[CH3:21]
Reactant: CCNc1cccc(N)c1C(N)=O
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCNc1cccc(NC(=O)COC(C)=O)c1C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(ethylamino)benzamide (3 g) in methylene chloride (100 ml) is added pyridine (3 ml), and thereto is added dropwise acetoxyacetyl chloride (2.0 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, the solvent is distilled off under reduced pressure. The resulting crude crystals are washed with water and ether and then are recrystallized from ethanol to give the title compound (2.5 g) having the following physical properties.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:13]3[N:14]=[C:15]([CH2:18][O:19][C:20]4[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:22]([CH3:32])[CH:21]=4)[S:16][CH:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl.CCOC(C)=O>C1COCC1.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:13]3[N:14]=[C:15]([CH2:18][O:19][C:20]4[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:22]([CH3:32])[CH:21]=4)[S:16][CH:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)COc1ccc(OCc2nc(-c3cccc(OC4CCCC4)c3)cs2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCc2nc(-c3cccc(OC4CCCC4)c3)cs2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The methyl 2-(4-((4-(3-(cyclopentyloxy)phenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetate from Step A is dissolved in THF (1 mL), then a solution of 1 M LiOH in H2O (0.2 mL) is added and the mixture is stirred for 3 h at rt. The mixture is acidified with 1 M HCl (0.25 mL). EtOAc (10 mL) is added, and the organic layer is washed with brine (5 mL). The organic layer is dried (MgSO4), filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound C1 as a white solid: 1H-NMR (400 MHz, CDCl3) δ=7.46 (s, 1H), 7.33 (m, 3H), 6.89 (m, 2H), 6.76 (dd, J=2.8, 8.8 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 5.41 (s, 2H), 4.84 (m, 1H), 4.64 (s, 2H), 2.28 (s, 3H), 1.88 (m, 4H), 1.82 (m, 2H), 1.63 (m, 2H). MS calcd. for C24H26NO5S (M+H+) 440.2. found 440.1.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([CH:8]([CH3:22])[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[O:5][N:4]=1.[NH3:23]>>[NH2:23][CH2:2][C:3]1[N:7]=[C:6]([CH:8]([CH3:22])[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[O:5][N:4]=1
Reactant: N
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCl)no1
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CN)no1
Reaction time: 8 h

Procedure:
A mixture of 6.0 g of 3-chloromethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole and 50 ml of liquid ammonia was allowed to stand in an autoclave at room temperature overnight. After evaporation of ammonia, the residue was chromatographed over silica gel using chloroform to give 4.05 g of 3-aminomethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole as a light brown oil, nD22 1.5878.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[Cl:7][SiH:8]([Cl:10])[Cl:9]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[Cl:7][Si:8]([Cl:10])([Cl:9])[C:2]([CH2:3][CH2:4][CH2:5][CH2:6][Si:8]([Cl:10])([Cl:9])[Cl:7])=[CH2:1]
Reactant: Cl[SiH](Cl)Cl
Reactant: C1=CCCC=C1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: C=C(CCCC[Si](Cl)(Cl)Cl)[Si](Cl)(Cl)Cl
Temperature: 180 °C
Yield: 44.7 %

Procedure:
As in Example 1, 1,3-cyclohexadiene (0.98 g, 12.23 mmol), trichlorosilane (6.63 g, 48.95 mmol) and tetrabutylphosphonium chloride (0.35 g, 1.19 mmol) were added in a 25 mL stainless steel tube under nitrogen atmosphere. After sealing the cylinder with a cap, the reactor was maintained at 180° C. for 12 hours. The resulting mixture was distilled to yield 1.92 g (yield: 45%) of 2,6-bis(trichlorosilyl)-1-hexene.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[S:5][C:6]=1Br.C([Li])CCC.CCCCCC.O>O1CCCC1>[Br:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[S:5][CH:6]=1
Reactant: Fc1ccc(-c2sc(Br)c(Br)c2-c2ccncc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Fc1ccc(-c2scc(Br)c2-c2ccncc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
4,5-Dibromo-2-(4-fluorophenyl)-3-(pyridin-4-yl)thiophene (13.88 g (33.6 mmol), prepared as described in 4)) was dissolved in tetrahydrofuran (140 ml). To the solution was added dropwise at −78° C. a solution of 1.59 M butyl lithium/hexane (23.3 ml, 37 mmol). The resulting mixture was stirred at −78° C. for 15 minutes. At the end of this time, water (24 ml) was added to the reaction mixture and it was allowed to warm to room temperature. The reaction mixture was partitioned between a saturated aqueous solution of ammonium chloride and ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue (solid) was washed with diethyl ether, to give the title compound (11.20 g) as a pale brown powder (yield quantitative).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([NH:19][CH3:20])[CH:11]=2)[CH:3]=1.[CH3:21]I>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[CH3:21][O:8][C:6]1[CH:5]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([CH:11]=2)[NH:19][CH3:20])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: CI
Reactant: CNc1cc(Oc2cc(C)nc(O)c2)ccc1[N+](=O)[O-]
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: CNc1cc(Oc2cc(C)nc(OC)c2)ccc1[N+](=O)[O-]
Yield: 90 %

Procedure:
A solution of 6-methyl-4-[3-(methylamino)-4-nitrophenoxy]pyridin-2-ol produced in Example (17a) (7.85 g, 18.7 mmol), methyl iodide (4.66 mL, 74.8 mmol) and silver carbonate (10.32 g, 37.4 mmol) in chloroform (100 mL) was stirred in a nitrogen atmosphere at room temperature for five days. The insoluble matter was separated by filtration and the filtrate was concentrated under reduced pressure. Then, the residue was purified by silica gel chromatography (hexane/ethyl acetate, 5:1) to obtain the title compound (4.87 g, 90%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: c1ccc2c(c1)CCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.3 %

Procedure:
1-tert-Butoxycarbonylpiperidin-4-one (2.50 g), indoline (1.50 g) and acetic acid (0.73 mL) were dissolved in 1,2-dichloroethane (75 mL), and sodium triacetoxyborohydride (5.32 g) was added thereto. The mixture was stirred at room temperature for 12 hr. The reaction mixture was added to iced water and the mixture was extracted with chloroform. The extract was dried and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give 1-tert-butoxycarbonyl-4-(1-indolinyl)piperidine (2.82 g).
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].N([O-])=[O:11].[Na+]>S(=O)(=O)(O)O.O>[OH:11][C@@H:2]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)[C@H](N)C(=O)O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)[C@H](O)C(=O)O
Reaction time: 24 h
Yield: 64.4 %

Procedure:
To a solution of 30.0 g (0.229 mol) of L-tert-leucine in 345 mL of 1 N sulfuric acid, cooled to 0° C., was added over 2 h a solution of 23.7 g (0.343 mol) of sodium nitrite in 83 mL of water. The temperature was maintained below 5° C. during the addition, and the mixture was then refrigerated for 24 h. The solution was then extracted with 150 mL of ether (3×) and the extract was washed with 100 mL of saturated aqueous sodium chloride. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated to afford 19.5 g (65%) of a pale yellow oil. The crude product was taken to the next step. 1H-NMR (300 MHz, CDCl3): δ 3.91 (s, 1H), 1.01 (s, 9H).
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]([Cl:14])[CH:7]=1.O[CH2:17][CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:14][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH:3]=[C:2]([Cl:1])[Cl:15])[CH:11]=[C:10]([Cl:12])[C:9]=1[O:13][CH2:17][CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1
Reactant: OCCc1cccs1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCc2cccs2)c(Cl)c1
Temperature: 25 °C
Yield: 62.5 %

Procedure:
To a solution of 0.44 g of 4-(3,3-dichloro-2-propenyloxy)-2,6-dichlorophenol, 0.20 g of 2-(2-hydroxyethyl)thiophene and 0.40 g of triphenylphosphine dissolved in 10 ml of tetrahydrofuran was added dropwise a solution of 0.31 g of diisopropyl azodicarboxylate dissolved in 5 ml of tetrahydrofuran, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was concentrated, to which 20 ml of diethyl ether was added, and the precipitate was filtered. The filtrate was concentrated, and the residue was subjected to silica gel chromatography, which afforded 0.38 g of 3,5-dichloro-4-(2-(2-thienyl)ethoxy)-1-(3,3-dichloro-2-propenyloxy)benzene (62% yield), nD25.6 1.5919.
Reaction SMILES: BrBr.C(O)(=O)C.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:17])[C:15]#[N:16])=[CH:10][CH:9]=1.[S-:18][C:19]#[N:20].[K+]>O>[NH2:20][C:19]1[S:18][C:13]2[CH:12]=[C:11]([CH:14]([CH3:17])[C:15]#[N:16])[CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CC(C#N)c1ccc(N)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C#N)c1ccc2nc(N)sc2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
27.4 g of bromine in 87.5 ml of 95% v/v acetic acid were added dropwise to a stirred mixture of 25 g of 2-(p-aminophenyl)propionitrile [British Pat. No. 1,198,212], 66.8 g of potassium thiocyanate and 300 ml of 95% v/v acetic acid at ambient temperature. The mixture was then stirred at 50° C. for a further 2 hours before being poured into 1.5 liters of water. The solution obtained was filtered through celite and sodium bicarbonate was then added to the filtrate until no further precipitation occurred. The precipitate was collected and crystallized from methanol/water to give 19.4 g (56%) of 2-amino-α-methyl benzothiazole-6-acetonitrile as yellow prisms melting at 165.1° C.
Reaction SMILES: N1CCCC1.[C:6]([O:10]CC)(=[O:9])[C:7]#[CH:8].C(N(CC)CC)C.[OH:20][N:21]=[C:22](Cl)[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>C(OCC)C>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]2[C:7]([C:6]([OH:10])=[O:9])=[CH:8][O:20][N:21]=2)=[CH:24][CH:25]=1
Reactant: COc1ccc(C(Cl)=NO)cc1
Reactant: C#CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: C1CCNC1
Solvent: CCOCC
Product: COc1ccc(-c2nocc2C(=O)O)cc1
Temperature: 0 °C
Yield: 2.7 %

Procedure:
A solution of pyrrolidine (0.63 mL, 7.5 mmol) in diethyl ether (6 mL) was added during 15 min to a solution of ethyl propiolate (0.76 mL, 7.5 mmol) in diethyl ether (6 mL) at 0° C. with stirring. The resulting solution was stirred for 30 min at rt, whereafter triethylamine (1.04 mL, 7.5 mmol) was added and the reaction was chilled to 0° C. again and a solution of N-hydroxy-4-methoxybenzenecarboximidoyl chloride (1.39 g, 7.5 mmol) in diethyl ether (10 mL) was added during 30 min. The temperature was allowed to go to rt and was washed with 1 M HCl and water, dried (Na2SO4) and evaporated. The crude intermediate was dissolved in acetic acid (3 mL) and conc. HCL (3 mL) and the mixture was refluxed for 2 h. The solvents were evaporated and the mixture was partioned between ethyl acetate and cold aqu. NaOH (0.5 M). The aqueous phase was acidified by conc. HCl and filtered. The crystals were purified by silica gel chromatography (DCM:MeOH 19:1 to 5:1) to give a white solid (45 mg), which was used in the next step without further analysis or purification (ca. 90% pure). MS 220 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[H][H]>C1COCC1.O.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[NH2:9]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: [H][H]
Reactant: C1COCCN1
Agent: [Pd]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(N2CCOCC2)c(F)c1
Reaction time: 0.7 h

Procedure:
3,4-Difluoronitrobenzene (25.196 g, 158.38 mmol) is added to a mixture of morpholine (60.0 ml, 688 mmol, 4.34 eq) in THF (30 ml) at −14°. The mixture is permitted to warm to 10° then maintained at 10-13° for 1 hr. A mixture of citric acid monohydrate (75 g, 357 mmol, 2.25 eq) in water (365 ml) is added with concomitant exotherm to 28°. The phases are separated and the aqueous phase is washed with toluene (95 ml). The organic phase is washed with water (315 ml) and concentrated under reduced pressure. Toluene (46 ml) and methanol (60 ml) are added followed by palladium on Carbon (5%, 50% water wet, 3.1603 g, 0.7426 mmol, 0.00469 eq) and the mixture sealed in a Parr shaker. Hydrogen pressure (40 psi) is applied and maintained while agitating for 42 min. The catalyst is then removed by filtration under reduced pressure and washed with toluene (60 ml). Heptane (150 ml) is added to the filtrate and the resultant slurry concentrated under reduced pressure. Heptane (300 ml) is added and the precipitate collected by filtration under reduced pressure and washed with heptane and dried to give the title compound, HPLC (stationary phase is 4.6×250 mm zorbax RX C-8 column; mobile phase is acetonitrile (650 ml), triethylamine (1.85 ml) and acetic acid (1.30 ml) and water of sufficient amount to make 1,000 ml; flow rate=3.0 ml/min; UV detection at 254 nm) RT=1.08 min, >99.3 area); NMR (Pyridine-D5) 2.95-2.98, 3.80-3.83, 5.38, 6.68, 6.78 and 6.90 δ; CMR (Pyridine-D5) 52.43, 67.33, 103.31, 110.63, 121.29, 130.80, 146.23 and 157.72 δ.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([F:17])=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22]([C:24](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:25])=[O:23])[CH3:20]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:16]([F:17])=[CH:15][C:12](/[CH:13]=[C:24](\[CH3:25])/[C:22]([O:21][CH2:19][CH3:20])=[O:23])=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(F)c(OCc2ccccc2)c(F)c1
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C/c1cc(F)c(OCc2ccccc2)c(F)c1

Procedure:
A solution of 4-(benzyloxy)-3,5-difluorobenzaldehyde (7) (1.32 g, 5.34 mmol) and (1-ethoxycarbonylethylidene)triphenyl phosphorane (2.32 g, 6.41 mmol) in tetrahydrofuran (53 mL) was refluxed for 2 hours. The reaction was concentrated in vacuo and was purified by flash column chromatography (0-100% EtOAc in hexanes) to give (E)-ethyl 3-(4-(benzyloxy)-3,5-difluorophenyl)-2-methylacrylate (8).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[C:29]([CH2:31][CH3:32])[CH:28]=[CH:27][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH:21]([CH2:23][OH:24])[O:20][C:19]2=[O:25])=[CH:14][C:13]=1[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl.O>[CH2:1]([O:8][C:9]1[CH:30]=[C:29]([CH2:31][CH3:32])[CH:28]=[CH:27][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH:21]([CH2:23][O:24][S:41]([CH3:40])(=[O:43])=[O:42])[O:20][C:19]2=[O:25])=[CH:14][C:13]=1[F:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCc1ccc(Oc2ccc(N3CC(CO)OC3=O)cc2F)c(OCc2ccccc2)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(Oc2ccc(N3CC(COS(C)(=O)=O)OC3=O)cc2F)c(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 43.1 %

Procedure:
To a solution of 3-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluoro phenyl]-5-hydroxymethyloxazolidin-2-one (240 mg, 0.54 mmol) in 5 ml of dry dichloromethane and 0.16 ml (1.1 mmol) of triethylamine, cooled to 0° C., was added a solution of methanesulfonyl chloride (0.06 ml, 0.76 mmol) in 0.5 ml of dichloromethane dropwise. The reaction was allowed to warm to rt overnight. The reaction mixture was diluted with 20 ml water, 20 ml of dichloromethane were added and the layers separated. The aqueous layer was extracted with dichloromethane and the combined dichloromethane fraction was dried over anhydrous Na2SO4 and concentrated. The crude residue obtained was column purified over silica gel using 20% ethyl acetate in petroleum ether as eluant to get 120 mg, 42.8% of the title compound.