Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[NH2:10])=[O:4].[Cl:11][C:12]([Cl:19])([Cl:18])[C:13]([N:15]=[C:16]=[O:17])=[O:14]>C1COCC1>[Cl:11][C:12]([Cl:19])([Cl:18])[C:13]([NH:15][C:16]([NH:10][C:6]1[S:7][CH:8]=[CH:9][C:5]=1[C:3]([O:2][CH3:1])=[O:4])=[O:17])=[O:14]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: COC(=O)c1ccsc1N
Solvent: C1CCOC1
Product: COC(=O)c1ccsc1NC(=O)NC(=O)C(Cl)(Cl)Cl
Reaction time: 1 h

Procedure:
To a stirred solution of 2-amino-thiophene-3-carboxylic acid methyl ester (1 eq) in anhydrous THF (mL) was added trichloroacetyl isocyanate (1 eq) slowly over a period of 5 min. After the addition was complete, a precipitate formed and the reaction stirred for an additional 1 h. The desired product was obtained by filtration to give methyl 2-({[(trichloroacetyl)amino]carbonyl}amino)thiophene-3-carboxylate (99%) as an off-white solid. The product was used in the next step without any further purification. LC/MS (ES, M+H=345).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(F)cc1F
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])c(F)cc1F
Yield: 61 %

Procedure:
2,4-Difluorobenzoic acid (5 g, 0.031 M) was dissolved in concentrated sulfuric acid (30 ml), and cooled to 0°. The mixture was stirred, and fuming nitric acid (d 1.567 g/ml, 1.91 ml, 0.047 M) added dropwise, keeping the temperature below 5°. After stirring for 3 hours, the mix was poured onto ice, and organics extracted into dichloromethane (2×75 ml). The combined organic layers were washed with water, dried (MgSO4), and evaporated to give 2,4-difluoro-5-nitrobenzoic acid (3.9 g, 61%). Nmr (DMSO-d6): δ 7.18 (t, 1H); 8.88 (t, 1H); 9.93 (br, 1H).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[CH3:12][C:13]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=1)=[O:14].[OH-].[Na+]>CO>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6](/[CH:7]=[CH:12]/[C:13]([C:15]3[CH:16]=[C:17]([O:23][CH3:24])[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=3)=[O:14])=[CH:5][C:4]=2[O:9]1
Reactant: COc1cc(OC)cc(C(C)=O)c1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OC)cc(C(=O)/C=C/c2ccc3c(c2)OCO3)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 25.4 %

Procedure:
To a stirred solution of Piperonal (1.00 g, 6.67 mmol) and 3,5-dimethoxyacetophenone (1.20 g, 6.67 mmol) in methanol (30 ml) was added a 50% w/v solution of aqueous NaOH (8 ml, 15 eq). A colourless solution had formed initially following the dissolution of the two starting materials in the solvent, but upon addition of NaOH, the solution became a yellow, creamy suspension. A pale yellow precipitate was noticed approximately 2 or 3 mins after adding the aqueous NaOH. A further 3 ml (˜5 eq) of base was added, after 5 h, in order to drive the reaction to completion. The mixture was stirred for a total of 6 h at room temperature. The precipitate was collected via vacuum filtration and the filtrate discarded. The solid was purified by recrystallisation from hot methanol and hot filtration. The product was collected and allowed to be dried under vacuum to afford the title compound as a pale yellow solid (0.53 g, 25%). 1H-NMR (CDCl3) δ 7.25 (1H, d, CH(9)), 7.30(2H, d, CH(6&8)), 6.85 (1H, d, CH(3)), 6.65 (1H, t, CH(4)), 6.00 (2H, s, CH2(1)), 3.85 (6H, s, OCH3(5&7)); 13C-NMR (CDCl3) δ 189.958 (C═O), 160.870, 149.928, 148.401, 144.756, 140.403, 129.325, 125.221, 120.112, 108.650, 106.659, 106.253, 104.879, 101.621, 55.608 (OCH3); Infrared Spectrum Vmax (KBr)/cm−1 1668.3 (C═O); Mass Spectrum (FAB) m/e 313 (m+1); Elemental Analysis: Molecular Compound C18H16O5, calculated C=69.23, H=5.19 and found C=69.15, H=5.18.
Reaction SMILES: N1CCCC1.[F:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]([OH:19])=[O:18])[C:11]([CH3:20])=[C:10]2[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([N:31]1[CH2:36]C[CH2:34][CH2:33][CH2:32]1)(=[O:30])=[O:29]>>[F:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]([OH:19])=[O:18])[C:11]([CH3:20])=[C:10]2[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([N:31]1[CH2:36][CH2:34][CH2:33][CH2:32]1)(=[O:30])=[O:29]
Reactant: Cc1c(Cc2ccccc2S(=O)(=O)N2CCCCC2)c2cc(F)ccc2n1CC(=O)O
Solvent: C1CCNC1
Product: Cc1c(Cc2ccccc2S(=O)(=O)N2CCCC2)c2cc(F)ccc2n1CC(=O)O

Procedure:
Pyrrolidine was used as starting material in Procedure Q, otherwise this compound was prepared in a similar manner to Compound 2, using Procedures N, P, Q & L.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[N:6]=1.[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([F:20])[CH:14]=1.Cl>CCCCO>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=3[N:6]=2)=[C:15]([F:20])[CH:14]=1
Reactant: Cc1cccc2sc(Cl)nc12
Reactant: Nc1ccc(Br)cc1F
Agent: Cl
Solvent: CCCCO
Product: Cc1cccc2sc(Nc3ccc(Br)cc3F)nc12
Temperature: 90 °C
Yield: 89.4 %

Procedure:
To a solution of 2-chloro-4-methyl-1,3-benzothiazole (0.25 g, 1.36 mmol) in n-BuOH (8 mL) was added 4-bromo-2-fluoroaniline (0.52 g, 2.72 mmol) and HCl (4.0 M in dioxane, 0.5 mL). The reaction was heated at 90° C. overnight. Solvent was removed by rotary evaporation and 1 N aqueous HCl was added. The aqueous layer was separated and extracted with EtOAc. The combined organic phases were washed with 1 N aqueous HCl and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was brought up in MeOH and the precipitate was collected by filtration, washed with MeOH, and dried in a vacuum oven to give N-(4-bromo-2-fluorophenyl)-4-methyl-1,3-benzothiazol-2-amine (0.41 g, 89%). 1H NMR (400 MHz, DMSO-d6) δ 2.62 (s, 3H), 7.07 (t, 1H), 7.15 (d, 1H), 7.36 (m, 2H), 7.51 (d, 1H), 8.72 (t, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:14]2[CH2:15][CH2:16][C:11]([CH3:17])([CH3:10])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CCNCC1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)CCN(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Yield: 57.2 %

Procedure:
A mixture of 4-bromobenzyl bromide (500 mg, 2.0 mmol) and 4,4-dimethylpiperidine (249 mg, 2.2 mmol) and potassium carbonate (331 mg, 2.4 mmol) in acetonitrile (20 mL) was heated under reflux for 2 h. The reaction mixture was then cooled to ambient temperature and the reaction mixture concentrated under reduced pressure. The resultant oil was loaded onto an SCX-2 cartridge (10 g) and eluted with 2N ammonia in methanol to afford the title compound (323 mg, 57%). 1H NMR (CDCl3, 300 MHz): 7.42 (d, J=8.31 Hz, 2H), 7.19 (d, J=8.24 Hz, 2H), 3.44 (s, 2H), 2.35 (t, J=5.44 Hz, 4H), 1.37 (t, J=5.60 Hz, 4H), 0.90 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])=[CH:4][CH:3]=1.[CH3:17][S:18][CH2:19][C:20]#[N:21].C(OCl)(C)(C)C>C(Cl)Cl>[NH2:15][C:10]1[C:9]([C:8](=[O:16])[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:14][CH:13]=[CH:12][C:11]=1[CH:19]([S:18][CH3:17])[C:20]#[N:21]
Reactant: CSCC#N
Reactant: Nc1ccccc1C(=O)c1ccc(Cl)cc1
Agent: CC(C)(C)OCl
Solvent: ClCCl
Product: CSC(C#N)c1cccc(C(=O)c2ccc(Cl)cc2)c1N
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To a solution of 46.3 g (0.2 mole) of 4'-chloro-2-aminobenzophenone and 17.4 g (0.2 mole) of methylthioacetonitrile in 1 liter of methylene dichloride at a temperature of -70° C. was added dropwise 22.2 g (0.21 mole) of tert. butyloxychloride at a rate to ensure that the reaction temperature did not exceed -65° C. The resulting solution was allowed to warm to ambient temperature, washed twice with water, dried over sodium sulphate, and concentrated to give a gum residue. The gum crystallized when it was triturated with diethyl ether. The solid was collected by filtration and recrystallized from 2-propanol to yield 43.0 g (68%) of the title compound as a tan solid, m.p. 122° C.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)([C:15]#[N:16])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N>CO.[Ni]>[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]([CH2:15][NH2:16])([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#CC1(c2cccc(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Agent: [Ni]
Agent: Cl
Agent: N
Solvent: CO
Product: NCC1(c2cccc(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Reaction time: 8 h

Procedure:
A mixture of 1.5 g of the compound obtained in step C of Preparation 1.4, 0.15 g of Raney® nickel and 5 ml of ammonia in 20 ml of MeOH is hydrogenated overnight at AT and under atmospheric pressure. The catalyst is filtered off and the filtrate is concentrated under vacuum. This gives 1.45 g of the expected product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:64][C:65]1[CH:66]=[C:67]2[C:71](=[CH:72][CH:73]=1)[CH2:70][CH2:69][CH2:68]2>C1(C)C=CC=CC=1>[CH2:70]1[C:71]2[C:67](=[CH:66][C:65]([NH:64][C:2]3[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=3[CH3:7])=[CH:73][CH:72]=2)[CH2:68][CH2:69]1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: COC(=S)c1cc(Br)c(C)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COC(=S)c1cc(Nc2ccc3c(c2)CCC3)c(C)s1
Yield: 73.4 %

Procedure:
The same procedure as in Example 254, step (a) was followed using 120 mg (0.449 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (as prepared in Example 241, step (a), 41 mg (10 mol %) of tris-(dibenzylidineacetone)dipalladium, 42 mg (15 mol %) of racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 205 mg (0.629 mmol) of cesium carbonate and 74.8 mg (0.56 mmol) of 5-aminoindan in 900 μL of toluene, and chromatographed as before using 40% CH2Cl2-hexane to afford 100 mg (73%) of the title compound as a yellow resin. 1H-NMR (CDCl3, 400 MHz) δ2.05-2.12 (m, 2H), 2.85-2.90 (m, 4H), 3.86 (s, 3H), 6,09 (s, 1H), 6.82 (d, 1H, J=8.0 Hz), 6.93 (s, 1H), 7.14 (d, 1H, J=8.0 Hz), 7.70 (s, 1H).
Reaction SMILES: Br.Br.[OH:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][C:5]=1[CH3:17].Cl[C:19]1[C:24]([CH3:25])=[C:23]([CH3:26])[N:22]=[C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:3][C:4]1[C:5]([CH3:17])=[CH:6][C:7]([N:11]2[CH2:12][CH2:13][N:14]([C:19]3[C:24]([CH3:25])=[C:23]([CH3:26])[N:22]=[C:21]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:20]=3)[CH2:15][CH2:16]2)=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc(N2CCNCC2)cc(C)c1O
Reactant: Cc1nc(-c2ccccc2)nc(Cl)c1C
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCN(c3nc(-c4ccccc4)nc(C)c3C)CC2)cc(C)c1O
Temperature: 90 °C
Reaction time: 6 h
Yield: 75.9 %

Procedure:
A mixture of 4.42 g (12 mmol) of 1-(4-hydroxy-3,5-dimethylphenyl)piperazine dihydrobromide, 2.84 g (13 mmole) of 4-chloro-5,6-dimethyl-2-phenylpyrimidine, 1.66 g (12 mmol) of powdered K2CO3 and 38 ml of absolute DMF was warmed to 90° C., and 277 mg of powdered K2CO3 were added at 90° C. with stirring in each case after 10 minutes, after a further 25 minutes and after a further 60 minutes (in total 6 mmol of K2CO3), and the mixture was stirred for a further 6 hours at 95° C. The DMF was subsequently removed by distillation in vacuo, the residue was taken up in CH2Cl2 /water, the phases were separated after through mixing, and the aqueous phase was extracted a further three times with CH2Cl2. The combined CH2Cl2 extracts were dried, filtered and evaporated in vacuo. The crystalline residue (5.2 g) was boiled with 15 ml of methanol, and the crystals were filtered off under suction after cooling in an ice bath. In this fashion, 3.54 g (=76% yield) of pure 1-(4-hydroxy-3,5-dimethylphenyl)-4-(5,6-dimethyl-2-phenylpyrimidin-4-yl)piperazine, melting point 188°-89° C., were obtained;
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH2:22])[O:4]1.O=[C:24]1[CH2:27][CH:26]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:25]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[NH2:22][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[C:19]=1[N:20]=[CH:21][N:13]2[C@H:5]1[C@@H:6]2[O:10][C:9]([CH3:12])([CH3:11])[O:8][C@@H:7]2[C@@H:3]([CH2:2][NH:1][CH:24]2[CH2:25][CH:26]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27]2)[O:4]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CN)O[C@H]2n1cnc2c(N)ncnc21
Reactant: CCOC(=O)CCC1CC(=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)CCC1CC(NC[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@@H]3OC(C)(C)O[C@@H]32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 9-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine (0.50 g, 1.6 mmol) and ethyl 3-(3-oxocyclobutyl)propanoate (0.27 g, 1.6 mmol) in methanol (10 mL) was treated with acetic acid (0.09 mL, 2 mmol) at rt and the flask was evacuated and flushed with nitrogen (×3). The reaction mixture was treated at rt with sodium cyanoborohydride (0.26 g, 4.1 mmol), which afforded instant gas evolution and a nearly colorless, clear solution in a few minutes. The reaction mixture was stirred for 1 h at rt; HPLC/LC MS indicated a ˜2:1 mixture of product to starting amine. At 1.5 h additional ethyl 3-(3-oxocyclobutyl)propanoate (66 mg, 0.39 mmol) in MeOH (1.0 mL) was added and the reaction mixture was stirred at rt for 30 min; HPLC/LC MS indicated ˜70% conversion and some dialkylation. At 2 h 15 min water (4.0 mL) was added and the mixture was concentrated in vacuo. The residual aqueous layer was diluted with saturated aqueous sodium bicarbonate (10 mL, to pH 9) and extracted with CH2Cl2 (3×15 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford the reductive amination product as a white foam, which was carried on without further purification: MS (ESI+) for C22H32N6O5 m/z 461.1 (M+H)+, 483.1 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]=[CH2:16])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[N:20]([CH2:27][C:28]2[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:35])[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:14]([N:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:12][N:11]([CH2:18][C:19]2[N:20]([CH2:27][C:28]3[C:29]([Cl:35])=[CH:30][CH:31]=[CH:32][C:33]=3[Cl:34])[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[N:23]=2)[C:10]1=[O:13])[CH:15]=[CH2:16]
Reactant: C=CCn1c(-c2ccc(Cl)cc2)n[nH]c1=O
Reactant: O=[N+]([O-])c1cn(Cc2c(Cl)cccc2Cl)c(CCl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCn1c(-c2ccc(Cl)cc2)nn(Cc2nc([N+](=O)[O-])cn2Cc2c(Cl)cccc2Cl)c1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
110 mg (0.47 mmol) of the compound from Example 12A were dissolved in 10 ml of DMF, and 150 mg (0.47 mmol) of the compound from Example 41A and 229 mg (0.70 mmol) of cesium carbonate were added. The mixture was stirred at 80° C. for 16 h. After cooling to RT, the reaction mixture was added to about 25 ml of ice-water and stirred for 10 min. This resulted in the formation of a precipitate which was filtered off with suction and washed with water. The solid was dried under high vacuum. This gave 120 mg (44% of theory) of the target compound of a purity of 90%.
Reaction SMILES: I[CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([F:22])[CH:10]=2)[CH2:4]1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C=O)C>[N:23]([CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([F:22])[CH:10]=2)[CH2:4]1)=[N+:24]=[N-:25]
Reactant: O=C1OC(CI)CN1c1cc(F)c(-c2cccnc2)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CN(c2cc(F)c(-c3cccnc3)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
(±)-5-(Iodomethyl)-3-[4-(3-pyridyl)-3,5-difluorophenyl]-2-oxazolidinone (PREPARATION 5, 577 mg, 1.31 mmol) in DMF (dried over 4A sieves, 15 ml) is combined with sodium azide (681 mg, 10.5 mmol, 8 eq). The reaction is placed under an atmosphere of nitrogen and heated to 55°. After 2 hr, the reaction is added to water (100 ml) and then extracted with ethyl acetate (4×25 ml). The combined organic extracts are combined and are washed with water then brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The crude azide is suitable for reduction without further purification. An analytical sample is prepared by preparative TLC (silica gel) eluting with acetonitrile/chloroform (10/90). The appropriate fractions are pooled and concentrated to give the title compound, mp 97°-98°; FTIR (mull) cm-1 3483, 2110, 1746, 1640, 1417, 1237, 1064 and 716; MS (EI, m/z) 331, 274, 258, 232, 217, 190 and 43; NMR (CDCl3) 8.72, 8.63, 7.79, 7.42-7.38, 7.34, 4.90-4.82, 4.11, 3.88, 3.77 and 3.63 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:18][CH:19]([CH3:21])[CH3:20])[C:12]3[CH2:13][NH:14][CH2:15][CH2:16][C:11]=3[C:10](=[O:17])[O:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:22]([N:29]=[C:30]=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[CH2:22]([NH:29][C:30]([N:14]1[CH2:15][CH2:16][C:11]2[C:10](=[O:17])[O:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)([CH2:18][CH:19]([CH3:21])[CH3:20])[C:12]=2[CH2:13]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC(C)CC1(c2cccc(Cl)c2)OC(=O)C2=C1CNCC2
Solvent: ClCCl
Product: CC(C)CC1(c2cccc(Cl)c2)OC(=O)C2=C1CN(C(=O)NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 104 %

Procedure:
A mixture of 3-(3-chlorophenyl)-3-isobutyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (70 mg, 0.23 mmol) and benzyl isocyanate (42 μL, 0.34 mmol) in dichloromethane (5 mL) was stirred at room temperature for 1 h. The solvent was removed and the resulting residue was purified on silica to give the desired product (105 mg, 100%). 1H NMR (300 Hz, CDCl3) δ 0.85 (d, J=6.0, 3H), 0.93 (d, J=6.0, 3H), 1.55-1.70 (m, 1H), 1.72-1.82 (m, 1H), 2.20-2.40 (m, 3H), 3.15-3.29 (m, 1H), 3.49-3.61 (m, 1H), 3.89 (d, J=18.0, 1H), 4.39 (d, J=3.0, 2H), 4.48 (d, J=18.0, 1H), 5.22 (t, J=6.0, 1H), 7.14-7.38 (m, 9H).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([OH:12])([CH3:11])[CH3:10].[Cl:13][C:14]1[CH:15]=[C:16]([N+:21]([O-:23])=[O:22])[CH:17]=[CH:18][C:19]=1F>CC(N(C)C)=O>[Cl:13][C:14]1[CH:15]=[C:16]([N+:21]([O-:23])=[O:22])[CH:17]=[CH:18][C:19]=1[O:12][C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1)([CH3:11])[CH3:10]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CC(C)(O)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(Oc1ccc([N+](=O)[O-])cc1Cl)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 220 mg, 5.50 mmol) was suspended in DMA (30 ml) and 2-pyridin-2-ylpropan-2-ol (obtained as described in Organometallics, 1997, 16, 3303, 754 mg, 5.50 mmol) was added under an atmosphere of nitrogen. The mixture was stirred for 30 minutes at ambient temperature, then cooled to 0° C. 3-Chloro-4-fluoronitrobenzene (878 mg, 5.00 mmol) was added as a solution in DMA (15 ml); the mixture was warmed to room temperature, and was stirred for 2 hours. The mixture was concentrated in vacuo, and the residue partitioned between ethyl acetate (75 ml) and water (75 ml). The aqueous layer was extracted with ethyl acetate (75 ml), and the extractions combined with the organic layer. The combined organics were dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography, eluting with 0 to 20% ethyl acetate in iso-hexane, giving 2-[1-(2-chloro-4-nitrophenoxy)-1-methylethyl]pyridine as a pale yellow solid (810 mg, 55%); NMR Spectrum (DMSO-d6, 400 MHz, CDCl3) 1.91 (s, 6H), 6.40 (d, 1H), 7.25 (ddd, 1H), 7.50 (d, 1H), 7.70 (ddd, 1H), 7.82 (dd, 1H), 8.30 (d, 1H), 8.65 (d, 1H); Mass spectrum MH+ 293.0, 295.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19]
Reactant: COCCOCOc1c(C(=O)OC)cccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COCCOCOc1c(N)cccc1C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To a solution of 2-((2-methoxyethoxy)methoxy)-3-nitrobenzoic acid methyl ester 5.0 g (17.5 mmol) of step 1 in methanol 50 mL was added 5% Pd/C 0.5 g, and the reactor was filled with hydrogen gas, after which the reaction mixture was stirred at room temperature for 24 hrs. The catalyst was removed off by celite filtration before concentrating the reaction mixture in a vacuum. Purification by column chromatography (developing solvent: ethylacetate/hexane=1/1) afforded 4.2 g of the title compound (yield 95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([CH3:11])[CH:5]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([F:25])([F:24])[F:13])=[C:6]([CH3:11])[CH:5]=1)=[O:12]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)c(C)c1
Temperature: 100 °C
Yield: 78.1 %

Procedure:
A mixture of 4-bromo-3-methylbenzoic acid methyl ester of Step A (2.0 g, 8.7 mmol), 2-trifluoromethyl-phenyl boronic acid (1.65 g, 8.7 mmol) and sodium carbonate (4.1 g, 38.7 mmol) in toluene:ethanol:water (50 mL:25 mL: 25 mL) was purged with nitrogen for 1 hour. After addition of the tetrakis(triphenylphosphine) palladium(0) catalyst (0.50 g, 0.43 mmol, the reaction was heated at 100° C. overnight. The cooled reaction mixture was filtered through Celite and the cake washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification by flash chromatography with a solvent gradient of 25% to 50% dichloromethane in hexane provided 2.0 g of the title compound as a colorless oil.