Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:13]=[C:12]3[CH:24]=[O:25])[CH:4]=1>O.O1CCOCC1.[N+]([O-])([O-])=O.[Ag+]>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:13]=[C:12]3[C:24]([OH:1])=[O:25])[CH:4]=1
Reactant: [OH-]
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(-c3cccnc3)cc12
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1nn(C2CCCCO2)c2ccc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
To a solution of silver nitrate (0.55 g, 3.25 mmol) in water (10 mL) was added a solution of sodium hydroxide (0.26 g, 6.50 mmol) in water (5 mL) to give a brown precipitate. 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (CXXXII) (0.40 g, 1.30 mmol) dissolved in 1,4-dioxane (3 mL) was added to the reaction which was stirred at room temperature for 2 h. The reaction was then extracted with diethyl ether. The aqueous layer was separated and carefully brought to pH=3 with 10% aqueous HCl. The aqueous layer was then extracted five times with iPrOH/chloroform (1/9). The combined organic layers were then dried (MgSO4) and concentrated to afford 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (CXXXIII) (0.30 g, 0.93 mmol, 70% yield) as a white solid. 1H NMR (DMSO-d6) δ ppm 13.28 (br, 1H), 8.93 (s, 1H), 8.60 (d, J=4.1 Hz, 1H), 8.32 (d, J=0.83 Hz, 1H), 8.14-8.12 (m, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.86 (dd, J=8.8, 1.7 Hz, 1H), 7.52 (dd, J=7.8, 4.7 Hz, 1H), 6.04 (dd, J=9.3, 2.3 Hz, 1H), 3.92-3.90 (m, 1H), 3.83-3.78 (m, 1H), 2.44-2.37 (m, 1H), 2.08-2.02 (m, 2H), 1.79-1.76 (m, 1H), 1.63-1.61 (m, 2H).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Br.[C:19]([OH:22])(=[O:21])[CH3:20]>>[C:19]([O:22][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)O
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: Br
Product: CC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 0 °C

Procedure:
In 400 ml of dioxane was dissolved 30 g of 4-methoxy-4'-acetoxy biphenyl. To this solution was dropped an aqueous solution composed of 84 g of sodium hydroxide, 400 ml of water and 30 ml of bromine and maintained at 40° C., and the solution was stirred for 30 minutes. Thereafter, 200 g of sodium hydrogen sulfate and 1 l of water were added to the solution, and the resultant reaction solution was concentrated under a reduced pressure, methyl bromide and dioxane were evaporated from the reaction solution, an aqueous concentrated hydrochloric acid solution was added to the solution and the solution was then allowed to stand to form a precipitate. The precipitate was recovered by filtration, washed with water and then dried to obtain 28 g of crude 4-methoxy-4'-biphenylcarboxylic acid. In 1.2 l of acetic acid was dissolved 28 g of this crude 4-methoxy-4'-biphenylcarboxylic acid. Thereafter, 240 ml of hydrogen bromide (48% concentration) was added to this solution and the mixed solution was refluxed for 10 hours. To this solution, 3 l of ice water was added, thereby forming a precipitate. The precipitate was recovered by filtration, washed with water, and then dried. The dried product was dissolved in a mixture of 50 ml of acetic anhydride and 25 ml of pyridine, and the solution was dropped in 200 ml of ice water to form a precipitate. The precipitate was recovered by filtration, washed with water and then dried. Recrystallization of the dried precipitate from acetic acid yielded 18 g of 4-acetoxy-4'-biphenylcarboxylic acid. 18 g of the 4-acetoxy-4'-biphenylcarboxylic acid was reacted with 20 g diazomethane to obtain methyl 4-acetoxy-4'-biphenylcarboxylate. The methyl 4-acetoxy-4'-biphenylcarboxylate was dissolved in 500 ml of tetrahydrofuran and an equimolar amount of a 1N aqueous lithium hydroxide solution was added to the resultant solution thereby to hydrolyze the methyl 4-acetoxy-4'-biphenylcarboxylate. The reaction mixture was extracted with ether to obtain 13 g of methyl 4-hydroxy-4'-biphenylcarboxylate.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:28]O.Cl>CO.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C@H:10]2[CH2:9][C@H:8]([C:6]3[O:7][NH:28][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])=[CH:19][CH:20]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(F)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(F)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 95.7 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorophenyl)piperidine-1-carboxylate (1.26 g, 3.59 mmol) (from example 25, step 1) was dissolved in MeOH (50 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.143 g, 3.59 mmol) dissolved in water (5.00 mL) was added during 5 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.220 mL, 3.59 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h 20 min. The mixture was transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (17.93 mL, 107.58 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield trans-methyl 2-(4-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.1 g, 95%) as a brown solid, 1.1 g. MS m/z 321 (M+H)+.
Reaction SMILES: [CH2:1]([N:7]=[C:8]=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[NH2:19]>N1C=CC=CC=1>[CH2:1]([N:7]1[C:12](=[O:11])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[NH:19][C:8]1=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COC(=O)c1cccnc1N
Reactant: CCCCCCN=C=O
Solvent: c1ccncc1
Product: CCCCCCn1c(=O)[nH]c2ncccc2c1=O
Yield: 30.8 %

Procedure:
17.46 g (137.3 mmol, 20 ml)n-hexyl isocyanate was added to a suspension of 5.31 g (34.9 mmol) 2-aminonicotinic acid methyl ester in 130 ml dry pyridine. The mixture was refluxed for 24 hours. The pyridine was removed under reduced pressure and the residue was treated with 160 ml ethanol. The mixture was refluxed for 10 minutes. The crude 3-hexyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione crystallized from the medium and was purified by preparative column chromatography on straight phase silica (eluent:ethyl acetate:cyclohexane 1:2). 3-hexyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione crystallized upon evaporation of the eluent. 2.66 g (310) of 3-hexyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione was isolated (m.p. 166-168° C.)
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[N:6][C:5]([Cl:10])=[C:4]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[N:3]=1.[CH2:20]([NH2:23])[CH2:21][CH3:22]>>[Cl:10][C:5]1[N:6]=[C:7]([CH:8]=[N:23][CH2:20][CH2:21][CH3:22])[C:2]([NH2:1])=[N:3][C:4]=1[S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCSc1nc(N)c(C=O)nc1Cl
Reactant: CCCN
Product: CCCCCCCCSc1nc(N)c(C=NCCC)nc1Cl

Procedure:
Following the procedures described above in Example 6, Step B, but employing instead 2-amino-5-chloro-3-formyl-6-(n-octylthio)pyrazine (100 mg; 0.342 mMol) prepared in Example 8, Step A, and n-propylamine (25 mg; 0.342 mMol and 20% excess), the title compound was prepared. Elemental Analysis for C16H27N4SCl
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[CH:20]=1>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Br:18])[CH:20]=2)[C@H:10]([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(Br)c1
Reactant: C[C@@H]1CN(Cc2ccccc2)CC[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2ccccc2)CC[C@@H]1Oc1cccc(Br)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Dissolve 1-benzyl-cis-3-methyl-piperidin-4-ol (preparation 6, 3.84 g, 18.73 mmol) in dry N,N-dimethylformamide (100 mL), treat with 60% sodium hydride (1.05 g, 26.22 mmol), heat and stir at 80° C. After 1 hr., add-1-bromo-3-fluoro-benzene (2.51 mL, 22.45 mmol), stir and heat at 110° C. After 16 hr., cool to ambient temperature. Partition between water (100 mL) and ethyl acetate (100 mL), wash the aqueous layer with ethyl acetate (2×100 mL), combine the organic layers, wash with water (5×100 mL) and aqueous NaCl solution (100 mL). Dry the organic layer over sodium sulfate, filter and concentrate. Purify the residue by silica gel flash chromatography eluting with 2% (2M NH3/methanol)/methylene dichloride to obtain the title compound as a mixture of enantiomers (1.69 g, 24%). 1H NMR (CDCl3): 7.3 (m, 5H), 7.1 (m, 3H), 6.8 (m, 1H), 4.3 (m, 1H), 3.5 (d, 2H), 2.5 (m, 2H), 2.4 (m, 2H), 2.0 (m, 2H), 1.8 (m, 1H), 1.0 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[N:9]=2)=[CH:4][CH:3]=1.[OH:17][C:18]([CH3:33])([CH3:32])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[O:30][CH3:31]>CO.O.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][N:11]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:18]([OH:17])([CH3:33])[CH3:32])=[C:22]([O:30][CH3:31])[CH:23]=3)[C:10](=[O:14])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(B(O)O)ccc1OCC(C)(C)O
Reactant: O=c1nc(COc2ccc(Cl)cc2)cc[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: O
Product: COc1cc(-n2ccc(COc3ccc(Cl)cc3)nc2=O)ccc1OCC(C)(C)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a mixture of 4-((4-chlorophenoxy)methyl)pyrimidin-2(1H)-one Part C (0.2 g, 0.845 mmol), 4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenylboronic acid Part D of Procedure 4 (0.304 g, 1.268 mmol), and copper (II) acetate monohydrate (0.169 g, 0.845 mmol) in MeOH (45 mL) and H2O (11 mL) was added N,N,N′N′-tetramethylethylenediamine (0.26 mL, 1.690 mmol). After stirring at RT for 45 minutes in the presence of air, the mixture was extracted with CH2Cl2 (200 mL). The organic phase was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica gel/100:0 to 0:100 hexanes-ethyl acetate to 95:5 CH2Cl2/MeOH gradient). The product thus obtained was re-purified using prep HPLC (Phen Luna Axia C18 5μ 10:90 to 90:10 MeOH/H2O) to afford the desired product 4-((4-chlorophenoxy)methyl)-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-2(1H)-one C-1 (16.9 mg, 0.036 mmol, 4.32% yield) as a yellow solid. 100 mg of starting material 4-((4-chlorophenoxy)methyl)pyrimidin-2(1H)-one was also recovered. LC/MS 431 (M+H)+, tR 0.81 min (method 5); 1H NMR (400 MHz, Chloroform-D) δ 7.73 (1H, d, J=6.78 Hz), 7.28-7.31 (2H, m), 6.94-7.03 (2H, m), 6.86-6.94 (3H, m), 6.66 (1H, d, J=7.03 Hz), 5.02 (2H, s), 3.87 (3H, s), 3.86 (2H, s), 1.36 (6H, s).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH2:13]([O:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[C:24]([OH:27])[CH:23]=[CH:22][CH:21]=2)=[O:17])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:47](O)[CH:48]([CH3:50])[CH3:49]>C1COCC1>[CH2:13]([O:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[C:24]([O:27][CH2:47][CH:48]([CH3:50])[CH3:49])[CH:23]=[CH:22][CH:21]=2)=[O:17])[CH3:14]
Reactant: CC(C)CO
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(OCC(C)C)cccc2[nH]1
Reaction time: 3 h

Procedure:
DEAD (10.2 ml, 65.28 mmol) is slowly added to a solution of 4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester 79 (9.57 g, 46.63 mmol), triphenylphosphine (17.12 g, 65.28 mmol) and isobutanol (5.9 ml, 63.42 mmol) in 100 ml of THF, so that the temperature always remained below 30° C. Stirring is continued for 3 hours and the solvent is then evaporated. The crude mixture is purified by chromatography on silicagel using first cyclohexane as eluent, then increasing amounts of EtOAc (from 5% to 50%).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19].Cl>N1C=CC=CC=1>[C:18]([O:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1)(=[O:20])[CH3:19]
Reactant: O=C(O)c1ccc(Cc2ccc(O)cc2)cn1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Cc2ccc(C(=O)O)nc2)cc1
Reaction time: 18 h

Procedure:
0.7 Gram of 5-(4-hydroxybenzyl)picolinic acid was dissolved in 6 ml. of pyridine. The resulting solution was then added with 2 ml. of acetic anhydride dropwise under ice-cooling and stirring. The whole was allowed to stand at room temperature for 18 hours. The reaction solution was acidified with hydrochloric acid and then subjected to extraction with ethyl acetate. After washing with water and drying, the solvent was distilled out and the residue was recrystallized from benzene to obtain 0.3 g of 5-(4-acetoxybenzyl)picolinic acid as colorless needle-like crystals of a melting point of 116°-119° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:1][CH2:2][C@@H:3]([NH:11][C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCCCO1
Reaction time: 1 h
Yield: 49 %

Procedure:
At 0° C., tert-butyl (2S)-1-hydroxy-3-(tetrahydro-2H-pyran-2-yl)propan-2-ylcarbamate (1.41 g, 5.44 mmol) in CH2Cl2 (50 mL) was treated with Et3N (2.3 mL, 16.3 mmol) followed by methanesulfonyl chloride (1.1 mL, 13.6 mmol). The reaction was allowed to stir for 1 h and quenched with water. The organic layer was washed with satd aq NaHCO3 and brine, dried over Na2SO4, and filtered. After removal of solvent, the crude material was purified using chromatography on silica gel (EtOAc/Hex) to afford (2S)-2-(tert-butoxycarbonylamino)-3-(tetrahydro-2H-pyran-2-yl)propyl methanesulfonate (0.90 g) as a solid. MS m/z 360 (M+Na).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:13]([N:14]2[N+:18]([O-:19])=[C:17]3[CH2:20][CH2:21][CH2:22][CH2:23][C:16]3=[N:15]2)=[CH:12][C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=1.[CH2:24](Br)[C:25]#[CH:26].O>CN(C)C=O>[CH2:26]([N:8]1[C:7]2[CH:12]=[C:13]([N:14]3[N+:18]([O-:19])=[C:17]4[CH2:20][CH2:21][CH2:22][CH2:23][C:16]4=[N:15]3)[C:4]([F:3])=[CH:5][C:6]=2[S:10][C:9]1=[O:11])[C:25]#[CH:24]
Reactant: O=c1[nH]c2cc(-n3nc4c([n+]3[O-])CCCC4)c(F)cc2s1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCn1c(=O)sc2cc(F)c(-n3nc4c([n+]3[O-])CCCC4)cc21

Procedure:
To a dispersion of sodium hydride (60% oil; 31 mg) in dry N,N-dimethylformamide (3 ml) was added 2-[6-fluoro-2(3H)-benzothiazolon-5-yl]-4,5,6,7-tetrahydro-2H-benzotriazole-1-oxide (220 mg) at 0° C., and the resultant mixture was stirred at the same temperature for 30 minutes, followed by addition of propargyl bromide (94 mg). The mixture was allowed to react at 50° to 60° C. for 3 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel thin layer chromatography using a mixture of ethyl acetate and toluene (1:9) as an eluent to give 2-[3-(2-propynyl)-6-fluoro-2(3H)-benzothiazolon-5-yl]-4,5,6,7-tetrahydro-2H-benzotriazole-1-oxide (Compound No. 5; 120 mg). nD25.4 1.5988.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][SH:13].[Na]>C(O)C>[CH3:12][S:13][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CS
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: [Na]
Solvent: CCO
Product: CSc1cccc(F)c1[N+](=O)[O-]
Reaction time: 2 h
Yield: 84.8 %

Procedure:
2,6-Difluoronitrobenzene (1.0 g, 6.3 mmol) was stirred in ethanol (10 mL) and treated with sodium methylmercaptan (0.44 g, 6.3 mmol) in several portions over 5 minutes. After stirring for 2 hours the mixture was evaporated and chromatographed on silica gel (70% hexane:30% ethyl acetate) to give 2-methylmercapto-6-fluoronitrobenzene (approximately 1.0 g), which was reduced in ethanol (30 mL) using 5% palladium on carbon (0.3 g) and hydrogen (50 psi) for 2 hours. The catalyst was removed by filtration through celite and the solvent evaporated to give 2-fluoro-6-(methylthio)benzenamine (0.69 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[CH:3]1[C:16]([OH:18])=[O:17].[C:20]([C@@H:22](O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:24]=1)#[N:21]>>[CH3:1][C:2]1([CH3:19])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[O:8])[C@H:3]1[C:16]([O:18][C@H:22]([C:20]#[N:21])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:24]=1)=[O:17]
Reactant: CC1(C)C(/C=C\C(=O)OC2CCCCC2)C1C(=O)O
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OC1CCCCC1
Yield: 42.4 %

Procedure:
Using the procedure of Step D in Example 7, 2.5 g of the product of Step C and 2.2 g of (S)α-cyano-3-phenoxy-benzyl alcohol were reacted and the product was chromatographed over silica gel. Elution with a 9-1 hexane-ether mixture yielded 1.883 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[Z-2-(cyclohexyloxycarbonyl)-ethenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+41°±2.5° (c=0.5% in chloroform).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([OH:13])=O.C(Cl)(=O)C([Cl:17])=O>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([Cl:17])=[O:13]
Reactant: O=C(O)CCc1ccc(F)cc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CCc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 3-(2,4-difluorophenyl) propanoic acid (28.7 g, 0.15 mol) and dimethylformamide (5 drops) at ambient temperature was added dropwise oxalyl chloride (50 mL, Aldrich). The mixture was stirred at ambient temperature for 18 h. The excess oxalyl chloride was removed by distillation in vacuo to give 3-(2,4-difluorophenyl)propionyl chloride. A solution of the 3-(2,4-difluorophenyl)propionyl chloride in dichloromethane (300 mL) was added dropwise to a mixture of aluminum chloride (23.4 g, 0.18 mol, Aldrich) in dichloromethane (300 mL) at ice bath temperature. After the addition was completed, the mixture was refluxed for 3.5 h and allowed to come to ambient temperature over-night. The reaction mixture was poured into ice water (I1500 mL), the two phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed successively with 0.1N aqueous sodium hydroxide and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to give 21.7 g of crude 4,6-difluoro-1-indanone. Chromatography on silica gel with hexanes: dichloromethane (3:1) as eluent gave 10.1 g of a light yellow solid. Recrystallization of 0.5 g from acetone: water mixtures gave 0.2 g of 4,6-difluoro-1-indanone as a white solid: mp 97°-99° C.; NMR (CDCl3): d 7.02-7.27 (m, 2H), 3.12 (t, 2H), 2.76 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccccc2)cc1
Solvent: CCO
Product: Nc1ccc(/C=C/c2ccccc2)cc1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 91.1 %

Procedure:
38 g of 4-nitrostilbene are hydrogenated in 120 g of ethanol with 6 g of a CoSx paste prepared according to Example 1, which was digested with ethanol and contains approx. 30% of CoSx, in a stainless steel stirred autoclave at 115° C under 80 bars of H2. The calculated amount of hydrogen for the reduction of the nitro group has been take up within 1 hour. The mixture is stirred for a further 10 minutes at 120° C and 80 bars of H2. The reduction mixture is filtered and the resulting solution gives 30 g of 4-amino-trans-stilbene; melting point 151° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]12[CH2:16][CH:12]3[CH2:13][CH:14]([CH2:15]1)[C:10]([NH2:17])([CH2:11]3)[CH2:9]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C:34]#[N:35])=[O:28]>CS(C)=O.CCOC(C)=O>[O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]12[CH2:16][CH:12]3[CH2:11][C:10]([NH:17][CH2:26][C:27]([N:29]4[CH2:33][CH2:32][CH2:31][C@H:30]4[C:34]#[N:35])=[O:28])([CH2:9]1)[CH:14]([CH2:13]3)[CH2:15]2
Reactant: NC12CC3CC1CC(CN1CCCS1(=O)=O)(C3)C2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(CN1CCCS1(=O)=O)(C3)C2
Reaction time: 3 h
Yield: 43.6 %

Procedure:
To a stirred mixture of the amine obtained in step IV (0.26 g, 0.96 mmol) and K2CO3 (0.42 g, 2.9 mmol) in DMSO (4.0 mL) at ice bath temperature was added under nitrogen atmosphere (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.17 g, 1.0 mmol). After stirring the reaction mixture for 3 h at r.t, it was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-[(1,1-dioxidoisothiazolidin-2-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as an off-white solid (0.17 g) in 43% yield. m/z (M+1) 407; 1H NMR (CDCl3) 300 MHz δ 4.87-4.76 (m, 1H), 3.70-3.40 (m, 2H), 3.44 (s, 2H), 3.32 (t, J=6.7 Hz, 2H), 3.10 (t, J=7.5 Hz, 2H), 2.93 (s, 2H), 2.41-2.10 (m, 8H), 1.90-1.46 (m, 7H), 1.43-1.35 (m, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[N:5][N:4]=1.[NH:18]1[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]1.C(N(CC)CC)C>C(#N)C>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:9]=[C:8]([N:7]2[C:3]([CH2:2][N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[N:4][N:5]=[N:6]2)[CH:13]=[CH:12][CH:11]=1
Reactant: FC(F)(F)c1cccc(-n2nnnc2CCl)c1
Reactant: O=S1(=O)CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=S1(=O)CCN(Cc2nnnn2-c2cccc(C(F)(F)F)c2)CC1
Temperature: 120 °C

Procedure:
To a solution of 5-(chloromethyl)-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole (300 mg, 1.14 mmol, commercially available from Otava, Kiev, Ukraine) in acetonitrile (4 mL) was added thiomorpholine 1,1-dioxide (309 mg, 2.29 mmol, Apollo Scientific, Stockport, UK) and triethylamine (0.175 mL, 1.26 mmol). The reaction mixture was heated at 120° C. for 20 minutes in a microwave reactor. The reaction mixture was cooled and then the solvent removed under vacuum. The residue was purified by MDAP. Fractions containing the desired product were combined and the solvent removed to yield a colourless gum. The product was partitioned between DCM (6 mL) and saturated aqueous NaHCO3 (3 mL) and the organic layer collected via a hydrophobic frit. The solvent was removed under a stream of argon to yield the title compound as a white solid (0.246 g)