Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:14]([CH:15]=[CH:16][N+:17]([O-])=O)=[C:13]([CH3:20])[C:12]([O:21][CH3:22])=[C:11]([CH3:23])[C:10]=1[CH3:24].[OH-].[Na+]>C1COCC1>[CH3:7][O:8][C:9]1[C:10]([CH3:24])=[C:11]([CH3:23])[C:12]([O:21][CH3:22])=[C:13]([CH3:20])[C:14]=1[CH2:15][CH2:16][NH2:17]
Reactant: COc1c(C)c(C)c(OC)c(C=C[N+](=O)[O-])c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1c(C)c(C)c(OC)c(CCN)c1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a stirring suspension of lithium aluminum hydride (1.63 g, 42.8 mmol, 6.0 equiv) in THF (15 mL) at 0° C. was added a solution of 1,4-dimethoxy-2,3,5-trimethyl-6-(2-nitrovinyl)benzene (1.8 g, 7.14 mmol) in THF (15 mL) over 30 min. Following addition, the mixture was warmed to 60° C. and stirred for 2 hr. After this time, the reaction was deemed complete by HPLC analysis, the mixture was slowly transferred to 100 mL 6M aqueous sodium hydroxide and stirred for 20 min. The resulting suspension was filtered in vacuo and the cake rinsed with i-propyl acetate (200 mL). The organics were removed and the remaining aqueous layer was extracted 2× with i-propyl acetate (200 mL), combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 1.6 g of light brown oil, which solidified on standing to give crude amine 2-(2,5-dimethoxy-3,4,6-trimethylphenyl)ethanamine. 1H NMR (CDCl3, 400 MHz) 3.63 (s, 3H), 3.59 (s, 3H), 2.79 (m, 2H), 2.63 (m, 2H), 2.20 (s, 3H), 2.15 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH2:19][NH2:20])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][CH:16]=1)[CH:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)=[O:6]
Reactant: NCC(c1ccc(Cl)cc1)C1CCOCC1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(NCC(c1ccc(Cl)cc1)C1CCOCC1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+): m/z=378.1, tR (minutes, Method G)=2.34
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:10]([O:12]C)=O)=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1.[NH3:14]>>[CH3:1][O:2][C:3]1[C:4]([C:10]([NH2:14])=[O:12])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1
Reactant: N
Reactant: COC(=O)c1ncc(C)nc1OC
Product: COc1nc(C)cnc1C(N)=O
Yield: 87 %

Procedure:
1 g (5.5 mmol) of methyl 3-methoxy-5-methylpyrazine-carboxylate was initially charged in 15 ml (198 mmol) of NH3 (25%) and the mixture was stied at 50° C. After concentration, 0.8 g of 3-methoxy-5-methylpyrazine-2carboxamide was obtained. The yield was 86 percent. Other data concerning the title product was:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1)=[N+]=[N-].O>C1COCC1.CCOCC>[NH2:29][CH2:28][C:27]1[CH:30]=[CH:31][C:24]([C:23]#[N:20])=[CH:25][CH:26]=1
Reactant: N#Cc1ccc(CN=[N+]=[N-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: N#Cc1ccc(CN)cc1
Reaction time: 1 h
Yield: 49.7 %

Procedure:
Triphenylphosphine (7.67 g) is added to a solution of 4-(azidomethyl)-benzonitrile (4.19 g) in THF (30 mL) and stirred for 1 hr. Water (10 mL) is added, and the solution is stiffed for 16 hrs. The reaction mixture is diluted with ether (50 mL) and extracted with HCl (3 N, 3×25 mL) and water (1×25 mL). The aqueous phases are combined and washed with ether (50 mL). Sodium hydroxide is added until the pH=12. After extracting with ether (2×50 mL), the solution is dried with MgSO4 and filtered. The solvent is evaporated under reduced pressure. The resulting crude mixture is then purified via bulb to bulb distillation at 150° C. and 1 torr to afford 1.74 g (50%) of the title compound as a clear, colorless oil.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:12]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:11][CH:10]2[N:18]([CH3:19])[CH:7]1[CH2:8][CH2:9]2)=O)C.C1(C)C=CC=CC=1.COCCO[AlH2-]OCCOC.[Na+].[OH-].[Na+]>O>[CH3:19][N:18]1[CH:10]2[CH2:9][CH2:8][CH:7]1[C@H:6]([CH2:4][OH:3])[C@@H:12]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:11]2
Reactant: CCOC(=O)[C@H]1C2CCC(C[C@@H]1c1cccs1)N2C
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1C2CCC1[C@H](CO)[C@@H](c1cccs1)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of (2R,3S)-8-methyl-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane-2-carboxylic acid ethyl ester (3.65 g, 13.75 mmol) and toluene (75 ml), Red-Al (6 ml, 65%, 20 mmol) was added at 0° C. The mixture was stirred at 0° C. for 1 h. A solution of aqueous sodium hydroxide (20 ml, 4 M) was added dropwise followed by warm water (50° C., 150 ml). The mixture was extracted with toluene (2×100 ml). The mixture was dried (MgSO4) and evaporated. The product was isolated as crystals. Mp: 153.7-157.5° C. Yield 2.04 g (63%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][CH3:33])[CH:27]=2)[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][CH3:33])[CH:27]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CCc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Solvent: Cc1ccccc1C
Product: CCc1cc(-c2cccc(C3=Nc4cc(Cl)c(Cl)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (133 mg, 0.75 mmol) and 3-[3-(2-ethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K20) (244 mg, 0.75 mmol) in xylene (7.5 ml) under reflux conditions for 1.5 h according to the general procedure M. Obtained as a light red solid (236 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:40])=[C:4]([S:9]([N:12]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:41][C:42]1[C:47]([Cl:48])=[CH:46][CH:45]=[CH:44][C:43]=1[N:49]=[C:50]=[O:51]>C1COCC1>[Cl:1][C:2]1[C:3]([OH:40])=[C:4]([S:9]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:50]([NH:49][C:43]3[CH:44]=[CH:45][CH:46]=[C:47]([Cl:48])[C:42]=3[Cl:41])=[O:51])[CH:15]=2)[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:29][CH:28]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CC(C)CNCc1cccc(CN(Cc2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Solvent: C1CCOC1
Product: CC(C)CN(Cc1cccc(CN(Cc2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1)C(=O)Nc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.1 %

Procedure:
To a solution of 3,5-dichloro-N-((4′-fluorobiphenyl-4-yl)methyl)-2-hydroxy-N-(3-((isobutyl amino)methyl)benzyl)benzene sulfonamide (Compound E of Example 184, 0.04 g, 0.0667 wool, 1.0 eq) in 25 mL of dry THF at 0° C. was added 2,3-dichlorophenyl isocyanate (0.012 g, 0.0667 mmol, 1.0 eq). The reaction mixture was stirred at ambient temperature for 15 min and concentrated. The residue was purified by preparative HPLC to afford the title compound (0.02 g, 40%). 1H NMR (400 MHz, DMSO-d6) δ 0.85-0.87 (d, 6H), 2.0 (m, 1H), 3.09-3.11 (d, 2H), 4.44-4.46 (m, 3H), 4.49 (s, 4H), 7.03-7.05 (d, 2H), 7.13-7.15 (d, 3H), 7.21-7.29 (m, 4H), 7.33-7.35 (m, 1H), 7.43-7.45 (d, 2H), 7.56-7.62 (m, 4H), 7.80 (s, 1H), 8.00 (s, 1H). MS (EP: 788.0 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([CH2:27]OS(C)(=O)=O)[C:13](=[O:26])[N:14]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([CH2:27][N:37]3[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]3)[C:13](=[O:26])[N:14]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CN1CCNCC1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Yield: 79.3 %

Procedure:
Following the procedure of Example 1(10), 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 79.3%).
Reaction SMILES: [NH2:1][C:2]([CH2:4][CH2:5][C:6]1[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=1[O:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=O.Cl.C(N)C.C(OCC)(=O)C>O1CCCC1>[NH2:1][CH2:2][CH2:4][CH2:5][C:6]1[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=1[O:8][C:9]([CH3:17])([CH3:18])[C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1CCC(N)=O
Agent: CCN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1CCCN
Temperature: 50 °C
Reaction time: 3 h

Procedure:
tert-Butyl 2-[2-(2-aminocarbonylethyl)phenoxy]-2-methylpropionate (2.7 g, 8.68 mmol) was dissolved in tetrahydrofuran (5 mL). Subsequently, under nitrogen atmosphere, borane-tetrahydrofuran complex in tetrahydrofuran solution [1.0M BH3-THF in THF (26.1 mL, 26.1 mmol)] was added thereto, the mixture was stirred for three hours at 50° C. Thereafter, concentrated hydrochloric acid was gradually added thereto at 0° C. The resultant mixture was stirred for one hour at room temperature and made basic with an aqueous ethylamine solution. Ethyl acetate was added thereto. The mixture was sequentially washed with water and saturated brine, followed by drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol=30/1), whereby the target compound was obtained (1.44 g, 4.91 mmol, 57%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)c2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and benzoyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[N:15]=[C:14]([C:16]([O:18]C)=[O:17])[CH:13]=[CH:12][C:11]=1[F:20].[Li+].[OH-]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[N:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:11]=1[F:20]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(C)cc2F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 6-(2,6-difluoro-4-methylphenyl)-5-fluoropicolinate (1.0 eq) in THF (0.1 M) was added LiOH (5.5 eq, 2 M) and allowed to stir at room temperature for 4 hrs. The volatiles were removed in vacuo, and the residual aqueous was acidified with 2 M HCl to pH 4. The precipitate was filtered and dried to yield 6-(2,6-difluoro-4-methylphenyl)-5-fluoropicolinic acid as a light yellow solid in 73.5%. LCMS (m/z): 268.0 (MH+), Rt=0.76 min.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([O:13]C)=O.O.[NH2:16][NH2:17]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:16][NH2:17])=[O:13]
Reactant: NN
Reactant: COC(=O)c1ccc2ccccc2n1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc2ccccc2n1
Temperature: 25 °C

Procedure:
Methyl quinoline-2-carboxylate 3.2 (10.1 g, 0.054 mol) was dissolved in 50 mL of ethanol and hydrazine hydrate (8.1 g, 0.16 mol) was added. The mixture was heated to reflux for 1 h and cooled down to RT at which point a precipitate formed. The mixture was concentrated to approximately ⅓ of the volume and the precipitate was filtered off, washed with small volumes of ethanol to afford intermediate 2a solvated by ½ equivalent of ethanol. Yield 10 g (99%). 1HNMR (DMSO-d6): δ: 9.95 ppm (s, 1H), 8.55 (d, 1H), 8.1 ppm (d, 2H), 8.05 ppm (d, 1H), 8.85 ppm (t, 1H), 7.65 ppm (t, 1H), 4.6 ppm (s, 2H), 4.3 ppm (t, 0.5H), 4.4 ppm (q, 1H), 1.05 ppm (q, 1.5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH:9]=[O:10])=[CH:5][CH:4]=1.C(C1C(=O)C(Cl)=C(Cl)[C:17](=[O:18])C=1C#N)#N.CO>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][C:9]([O:18][CH3:17])=[O:10])=[CH:5][CH:4]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: COc1ccc(C=CC=O)cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C=Cc1ccc(OC)cc1
Yield: 91 %

Procedure:
A homogeneous mixture containing 4-methoxycinnamaldehyde (7.5 mmol), DDQ (11.3 mmol), MeOH (15 mL) and toluene (10 mL) is taken in a round bottom flask and catalytic amount of AMBERLITE® IR 400 (0.1 g) is added to it. The mixture is refluxed for 6 hrs under Dean Stark apparatus. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with MeOH (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. Methyl 4-methoxycinnamate (from formula I where X1═H, X2═H, X3═OCH3, X4═H, X5═H, R═CH3) is isolated in 91% yield. 1H-NMR (CDCl3, 300 MHz) δ7.56 (1H, d, J=16.55 Hz), 7.37 (2H, d), 6.80 (2H, d), 6.22 (1H, d, J=16.55 Hz), 3.73 (3H, s), 3.70 (3H, s); 13C-NMR (CDCl3, 75.4 MHz) δ167.7, 161.4, 144.5, 129.7, 127.1, 115.2, 114.3, 55.3, 51.5.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1.FC(F)(F)C(O)=O.C[O-].[Na+]>ClCCl.CO>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)cc1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCNCC2)c(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
To a stirred solution of 1,1-dimethylethyl 4-[2-methyl-5-(methyloxy)-4-nitrophenyl]-1-piperazinecarboxylate (4.8 g, 13.67 mmol) in 80 mL of dichloromethane was added trifluoroacetic acid (˜5.5 mL). The mixture stirred at room temperature for 24 hours. The solvent was rotovaped down. The crude product was taken up in 50 mL of methanol and neutralized with 0.5 N sodium methoxide. 12 g of Silica gel was added and the solvent was rotovaped down. The crude product was purified by flash chromatography to give 1-[2-methyl-5-(methyloxy)-4-nitrophenyl]piperazine (3.43 g, 13.53 mmol, 98%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (s, 1 H), 6.69 (s, 1 H), 3.88 (s, 3 H), 3.08-3.18 (m, 8 H), 2.15-2.21 (m, 3 H).
Reaction SMILES: BrC1C=CC=C(Br)C=1O.[C:10]([CH:15]([CH2:19][CH:20]=[CH2:21])[CH2:16]C=C)([O:12][CH2:13][CH3:14])=[O:11]>O(Cl)Cl.[W].C1(C)C=CC=CC=1>[CH:15]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:16][CH:21]=[CH:20][CH2:19]1
Reactant: C=CCC(CC=C)C(=O)OCC
Agent: [W]
Agent: ClOCl
Agent: Oc1c(Br)cccc1Br
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC=CC1
Temperature: 90 °C
Yield: 71.1 %

Procedure:
A flame-dried 500 ml flask was charged with 2,6-dibromophenol (1.20 g, 4.76 mmol), tungsten oxychloride (0.813 g, 2.38 mmol), and anhydrous toluene (25 mL). The resulting suspension was heated at reflux under nitrogen for 1 h, and then the solvent was evaporated in vacuo. The solid residue was broken up with a spatula and dried in vacuo for 30 min. To the residue were added toluene (160 mL), Et4Pb (1.54 g, 4.76 mL), and 702 (22 g, 131.0 mmol). The mixture was heated at 90° C. under nitrogen for 1.5 h. After being cooled to r.t., the mixture was filtered through a celite, and the celite was rinsed with t-BuOMe. The combined filtrates were washed with 1% NaOH soln, water, and brine, and concentrated by evaporation at reduced pressure. The residue was distilled (37-38° C./1 Torr) to give 13.06 g (71%) of 703 as a colorless liquid. 1H NMR (400 MHz, CDCl3) 65.67 (s, 2H, CH═CH), 4.14 (q, 2H, J=7.2 Hz, OCH2), 3.11 (pentuplet, J=7.6 Hz, 1H, CH), 2.65 (d, J=7.6 Hz, 4H, 2 CH2), 1.27 (t, J=7.2 Hz, 3 H, CH3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.N1CCCC1.[C:17]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:17]1([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:9][C:8]2=[O:10]
Reactant: O=C1CCCCC1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: C1CCNC1
Solvent: CO
Product: O=C1CC2(CCCCC2)Oc2ccc(Br)cc21
Yield: 108.9 %

Procedure:
To a solution of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (60 g, 280 mmol) and pyrrolidine (37.8 g, 532 mmol) in methanol (1200 mL) was added cyclohexanone (55 g, 560 mmol), and the mixture was reflux overnight. The solvent was removed in vacuo, and then added H2O and HCl to make the mixture to PH=1, extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromospiro[chroman-2,1′-cyclohexan]-4-one (90 g, 100%). 1H NMR (CDCl3): 1.49 (d, 4H), 1.64 (d, 4H), 1.83 (s, 1H), 1.98 (d, 2H), 2.11 (t, 1H), 2.31 (s, 1H), 2.68 (s, 1H), 6.87 (d, 1H), 7.50 (d, 1H), 7.92 (s, 1H).
Reaction SMILES: [O:1]1[C:19]([CH3:22])([CH2:20][CH3:21])[CH:2]1[CH2:3][CH2:4][C:5]([CH3:18])=[CH:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]2[CH2:13][CH2:14][O:15][C:11]=2[CH:10]=1.[H][H]>[Pt]=O.C(OCC)(=O)C>[O:1]1[C:19]([CH3:22])([CH2:20][CH3:21])[CH:2]1[CH2:3][CH2:4][CH:5]([CH3:18])[CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]2[CH2:13][CH2:14][O:15][C:11]=2[CH:10]=1
Reactant: [H][H]
Reactant: CCC1(C)OC1CCC(C)=CCOc1ccc2c(c1)OCC2
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCC1(C)OC1CCC(C)CCOc1ccc2c(c1)OCC2

Procedure:
1.0 g. of 6-[(6,7-epoxy-3,7-dimethyl-2-nonenyl)-oxy]-2,3-dihydrobenzofuran is dissolved in 25 ml. of ethyl acetate and hydrogenated in the presence of 50 mg. of platinum oxide until the theoretical amount of hydrogen has been taken up. The catalyst is then removed by filtration and the filtrate evaporated. By chromatography on silica gel using hexane/diethyl ether (19:1 parts by volume) there is obtained pure 6-[(6,7-epoxy-3,7-dimethylnonyl)-oxy]-2,3-dihydrobenzofuran; nD20 = 1.5118.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15](OC)=[O:16])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1cnoc1-c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1cnoc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of methyl 3-[5-(4-fluorophenyl)-4-isoxazolyl]propionate (3.21 g) in tetrahydrofuran (30 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 30 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[5-(4-fluorophenyl)-4-isoxazolyl]propan-1-ol (2.48 g, yield 87%) was obtained as a pale yellow oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). NMR (CDCl3) δ: 1.38 (1H, br s), 1.82–2.02 (2H, m), 2.70–2.84 (2H, m), 3.64–3.80 (2H, m), 7.10–7.26 (2H, m), 7.64–7.80 (2H, m), 8.21 (1H, s).
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].ClC1C=C(OC2COC(C3C=CC=CC=3)OC2)N=C(SCC2C=CC=C(F)C=2F)N=1.Cl[C:46]1[CH:51]=[C:50]([O:52][C@@H:53]([C@H:55]2[CH2:59][O:58][C:57]([CH3:61])([CH3:60])[O:56]2)[CH3:54])[N:49]=[C:48]([S:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([F:70])[C:65]=2[F:71])[N:47]=1.[Cl-].[NH4+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:71][C:65]1[C:66]([F:70])=[CH:67][CH:68]=[CH:69][C:64]=1[CH2:63][S:62][C:48]1[N:47]=[C:46]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[CH:51]=[C:50]([O:52][C@@H:53]([C@H:55]2[CH2:59][O:58][C:57]([CH3:60])([CH3:61])[O:56]2)[CH3:54])[N:49]=1
Reactant: C[C@@H](Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1)[C@H]1COC(C)(C)O1
Reactant: NS(=O)(=O)N1CCC1
Agent: [Pd]
Agent: Fc1cccc(CSc2nc(Cl)cc(OC3COC(c4ccccc4)OC3)n2)c1F
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H](Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@H]1COC(C)(C)O1
Temperature: 100 °C

Procedure:
A mixture of azetidine-1-sulphonamide (prepared according to patent WO 2004/011443, 0.20 g), tris(dibenzylideneacetone)-dipalladium (0) (33 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-diphenyl (XPHOS) (17 mg), cesium carbonate (0.18 g) and 4-chloro-2-[[(2,3-difluorophenyl)-methyl]thio]-6-[(2-phenyl-1,3-dioxan-5-yl)oxy]-pyrimidine (the product of step v) (0.15 g) in dioxane (5 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 25 min. Saturated aqueous ammonium chloride was added and the resulting mixture extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using EtOAc/isohexane (1:19 to 3:7 gradient) as eluent to give the subtitle compound as a yellow oil. Yield: 0.14 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:11])[CH2:9][CH3:10].[N+:12]([O-])([OH:14])=[O:13].O>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[C:8](=[O:11])[CH2:9][CH3:10]
Reactant: CCC(=O)c1ccccc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCC(=O)c1cc([N+](=O)[O-])ccc1F
Temperature: -30 °C
Reaction time: 0.25 h

Procedure:
To a solution of the 1-(2-fluoro-phenyl)-propan-1-one (99 mmol) in concentrated sulfuric acid (80 ml) cooled down to −30° C. was added slowly fuming nitric acid (8 ml) over 20 min and the solution was stirred at −30° C. for 15 min. The mixture was slowly poured into a stirred mixture of 200 ml of water and 400 g ice. The aqueous phase was extracted with ethyl acetate, the organic layer was extracted again with water and aqueous NaHCO3 1M. The organic layer was dried over Na2SO4, evaporated and the residue was purified by chromatography on silica using a mixture of heptane and ethylacetate as eluent to afford the pure nitro intermediate J. MS (ISP): m/z=198.1 [M+H]+.