Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.ClC1C=CC=C(C(OO)=[O:29])C=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl.O>[Br:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=3[O-:29])[C:6]=2[CH:19]=1
Reactant: CC1(C)N=C(c2ccccn2)c2cc(Br)c(Cl)cc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC1(C)N=C(c2cccc[n+]2[O-])c2cc(Br)c(Cl)cc2O1
Reaction time: 5 h
Yield: 25.8 %

Procedure:
To a solution of Compound 88(10.0 g) in dichloromethane (130 ml) was added 70% m-chloroperbenzoic acid (20.0 g) at 0° C. and the mixture was stirred at 2° to 4° C. for 5 hours. A solution of sodium sulfite (32 g) in water (130 ml) was added slowly and stirred for 1 hour with ice-cooling. The organic layer was separated, washed successively with 5% aqueous sodium carbonate solution and saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by chromatography on silica gel and crystallized from diethyl ether to obtain 2-(6-bromo-7-chloro-2,2-dimethyl-2H-1,3-benzoxazin-4-yl)pyridine 1-oxide (2.7 g) (Compound 89).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([B:9]2[O:13][CH2:12][CH2:11]O2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17]C=1COCOC>>[F:21][C:19]1[CH:18]=[CH:17][C:11]2[CH2:12][O:13][B:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[C:1]#[N:2])[C:15]=2[CH:20]=1
Reactant: N#Cc1cccc(B2OCCO2)c1
Reactant: COCOCc1ccc(F)cc1Br
Product: N#Cc1cccc(B2OCc3ccc(F)cc32)c1

Procedure:
This was prepared as per the procedure in Example 11, from 2-(3-cyanophenyl)-[1,3,2]-dioxaborolane and 1-bromo-5-fluoro-2-((methoxymethoxy)methyl)benzene to afford white crystalline product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.Cl[CH:11]([C:17]([CH3:19])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[NH2:8][C:7]1[C:2]2[N:3]([C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:17]([CH3:19])[N:1]=2)[CH:4]=[C:5]([Br:9])[CH:6]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1cc(Br)cnc1N
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(N)cc(Br)cn12
Yield: 39.1 %

Procedure:
A mixture of 2,3-diamino-5-bromopyridine (2.5 g, 13.31 mmol) and ethyl 2-chloroacetoacetate (2.41 g, 14.64 mmol) in 35 ml abs. Ethanol was refluxed for 14 h. The ethanol was evaporated under reduced pressure. The residue was dissolved in methylene chloride and neutralized by aqueous NaHCO3. The organic layer was separated, dried and evaporated in vacuo. The residue was purified by column chromatography on silica gel with methylene chloride:methanol (100:3.5) as eluent to give 1.55 g (39%) of the title compound.
Reaction SMILES: Br[C:2]1[N:3]([CH3:17])[C:4](=[O:16])[C:5]2[N:6]=[CH:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[N:10]=1.ClC1N(C)C(=O)C2N=CN(C3CCCC3)C=2N=1.[NH2:35][C@@H:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[OH:41].C(N(CC)CC)C>CC#N>[OH:41][C@@H:37]1[CH2:38][CH2:39][CH2:40][C@H:36]1[NH:35][C:2]1[N:3]([CH3:17])[C:4](=[O:16])[C:5]2[N:6]=[CH:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[N:10]=1
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: Cn1c(Br)nc2c(ncn2C2CCCC2)c1=O
Agent: Cn1c(Cl)nc2c(ncn2C2CCCC2)c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1c(N[C@@H]2CCC[C@H]2O)nc2c(ncn2C2CCCC2)c1=O

Procedure:
A mixture of 2-bromo-1-methyl-9-cyclopentylpurin-6-one and 2-chloro-1-methyl-9-cyclopentylpurin-6-one (1.4 g) is mixed with (±) trans-2-aminocyclopentanol (1.2 g, 11 mmol) and triethylamine (1.2 ml) in CH3CN (20 ml) and heated to reflux for 12 hr. The resultant mixture is cooled, concentrated in vacuo, and partitioned between EtOAc/THF 1:1 and brine. The organic layers are concentrated in vacuo and the residue is purified by flash chromatography using 6% EtOH in CH2Cl2 to give 2-(trans-2-hydroxycyclopentylamino)-1-methyl-9-cyclopentylpurin-6-one, a solid (1.4 gm, MS FAB: M+H=318). The 2-(trans-2-hydroxy cyclopentylamino )-1-methyl-9-cyclopentylpurin-6-one (1.3 g, 4.1 mm), triphenylphosphine dibromide (prepared from triphenylphosphine (1.2 g) and bromine (0.2 ml)) in DMF (20 ml) is stirred at room temperature for 18 hr and heated to 70° C. for 12 hr. Dilute NaOH is added to the cooled reaction mixture to adjust the pH to 10, and the resultant solution is extracted with EtOAc/THF 1:1. The organic layer is concentrated in vacuo and purified by flash chromatography using 15% EtOH in CH2Cl2 and recrystallized from CH2Cl2 /hexane, to give the title compound, a solid, mp 194°-195° C.
Reaction SMILES: O1C=NC=N1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C@@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C@H:16]([CH2:26][N:27]3[CH:31]=[C:30]([C:32](O)=[O:33])[N:29]=[N:28]3)[O:15][C:14]2=[O:35])=[CH:9][CH:8]=1.[C:36](=[N:39]O)([NH2:38])[CH3:37]>O1CCOCC1.C(#N)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C@@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C@H:16]([CH2:26][N:27]3[CH:31]=[C:30]([C:32]4[O:33][N:39]=[C:36]([CH3:37])[N:38]=4)[N:29]=[N:28]3)[O:15][C:14]2=[O:35])=[CH:11][CH:12]=1
Reactant: CC(N)=NO
Reactant: COc1cccc([C@H]2[C@H](Cn3cc(C(=O)O)nn3)OC(=O)N2c2ccc(Cl)cc2)c1
Agent: c1ncon1
Solvent: C1COCCO1
Solvent: CC#N
Product: COc1cccc([C@H]2[C@H](Cn3cc(-c4nc(C)no4)nn3)OC(=O)N2c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Reference for 1,2,4-oxadiazole formation: Bioorg. Med. Chem. Lett. 1999, 9, 209. A solution of 1-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (32 mg, 0.07 mmol) in dioxane (0.5 mL) is treated with N,N′-carbonyldiimidazole and stirred at room temperature for 30 min. Acetamide oxime (10 mg, 0.13 mmol) is then added and the mixture stirred for 2 h at room temperature then at 100° C. for 18 h. The reaction solution is then diluted with acetonitrile and filtered through a Whatman 0.42 μM and purified by preparative HPLC (C-18, 10-90% ACN/water (0.05% TFA)) HPLC to give the title compound. 1H NMR (acetone-d6, 400 MHz) δ 8.93 (s, 1H), 7.47-7.44 (m, 2H), 7.33-7.28 (m, 3H), 7.05-7.00 (m, 2H), 6.88 (ddd, J=7.9, 2.5, 0.8 Hz, 1H), 5.62 (d, J=5.0 Hz, 1H), 5.25-5.24 (m, 2H), 5.03 (ddd, J=5.7, 5.5, 4.9 Hz, 1H) 3.76 (s, 3H), 2.40 (s, 3H); HPLC-MS calculated C22H19ClN6O4 (M+H+) 467.1, found 467.1.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:10]3([CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:19]([OH:21])=[O:20])[CH:16]=4)[CH2:11]3)[C:9](=[O:22])[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:23][N:24](C)C(=O)C>[C-]#N.[Zn+2].[C-]#N.[Zn].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].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:23]([C:2]1[CH:3]=[C:4]2[C@@:10]3([CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:19]([OH:21])=[O:20])[CH:16]=4)[CH2:11]3)[C:9](=[O:22])[NH:8][C:5]2=[N:6][CH:7]=1)#[N:24]
Reactant: CC(=O)N(C)C
Reactant: O=C(O)c1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncc(Br)cc21
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1cnc2c(c1)[C@]1(Cc3ccc(C(=O)O)cc3C1)C(=O)N2
Temperature: 120 °C

Procedure:
Argon was bubbled through a stirred mixture of (2R)-5′-bromo-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylic acid (433 mg, 1.21 mmol), zinc cyanide (205 mg, 1.75 mmol), and zinc (31 mg, 0.47 mmol) in N,N-dimethylacetamide (10 mL) for 10 min. To the resulting mixture was added tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.030 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (23 mg, 0.041 mmol) and argon was bubbled through the mixture for an additional 5 min. The reaction mixture was heated at 120° C. for 4 h, cooled to ambient temperature, and partitioned between EtOAc (100 mL) and 1 N aqueous hydrochloric acid (100 mL). The organic layer was washed with brine, then dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The residue was dissolved in a minimal volume of DMF and H2O was added to produce a precipitate. The precipitate was isolated by filtration, washing with H2O, and dried to give the title compound. MS: m/z=306.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ 12.81 (br s, 1H), 11.68 (s, 1H), 8.59 (d, 1H, J=1.9 Hz), 7.86-7.83 (m, 2H), 7.80 (dd, 1H, J=2.0, 0.5 Hz), 7.39 (d, 1H, J=8.3 Hz), 3.42-3.29 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[CH:17][N:16]2[CH:24]=1.[CH2:25]([NH2:31])[C:26]1[O:30][CH:29]=[CH:28][CH:27]=1>>[O:30]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:25][NH:31][C:21]([C:19]1[CH:18]=[CH:17][N:16]2[CH:24]=[C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])[N:14]=[C:15]2[CH:20]=1)=[O:23]
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Reactant: NCc1ccco1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)NCc3ccco3)cc2n1
Yield: 72 %

Procedure:
As described for Example 11b, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid (64 mg, 0.2 mmol) was converted, using furfurylamine instead of aminomethylcyclopropane, to the title compound (57 mg, 72%) which was obtained as a yellow foam. MS: m/e=399.1 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=2[N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:4]=1)=O.[NH2:23][CH2:24][CH:25]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]1.C([BH3-])#N.[Na+]>CO.CC(O)=O>[C:33]([O:32][C:30]([N:27]1[CH2:28][CH2:29][CH:25]([CH2:24][NH:23][CH2:1][C:3]2[C:11]3[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=3[N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:4]=2)[CH2:26]1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: COC(=O)c1ccnc2c1c(C=O)cn2C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccnc2c1c(CNCC1CCN(C(=O)OC(C)(C)C)C1)cn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a solution of 1-tert-butyl 4-methyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate (91 mg, 0.3 mmol) in MeOH (2 mL) was added AcOH (5 drops) and tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate (90 mg, 0.45 mmol). After stirring for 60 min at rt, the reaction mixture was cooled to 0° C. Sodium cyanoborohydride (57 mg, 0.9 mmol) was added, and the reaction mixture was stirred for an additional 3 h at rt. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers washed with saturated NaHCO3 and with brine, dried over Na2SO4, and concentrated in vacuo to give 125 mg of crude 1-tert-butyl 4-methyl 3-(((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate as a colorless oil which was used without further purification. [M+H] found 489.40.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([CH:14]([CH3:16])[CH3:15])[CH2:3]1.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[CH3:15][CH:14]([C@H:4]1[NH:5][CH2:6][C@H:2]([OH:1])[CH2:3]1)[CH3:16].[C:19]([OH:21])([C:18]([F:23])([F:22])[F:17])=[O:20]
Reactant: CC(C)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (2S,4R)-4-hydroxy-2-(propan-2-yl)pyrrolidine-1-carboxylate (500 mg, 2.180 mmol) dissolved in dichloromethane (5.4 mL) was added trifluoroacetic acid (1.8 mL). The reaction was stirred for 16 hours at room temperature. The mixture was concentrated to afford (3R,5S)-5-(propan-2-yl)pyrrolidin-3-ol as a TFA salt. 1H NMR (500 MHz, CDCl3) δ 3.91-3.62 (m, 1H), 3.60-3.36 (m, 2H), 2.47-2.10 (m, 2H), 2.05-1.79 (m, 2H), 1.07 (d, J=6.6, 3H), 1.01 (d, J=6.7, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[F:11][C:12]([F:21])([F:20])[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:16]2[CH:17]=[CH:18][C:13]([C:12]([F:11])([F:20])[F:21])=[CH:14][CH:15]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: O=Cc1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1cc(Cl)ccc1Oc1ccc(C(F)(F)F)cc1
Yield: 58.2 %

Procedure:
In a manner similar to the method described in Example 50a, 5-chloro-2-fluorobenzaldehyde (0.88 g, 5.6 mmol) (Beta Pharma) was reacted with 4-trifluoromethylphenol (1 g, 6.6 mmol)(Aldrich) and K2CO3 in N,N-dimethylacetamide to give 5-chloro-2-(4-trifluoromethyl-phenoxy)-benzaldehyde as a yellow solid (Yield 0.98 g, 58%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH2:18][C:19]#[CH:20])[C:9]1[S:10][CH:11]=[C:12]([C:14](OC)=[O:15])[N:13]=1.O>O1CCCC1>[CH3:7][N:8]([CH2:18][C:19]#[CH:20])[C:9]1[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=1
Reactant: C#CCN(C)c1nc(C(=O)OC)cs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCN(C)c1nc(CO)cs1
Yield: 86.5 %

Procedure:
Lithium aluminum hydride (900 mg) was added to anhydrous tetrahydrofuran (20 ml) and a solution of 2-(N-methyl-2-propynylamino)-4-methoxycarbonylthiazole (h) (5.0 g) in tetrahydrofuran (30 ml) was added dropwise thereto with stirring under ice-cooling. The mixture was refluxed for 2 hours, to which water was carefully added under ice-cooling, and evaporated to remove the tetrahydrofuran. The residue was extracted with chloroform. The extract was washed with water, dried and recrystallized from ether-hexane to give 2-(N-methyl-2-propynylamino)-4-hydroxymethylthiazole (i) (3.75 g, yield 86.5%): mp. 69°-70° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([O:18]CC=C)[CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].CN(C)[C:24]1[CH:29]=CC=C[CH:25]=1>>[C:1]([C:5]1[C:10]([O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:14])[CH3:15])=[CH:9][C:8]([CH2:29][CH:24]=[CH2:25])=[C:7]([OH:18])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1ccc(OC(=O)C(C)(C)C)c(C(C)(C)C)c1
Product: C=CCc1cc(OC(=O)C(C)(C)C)c(C(C)(C)C)cc1O

Procedure:
4.30 g of 3-t-butyl-4-trimethylacetoxy-1-(2-propenyloxy)benzene was dissolved in 30 ml of dimethylaniline and the solution was refluxed overnight under a nitrogen stream. The solution was allowed to attain room temperature and concentrated under reduced pressure, then extracted with ethyl acetate and 5% hydrochloric acid and the organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 0.5% ethyl acetate) to give 1.70 g of 5-t-butyl-4-trimethylacetoxy-2-(2-propenyl)phenol as a colorless solid.
Reaction SMILES: B(F)(F)F.CCOCC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([S:18][CH2:19][CH:20]=O)[CH:15]=[CH:16][CH:17]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]2[CH:20]=[CH:19][S:18][C:14]=2[CH:13]=1
Reactant: COc1cccc(SCC=O)c1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc2ccsc2c1
Temperature: 0 °C
Yield: 60.7 %

Procedure:
Boron trifluoride etherate (8.15 mL) dissolved in dry dichloromethane (407 mL) was stirred rapidly at 0° C. under nitrogen and a solution of (3-methoxyphenylsulphanyl)acetaldehyde (11.5 g, 63.10 mmol) in dry dichloromethane (29 mL) was added dropwise over 25 min. The resultant green solution was stirred for 2 min and then saturated aqueous sodium bicarbonate solution (150 mL) was added at a rate so as to maintain the temperature <8° C. The reaction mixture was stirred for 5 min and then the layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate solution (100 mL) and water (100 mL). The organic phase was dried (MgSO4), and concentrated in vacuo. The product was purified by distillation to afford the title compound as a colourless oil (6.29 g, 61%, b.p. 83-88° C. at 16 mBar).
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[F:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[N+:26]([O-:28])=[O:27])=[C:20]([CH3:29])[CH:19]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:5][CH:25]([N+:26]([O-:28])=[O:27])[CH:24]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][C:20]=2[CH3:29])[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: Cc1cc(F)ccc1/C=C/[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(F)ccc1C1CN(Cc2ccccc2)CC1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (1.95 g, 8.21 mmol) in CH2Cl2 (30 ml) was added drop wise, over a 30 minutes period, to a stirred solution of 4-fluoro-2-methyl-1-((E)-2-nitro-vinyl)-benzene (1.49 g, 8.22 mmol) and trifluoroacetic acid (0.60 ml, 0.82 mmol) in CH2Cl2 (30 ml) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:6) afforded 0.77 g (30%) of the title compound as a light yellow oil. ES-MS m/e: 315.2 (M+H+).
Reaction SMILES: CS(C)=O.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:8][CH:7]=1.[OH-].[K+].Br[C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[Br:37]>C1(C)C=CC=CC=1>[Br:37][C:36]([F:39])([F:38])[C:35]([F:41])([F:40])[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2([C:25]3[CH:26]=[CH:27][C:28]([O:31][C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[Br:37])=[CH:29][CH:30]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]3[C:24]2=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][CH:11]=1
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: Oc1ccc(C2(c3ccc(O)cc3)c3ccccc3-c3ccccc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: FC(F)(Br)C(F)(F)Oc1ccc(C2(c3ccc(OC(F)(F)C(F)(F)Br)cc3)c3ccccc3-c3ccccc32)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
Into a 2 liter 5-necked round bottom flask fitted with a mechanical stirrer, Dean-Stark trap topped with a nitrogen padded reflux condenser and a thermocouple attached to a temperature controller, are placed DMSO (650 ml) and toluene (200 ml). While the stirred solution is purged with nitrogen, 9,9-bis(4'-hydroxyphenyl)fluorene (200.0 g, 0.57 mole) is added to the flask. While purging with nitrogen continues, potassium hydroxide (85% pellets, 77.5 g, 1.17 mole) is added all at once, and the mixture is heated to 100° C. with constant stirring. After two hours, the temperature is increased until the solution begins to reflux (130° C.). Water is removed by azeotropic distillation for 24 hours. The Dean-Stark trap is replaced by a Soxhlet extractor containing anhydrous sodium sulfate, and the toluene is refluxed through the Soxhlet for 5 hours. A small amount of toluene (60 ml) is then removed by simple distillation. Then the reactor is cooled to 35° C. Addition of 1,2-dibromotetrafluoroethane (315 g, 1.21 mole) via dropping addition funnel is then maintained at a rate that keeps the reaction temperature at 35°-38° C. When the addition is complete, the mixture is heated at 50° C. for 8 hours, then cooled to room temperature with constant stirring. The mixture is filtered, and the precipitate is washed twice with acetone. The filtrates are combined and evaporated thoroughly. The residue from the evaporation is washed with water to remove residual potassium bromide (KBr). After the residue is air dried for 24 hours, it is purified by column chromatography (on neutral alumina, using hexane eluent) to provide as product, 9,9-bis(4'-[2"-bromotetrafluoroethoxy]phenyl)fluorene (331.4 g, 0.468 mole, 82% yield), melting point 157°-158° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][C:9]=1[N+:17]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:15])[CH3:16])=[CH:10][C:9]=1[NH2:17])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Product: CC(C)c1ccc(NC(=O)OC(C)(C)C)c(N)c1

Procedure:
Prepared from (4-isopropyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A2) by catalytic hydrogenation with Pd/C according to the general procedure G (method a). Obtained as a white solid (12.59 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]2=[N:6][CH:7]=1.C([Li])CCC.[CH:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>O1CCCC1.CCCCCC.C(OCC)C>[CH3:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]2=[N:6][C:7]=1[CH:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:25]
Reactant: O=Cc1ccccc1
Reactant: Cc1cnc2c(c1)CCCCC2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: Cc1cc2c(nc1C(O)c1ccccc1)CCCCC2
Temperature: 0 °C

Procedure:
6,7,8,9-Tetrahydro-3-methyl-5H-cyclohepta[b]pyridine (4.42 g, 0.025 m) in tetrahydrofuran (50 ml) was cooled to -40° C. under nitrogen and treated with n-butyl lithium in n-hexane (1.57 molar soln, 16 ml) and allowed to warm to 0° C. The solution was cooled to -70° C. and treated with a solution of benzaldehyde (4 ml) in tetrahydrofuran (10 ml) and allowed to warm to room temperature, then water and diethyl ether were added. The organic phase was separated and extracted with 2N hydrochloric acid. The acid phase was made basic with solid sodium carbonate and then extracted with chloroform. The combined chloroform extract was washed with water, dried (MgSO4) and evaporated under reduced pressure to give a gum. This was dissolved in n-hexane and the crystallised material collected by filtration. This was purified by chromatography on silica using diisopropyl ether:chloroform (9:1 by volume) as eluent. The isolated solid was triturated in diisopropyl ether give 1-(6,7,8,9-tetrahydro-3-methyl-5H-cyclohepta[b]pyrid-2-yl)-1-phenylmethanol (1.1 g) m.p. 130°-2° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([OH:12])=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(=O)(N(C)C)N(C)C.[CH3:34][C:35]1[CH:36]=[C:37]([CH:46]=[CH:47][CH:48]=1)[CH2:38][C:39]1[CH:43]=[CH:42][NH:41][C:40]=1[CH2:44]Br>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH:9]([C:10]([O:12][CH2:44][C:40]3[NH:41][CH:42]=[CH:43][C:39]=3[CH2:38][C:37]3[CH:46]=[CH:47][CH:48]=[C:35]([CH3:34])[CH:36]=3)=[O:11])[C:8]2([CH3:13])[CH3:14])=[CH:15][CH:16]=1
Reactant: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)O
Reactant: Cc1cccc(Cc2cc[nH]c2CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: Cc1cccc(Cc2cc[nH]c2COC(=O)C2C(Oc3ccc(Cl)cc3)C2(C)C)c1
Temperature: 25 °C

Procedure:
To a mixture of 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylic acid (2.77 mmol), potassium carbonate (3.25 mmol) and hexamethylphosphoric triamide (HMPT) (3 ml), with stirring and under nitrogen, at RT, is added 3-(3-methylbenzyl)-pyrrolylmethyl bromide (2.77 mmol) in THF. The reaction is stirred at RT for about 48 hours and then worked up by partition between water/ether. The organic phase is washed with water and brine, dried over potassium carbonate, filtered and the solvent is removed from the filtrate. The residue is plated on preparatory TLC plates developing with 10% ether/hexane to yield 3-(3-methylbenzyl)-pyrrolylmethyl 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylate.