Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10]Cl)=[C:4]([Cl:12])[CH:3]=1>CN(C=O)C.[H-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]=[CH2:10])=[C:4]([Cl:12])[CH:3]=1
Reactant: ClCCOc1ccc(Br)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=COc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-bromo-2-chloro-1-(2-chloro-ethoxy)-benzene (5.84 g, 17.4 mmol, 1 eq.) in DMF (22 mL), sodium hydride 60% dispersion in mineral oil (1.40 g, 34.9 mmol, 2 eq.) was added portionwise at r.t. The resulting mixture was stirred at r.t. for 18 hours. The mixture was partitioned between water (70 mL) and AcOEt (250 mL). The layers were separated and the org. layer was washed with water (4×100 mL), dried over MgSO4, filtered, and concentrated in vacuo. To a solution of the residue in DMF (22 mL), sodium hydride 60% dispersion in mineral oil (1.40 g, 34.9 mmol, 2 eq.) was added portionwise at r.t. The resulting mixture was stirred at r.t. for 48 hours. The mixture was partitioned between water (70 mL) and AcOEt (250 mL). The layers were separated and the org. layer was washed with water (4×100 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane 100% to Heptane+5% AcOEt) to give 4-bromo-2-chloro-1-vinyloxy-benzene as a colorless oil.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:9]([C:13]1[CH:14]=[CH:15][C:16]([S:19][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[NH2:4])=[CH:17][CH:18]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: Nc1ccccc1I
Reactant: CC(C)(C)c1ccc(S)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: CC(C)(C)c1ccc(Sc2ccccc2N)cc1
Yield: 89.7 %

Procedure:
The general procedure in example 39 was followed. 2-Iodoaniline (219 mg, 1.0 mmol), 4-tert-butylthiophenol (166 mg, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 2-(4-tert-butylphenyl)sulfanylaniline (231 mg, 90% yield) as light yellow liquid. Column chromatographic solvent (hexane/ethyl acetate=20/1). Rf=0.4 (hexane/ethyl acetate=10/1). 1H NMR (CDCl3, 300 MHz) δ 7.42 (dd, 1 H, J=1.5 Hz, 7.5 Hz), 7.17-7.24 (m, 4 H), 7.00 (dt, 2 H, J=1.8 Hz, 8.4 Hz), 6.70-6.78 (m, 2 H), 4.28 (brs, 2 H), 1.26 (s, 9 H). 13C NMR (CDCl3, 75 MHz) δ 148.8, 148.7, 137.5, 133.3, 131.1, 126.5, 126.3, 118.9, 115.5, 115.0, 34.8, 31.7. IR (neat, cm−1) 3471, 3375, 3072, 3062, 3020, 2962, 2902, 2867. MS (EI) m/z (relative intensity) 257 (70), 242 (100). Anal. Cald. for C16H19NS, Cald. C, 74.66; H, 7.44. Found C, 74.64; H, 7.30.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: O=C(Nc1ccc2[nH]cc(C3CCNCC3)c2n1)c1ccc(F)cc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.062 mMol) 4-fluorobenzoyl chloride, the title compound was prepared.
Reaction SMILES: [NH2:1][C@@:2]1([C:14]([F:18])([F:17])[CH2:15][OH:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1.C([O-])(=O)C.[Na+].[N:24]#[C:25]Br.CCCCCC>C(O)C.C(OCC)(=O)C>[F:18][C:14]([C@:2]1([NH:1][C:25]#[N:24])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1)([F:17])[CH2:15][OH:16]
Reactant: N#CBr
Reactant: N[C@]1(C(F)(F)CO)CCc2ccc([N+](=O)[O-])cc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#CN[C@]1(C(F)(F)CO)CCc2ccc([N+](=O)[O-])cc21
Temperature: 40 °C
Reaction time: 16 h
Yield: 45.6 %

Procedure:
A mixture of 2-((R)-1-amino-6-nitro-indan-1-yl)-2,2-difluoro-ethanol (intermediate A5.6), (1.6 g, 6.2 mmol) and sodium acetate (1.54 g, 18.6 mmol) in ethanol (30 ml) was warmed to 40° C. The mixture was then treated with cyanogen bromide (724 mg, 6.82 mmol) and allowed to stir at 40° C. for 16 hours. Removal of the solvent at reduced pressure followed by purification of the resultant crude material by column chromatography on silica gel using a 3:2-mixture of hexane and ethyl acetate as the eluent yielded the (R)-1-(1,1-difluoro-2-hydroxy-ethyl)-6-nitro-indan-1-yl-cyanamide (800 mg, 42% yield) as colorless sticky solid. MS (ISP): m/z=284.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][Si:4](OCC)(OCC)[C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:28]2[CH:33]=[CH:32][C:31]([Si:34](OCC)(OCC)[O:35][CH2:36][CH3:37])=[CH:30][CH:29]=2)[C:12]2[CH:17]=[CH:16][C:15]([Si:18](OCC)(OCC)[O:19][CH2:20][CH3:21])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].[CH2:50]([Mg]Br)[CH:51]=[CH2:52].Cl>CCOCC>[CH2:50]([CH:37]([CH2:16][CH:15]=[CH2:14])[CH2:36][O:35][SiH2:34][C:31]1[CH:32]=[CH:33][C:28]([N:11]([C:12]2[CH:13]=[CH:14][C:15]([SiH2:18][O:19][CH2:20][CH:21]([CH2:10][CH:5]=[CH2:6])[CH2:17][CH:12]=[CH2:13])=[CH:16][CH:17]=2)[C:8]2[CH:9]=[CH:10][C:5]([SiH2:4][O:3][CH2:1][CH:2]([CH2:33][CH:28]=[CH2:29])[CH2:9][CH:8]=[CH2:7])=[CH:6][CH:7]=2)=[CH:29][CH:30]=1)[CH:51]=[CH2:52]
Reactant: CCO[Si](OCC)(OCC)c1ccc(N(c2ccc([Si](OCC)(OCC)OCC)cc2)c2ccc([Si](OCC)(OCC)OCC)cc2)cc1
Reactant: C=CC[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: C=CCC(CC=C)CO[SiH2]c1ccc(N(c2ccc([SiH2]OCC(CC=C)CC=C)cc2)c2ccc([SiH2]OCC(CC=C)CC=C)cc2)cc1
Yield: 34 %

Procedure:
Firstly, dist. ether (5 mL) was added to tris(4-triethoxysilylphenyl)amine (242 mg, 0.33 mmol) under a nitrogen atmosphere. Then, 1-M allylmagnesium bromide (4 mL (solvent: ether), 4 mmoL) was added dropwise at 0° C. The resultant mixture was stirred under a nitrogen atmosphere at room temperature for 20 hours to obtain a mixture. Subsequently, the mixture was added with an aqueous solution of HCl of 10% by mass to cease the reaction, and the pH of an aqueous layer was adjusted to 4 by using an aqueous solution of HCl of 10% by mass. After that, an organic layer was separated, and the aqueous layer was extracted with ether. The organic layer thus collected was washed with sat. NaHCO3 and sat. NaCl, and was dried with MgSO4. The dried organic layer was then filtered and concentrated to obtain a crude product. Subsequently, the crude product was separated and purified by PTLC (hexane/EtOAc=10/1) to obtain tris(4-diallylethoxysilylphenyl)amine (80 mg, 34% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[C:14]2[CH:13]=[C:12]([C:15]3[CH:27]=[CH:26][C:25]4[C:24]5[C:19](=[CH:20][C:21]([C:28]#[C:29][Si](C)(C)C)=[CH:22][CH:23]=5)[C:18]([CH3:35])([CH3:34])[C:17]=4[CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([NH:36][C:37](=[O:39])[CH3:38])=[CH:6][CH:7]=2.I[C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=1>>[CH3:1][C:2]1([CH3:40])[C:14]2[CH:13]=[C:12]([C:15]3[CH:27]=[CH:26][C:25]4[C:24]5[C:19](=[CH:20][C:21]([C:28]#[C:29][C:42]6[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=6)=[CH:22][CH:23]=5)[C:18]([CH3:35])([CH3:34])[C:17]=4[CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([NH:36][C:37](=[O:39])[CH3:38])=[CH:6][CH:7]=2
Reactant: CC(=O)Nc1ccc2c(c1)C(C)(C)c1cc(-c3ccc4c(c3)C(C)(C)c3cc(C#C[Si](C)(C)C)ccc3-4)ccc1-2
Reactant: O=[N+]([O-])c1ccc(I)cc1
Product: CC(=O)Nc1ccc2c(c1)C(C)(C)c1cc(-c3ccc4c(c3)C(C)(C)c3cc(C#Cc5ccc([N+](=O)[O-])cc5)ccc3-4)ccc1-2

Procedure:
FIG. 3 shows a synthetic scheme (30) for the production of compound 20 (FIG. 2), where X is hydrogen. Compound 31, 7′-bromo-9,9,9′,9′-tetramethyl-9H,9′H-[2,2′]bifluoreny-7-ylamine, is acetylated and subsequently coupled with trimethylsilylacetylene to provide N-(9,9,9′,9′-tetramethyl-7′-trimethylsilanylethynyl-9H,9′H-[2,2′]bifluorenyl-7-yl)-acetamide 32. Trimethylsilyl derivative 32 is subjected to an organometallic cross-coupling reaction in the presence of 4-iodo-nitrobenzene to afford N-[9,9,9′,9′-tetramethyl-7′-(4-nitro-phenylethynyl)-9H,9′H-[2,2′]bifluoreny-7-yl]-acetamide 33. Acetylene 33 is converted to ketone 34—2-(7′-amino-9,9,9′,9′-tetramethyl)-9H,9′H-[[2,2′]bifluoreny-7-yl]-1-(4-nitro-phenyl)-ethanone—through the addition of H2O, which also effects the hydrolysis of the terminal acetamide. Alkylation of 34 provides the desired compound 35, 2-[7′-(2-mercapto-ethylamino)-9,9,9′,9′-tetramethyl-9H,9′H-[2,2′]bifluoreny-7-yl]-1-(4-nitro-phenyl)-ethanone.
Reaction SMILES: [C:1]([NH:9][C@H:10]1[CH2:14][N:13]([C:15](=[O:25])[CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:12]([C:26]([O:28]C)=[O:27])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.Cl>>[C:1]([NH:9][C@H:10]1[CH2:14][N:13]([C:15](=[O:25])[CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[C@H:12]([C:26]([OH:28])=[O:27])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C[C@@H](NC(=O)c2ccccc2)CN1C(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(=O)N1C[C@H](NC(=O)c2ccccc2)C[C@H]1C(=O)O
Temperature: -2 °C
Reaction time: 2.5 h
Yield: 100.1 %

Procedure:
To a solution of (2S,4R)-methyl 4-benzamido-1-(2-(tert-butoxycarbonyl-amino)acetyl)pyrrolidine-2-carboxylate (23.33 g, 0.0575 mol) in methanol (450 mL) NaOH (0.2875 mol, 144 mL of 2N aqueous solution) was added at −1 to 1° C. over 15 min. The mixture was stirred at −5 to 1° C. for 2.5 h. HCl (0.2875 mol, 144 mL of 2N aqueous solution) was added at −3 to 1° C. over 25 min. MeOH was distilled off in vacuum. 500 mL of EtOAc were added. Aqueous phase was saturated with NaCl. Phases were separated. Aqueous phase was extracted with 2×250 mL of EtOAc. Combined EtOAc solution was dried over MgSO4, and concentrated to afford 22.54 g of the title product as a white foamy solid (contains 6.6 wt % EtOAc; 94% yield adjusted to residual EtOAc). 1H NMR (CD3OD, δ, ppm): 7.87-7.79 (m, 2H), 7.58-7.42 (m, 3H), 4.81-4.7 (m 1H), 4.69-4.56 (m, 1H), 4.05-3.72 (m, 3H), 3.67-3.49 (m, 1H), 2.64-2.28 (m, 2H), 1.43 (s, 9H). MS (m/z, positive ESI) for M+H: 392; for M+Na: 414.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH:14]=[C:15]3[CH2:26][C:18]4[NH:19][C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=5[C:17]=4[C:16]3=[O:27])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1(CC2CCN(CC3C=CC=CC=3)CC2)CN2C3C=CC(OC)=CC=3C=C2C1=O>C(OCC)(=O)C.C(O)C>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH:15]3[CH2:26][C:18]4[NH:19][C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=5[C:17]=4[C:16]3=[O:27])[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C(=CC2CCN(Cc3ccccc3)CC2)Cc2[nH]c3ccccc3c21
Agent: COc1ccc2c(c1)cc1n2CC(C)(CC2CCN(Cc3ccccc3)CC2)C1=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1c2c([nH]c3ccccc23)CC1CC1CCN(Cc2ccccc2)CC1

Procedure:
the title compound of Example 42 (176 mg, 0.5 mmol) was dissolved in a mixture solvents of ethyl acetate (31 ml) and ethanol (31 ml) and treated with PtO 2 (23 mg) and hydrogenated at 35 psi at r.t. for 2 hours. The mixture was filtered through diatomaceous earth (Celite (trademark)) and the filtrate was concentrated to give compound the title compound as off-white solid. 1HNMR (CDCl3)δ 1.3-1.65 (m, 4H), 1.65-1.8 (m, 2H), 1.9-2.1 (m, 3H), 2.65 (dd, 1H), 2.9-3.1 (m, 3H), 3.2 (dd, 1H), 3.55 (s, 2H), 7.15-7.4 (m, 8H), 7.9 (dd, 1H), 9.15 (s, 1H) ppm.
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:19])[CH:17]=[CH2:18]>CCCCCC.C(OCC)(=O)C>[C:1]([C:9]1([CH2:18][CH2:17][C:16]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)=[O:19])[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1C(=O)c1ccccc1
Reactant: C=CC(=O)OCc1ccc(OC)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)CCC2(C(=O)c3ccccc3)CCCCC2=O)cc1
Yield: 65.5 %

Procedure:
The title compound was prepared in 65.5% yield after chromatography (silica gel, hexane/ethyl acetate 4:1) from 2-benzoylcyclohexanone and p-methoxybenzyl acrylate using a similar method to that used in Preparation 2. (M+ 394.13, 53%). Rf. 0.39 (silica, hexane/ethyl acetate 2:1). 1H-NMR (300 MHz, CDCl3):=1.38-1.49 (m, 1H), 1.68-1.82 (m, 3H), 1.98-2.57 (m, 7H), 2.82-2.91 (m, 1H), 3.82 (s, 3H), 5.03 (s, 2H), 6.87 (d, 2H), 7.26 (d, 2H), 7.42 (t, 2H), 7.56 (t, 1H), 7.88 (d, 2H) ppm. Analysis %: Found: C, 73.05; H, 6.74; C24H26 O5 requires: C, 73.08; H, 6.64.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:27])[C:5]2[C:11]([CH3:12])=[C:10]([CH2:13][NH:14]C3C=C(OC)C(OC)=C(OC)C=3)[CH:9]=[N:8][C:6]=2[N:7]=1.Cl.NC(N)=N>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([NH2:27])[C:5]2[C:11]([CH3:12])=[C:10]([C:13]#[N:14])[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: COc1cc(NCc2cnc3nc(N)nc(N)c3c2C)cc(OC)c1OC
Agent: Cl
Agent: N=C(N)N
Solvent: CCO
Product: Cc1c(C#N)cnc2nc(N)nc(N)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Compound I was made in the following manner. Dried and pulverized guanidine hydrochloride (30.9 g; 0.323 mol.) was added to a solution prepared by dissolving Na metal (7.44 g; 0,323 mol.) in absolute ethyl alcohol (1.5 liter). This mixture was stirred rapidly at about 25° C. for about 30 minutes, and then 2-amino-3,5-dicarbonitrile-4-methylpyridine (24.7 g; 0.56 mol.) was added. The resulting mixture was refluxed with stirring for about seven days. The ethyl alcohol insoluble product (2,4-diamino-5-methylpyrido[2,3-d]pyrimidine-6-carbonitrile) and NaCl were filtered from the boiling mixture. The solid cake was then stirred with boiling ethyl alcohol, washed with hot water, ethyl alcohol and Et2O (ethyl ether) in that order to yield pure 2,4-diamino-5-methylpyrido[2,3-d]pyrimidine-6-carbonitrile in 65% yield and having a melting point greater than 300° C. A stirred solution of 2,4-diamino-5-methylpyrido[2,3-d]pyrimidine-6-carbonitrile (3.5 g; 17.5 mmol) and trimethoxyaniline (4.6; 2.51 mmol) in about 70% acetic acid (600 ml) containing damp Raney Ni (about 10 g) was kept under H2 at atmospheric pressure for about 24 hours. The mixture was then treated with Norit and filtered (celite mat). Acetic acid was removed from the filtrate by evaporation under reduced pressure (H2O aspirator, bath at 40° C.) with the aid of added portion of ethanol. Then a solution of the residue, in warm ethanol (20 ml), was added in a thin stream to a stirred saturated sodium carbonate solution (200 ml) at room temperature. The mixture was stirred at about 10° C. for about 20 minutes and the yellow precipitate that formed was collected, washed with H2O and dried. The crude product contained unchanged trimethoxyaniline, which was removed by repeated treatment with acetone and methanol (50 ml). The insoluble material was suspended and stirred in about 200 ml of ethanol for about 1 hour. The solid was collected by filtration, and dissolved in glacial acetic acid. The cloudy solution was clarified (using celite), concentrated, diluted with methanol (80 ml) and left for about 16 hours in a refrigerator when the desired product 2,4-diamino-5-methyl-6[[(3,4,5-trimethoxyphenyl)amino]methyl]pyrido[2,3-d]pyrimidine (Compound I) separated as a yellow solid (2.2 g) at a yield of 38.5%. 1HNMR δ 2.65(s, 3H, CH3), 3.56 (s,3H, OCH3), 3.67 (s, 6H, 20CH3), 4.17 (S,CH2, 2H), 5.66 (t, 1H, exchangeable), 5.93 (s, 2H, Ar-H), 6.21 (s, 2H, exchangeable), 6.99 (s,2H, exchangeable), 8.48 (s, 1H, aromatic H's). Microanalyses calculated for C18H22N6O3.0.4 CH3COOH.2H2O. C 52.46, H 6.46, N 19.52; Found C 52.60, H 6.22, N 19.71
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:15]=[C:14]([Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[C:13]([F:23])=[CH:12][N:11]=1.[F:24][CH2:25][C:26](OCC)=[O:27]>O1CCCC1.CCCCCCC.C(C1C=CC=CC=1)C.C1COCC1>[Br:9][C:10]1[N:11]=[C:12]([C:26](=[O:27])[CH2:25][F:24])[C:13]([F:23])=[C:14]([Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:15]=1
Reactant: CCOC(=O)CF
Reactant: CC[Si](CC)(CC)c1cc(Br)ncc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: CC[Si](CC)(CC)c1cc(Br)nc(C(=O)CF)c1F
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 93.7 %

Procedure:
To a 3-neck 500-mL round bottomed flask was added THF (180 mL). The solvent was cooled to −78° C. and lithium diisopropylamide, (Aldrich; 40.3 mL, 81 mmol, 2.0 M solution in tetrahydrofuran/heptane/ethylbenzene) was added over 2 min. To the solution was added 2-bromo-5-fluoro-4-(triethylsilyl)pyridine (11a, synthesized according to procedure in WO 2012/095469 A1; 18.0 g, 62.0 mmol) in 5 mL THF over 5 min. The temperature was not allowed to go above −70° C. during the addition. After 50 min, ethyl fluoroacetate (Aldrich; 7.79 mL, 81 mmol) was added over 3 min. The temperature was not allowed to go above −60° C. during the addition. The solution was stirred at −78° C. for 10 min and then the cold bath was removed and the solution was allowed to warm to −40° C. At that point the solution was poured into a solution of 1 N HCl/10% NH4Cl (1:1, 200 mL). The solution was extracted with EtOAc (3×200 mL) and the combined extracts were washed with brine (100 mL), dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (Gradient: 0.0 to 20% EtOAc/hexane) afforded 1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2-fluoroethanone (20.35 g, 58.1 mmol, 94% yield) as a yellow oil. MS m/z=350.0 [M+H]+. Calculated for C13H18BrF2NOSi: 349.0.
Reaction SMILES: [C:1]1(=N)[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1.Cl.[C:16]([O:20][C:21](=[O:24])[CH2:22][NH2:23])([CH3:19])([CH3:18])[CH3:17].C(Cl)Cl>C(OCC)C.CCCCCC>[C:16]([O:20][C:21](=[O:24])[CH2:22][N:23]=[C:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)([CH3:19])([CH3:18])[CH3:17]
Reactant: N=C1C=CC=C2C1=Cc1ccccc12
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN=C1c2ccccc2-c2ccccc21
Yield: 47.4 %

Procedure:
The fluorenone imine (1.52 g, 8.48 mmol) and the glycine tert-butylester hydrochloride (1.42 g, 8.48 mmol) were stirred in the methylene chloride for five hours at room temperature. The reaction solution was filtered with celite, and the solvent was removed by the distillation under reduced pressure. The obtained residual was allowed to dissolve in the diethyl ether. And, it was filtered with the celite. The obtained ether solution was cleaned with water and a saturated sodium chloride aqueous solution. And, it was dried over sodium sulfate. After the filtering and the concentration under reduced pressure were conducted, the obtained crude product was refined with the diethyl ether/hexane (recrystallization). And, (Fluoren-9-ylideneamino)-acetic acid tert-butyl ester (1.18 g, 66%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8](=[O:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:11]([Mg]Br)#[CH:12]>C1COCC1>[CH3:1][C:2]1[C:3]([C:8]([OH:10])([C:11]#[CH:12])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#C[Mg]Br
Reactant: CC(=O)c1ncccc1C
Solvent: C1CCOC1
Product: C#CC(C)(O)c1ncccc1C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure A. 1-(3-Methylpyridin-2-yl)ethan-1-one. (3.2 g, 23.68 mmol, 1.00 equiv) was dissolved in 6 mL of THF under inert nitrogen atmosphere in a 100-mL 3-necked round-bottom flask. Then ethynylmagnesium bromide (2M in THF, 61 mL, 1.30 equiv) was added dropwise into the solution at 0° C. The resulting solution was stirred for 10 min and then allowed to rise to room temperature and stirred for additional 2 h. The reaction was then quenched by the addition of 20 mL of sat. aqueous NH4Cl and the resulting solution was extracted with 2×25 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to get a residue, which was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to obtain 3.5 g (88%) of 2-(3-methylpyridin-2-yl)but-3-yn-2-ol as a light yellow solid.
Reaction SMILES: Br[C:2]1[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:4]([Br:8])=[C:5]([Br:7])[N:6]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[Br:7][C:5]1[N:6]=[C:2]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:4]=1[Br:8]
Reactant: C[Si](C)(C)CCOCn1c(Br)nc(Br)c1Br
Reactant: C1CNCCN1
Product: C[Si](C)(C)CCOCn1c(N2CCNCC2)nc(Br)c1Br
Yield: 28.2 %

Procedure:
A mixture of 2,4,5-tribromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (653 mg, 1.5 mmol) and piperazine (1.03 g, 12.0 mmol) under Ar was irradiated at 130° C. for 15 min in a microwave reactor. The reaction mixture was partitioned between DCM and water (100 mL, 1/1). The layers were separated and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The resulting was purified by flash chromatography (SiO2, 100:0-90:10 DCM-MeOH) to provide 186 mg of 1-(4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)piperazine as a colorless oil:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:11])[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1.C1C(=O)N([Cl:19])C(=O)C1>CC(O)=O>[Cl:19][C:9]1[S:8][C:6]2[N:7]=[C:2]([CH3:1])[NH:3][C:4](=[O:11])[C:5]=2[CH:10]=1
Reactant: Cc1nc2sccc2c(=O)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: Cc1nc2sc(Cl)cc2c(=O)[nH]1
Temperature: 40 °C
Reaction time: 48 h
Yield: 91.1 %

Procedure:
To a mixture of 2-methylthieno[2,3-d]pyrimidin-4(3H)-one (5.0 g) and AcOH (50 mL) was added NCS (4.8 g), followed by heating and stirring at 40° C. for 2 days. The reaction mixture was concentrated under reduced pressure. To the residue was added water, followed by stirring, and the precipitate was collected by filtration and then dried to obtain 6-chloro-2-methylthieno[2,3-d]pyrimidin-4(3H)-one (5.5 g).
Reaction SMILES: [PH2:1](=[O:3])[OH:2].[CH2:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>O1CCCC1.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)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH2:4]([P:1]([OH:2])[OH:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C=CCCCCCC
Reactant: O=[PH2]O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCP(O)O
Yield: 87.5 %

Procedure:
99 g (0.75 mol) of phosphinic acid, 86 g (0.76 mol) of octene, 34 mg of tris(dibenzylideneacetone)dipalladium and 48 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene in 750 g of tetrahydrofuran are reacted at about 70° C. for 9 hours, passed through a column charged with Deloxan® THP II for purification and freed of solvent in a rotary evaporator. The residue is admixed with 500 g of completely ion-free water and stirred, and then filtered, the filtrate is extracted with ethyl acetate. This is followed by removal of solvent in a rotary evaporator to obtain 117 g (84% of theory) of octylphosphonous acid.