Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[N:32][CH:31]=1>>[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:8](=[O:9])[CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:32][CH:31]=1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Reactant: COC(=O)c1ccc(N)nc1
Product: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3c(F)cccc3F)cc2=O)nc1

Procedure:
Using the method described in Example 66, 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 47) and 6-amino-nicotinic acid methyl ester afforded 6-{3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionylamino}-nicotinic acid methyl ester as a pale, yellow solid (720 mg, 66%); ES+-HRMS m/e calcd for C25H24N4O5F2 [M+H+] 499.1788 found 499.1784. 1H NMR (300 MHz, CDCl3) δ ppm 1.19 (br s, 2H) 1.41-1.91 (m, 7H) 2.13-2.44 (m, 2H) 3.93 (s, 3H) 5.65 (dd, J=8.6, 6.5 Hz, 1H) 6.04 (br s, 1H) 7.00-7.16 (m, 2H) 7.28-7.34 (m, 1H) 8.03 (d, J=2.4 Hz, 1H) 8.14-8.44 (m, 2H) 8.88 (s, 1H) 9.11 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:11][C:12]#[N:13])(=[O:10])=[O:9].ClC1C=C[C:18]([S:21]([CH2:24]C#N)(=[O:23])=[O:22])=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11](=[C:24]([S:8]([CH3:3])(=[O:10])=[O:9])[S:21]([CH3:18])(=[O:23])=[O:22])[C:12]#[N:13])(=[O:10])=[O:9]
Reactant: N#CCS(=O)(=O)c1ccccc1Cl
Reactant: N#CCS(=O)(=O)c1ccc(Cl)cc1
Product: CS(=O)(=O)C(=C(C#N)S(=O)(=O)c1ccccc1Cl)S(C)(=O)=O

Procedure:
The titled compound was prepared in an analogous fashion to Intermediate 2 except that 2-(2-chlorobenzenesulfonyl) acetonitrile is utilized in place of 2-(4-chlorobenzenesulfonyl) acetonitrile.
Reaction SMILES: [CH2:1]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[CH2:19][CH2:20][CH2:21][OH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:10]([N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:19][CH2:20][CH2:21][OH:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCNCCCCCCCC
Reactant: OCCCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCN(CCCO)CCCCCCCC
Yield: 66.8 %

Procedure:
A mixture of 24 g of di-n-octylamine, 10 g of 3-chloro-1-propanol and 11 g of triethylamine in 200 ml of toluene was refluxed for 24 hours. The toluene solution was washed twice with water to remove the triethylamine hydrochloride formed and then evaporated. The residue was distilled and gave 19.9 g of N,N-di-n-octyl-3-amino-1-propanol, b.p. 125°-130° C./0.01 mm Hg, nD22 = 1.4613.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][N:7]([C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=3)[CH:8]=2)[CH2:3][CH2:2]1>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[CH:1]1([C:4]2[CH:5]=[N:6][N:7]([C:9]3[N:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=3)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(-n2cc(C3CC3)cn2)nc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Nc1ccc(-n2cc(C3CC3)cn2)nc1
Yield: 37.9 %

Procedure:
A solution of 2-(4-cyclopropyl-1H-pyrazol-1-yl)-5-nitropyridine (2.91 g, 12.7 mmol) in ethyl acetate (250 ml) was passed through an H-Cube reactor equipped with a 10% Pd(OH)2/C cartridge at 50° C., 50 bar, at 1 ml/min. The solution was concentrated in vacuo. The crude material was purified via ISCO MPLC (SiO2, 0-100% ethyl acetate in heptane) to yield the product (964 mg, 38%) as a solid. 1H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 7.85 (d, J=2.7 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.48 (s, 1H), 7.12 (dd, J=8.7, 2.8 Hz, 1H), 3.70 (br. s., 2H), 1.75 (tt, J=8.6, 5.3 Hz, 1H), 0.88 (ddd, J=8.4, 6.3, 4.5 Hz, 1H), 0.59 (dt, J=5.7, 4.5 Hz, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:17])[O:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([OH:13])[C:7]=2[CH2:14][CH2:15][CH3:16])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:24][CH2:25][CH2:26][CH2:27]Br>CN(C=O)C.C(OCC)(=O)C.[Cl-].[NH4+]>[Br:24][CH2:25][CH2:26][CH2:27][O:13][C:8]1[C:7]([CH2:14][CH2:15][CH3:16])=[C:6]2[C:11]([CH:12]=[C:3]([CH2:1][CH3:2])[C:4](=[O:17])[O:5]2)=[CH:10][CH:9]=1
Reactant: BrCCCBr
Reactant: CCCc1c(O)ccc2cc(CC)c(=O)oc12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCBr)ccc2cc(CC)c(=O)oc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-ethyl-7-hydroxy-8-propylcoumarin (37 mg, 0.1593 mmol) and potassium carbonate (44 mg, 0.3186 mmol) in 0.7 mL DMF was added 1,3-dibromopropane (161 mg, 0.08 mL). The mixture was stirred at ambient temperature for 2 hours and diluted with ethyl acetate and saturated (aqueous) ammonium chloride. After the layers were separated, the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, concentrated in vacuo, and the crude residue was purified by flash chromatography on silica gel (gradient elution: 5% then 10% then 20% ethyl acetate/hexane). This provided the title compound.
Reaction SMILES: [Li]CCCC.[C:6]([Si:10]([O:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH3:22])([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].CN(CCN(CCN(C)C)C)C.[CH3:35][N:36]1[C:40]([CH:41]=[O:42])=[N:39][C:38]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[N:37]1>C1COCC1.O>[Si:10]([O:13][C:14]1[C:15]([CH2:21][CH3:22])=[CH:16][C:17]([CH:41]([C:40]2[N:36]([CH3:35])[N:37]=[C:38]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:39]=2)[OH:42])=[C:18]([F:20])[CH:19]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:12])[CH3:11]
Reactant: CCc1ccc(F)cc1O[Si](C)(C)C(C)(C)C
Reactant: Cn1nc(-c2ccccc2)nc1C=O
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(C(O)c2nc(-c3ccccc3)nn2C)c(F)cc1O[Si](C)(C)C(C)(C)C
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
BuLi (0.67 mL, 1.6 M in hexanes, 1.1 mmol) was added dropwise to a solution of Intermediate 386.3 (250 mg, 0.98 mmol) and PMDTA (0.20 mL, 0.98 mmol) in THF (4 mL) at −78° C. The mixture was warmed to −40° C. and stirred for 30 min. After recooling the reaction to −78° C., Intermediate 386.1 (203 mg, 1.08 mmol) in THF (2 mL) was added and the mixture was warmed to ambient temperature over 2 h. Water was added to the mixture and it was extracted with EtOAc. The organics were combined, washed with brine, dried (Na2SO4) and concentrated. Purification by flash chromatography (hexanes, EtOAc) yielded 292 mg of Intermediate 386.4 as a clear oil. LCMS 442.34 (M+H).
Reaction SMILES: [F:1][CH2:2][C:3]([CH3:12])([C:8]([F:11])([F:10])[F:9])[C:4]([OH:7])([F:6])[F:5].C(N(CC)CC)C.F[C:21](=[CH2:25])[C:22](F)=[O:23]>C(Cl)(Cl)Cl>[C:22]([O:7][C:4]([F:5])([F:6])[C:3]([CH3:12])([CH2:2][F:1])[C:8]([F:9])([F:10])[F:11])(=[O:23])[CH:21]=[CH2:25]
Reactant: C=C(F)C(=O)F
Reactant: CC(CF)(C(O)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CC(=O)OC(F)(F)C(C)(CF)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
Into a 200-ml, four-necked glass flask provided with a thermometer, a dropping funnel, a stirrer and a reflux condenser were placed 58.83 g (0.3 mol) of hexafluoroneopentyl alcohol, 30.36 g (0.3 mol) of triethylamine and 50 g of chloroform. Subsequently, to the mixture was added dropwise 30.37 g (0.33 mol) of 2-fluoroacrylic fluoride at a temperature of up to 10° C. with ice-cooling. After addition, the mixture was stirred at room temperature for 30 minutes. The mixture was washed with an aqueous solution of sodium bicarbonate (5%) and then with pure water, followed by evaporation to remove chloroform, producing hexafluoroneopentyl acrylate. The amount of the obtained product was 67.17 g and the yield was 76.7%. To the product was further added 0.1 g of t-butyl catechol as a polymerization inhibitor and the mixture was distilled under reduced pressure for purification. The boiling point was 55° to 56° C./20 mm·Hg. The identification was performed with 1H-NMR spectrum, 19 F-NMR spectrum and 13C-NMR spectrum (in every case, sovent: acetone-d6).
Reaction SMILES: [ClH:1].CC1C2COC(=O)C=2C=CC=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.Br[C:22]1[CH:31]=[CH:30][C:25]2[C:26](=[O:29])[O:27][CH2:28][C:24]=2[C:23]=1[C:32]([F:35])([F:34])[F:33]>>[ClH:1].[N:15]1([CH2:14][CH2:13][C:22]2[CH:31]=[CH:30][C:25]3[C:26](=[O:29])[O:27][CH2:28][C:24]=3[C:23]=2[C:32]([F:35])([F:34])[F:33])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Reactant: O=C1OCc2c1ccc(Br)c2C(F)(F)F
Agent: Cl
Product: O=C1OCc2c1ccc(CCN1CCNCC1)c2C(F)(F)F

Procedure:
5-[2-(piperazin-1-yl)ethyl]-4-(trifluoromethyl)-2-benzofuran-1(3H)-one hydrochloride was prepared in an analogous fashion to that described for the synthesis of 4-methyl-5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one hydrochloride above starting from 5-bromo-4-(trifluoromethyl)-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 315 [M+1]+;
Reaction SMILES: [N+:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)([O-])=O>[Pd]>[NH2:1][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: O=[N+]([O-])N1CCc2ccccc21
Agent: [Pd]
Product: NN1CCc2ccccc21

Procedure:
Alternatively, substituted amino-indolines 67 are prepared from the nitroindoline 62. Nitroindoline 62, is reacted with an acid chloride to form an amide. Further treatment with a primary or secondary amine, preferably a secondary amine, such as in the presence of NaI, at a temperature above about 50° C., and preferably at about 70° C. yields the nitroindoline 65. The nitro compound 65 is hydrogenated, such as with H2 in the presence of a catalyst, such as Pd/C, to yield the amino-indoline 66. The carbonyl is reduced, such as with BH3-THF yields 1-aminoalkyl-indolines 67.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CN1CCCC1=O>[N:17]1([C:2]2[N:7]=[N:6][C:5]([C:8]3[NH:12][C:11]4[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=4[N:9]=3)=[CH:4][CH:3]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: C1CNCCN1
Reactant: Clc1ccc(-c2nc3ccccc3[nH]2)nn1
Solvent: CN1CCCC1=O
Product: c1ccc2[nH]c(-c3ccc(N4CCNCC4)nn3)nc2c1
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-(6-chloropyridazin-3-yl)-1H-benzoimidazole (0.280 g, 2.040 mmol) and piperazine (0.516 g, 6.000 mmol) in 1-methyl-2-pyrrolidone (35 mL) was heated to 140° C. with stirring for 30 minutes. The solvent was evaporated in vacuo, the residue was diluted with water (100 mL) and stirred for 15 minutes. A white precipitate was formed which was collected by filtration and dried to afford the title compound.
Reaction SMILES: C([O:5][C:6](=[O:48])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([C:18]2[N:19]=[C:20]3[C:26]([C:27](=[O:39])[NH:28][C@H:29]([CH3:38])[C:30]([N:32]4[CH2:35][CH:34]([C:36]#[N:37])[CH2:33]4)=[O:31])=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]3=[N:22][CH:23]=2)=[N:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([C:18]3[N:19]=[C:20]4[C:26]([C:27](=[O:39])[NH:28][C@H:29]([CH3:38])[C:30]([N:32]5[CH2:35][CH:34]([C:36]#[N:37])[CH2:33]5)=[O:31])=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[N:9][N:8]2[CH2:7][C:6]([OH:48])=[O:5])=[CH:12][CH:13]=1
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC(=O)OC(C)(C)C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(CC(=O)O)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.7 %

Procedure:
In a 5 mL pear-shaped flask, {6-chloro-3-[7-[(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethylcarbamoyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-indazol-1-yl}-acetic acid tert-butyl ester (30 mg, 0.043 mmol) was combined with CH2Cl2 (1 ml) to give a light yellow solution. TFA (0.10 ml, 1.3 mmol) was added and the reaction was stirred at room temperature for 2 h. The crude reaction mixture was concentrated in vacuo and redissolved in CH2Cl2. Ethylenediamine (88 μl, 1.3 mmol) was added dropwise and the reaction was stirred at room temperature for 30 min. The crude reaction mixture was concentrated in vacuo. The residue was dissolved in water and it was lyophilized overnight. The yellow waxy solid was suspended in water and filtered, washing with water then dried on high vacuum to give 8 mg (32%) of (6-Chloro-3-{7-[(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethylcarbamoyl]-5H-pyrrolo[2,3-b]pyrazin-2-yl}-indazol-1-yl)-acetic acid as a yellow solid. MS: (M+H)+=507.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:64][N:65]([CH3:69])[CH2:66][CH2:67][NH2:68]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:68][CH2:67][CH2:66][N:65]([CH3:69])[CH3:64])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CN(C)CCN
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccccc2)C[C@@H]1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCN(C)C)cc3)cc2[C@H](Nc2ccccc2)C[C@@H]1C
Temperature: 25 °C
Yield: 20 %

Procedure:
4-((2S,4R)-1-Acetyl-2-methyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 35) (90 mg, 0.225 mmol) was dissolved in anhydrous DMF (3 ml and HATU (103 mg, 0.270 mmol) added. DIPEA (0.118 ml, 0.674 mmol) was added to the mixture and after a further 5 min of stirring at r.t. N1,N1-dimethylethane-1,2-diamine (0.030 ml, 0.449 mmol). The reaction mixture was stirred at r.t. overnight, concentrated and partitioned between EtOAc and water. The Organic phase was separated, dried (Na2SO4) and concentrated. The yellow residue was purified by chromatography a silica cartridge (10 g), eluting with MeOH/DCM (1-6% over 120 mls, followed by 6-20% over 120 mls) to give 4-((2S,4R)-1-acetyl-2-methyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-N-(2(dimethylamino)ethyl)benzamide (24 mg, 0.05 mmol, 20% yield) as a light brown solid. LCMS (Formic, 2 min), Rt=0.79 min, MH+=471.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[N:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[C:9]1([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][C:18]3[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=3)=[CH:8][N:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccncc1
Reactant: BrCc1ccc(-c2ccccc2)nc1
Product: c1ccc(-c2ccc(Cc3ccncc3)cn2)cc1
Reaction time: 0.5 h

Procedure:
Synthesized using compound 61a (355 mg, 1.43 mmol) and 4-pyridineboronic acid (264 mg, 2.15 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (2:1) as eluent. After flash chromatography the product was solved in ethyl acetate and a few drops of conc. HCl and water were added. After stirring for 30 minutes the phases were separated and water phase was neutralized with aqueous Na2CO3-solution (2M). After extraction with ethyl acetate and drying over MgSO4 the solvent was removed under vacuum. Beige solid. Yield: 140 mg, 40%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=3.77 (s, 2H), 6.88-6.93 (m, 2H), 7.15-7.21 (m, 1H), 7.21-7.31 (m, 3H), 7.45 (dd, J=8.2, 0.9 Hz, 1H), 7.72-7.78 (m, 2H), 8.28-8.33 (m, 2H), 8.33-8.37 (m, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=38.0, 120.3, 124.0, 126.7, 128.7, 128.9, 132.7, 137.1, 138.9, 148.7, 149.9, 150.0, 156.0; (ESI): m/z=246.85 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:14][C:15](=[O:18])[CH2:16]Cl)([CH2:12][OH:13])[CH:9]([F:11])[F:10])[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].O>C(O)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:9]([F:11])[F:10])[NH:14][C:15](=[O:18])[CH2:16][O:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCl)NC(CO)(c1cccc(Br)c1)C(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C1COCC(c2cccc(Br)c2)(C(F)F)N1

Procedure:
N-[1-(3-Bromo-phenyl)-2,2-difluoro-1-hydroxymethyl-ethyl]-2-chloro-acetamide (8.10 g, 23.65 mmol) and potassium tert-butoxide (5.31 g, 47.3 mmol) were heated to 95° C. in 118 ml tert-butanol for 30 minutes. After completion water was added and the reaction was evaporated. The residue was put between ethyl acetate and water. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The organic phases were washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to yield the title compound as off-white solid. 1H-NMR (360 MHz, DMSO-d6): 9.13 (s, 1H, NH), 7.78 (s, 1H), 7.59 (m, 2H), 7.42 (t, 1H), 6.48 (t, 1H, CHF2), 4.28 (d, 1H), 4.10 (m, 2H), 3.92 (m, 1H); MS: 306 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[CH:12]([Mg]Br)=[CH2:13]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]2[C:3]=1[NH:9][CH:13]=[CH:12]2
Reactant: Cc1ccc([N+](=O)[O-])c(Br)c1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: Cc1cc(Br)c2[nH]ccc2c1
Temperature: -65 °C
Yield: 52 %

Procedure:
3.3 g of 2-bromo-4-methyl-1-nitro-benzene (15 mmol) were dissolved in 200 ml THF and the solution was cooled to −65° C. Then 46 ml of a 1 molar solution of vinyl magnesium bromide in THF were added in a way, that the temperature of the reaction mixture stayed below −40° C. After 30 min at −40° C. the reaction was quenched with saturated ammonium chloride solution and was extracted with EtOAc. The combined organic phases were washed with brine and dried with magnesium sulfate. After filtration and evaporation of the solvent the crude product was purified by chromatography (silica gel; cyclohexane/EtOAc 4:1). 1.68 g (52%) of 7-bromo-5-methyl-indole were isolated as brown liquid. 1H NMR (DMSO-d6, 300 MHz): δ 2.36 (s, 3H), 6.45 (m, 1H), 7.14 (s, 1H), 7.34 (m, 2H), 11.16 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH:22][CH:23]=O)[N:20]=[C:15]2[CH:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>O1CCOCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[C:16]2[N:17]=[CH:18][C:19]3[N:20]([CH:23]=[N:22][CH:21]=3)[C:15]=2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CNC=O)cnc3n1COCC[Si](C)(C)C)cn2C
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cncn43)n1COCC[Si](C)(C)C)cn2C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
N-((6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)formamide (0.10 g, 0.22 mmol) in 1,4-dioxane (4 mL) was treated with Lawesson's Reagent (0.053 g, 0.13 mmol) and heated to about 80° C. in an oil bath for about 15 min. The mixture was cooled and mercuric acetate (0.073 g, 0.23 mmol, Fluka) was added. The mixture was stirred for about 30 min at ambient temperature and another portion of mercuric acetate (0.073 g, 0.228 mmol, Fluka) was added and stirring was continued for about 2 h at ambient temperature. The mixture was diluted with EtOAc (20 mL) and filtered. The solvent was evaporated under reduced pressure then the material was purified by silica gel chromatography eluting with DCM/MeOH (95:5). The material obtained after concentration of the product-containing fractions was further purified by silica gel chromatography eluting with EtOAc to give 7-(5-methoxy-1-methyl-1H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.048 g, 49%): LC/MS (Table 2, Method a) Rt=3.16 min; MS m/z: 448 (M+H)+.
Reaction SMILES: C(O[C:4]([C:6]1[O:7][C:8]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:9][N:10]=1)=[O:5])C.[CH3:20][NH2:21]>C1COCC1>[C:16]([O:15][C:13](=[O:14])[NH:12][CH2:11][C:8]1[O:7][C:6]([C:4](=[O:5])[NH:21][CH3:20])=[N:10][N:9]=1)([CH3:17])([CH3:18])[CH3:19]
Reactant: CCOC(=O)c1nnc(CNC(=O)OC(C)(C)C)o1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1nnc(CNC(=O)OC(C)(C)C)o1

Procedure:
Prepared in an analogous fashion to Description 35 from 5-[[[(1,1-dimethylethoxy)carbonyl]amino]methyl]-1,3,4-oxadiazole-2-carboxylic acid ethyl ester (prepared as described in JOC (1995), 60(10), 3112-20) (0.150 g) using 2.0M methylamine in THF.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl.[Cl:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1.N1C=CC=C(CCCO)C=1>>[ClH:28].[N:34]1[CH:35]=[CH:36][CH:37]=[C:32]([CH2:31][CH2:30][CH2:29][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]4[CH:24]=[CH:25][S:26][C:20]=4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH:33]=1
Reactant: ClCCCc1cccnc1
Reactant: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(O)cc12
Agent: Cl
Agent: OCCCc1cccnc1
Product: ON=c1cc(-c2cc3sccc3cn2)oc2ccc(OCCCc3cccnc3)cc12

Procedure:
6-(3-Pyridin-3-yl-propoxy)-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one oxime, hydrochloride was prepared in 10% overall yield using the method described in example 127, starting from 6-hydroxy-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl oxime (example 127A) and 3-(3-Chloro-propyl)-pyridine hydrochloride, prepared from 3-pyridine propanol (U.S. Pat. No. 6,362,336).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:3][CH2:2]2.[N:11](OCCCC)=[O:12].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[Cl-].[NH4+]>O1CCCC1>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[C:3](=[N:11][OH:12])[CH2:2]2
Reactant: CCCCON=O
Reactant: O=C1CCN2CCC1CC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C(=NO)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
A solution of 1-azabicyclo[3.2.2]nonan-4-one (1.39 g, 10 mmol) in anhydrous tetrahydrofuran (20 mL) under nitrogen was cooled (-65° C.), and treated with n-butyl nitrite (1.30 mL, 11 mmol). 1.0N Lithium bis(trimethylsilyl)amide/THF (16 mL, 16 mmol) was added dropwise so as to keep the pot temperature below -58° C. After the addition was complete the mixture was warmed to room temperature over one h, stirred for 30 min, cooled on an ice bath, and treated with saturated ammonium chloride (6 mL). The solution was concentrated in vacuo, diluted with toluene, and reconcentrated to remove most of the water. The residue was chromatographed on silica gel (eluted with 5% methanol/methylene chloride, then with 10% methanol/methylene chloride), then triturated from ether to afford 1-azabicyclo[3.2.2]nonan-3,4-dione-3-oxime (0.92 g, 55%) as a white solid.