Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[CH:8][N:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:45]=[CH:44][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:19]2=[O:43])=[CH:15][CH:14]=1.C(O)(=O)C>O>[CH3:1][N:2]1[C:6]2[N:7]=[CH:8][N:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[NH:20][C:19]2=[O:43])=[CH:44][CH:45]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cncnc21
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2cncnc21

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 0.24 g of 5-{4-(3-methylimidazo[5,4-d]pyrimidin-2-ylmethoxy)benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 51) and 8 ml of a 3:1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and ethanol in ratios ranging from 1:0 to 10:1 by volume as the eluent, to give 30 mg of the title compound, melting at 245-246° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](O)=[O:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O.C(#N)C.CCOC(C)=O>[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=3)=[O:20])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccccn1
Reactant: Brc1ccc2c(c1)CNCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1ccccn1)N1CCc2ccc(Br)cc2C1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
To a suspension of 7-bromo-1,2,3,4-tetrahydro-isoquinoline hydrochloride (500 mgs, 2.0 mmol), pyridine-2-carboxylic acid (322 mgs, 2.61 mmol), HATU (992 mgs, 2.61 mmol), in DMF (2.5 mL) was added NMM (0.7 mL, 6.0 mmol) and the resulting solution was stirred at 23° C. for 3 h. The reaction mixture was then diluted with water/acetonitrile (15:1) and the resulting oil was then taken into EtOAc and washed with 1N HCl, NaHCO3, brine and dried (MgSO4). The mixture was the filtered and concentrated) to provide (7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)(pyridin-2-yl)methanone.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-:3].[Cl-:4].[F:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[CH:8][C:7]=1[C:15](F)(F)F>C(Cl)Cl>[F:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[CH:8][C:7]=1[C:15]([Cl:4])([Cl:3])[Cl:1]
Reactant: [Cl-]
Reactant: Fc1cc(C(F)(F)F)c(F)c(F)c1F
Agent: [Al+3]
Solvent: ClCCl
Product: Fc1cc(C(Cl)(Cl)Cl)c(F)c(F)c1F
Temperature: 0 °C

Procedure:
85 g (0.64 mol) of aluminum chloride (anhydrous) are initially introduced into 500 ml of methylene chloride, and 109 g (0.5 mol) of 2,3,4,5-tetrafluoro-benzotrifluoride are added dropwise at room temperature; while stirring. The mixture is then subsequently stirred at 40° C. for 1 hour, allowed to cool and poured onto 600 g of ice, the organic phase is separated off, the aqueous phase is extracted with ether and the combined phases are washed with water and dried over anhydrous magnesium sulphate. After concentration, the residue is distilled. 108.3 g (81% of theory) of product are obtained; boiling point: 89-90° C./22 mbar.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.CCO>CCOC(C)=O>[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)CCCCCCCCCCCCCCCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCCCCCCCCCCCCCCCO
Yield: 92.3 %

Procedure:
Ethyl 17-(tetrahydropyran-2-yl-oxy)-heptadecanoate 78 (365 mg, 0.916 mmol) and PPTS (12 mg, 0.046 mmol) were dissolved in abs. EtOH (6 ml) and the reaction mixture was stirred at 45° C. for 10 h. Reaction mixture was diluted with EtOAc and washed with H2O. The extract was dried over Na2SO4 and evaporated. The residue was purified by silica gel chromatography in hexane-EtOAc (95:5, 90:10) to yield the product 79 (266 mg, 92%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2([OH:22])[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH2:26][CH:25]([NH:27][C:28]([CH2:30][NH:31][C:32](=[O:43])[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)=[O:29])[CH2:24]1>>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2([OH:22])[CH2:20][CH2:19][CH:18]([N:23]3[CH2:26][CH:25]([NH:27][C:28]([CH2:30][NH:31][C:32](=[O:43])[C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:40])[F:41])[CH:34]=4)=[O:29])[CH2:24]3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(O)(c2ccc(OCc3ccccc3)nc2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(OCc4ccccc4)nc3)CC2)C1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-(6-benzyloxy-pyridin-3-yl)-4-hydroxy-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:16]3[N:15]([CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[C:14]4[CH2:29][CH:30]5[NH:34][CH:33]([C:13]=4[C:12]=3[C:11]=2C(OC(C)(C)C)=O)[CH2:32][CH2:31]5)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH2:19][CH2:20][OH:21])[C:14]2[CH2:29][CH:30]4[NH:34][CH:33]([C:13]3=2)[CH2:32][CH2:31]4)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)c1c(S(=O)(=O)c2ccccc2)ccc2c1c1c(n2CCO[Si](C)(C)C(C)(C)C)CC2CCC1N2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)c1c(n2CCO)CC2CCC1N2
Reaction time: 8 h
Yield: 87.2 %

Procedure:
To a solution of the product of step A (110 mg, 0.30 mmol) in dichloromethane at 0° C. was added trifluoroacetic acid (0.57 ml, 7.5 mmol) and the reaction was stirred overnight. The reaction mixture was made basic with saturated sodium bicarbonate solution and extracted with dichloromethane. The dichloromethane layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was crystallized from dichloromethane to give 2-phenylsulfonyl-5-(2-hydroxy)ethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole (100 mg, 87%) as a white crystalline solid: 1H NMR (CDCl3, 300 MHz), δ 8.27 (s, 1H), 7.93-7.96 (m, 2H), 7.71 (dd, J=9.0, 1.2 Hz, 1H), 7.52-7.62 (m, 4H), 5.29-5.31 (m, 1H), 4.53 (br s, 1H), 4.24 (t, J=5.1 Hz, 2H), 3.81 (t, J=5.1 Hz, 2H), 3.54 (dd, J=17.4, 4.5 Hz, 1H), 3.12 (d, J=20.7 Hz, 1H), 2.23-2.46 (m, 3H), 1.93-1.97 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[C:9]1([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:17][S+:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][CH2:28]1.CCOCC>C(O)C>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[C:9]1([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[C:17]([C:33]3[CH:32]=[C:31]4[C:36](=[CH:35][CH:34]=3)[NH:27][CH2:28][CH2:29][CH2:30]4)[S+:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc2c(c1)CCCN2
Reactant: c1ccc(-c2cc[s+]c(-c3ccccc3)c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOCC
Solvent: CCO
Product: c1ccc(-c2cc(-c3ccccc3)[s+]c(-c3ccc4c(c3)CCCN4)c2)cc1

Procedure:
2,4-diphenylthiopyrylium trifluoromethane sulfonate (2.0 g) and 1,2,3,4-tetrahydroquinoline (1.4 g) in ethanol (20 ml) were heated at 90° for 30 minutes. After cooling the solution was poured into ether (50 ml) and the precipitated dye was filtered, washed with ether and recrystallized from ethanol as black needles having a melting point of 233° C., λ max (CHCl3) 656 nm.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[OH-].[K+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1.Cl>CN(C=O)C>[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1
Reactant: Ic1cccs1
Reactant: Fc1ccc(S)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1ccc(Sc2cccs2)cc1
Temperature: 135 °C
Yield: 68.9 %

Procedure:
To a degassed mixture of 2-iodothiophene (0.87 mL, 7.88 mmol), Cu2O (0.56 g, 3.9 mmol) and KOH (0.44 g, 7.8 mmol) in DMF (7.8 mL) was slowly added 4-fluorobenzenethiol (0.33 mL, 7.8 mmol). The resulting mixture was heated at 135° C. for 15 h, allowed to cool to room temperature and poured into a 0° C. 6N HCl solution. After 15 min. the precipitate was filtered and washed with benzene. The filtrate was extracted with benzene, dried (MgSO4) and concentrated under reduced pressure to give 2-(4-fluorophenylthio)thiophene (1.13 g, 69%) as a pale yellow oil: TLC (10% EtOAc/hex) Rf 0.49; HPLC ES-MS m/z (rel intensity) 210 (M+, 100).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Li+].CC([N-]C(C)C)C.[C:23](N1C=CN=C1)(=[O:25])[CH3:24]>C1COCC1>[C:23]([CH:7]1[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]1)(=[O:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(=O)n1ccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (6.00 g) in THF was added LDA (16 mL, 1 M) dropwise at −78° C. The mixture was stirred at −78° C. for 2 h. To this, a solution of N-acetylimidazole (3.50 g) in THF was added, and the reaction mixture was stirred at −78° C. for another 7 h, then quenched with 10 mL of ice-water and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 3:1 (v/v) PE/EA) to give the title compound as yellow oil (2.98 g, 41.00%), HPLC: 89.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 242.4 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 2.13 (s, 3H), 2.28 (s, 1H), 2.44 (t, J=4.0 Hz, 2H), 3.58 (t, J=8.0 Hz, 2H), 3.97 (s, 2H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28][Si:29]([CH2:32][CH2:33][O:34][CH2:35]Cl)([CH3:31])[CH3:30]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[C:14]1[N:18]([CH2:35][O:34][CH2:33][CH2:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)[N:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(C)OC(=O)N1CC(O)CC1c1ncc(-c2ccc(Br)cc2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(O)CC1c1nc(-c2ccc(Br)cc2)cn1COCC[Si](C)(C)C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg) was dissolved in DMF (8 mL), and NaH (54 mg) was added. The mixture was stirred over 10 min. and SEM-Cl was added slowly, and then stirred for 2 hours. The mixture was quenched with 3 mL of sat. NH4Cl and was taken up in ethyl acetate (100 mL). The organic phase was washed with saturated sodium bicarbonate (1×100 mL) and dried over sodium sulfate. After the solvent was removed, the resulting oil was subjected to silica gel chromatography using effluent of 20-50% ethyl acetate and hexanes. The fractions containing product were combined and the solvent was removed under reduced pressure to provide 2-[4-(4-Bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (648 mg, 98%) as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:15]=2[S:22]([NH2:25])(=[O:24])=[O:23])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[C:26]([CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)#[CH:27]>>[CH:28]1([C:26]#[C:27][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:15]=3[S:22]([NH2:25])(=[O:24])=[O:23])(=[O:12])=[O:11])=[CH:4][CH:3]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NS(=O)(=O)c1cc(CO)ccc1NS(=O)(=O)CCc1ccc(Br)cc1
Reactant: C#CC1CCCC1
Product: NS(=O)(=O)c1cc(CO)ccc1NS(=O)(=O)CCc1ccc(C#CC2CCCC2)cc1
Yield: 11 %

Procedure:
The title compound was synthesized as described for Example 210 in 11% yield, starting from 2-[2-(4-bromo-phenyl)-ethanesulfonylamino]-5-hydroxymethyl-benzenesulfonamide and ethynyl-cyclopentane. Purification by preparative HPLC.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:11][C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)#[N:2].S(=O)(=O)(O)O>[Pt]=O.C(O)(=O)C>[NH2:2][CH2:1][CH2:3][CH:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:11][C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: N#CCC1c2ccccc2Oc2ccccc21
Agent: O=[Pt]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: NCCC1c2ccccc2Oc2ccccc21

Procedure:
After the addition of 2 g. platinum oxide; 45 g. (0.21 mol) 9-cyanomethyl-xanthene in a mixture of 500 ml. glacial acetic acid and 5 ml. concentrated sulphuric acid are catalytically hydrogenated for 4 hours without the use of pressure. Subsequently, the acetic acid is substantially removed by evaporation in a vacuum (about 3/4 of the volume). The residue is taken up in water and the neutral products are removed by extraction with ether. The basic products are then liberated by the addition of 2N sodium hydroxide solution and isolated by extraction with ether. The evaporation residue of the ethereal solution gives, after high vacuum distillation, 28.4 g. (60% of theory) 9-(2-aminoethyl)-xanthene of b.p. 145° - 148° C./0.5 mm.Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].ClC1C=C(OC)C=CC=1[O-].[K+].Cl[C:23]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=1[N+:36]([O-:38])=[O:37]>C(O)C>[N+:33]([C:32]1[CH:31]=[C:26]([CH:25]=[C:24]([N+:36]([O-:38])=[O:37])[C:23]=1[O:10][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[Cl:1])[C:27]([O:29][CH3:30])=[O:28])([O-:35])=[O:34]
Reactant: COc1ccc(O)c(Cl)c1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: COc1ccc([O-])c(Cl)c1
Agent: [K+]
Solvent: CCO
Product: COC(=O)c1cc([N+](=O)[O-])c(Oc2ccc(OC)cc2Cl)c([N+](=O)[O-])c1
Yield: 66 %

Procedure:
The dinitro precursor was prepared by reacting 2-chloro-4-methoxyphenol (Aldrich Chemical Co., Milwaukee, Wis.) as the potassium 2-chloro-4-methoxyphenolate with methyl 4-chloro-3,5-dinitrobenzoate, as described in Example 1.2.1. The methyl 3,5-dinitro-4-(2′-chloro-4′-methoxyphenoxy)benzoate product (66% yield) was crystallized from ethanol to give orange crystals. Melting point: 116-119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:26][CH2:27][C:28]#[CH:29])[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=O)=[CH:4][CH:3]=1.C1C=CC=CC=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:45]2)=CC=1>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:26][CH2:27][C:28]#[CH:29])[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[S:45])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C#CCOc1ccc(CCNC(=O)C(OCC#C)c2ccc(Cl)cc2)cc1OC
Solvent: CCOCC
Solvent: c1ccccc1
Product: C#CCOc1ccc(CCNC(=S)C(OCC#C)c2ccc(Cl)cc2)cc1OC
Reaction time: 7 h

Procedure:
2-(4-Chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-(prop-2-ynyloxy)-acetamide (0.822 g) and benzene (30 ml) are stirred at +55° C. 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (“Lawesson's reagent”; 1.61 g) is added. The reaction mixture is stirred for additional 7 hours at +55° C. to +60° C. After cooling to room temperature diethylether (100 ml) is added. The mixture is then filtered. The solvent of the filtrate is evaporated. 2-(4-Chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-(prop-2-ynyloxy)-thioacetamide is obtained which is purified by flash-column-chromatography on silica gel using ethyl acetate/hexane. The purified product is in form of a resin. 1H-NMR (300 MHz, CDCl3, δ(ppm)): 2.45–2.55(m, 2H), 2.95(t, 2H), 3.85(s, 3H), 3.9–4.2(m, 4H), 4.75(d, 2H), 5.35(s, 1H), 6.65–6.8(m, 2H), 7.0(d, 1H), 7.2–7.4(m, 4H), 8.4–8.6(m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.C(OC(Cl)=O)C.[NH2:26][C:27]1[C:28](=[O:34])[NH:29][C:30](=[O:33])[NH:31][CH:32]=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:26][C:27]2[C:28](=[O:34])[NH:29][C:30](=[O:33])[NH:31][CH:32]=2)=[O:10])=[CH:11][CH:12]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: Nc1c[nH]c(=O)[nH]c1=O
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(COc1ccc(Cl)cc1)Nc1c[nH]c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
1.87 g (0.01M) p-chlorophenoxyacetic acid is suspended with stirring in 30 ml dry dimethylformamide and dissolved by addition of 1. g (0.01M) triethylamine. The reaction mixture is cooled to 0° to 5° C. internal temperature, mixed with 1.1 g (0.1M) chloroformic acid ethyl ester and stirred one minute at its reaction temperature. To the reaction mixture of the mixed anhydrides one rapidly adds a solution of 1.27 g (0.01M) 5-aminouracil in dry dimethylformamide and stirs for 30 minutes. Subsequently the reaction mixture is poured into 1 liter ice water, the precipitate is filtered with suction, dried and recrystallized from water in the ratio 1:1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[CH:4][CH:3]=1.[CH3:9][N:10](C)C(Cl)=O.C(#N)C.C[Si](C#N)(C)C>O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:9]#[N:10])[CH:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: [O-][n+]1ccc(Cl)cc1
Agent: C[Si](C)(C)C#N
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: N#Cc1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
4-Chloropyridine N-oxide (7.53 g, 58.1 mmol) and N,N-dimethylcarbamoyl chloride (9.36 g, 87.0 mmol) were added to acetonitrile (200 ml), and trimethylsilyl cyanide (11.5 g, 116 mmol) was added dropwise thereto. The mixture was stirred at room temperature for 18 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (200 g) column chromatography. The fractions eluted with n-hexane-ethyl acetate (3:1, v/v) were collected, concentrated to give the titled compound (8.05 g, 99%) as a pale yellow oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[CH:25]=[N:24][CH:23]=[C:22]([N:26]2[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27]2)[N:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C(Cl)(Cl)Cl>[F:32][C:28]1([F:31])[CH2:29][CH2:30][N:26]([C:22]2[N:21]=[C:20]([C:9]3[CH:10]=[C:11]4[CH:17]=[CH:16][NH:15][C:12]4=[N:13][CH:14]=3)[CH:25]=[N:24][CH:23]=2)[CH2:27]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: FC1(F)CCN(c2cncc(Cl)n2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: FC1(F)CCN(c2cncc(-c3cnc4[nH]ccc4c3)n2)C1
Temperature: 100 °C

Procedure:
A stirred solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (50 mg, 1 eq) and 2-chloro-6-(3,3-difluoropyrrolidin-1-yl)pyrazine (54) (1 eq) in 1,4-dioxane (5 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (2 eq) followed by addition of Pd(dpp)Cl2 (0.04 eq) and degassing and purging under argon for additional 10 min. The reaction mixture was heated at 100° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through Celite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 1% MeOH/CHCl3 to obtain pale yellow solid compound 5-(6-(3,3-difluoropyrrolidin-1-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine 135 in 6 mg quantity.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH2:9]([N:16]=[C:17]=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:9]([NH:16][C:17]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C=NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1CCCN1C(=O)NCc1ccccc1

Procedure:
L-Proline (23.3 g), benzyl isocyanate (22.9 g) and triethylamine (20.5 g) were stirred at room temperature for 1 hour in DMF (250 ml) to give a solution of N-(benzylaminocarbonyl)-L-proline. Thereto were added HOBt (29.7 g), water-soluble carbodiimide hydrochloride (42.13 g), L-proline benzyl ester hydrochloride (48.3 g) and triethylamine (27.9 ml) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with 10% potassium hydrogensulfate, a saturated aqueous solution of sodium bicarbonate and water in order, dried over anhydrous sodium sulfate, and concentrated to give the title compound (73.6 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH:6]=[CH:5]2.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc2cc(F)ccc2[nH]1
Product: Fc1ccc2nc(Cl)ccc2c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 78.3 %

Procedure:
6-fluoro-1,2-dihydroquinolin-2-one (7.8 g, 47.8 mmol) was suspended in phosphorus oxychloride (72.2 g, 470.9 mmol) and stirred for 4 hours at 100° C. in an oil bath. The reaction mixture was concentrated under vacuum to remove the excess phosphorus oxychloride and then ice-water (200 ml) was added. The precipitate that formed was washed with water (2×80 ml) and dried to give 2-chloro-6-fluoroquinoline as a off-white solid (6.8 g, 78%); (ES, m/z): [M+H]+ 182; 1H NMR (300 MHz, DMSO): δ 8.43 (d, J=8.4 Hz, 1H), 8.01 (dd, J=5.4 Hz, 9.3 Hz, 1H), 7.87 (dd, J=3.0 Hz, 9.3 Hz, 1H), 7.72-7.78 (m, 1H), 7.45 (d, J=8.4 Hz, 1H).