Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:24][C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([NH:16]C(OC(C)(C)C)=O)[C:14]=3[S:15][C:7]=2[C:6]=1[O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:24][C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([NH2:16])[C:14]=3[S:15][C:7]=2[C:6]=1[O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:4]
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1c(NC(=O)OC(C)(C)C)cccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1c(N)cccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Step H Deprotection: A solution of 7-tert-Butoxycarbonylamino-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (170 mg, 0.37 mmol) in DCM (6 mL) was cooled to 0° C. Trifluoroacetic acid (1.2 mL) was then added, and the solution was allowed to warm to ambient temperature, stirring a total of four hours, after which the reaction was judged complete by TLC. The reaction mixture was concentrated in vacuo, dissolved in ethyl acetate, and washed with sodium bicarbonate (3×10 mL). The organic layer was then concentrated in vacuo, affording 7-Amino-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester in a quantitative yield.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:3]=1[C:4]([NH:6][OH:7])=[O:5].[OH-].[K+]>C(O)CCC>[OH:5][C:4]1[C:3]2[C:8]([O:12][CH3:13])=[CH:9][CH:10]=[CH:11][C:2]=2[O:7][N:6]=1
Reactant: COc1cccc(F)c1C(=O)NO
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: COc1cccc2onc(O)c12
Yield: 90.1 %

Procedure:
2-fluoro-6-methoxybenzhydroxamic acid (2.55 g) and potassium hydroxide (4.50 g) were dissolved in butanol (25 ml) and refluxed for 4 hours. After the completion of the reaction, the reaction mixture was adjusted to acidic, extracted with ethyl acetate and the extract was washed with water and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure and the residue was recrystallized from isopropylether, to give the title compound (2.05 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:16][O:17][C:18]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:19]=1[NH2:20].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.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]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:20][C:19]2[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:18]=2[O:17][CH3:16])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Reactant: COc1ccc(N)c(OC)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cccc(Nc2ccc(OC)cc2OC)c1C(=O)OC
Yield: 81 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), 2,4-dimethoxyaniline (0.48 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 24 hours. The reaction mixture was cooled, diluted with CH2Cl2 (10 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (30 mL). The filtrate was evaporated, and the residue was chromatographed using a hexanes-ethyl acetate gradient, eluting 0.87 g of the product at 70:30 hexanes-ethyl acetate, in 81% yield: 1H NMR (CDCl3) δ 3.81 (s, 6H), 3.87 (s, 6H), 6.46 (dd, J=8.6 Hz, J=2.6 Hz, 1H), 6.54 (d, J=2.6 Hz, 1H), 6.98 (dd, J=7.3 Hz, J=0.9 Hz, 1H), 7.09 (dd, J=8.0 Hz, J=0.9 Hz, 1H), 7.16 (d, J=8.6 Hz, 1H), 7.23 (t, J=7.3 Hz, 1H), 7.92 (br, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:31][CH3:32])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16].ClC1C=[C:38]([O:40]C)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H](OCC)CNC2)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([O:40][CH3:38])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:31][CH3:32])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC
Product: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl}-3,6-diethylpyrazin-2-amine but starting with 5-(2-chloro-4-methoxyphenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine provided the title compound as an amorphous solid. 1H NMR (CDCl3) δ 1.17, 1.25˜1.35, 2.50, 2.72, 3.45, 3.58, 3.75, 3.86, 4.04, 4.27, 4.93, 5.26, 6.55, 6.90, 7.02, 7.24; IR (diffuse reflectance) 2970, 2351 (w), 2337 (w), 2063 (w), 1604, 1568, 1549 (s), 1537 (s), 1482 (s), 1397, 1359, 1286, 1228, 1199, 1043 cm−1 HRMS (ESI) calcd for C24H30N5O2SCl+H1 488.1887. found 488.1880.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([OH:16])=O)=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1.[CH2:19]([O:21][C:22](=[O:30])[CH2:23][C:24]1[N:25]=[C:26]([NH2:29])[S:27][CH:28]=1)[CH3:20]>>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([NH:29][C:26]3[S:27][CH:28]=[C:24]([CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:30])[N:25]=3)=[O:16])=[C:9]([O:10][CH:11]([CH3:12])[CH3:13])[C:5]=2[CH:4]=1
Reactant: COc1ccc2sc(C(=O)O)c(OC(C)C)c2c1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NC(=O)c2sc3ccc(OC)cc3c2OC(C)C)n1
Yield: 72.4 %

Procedure:
Following a procedure analogous to Example 2, 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxylic acid (1.033 g, 3.88 mmol) and ethyl-2-amino-4-thiazoleacetate (709 mg, 4.37 mmol) gives 1.22 g (73%) of product; mp 91°-92° C.
Reaction SMILES: [K].[N+:2]([C:5]1[NH:9][C:8]([N+:10]([O-:12])=[O:11])=[N:7][C:6]=1[N+:13]([O-:15])=[O:14])([O-:4])=[O:3].[CH3:16]OS(OC)(=O)=O>O>[CH3:16][N:9]1[C:5]([N+:2]([O-:4])=[O:3])=[C:6]([N+:13]([O-:15])=[O:14])[N:7]=[C:8]1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1nc([N+](=O)[O-])c([N+](=O)[O-])[nH]1
Reactant: COS(=O)(=O)OC
Agent: [K]
Solvent: O
Product: Cn1c([N+](=O)[O-])nc([N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 80 °C
Yield: 71.9 %

Procedure:
A mixture of potassium salt of trinitroimidazole (100 mg, 0.41 mmol) and dimethylsulfate (1.0 g, excess) was heated in a preheated oil bath at 80° C. for about 2 h. The reaction mixture was diluted with water (50 mL) and extracted with ether (3×25 mL). The combined organic layer was washed with water (3×25 mL), brine (1×25 mL) and dried (Na2SO4). The solvent was evaporated under reduced pressure and the pale yellow syrupy residue thus obtained was purified via Si-gel column chromatography (eluent: 10% ethyl acetate-hexane). The pure product (64 mg, 71%) was obtained as a pale yellow solid. m.p: 84-85° C.; DSC: 84.81° C. (5° C./min); 1H NMR (Acetone-d6): 4.37 ppm; 13C NMR (Acetone-d6): 37.64, 133.46 (t), 136.05 (br) and 139.97 (t).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[C:17]([C:19](O)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[CH2:26]([N:28]([CH2:29][CH3:30])[C:19]([C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:18]=1)=[O:20])[CH3:27]
Reactant: COc1ccc(-c2cc(C(=O)O)c3ccccc3n2)cc1
Reactant: CCNCC
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1cc(-c2ccc(OC)cc2)nc2ccccc12

Procedure:
The procedure of Example 3 is followed using 2-(4-methoxyphenyl)-quinoline-4-carboxylic acid (5 g), thionyl chloride (15 ml) and diethylamine (18.4 ml) as the starting materials.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]2[C:17](=[O:18])[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[N:9]2[C:23]=1[CH2:24][P:25]([OH:28])([OH:27])=[O:26])=[O:5])C>Br>[C:4]([C:6]1[N:7]=[C:8]2[C:17](=[O:18])[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)[N:9]2[C:23]=1[CH2:24][P:25]([OH:27])([OH:28])=[O:26])([OH:5])=[O:3]
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1CP(=O)(O)O
Agent: Br
Product: O=C(O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1CP(=O)(O)O
Yield: 97.1 %

Procedure:
2-Ethoxycarbonyl-1-phosphonomethyl-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (example 30) (210 mg, 0.5 mmol) in hydrobromic acid (48% in water) (20 ml) was stirred at 80° C. for 16 h. The mixture was concentrated in vacuo and the residue stirred with ether. The product, which was isolated by filtration was washed with cold water to afford 190 mg (97%) of the title compound. M.p. >250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C@@H:11]1[C@@:17]([CH3:29])([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:16][C@H:13]([O:14][CH3:15])[C@@H:12]1[OH:30].[CH3:31]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C@@H:11]1[C@@:17]([CH3:29])([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:16][C@H:13]([O:14][CH3:15])[C@:12]1([CH3:31])[OH:30]
Reactant: CO[C@H]1O[C@](C)(COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1O
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CO[C@H]1O[C@](C)(COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@@]1(C)O
Temperature: -30 °C
Reaction time: 5 h
Yield: 68.6 %

Procedure:
The product (2.0 g, 4.0 mmol) from Step B and Dess-Martin periodinane (2.0 g) in dichloromethane (30 mL) were stirred overnight at room temperature and was then concentrated under reduced pressure. The residue was triturated with ether ether (50 mL) and filtered. The filtrate was washed with a solution of Na2S2O3.5H2O (2.5 g) in saturated aqueous sodium bicarbonate solution (50 mL), dried (MgSO4), filtered and evaporated. The residue was dissolved in anhydrous Et2O (20 mL) and was added dropwise to a solution of MeMgBr in Et2O (3 M, 10 mL) at −78° C. The reaction mixture was allowed to warm to −30° C. and stirred at −30° C. to −15° C. for 5 h, then poured into saturated aqueous ammonium chloride (50 mL). The two layers were separated and the organic layer was dried (MgSO4), filtered and concentrated. The residue was chromatographed on silica gel (EtOAc/hexane: 1/9) to afford the title compound as a syrup (1.40 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:10][CH:11]([F:23])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][C:21]#[N:22]>>[F:10][CH:11]([F:23])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]1[C:21]([NH2:22])=[N:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: Nc1ccccc1C=O
Reactant: N#CCCc1ccccc1OC(F)F
Product: Nc1nc2ccccc2cc1Cc1ccccc1OC(F)F

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-aminobenzaldehyde and 3-(2-difluoromethoxyphenyl)propionitrile.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[C:5]2I.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:34]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[C:5]2[C:30]1[CH:31]=[N:32][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:34]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(F)c(F)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)n1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)c(F)cc23)cn1
Temperature: 90 °C
Reaction time: 12 h
Yield: 61.7 %

Procedure:
To a solution of 5,6-difluoro-3-iodo-1-(phenylsulfonyl)-1H-indole (Intermediate 28; 300 mg; 0.716 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (273.6 mg; 0.93 mmol), K3PO4 (455 mg; 2.15 mmol) in dioxane (10 mL) and water (1 mL) was added Pd(dppf)Cl2 (59 mg; 0.072 mmol) under argon. The reaction mixture was stirred at 90° C. for 12 hours. The mixture was filtered through Celite and washed with EtOAc (50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated, and purified by a silica gel chromatography (petroleum ether/EtOAc=1/1) to afford 203 mg (62%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([B:8]2[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:12])([CH3:11])[O:9]2)[CH:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[CH3:17][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:30](=[O:31])[C:29]2[CH:28]=[CH:27][C:26]([CH2:25][N:22]3[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]3)=[CH:34][CH:33]=2)=[CH:7][C:6]=1[B:8]1[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:11])([CH3:12])[O:9]1
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1B1OC(C)(C)C(C)(C)O1
Yield: 23.6 %

Procedure:
A solution of 5-amino-2-methylphenylboronic acid pinacol ester (1.001 g, 4.294 mmol), 4-((4-methylpiperazin-1-yl)methyl)benzoic acid (1.112 g, 4.746 mmol) and (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (2.446 g, 4.691 mmol) in DMF (20 mL) at ambient temperature was added ethyldiisopropylamine (0.98 mL, 5.6 mmol), the mixture stirred at room temperature for 3d and poured into water (100 ml). The aqueous phase was washed with diethyl ether, treated with saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, ISCO, 10-100% ethyl acetate in heptane, and then 0-20% methanol in DCM modified with 1% ammonia) to afford the title compound as a white solid (456 mg, 24%). 1H NMR (400 MHz, CDCl3) δ 7.97 (dd, J=8.2, 2.0 Hz, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.74 (s, 1H), 7.64 (d, J=2.3 Hz, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.19 (d, J=8.3 Hz, 1H), 3.57 (s, 2H), 2.52 (s, 3H), 2.5 (br s, 8H), 2.31 (s, 3H), 1.35 (s, 12H). LCMS: M+H+=450.4.
Reaction SMILES: BrCCCOC1C=CC=CC=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>>[O:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)CBr
Agent: BrCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)COc1ccccc1
Yield: 76.6 %

Procedure:
The compound 34 was prepared according to the method described for compound 26 employing phenol (4.5 g, 0.05 mol), ethyl bromoacetate (31 g, 0.19 mol) and potassium carbonate (33 g, 0.24 mol) to give a colorless oily compound 34 (6.9 g, 81%). 1H NMR (300 MHz, CD2Cl2) δ 1.30 (t, J=7.0 Hz, 3H), 4.27 (q, J=7.0 Hz, 2H), 4.62 (s, 2H), 6.91 (d, J=7.9 Hz, 2H), 6.99 (t, J=7.0 Hz, 1H), 7.29 (t, J=7.6 Hz, 2H).
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[C:20]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:19]=[C:18]([C:30]#[C:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:17]=2)=[CH:8][C:7]=1[CH3:39].[Li+].[OH-].O.Cl>C1COCC1.CO>[CH3:39][C:7]1[CH:8]=[C:9]([O:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[C:20]([C:22]#[C:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:19]=[C:18]([C:30]#[C:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:17]=2)[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]([OH:40])=[O:2]
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(C#CCN3CCOCC3)cc(C#Cc3ccccc3)c2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCC#Cc2cc(C#CCN3CCOCC3)cc(C#Cc3ccccc3)c2)ccc1OCC(=O)O
Temperature: 0 °C
Reaction time: 7.67 h

Procedure:
To a solution of (2-methyl-4-{3-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-phenylethynylphenyl]-prop-2-ynyloxy}-phenoxy)-acetic acid methyl ester (70 mg, 0.13 mmol) in THF (1.25 ml) and methanol (0.25 ml) was added a ice-cold solution of LiOH (1 M, 1.25 ml). The reaction mixture was stirred at 0° C. for 460 min., after which water (10 ml) and aqueous HCl (1M, 1.75 ml) were added. The mixture was extracted with ethyl acetate (2×10 ml), and the combined organic phases were dried and evaporated to give the title compound in 68 mg (100%) yield.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:27][OH:28])=[N:16][C:17]=1[N:18]1[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I(C1C=CC=CC=1C(O)=O)(=O)=O>ClCCCl>[Si:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH:27]=[O:28])=[N:16][C:17]=1[N:18]1[CH2:23][CH2:22][N:21]([CH:24]([CH3:25])[CH3:26])[CH2:20][CH2:19]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2nc(CO)ccc2OCCO[Si](C)(C)C(C)(C)C)CC1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: ClCCCl
Product: CC(C)N1CCN(c2nc(C=O)ccc2OCCO[Si](C)(C)C(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 59.2 %

Procedure:
To a solution of (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)methanol (1.07 g, 2.61 mmol) in 1,2-dichloroethane (20 mL) under nitrogen was added 2-iodoxybenzoic acid (0.88 g, 3.14 mmol) at rt. The reaction mixture was stirred at 80° C. for 1.5 h. After that time the reaction was cooled to rt and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 95:5 dichloromethane/methanol) to give 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-isopropylpiperazin-1-yl)picolinaldehyde (0.63 g, 59%) as a brown solid: 1H NMR (400 MHz, CDCl3): δ 9.85 (s, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 4.19-4.15 (m, 2H), 4.02-3.88 (m, 6H), 3.56-3.48 (m, 1H), 3.20 (br s, 4H), 1.37 (d, J=6.4 Hz, 6H), 0.90 (s, 9H), 0.09 (s, 6H); ESI MS m/z 408 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:20]([O:22][C@H:23]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=1)[CH3:21].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)[C:31](=[O:32])[CH2:30][O:29][C:28]2[CH:27]=[CH:26][C:25]([CH2:24][C@H:23]([O:22][CH2:20][CH3:21])[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:35][CH:34]=2)=[CH:18][CH:19]=1
Reactant: CC(C)c1ccc(CNCc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(Cc2ccc(Cl)cc2)Cc2ccc(C(C)C)cc2)cc1)OCC
Reaction time: 8 h
Yield: 46.4 %

Procedure:
To a solution of N-(4-chlorobenzyl)-N-(4-isopropylbenzyl)amine (1.64 g, 6.0 mmol) in methylene chloride (50 mL) at 0° C. were added {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (1.48 g, 5.0 mmol) and N,N-diisopropylethylamine (2.0 mL, 11.5 mmol) followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.93 g, 6.0 mmol) and the reaction mixture was stirred overnight. The mixture was diluted with methylene chloride (100 mL) and the organic phase was washed with 2 M HCl (3×75 mL), saturated aqueous NaHCO3 (2×75 mL, some emulsions), and brine (75 mL), dried over Na2SO4, and concentrated in vacuo. Twice repeated purification on silica gel with methanol (0-5% gradient) in methylene chloride as the eluent and collection of pure fractions afforded 1.28 g (46%) of a colourless oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]=[CH:18][N+:19]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[NH2:19][CH2:18][CH2:17][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=2)[NH:13][CH:12]=1
Reactant: O=[N+]([O-])C=Cc1c[nH]c2ccc(Cc3ccccc3)cc12
Solvent: C1CCOC1
Product: NCCc1c[nH]c2ccc(Cc3ccccc3)cc12
Yield: 39.9 %

Procedure:
A solution of the 5-benzyl-3-(2-nitroethenyl)indole (0.1 g, 0.4 mmol)in dry THF was added dropwise to a cooled (ice bath) suspension of LiAIH4 (0.1 g, 2.4 mmol)in 5 ml of dry THF under nitrogen. The mixture was heated at reflux for 45 min. Excess LiAIH4 was destroyed by successive addition of H2O (0.15 ml), 15% NaOH (0.15 ml) and H2O (0.4 ml). The white precipitate was removed by filtration and washed with THF (10 ml). After drying (MgSO4), the flitrate was evaporated under reduced pressure to give 0.04 g (45%) of 3-(2-aminoethyl)-5-benzylindole as a free base. The free base was converted to the fumarate salt, mp 150°-153° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>>[CH2:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH:10][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][Br:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1Cc1ccccc1
Reactant: O=C(Cl)CCCCCBr
Product: O=C(CCCCCBr)Nc1ccccc1Cc1ccccc1

Procedure:
2-benzylaniline and 6-bromohexanoyl chloride were used to produce the above compound in the same way as Reference Example 8.
Reaction SMILES: [OH-].[K+].[CH:3]1([O:8][C:9]2[C:10]([CH3:19])=[N:11][CH:12]=[C:13]([CH:18]=2)[C:14]([O:16]C)=[S:15])[CH2:7][CH2:6][CH2:5][CH2:4]1>O.CO>[CH:3]1([O:8][C:9]2[C:10]([CH3:19])=[N:11][CH:12]=[C:13]([CH:18]=2)[C:14]([OH:16])=[S:15])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=S)c1cnc(C)c(OC2CCCC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ncc(C(O)=S)cc1OC1CCCC1
Reaction time: 6 h
Yield: 73.7 %

Procedure:
A solution of potassium hydroxide (582 mg) in water (6 mL) is added to a stirred solution of methyl 5-cyclopentyloxy-6-methylthionicotinoate (920 mg) in methanol at room temperature and the mixture stirred for 6 hours. After concentrating in vacuo the mixture is diluted with water and acidified to pH 1 with aqueous 2 M hydrochloric acid. The product is extracted into ethyl acetate, the extracts treated with decolourising charcoal, dried (MgSO4) and evaporated. The residue is triturated with n-pentane to give 5-cyclopentyloxy-6-methylthionicotinic acid (640 mg) as a white solid, m.p. 177-8° C. [Elemental analysis: C, 56.90; H, 6.02; N, 5.52%. calculated: C, 56.90; H, 5.97; N, 5.53%.].