Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1([CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[C:8]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][C:20]=3[S:19](=[O:33])(=[O:32])[N:18]=2)[C:7]1=[O:34])=[O:4].[C:40](OC(=O)C)(=[O:42])[CH3:41].C(N(CC)CC)C>ClCCl>[C:40]([NH:1][CH2:2][C:3]([NH:5][C:6]1([CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[C:8]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][C:20]=3[S:19](=[O:32])(=[O:33])[N:18]=2)[C:7]1=[O:34])=[O:4])(=[O:42])[CH3:41]
Reactant: CC(C)CCC1(NC(=O)CN)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCC(=O)NC1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.6 %

Procedure:
To a solution of the product of Example 46 (10 mg, 0.017 mmol) in dichloromethane (0.25 mL) was added acetic anhydride (8 μL, 0.087 mmol) followed by addition of triethylamine (7 μL, 0.052 mmol). The reaction mixture was stirred at room temperature for 18 h. The solution was then diluted with dichloromethane (1 mL) and washed with aqueous 1 N HCl (2×0.5 mL), dried (Na2SO4), and concentrated in vacuo. The resulting residue was dissolved in methanol (0.5 mL) and treated with excess K2CO3 for 30 min. The heterogeneous solution was filtered and the filtrate concentrated in vacuo. The residue was then taken up in ethyl acetate (1 mL), washed with aqueous 1 N HCl (2×1 mL), dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (10% methanol/dichloromethane) afforded the title compound as a light yellow solid (5 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.61-0.75 (m, 6H), 0.79-0.97 (m, 1H), 1.16-1.35 (m, 2H), 1.56-1.71 (m, 1H), 1.78 (s, 3H), 1.83-1.97 (m, 1H), 2.99 (s, 3H), 3.64-3.88 (m, 2H), 7.26-7.34 (m, 2H), 7.35-7.44 (m, 2H), 7.46 (d, J=2.21 Hz, 1H), 7.91 (t, J=5.52 Hz, 1H), 7.96-8.02 (m, 1H), 8.36 (s, 1H), 9.86 (s, 1H), 15.39 (s, 1H); MS m/z 618.0 (M+H)+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([C:19]1[CH:20]=[C:21]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=2)[C:22]([OH:27])=[C:23]([CH:26]=1)[CH:24]=O)([CH3:18])([CH3:17])[CH3:16].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.C(O)C.[ClH:48]>O1CCCC1>[ClH:48].[ClH:48].[C:15]([C:19]1[CH:20]=[C:21]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=2)[C:22]([OH:27])=[C:23]([CH2:24][N:42]2[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]2)[CH:26]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCN(Cc2cc(C(C)(C)C)cc(-c3ccc(C(F)(F)F)nc3)c2O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
Sodium triacetoxyborohydride (0.30 g, 1.4 mmol) was added to a solution of 5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)benzaldehyde (0.35 g, 1.1 mmol) and 1-methyl piperazine (0.14 mL, 1.3 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature under nitrogen for 16 hours. The reaction was partitioned between ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate solution (25 mL). The organic phase was dried with sodium sulfate, filtered and concentrated under reduced pressure to give a yellow syrup. The product was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% ethyl acetate in hexanes to give a yellow syrup which was dissolved in 1.25 M hydrochloric acid in ethanol (10 mL, 12.5 mmol). The mixture stood for 20 minutes and was then concentrated under reduced pressure to give a white solid which was triturated with diethyl ether (10 mL) and solid was filtered off to afford 4-(tert-butyl)-2-((4-methylpiperazin-1-yl)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl)phenol dihydrochloride (0.26 g, 53% yield) as a white solid.
Reaction SMILES: Cl[Si](C)(C)C.BrCCBr.CN(C)C=O.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19]Br.Br[C:26]1[N:27]=[C:28]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[S:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]>[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:24][C:23]1[CH:22]=[CH:21][C:18]([CH2:19][C:26]2[N:27]=[C:28]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)[S:29][C:30]=2[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:17][C:16]=1[F:15]
Reactant: CCOC(=O)c1sc(N2CCOCC2)nc1Br
Reactant: Fc1cc(CBr)ccc1Cl
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: BrCCBr
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(F)c1
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
In a 50 ml flame-dried round bottom flask, a suspension of zinc (0.183 g, 0.00280 mol), chlorotrimethylsilane (8.9 uL, 0.000070 mol) and 1,2-dibromoethane (6.0 uL, 0.000070 mol) in N,N-dimethylformamide (2.4 mL, 0.031 mol) was stirred for 15 minutes. To this was added a solution of 3-fluoro-4-chlorobenzylbromide (0.626 g, 0.00280 mol) in N,N-dimethylformamide (4.8 mL, 0.062 mol), and the resulting suspension was stirred overnight at room temperature. To a flame-dried 50 ml round bottom flask containing ethyl 4-bromo-2-morpholin-4-yl-1,3-thiazole-5-carboxy late (0.300 g, 0.000934 mol) and bis(tri-t-butylphosphine)palladium(0) (36 mg, 0.000070 mol) was added the organozinc solution from above, and the reaction was heated with stirring at 60° C. for 60 min. Reaction was quenched with saturated ammonium chloride, and then transferred to a separatory funnel containing water (10 mL) and EtOAc (40 mL). The layers were separated, and the aqueous layer was extracted 2×30 mL with EtOAc. The combined organic layers were washed 1× brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM, adsorbed onto silica gel and purified via column chromotography (24 gram Isco column, gradient elution, 0-50% EtOAc/hexanes) to afford ethyl 4-(4-chloro-3-fluorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylate (245 mg, yield 68.2%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:9]=1)=[O:4].[CH3:32]I>CN(C)C=O.C(OCC)(=O)C.[Ag]>[CH3:1][O:2][C:3]([CH:5]([N:24]([CH3:32])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:9]=1)=[O:4]
Reactant: COC(=O)C(CCc1cn(C(=O)OC(C)(C)C)c2ccccc12)NC(=O)OC(C)(C)C
Reactant: CI
Agent: [Ag]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(CCc1cn(C(=O)OC(C)(C)C)c2ccccc12)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
295 g of silver(l) oxide are added, with stirring, to a solution of 75 g of N-tert-butyloxycarbonyl-amino-3-(1-tert-butyloxycarbonyl-indol-3-yl)-propanecarboxylic acid methyl ester in 770 ml of N,N-dimethylformamide. 75 ml of methyl iodide are then added dropwise. The reaction mixture rises to a temperature of 40° and is stirred at room temperature for 2 days and then diluted with 800 ml of ethyl acetate, filtered and concentrated by evaporation. The residue is purified by chromatography (silica gel, hexane/ethyl acetate 3:2). In this way the title compound is obtained in the form of a yellow oil.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2([C:14](=[O:16])[CH3:15])[CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1>ClCCl.CO>[Br:1][CH2:15][C:14]([C:10]1([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=2)[CH2:13][CH2:12][CH2:11]1)=[O:16]
Reactant: BrBr
Reactant: CC(=O)C1(c2cccc(Cl)c2)CCC1
Solvent: CO
Solvent: ClCCl
Product: O=C(CBr)C1(c2cccc(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of bromine (9.9 ml) in dichloromethane (50 ml) was added dropwise at 10°-15° C. over 3 hours to a stirred solution of 1-[1-(3-chlorophenyl)cyclobutyl]-ethanone (38 g) in a mixture of methanol (75 ml) and dichloromethane (15 ml). When the addition was complete, the mixture was stirred at ambient temperature for 2.5 hours, then poured onto an excess of ice-water. The aqueous layer was separated and the product extracted into dichloromethane (3×90 ml). The combined organic solutions were washed with saturated aqueous sodium hydrogen carbonate solution (2×100 ml) and water (100 ml), dried over calcium chloride and the solvent removed in vacuo to leave 2-bromo-1-[1-(3-chlorophenyl)cyclobutyl]ethanone as an oil (47 g).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8](F)[N:7]=1)=[O:4].[NH3:20].O>CC(O)C>[NH2:20][C:8]1[N:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:19])([CH3:18])[CH3:1])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1ccc(NC(=O)C(C)(C)C)nc1F
Reactant: N
Solvent: O
Solvent: CC(C)O
Product: CCOC(=O)c1ccc(NC(=O)C(C)(C)C)nc1N
Temperature: 70 °C
Yield: 55 %

Procedure:
To a stirred solution of ethyl 6-[(2,2-dimethylpropanoyl)amino]-2-fluoronicotinate (M. C. Coldwell et al., Bioorg. Med. Chem. Lett., 1995, 39, 5, 1.5 g, 5.59 mmol) in 2-propanol (16 mL) was added 25% aqueous ammonia (4 mL) and the mixture was heated in a sealed tube at 70° C. for 4.5 h. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The separated organic layer was concentrated in vacuo and the residue was chromatographed on a column of silica gel eluting with ethyl acetate/pentane (1:6 to 1:2) to give 810 mg (55%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][C@@H:10]([CH2:13][OH:14])[CH2:9][CH2:8]2.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:14][CH2:13][C@H:10]2[CH2:9][CH2:8][C:7]3[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=3)[O:11]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: COc1cccc2c1O[C@@H](CO)CC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CC2
Temperature: 50 °C
Yield: 72 %

Procedure:
To a solution of [(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methanol (5.00 g, 25.7 mmol) in dichloromethane (250 mL) was added p-toluenesulfonyl chloride (9.82 g, 51.5 mmol), 4-(dimethylamino)pyridine (0.62 g, 5.15 mmol), and N,N-diisopropylethylamine (8.32 g, 64.4 mmol) and the reaction mixture was heated to 50° C. for 12 h. The reaction mixture was quenched by the addition of water (500 mL). The aqueous layer was separated and extracted with dichloromethane (200 mL). The combined organic extracts were washed with aqueous hydrogen chloride (1.0 M, 200 mL), water (200 mL), aqueous sodium chloride (200 mL), dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:3) gave 6.45 g (72%, 40% ee) of [(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate as a white crystalline solid. [α]D25=−20.30 (c 13.1 in chloroform, 40% ee); Rf=0.71 (silica, ethyl acetate:hexanes 2:3); mp 115-117° C.; Anal. Calcd. for C18H20O5S: C, 62.05; H, 5.79. Found: C, 61.99; H, 5.81.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:23]=[CH:22][O:21][CH:20]=3)=[CH:13][C:12]2=[O:24])=[CH:5][CH:4]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)Cl>[O:21]1[CH:22]=[CH:23][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:4][CH:5]=3)[C:12](=[O:24])[CH:13]=2)=[CH:20]1
Reactant: O=c1cc(OCc2ccoc2)ccn1CCc1ccc(CBr)cc1
Reactant: C1CCNC1
Solvent: ClCCl
Product: O=c1cc(OCc2ccoc2)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 150 mg (85% purity, 0.33 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(furan-3-ylmethoxy)-1H-pyridin-2-one (example 5.1b) in 1.5 mL DCM is added 108 μL (1.31 mmol) pyrrolidine at RT. The reaction mixture is stirred for 2 h at RT and is directly transferred to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6](=O)[C:7]([OH:9])=[O:8])=[CH:2]1.[C:11]([O:15][C:16]([CH2:18][O:19][NH2:20])=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(Cl)(Cl)(Cl)Cl>[C:11]([O:15][C:16]([CH2:18][O:19][N:20]=[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[C:7]([OH:9])=[O:8])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)C(=O)c1ccsc1
Reactant: CC(C)(C)OC(=O)CON
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1ccsc1

Procedure:
Thien-3-ylglyoxylic acid and t-butoxycarbonylmethoxyamine were reacted as described in Preparation 1 to give the title compound, m.p. 102.6°-104.4° (from carbon tetrachloride); λmax (pH6 phosphate buffer) 258 nm (ε 13,700).
Reaction SMILES: [C:1]([C:3]1[C:4]([F:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[F:10][C:11]1[CH:16]=[CH:15][C:14](I)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1.C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:9][C:4]1[C:3]([C:1]#[C:2][C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][C:13]=2[N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: C#Cc1cccnc1F
Reactant: O=[N+]([O-])c1cc(F)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)ccc1C#Cc1cccnc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
Into a round bottom flask was added 3-ethynyl-2-fluoropyridine (0.3 g, 0.002 mol), 4-fluoro-1-iodo-2-nitrobenzene (0.675 g, 0.00253 mol), bis(triphenylphosphine)palladium(II) chloride (0.09 g, 0.1 mmol), copper(I) iodide (0.04 g, 0.2 mmol), and triethylamine (0.52 mL, 3.7 mmol) in N,N-dimethylformamide (4 mL). The reaction was stirred at room temperature for 2 hours. The reaction was extracted with ethyl acetate, and the combined organic extracts were washed with brine (3×), dried over MgSO4, and purified by column chromatography on silica gel (10% ethyl acetate 90% hexanes), to give 0.443 g of product. 1H NMR (400 MHz, CDCl3): δ 8.44-8.50 (m, 1H), 7.99-8.02 (m, 1H), 7.79-7.90 (m, 1H), 7.78-7.82 (m, 1H), 7.37-7.42 (m, 1H), 7.23-7.29 (m, 1H). MS [M+H]=261.0.
Reaction SMILES: [CH3:1][NH2:2].CO.[CH:5]([C:7]1[NH:8][C:9]2[C:14]([C:15]=1[C:16]#[N:17])=[CH:13][CH:12]=[CH:11][CH:10]=2)=O.[BH4-].[Na+]>O>[CH3:1][NH:2][CH2:5][C:7]1[NH:8][C:9]2[C:14]([C:15]=1[C:16]#[N:17])=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: N#Cc1c(C=O)[nH]c2ccccc12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNCc1[nH]c2ccccc2c1C#N
Temperature: 0 °C
Reaction time: 5 h
Yield: 75.3 %

Procedure:
Methylamine (6.2 mL, 49.4 mmol, 33% in EtOH) was added to a MeOH (50 mL) solution of 2-formyl-1H-indole-3-carbonitrile (2.80 g, 16.5 mmol) at 0° C. Upon stirring for 5 h at 0° C., NaBH4 (740 mg, 19.8 mmol) was added to the solution and the stirring was continued for 16 h. The mixture was diluted with water, extracted with methylene chloride; the organic layer was dried and evaporated. The crude residue was subjected to chromatography (1-5% MeOH in methylene chloride). The desired fractions were collected and concentrated; the residue was recrystallized from a methylene chloride/hexane mixture to afford the title compound (2.30 g, 75%). 1H NMR (300 MHz, DMSO-d6, δ): 7.54 (m, 1H), 7.48 (m 1H), 7.21 (m, 2H), 3.93 (s, 2H), 2.31 (s, 3H). MS (ESI): m/e 186 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:32]=[C:18]3[C:19]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[C:24]=4[F:31])=[CH:20][CH:21]=[CH:22][N:17]3[N:16]=2)[C:10]([F:34])([F:33])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:34][C:10]1([F:33])[CH:11]([NH:14][C:15]2[N:32]=[C:18]3[C:19]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[C:24]=4[F:31])=[CH:20][CH:21]=[CH:22][N:17]3[N:16]=2)[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3c(-c4ccc(F)c(F)c4F)cccn3n2)C(F)(F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(-c2cccn3nc(NC4CCNCC4(F)F)nc23)c(F)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To solution of 3,3-difluoro-4-[8-(2,3,4-trifluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (110 mg, 228 μmol) in CH2Cl2 (4 mL) at 0° C. was added TFA (182 mg, 123 μl, 1.59 mmol) and stirred at room temperature for 18 hours. Further TFA (182 mg, 123 μl, 1.59 mmol) was added and stirred at 50° C. for 6 hours. The reaction mixture was extracted with saturated NaHCO3 solution and ethyl acetate, the organic layers combined, dried over Na2SO4, filtered and the solvents evaporated. The product was coevaporated four times with toluene. The title compound was obtained as light yellow foam (87 mg, 100%). MS ISP (m/e): 384.2 (100) [(M+H)+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][N:13]([C@@H:16]([CH3:27])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[O:25][CH2:24][CH2:23][C:22]=3[CH:26]=2)[CH2:14][CH3:15])[CH2:8][CH2:7]1)=[O:5].C(N(C(C)C)CC)(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[O:25]1[C:21]2[CH:20]=[CH:19][C:18]([CH2:17][C@@H:16]([N:13]([CH2:12][CH:9]3[CH2:10][CH2:11][N:6]([C:4](=[O:5])[CH2:3][CH2:2][NH:1][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:7][CH2:8]3)[CH2:14][CH3:15])[CH3:27])=[CH:26][C:22]=2[CH2:23][CH2:24]1
Reactant: CCN(CC1CCN(C(=O)CCN)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC1CCN(C(=O)CCNS(C)(=O)=O)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.2 %

Procedure:
To (S)-3-amino-1-[4-({[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]ethylamino}-methyl)piperidin-1-yl]propan-1-one (0.4 grams, 1.07 mmol) and diisopropylethylamine (0.21 grams, 1.62 mmole) in dichloromethane (10 ml) at 0° C. was added methanesulfonyl chloride (0.16 grams, 1.39 mmole). The reaction mixture was stirred at room temperature for 3 hours. The mixture was washed with water, dried over potassium carbonate and concentrated to give a residue which was purified by flash chromatography on silica gel using 3% methanol in dichloromethane containing 0.1% ammonium hydroxide. Appropriate fractions were combined and evaporated to give (S)-N-{3-[4-({[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]ethylamino}methyl)piperidin-1-yl]-3-oxopropyl}methanesulfonamide as an oil (0.32 grams, 66%), M+H 452. Analysis % of the hydrochloride salt: Found: C, 51.83; H, 7.38; N, 7.87. Requires: C, 51.82; H, 7.56; N, 7.88.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[N:6]([CH2:16][CH2:17][CH3:18])[C:5]=2[N:4]=[C:3]1/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl[S:28]([OH:31])(=[O:30])=[O:29]>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[N:6]([CH2:16][CH2:17][CH3:18])[C:5]=2[N:4]=[C:3]1/[CH:19]=[CH:20]/[C:21]1[CH:22]=[CH:23][C:24]([S:28]([OH:31])(=[O:30])=[O:29])=[CH:25][CH:26]=1
Reactant: O=S(=O)(O)Cl
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3ccccc3)n2C)n(CCC)c1=O
Solvent: ClC(Cl)Cl
Product: CCCn1c(=O)c2c(nc(/C=C/c3ccc(S(=O)(=O)O)cc3)n2C)n(CCC)c1=O
Temperature: 0 °C
Yield: 39.1 %

Procedure:
(E)-7-Methyl-1,3-dipropyl-8-styrylxanthine (WO92/06976) (500 mg, 1.42 mmol) was dissolved in chloroform (5 ml), and chlorosulfonic acid (0.28 ml, 4.26 mmol) was added dropwise thereto at 0° C. The resulting solution was heated under reflux for 3 hours and then poured into 20 ml of ice-water. The chloroform layer was separated and the aqueous layer was extracted 5 times with tetrahydrofuran. The combined organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 240 mg (yield 39%) of Compound 31 as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.S(Cl)(Cl)=O.[NH3:26]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([NH2:26])=[O:21])=[CH:5]2
Reactant: N
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: NC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 29.1 %

Procedure:
A suspension, stirred at 20° C., of 2 g (6.96 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid, prepared according to the protocol described in step 1.1, in 80 ml of dry toluene is admixed with 5.08 ml (69.62 mmol) of thionyl chloride. The reaction mixture is stirred at reflux for 2 hours and then concentrated under reduced pressure. The resulting product is taken up in 10 ml of dichloromethane and this solution is poured dropwise into a solution of 9.12 ml (69.62 mmol) of 30% aqueous ammonia. The reaction mixture is stirred at 20° C. for 14 hours. After this time a solid is recovered by filtration and triturated in 50 ml of diisopropyl ether. Filtration and drying under reduced pressure give 0.58 g of expected product.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.Br[CH2:15][CH2:16][CH2:17][NH2:18].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>CCO>[NH2:18][CH2:17][CH2:16][CH2:15][N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: NCCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Product: NCCCN1CCN(c2ccccc2)CC1
Yield: 56.3 %

Procedure:
4-Phenylpiperazine (5.00 g, 30.8 mmol, 1.00 equiv, Aldrich), 3-bromopropylamine hydrobromide (8.09 g, 37.0 mmol, 1.20 equiv) and potassium carbonate (8.51 g, 61.6 mmol, 2.00 equiv) were stirred in refluxing acetone (200 mL) and EtOH (40 mL) for 14 hours. After removal of the solvents, water (250 mL) was added and the pH was adjusted to 11-12 by addition of 1 N aqueous NaOH. The mixture was extracted with CH2Cl2 (4×250 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, CHCl3-MeOH-NH (2 M in MeOH) 100:10:5 to 100:20:10) to give 3.80 g (56%) of yellow oil, which was characterized spectroscopically.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)=[N:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:38]([C:35]1[CH:36]=[CH:37][C:32]([O:31][C:17]2[C:16]([C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:15])=[CH:21][CH:20]=[C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[N:18]=2)=[CH:33][CH:34]=1)#[N:39]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(C#N)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(Oc2ccc(C(=O)N3CCNCC3)c(Oc3ccc(C#N)cc3)n2)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
4-[2,6-Bis-(4-cyano-phenoxy)pyridine-3-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester 1.2 g (2.28 mmol) was dissolved in 5 ml of DCM at 5° C. under inert atmosphere. 0.7 ml of TFA was added over a 10 min period, while the temperature was maintained at 5° C. Stirring was continued for 1 h at RT and reaction progress was monitored by TLC. The reaction mixture was concentrated under reduced pressure and the residual crude product was purified by column chromatography using chloroform: ethylacetate (8:2) as eluant to afford 0.9 g of the required product. Percentage purity (LCMS): 88.2%, (M+1): 425.1. 1H NMR (DMSO-d6): δ 3.15 (2H, m), 3.22 (2H, m), 3.64 (2H, m), 3.85 (2H, m), 7.00 (1H, d), 7.34 (4H, t), 7.82 (4H, t), 8.08 (1H, d), 9.02 (1H, brs).