Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].ClC(OC)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cncc(Cl)c1
Agent: COC(=O)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1cncc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a solution of 5-chloro-nicotinic acid (2 g, 12.7 mmol) and TEA (1.52 g, 15 mmol) in THF (30 mL) was added slowly methyl chloroformate (1.42 g, 15 mmol) at 0° C. The resulting mixture was stirred at room temperature overnight. The reaction was diluted with ethyl acetate, washed with saturated ammonia chloride and dried over anhydrous sodium sulfate. The organic layer was concentrated to give the crude product (2.8 g, crude), which was dissolved in THF (40 mL) and cooled to −78° C. Lithium aluminium hydride (570 mg, 15 mmol) was added portion-wise. The resulting mixture was stirred for 30 min. The reaction was quenched with aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography (30% ethyl acetate in petroleum ether) to afford the title compound (1.4 g, 9.72 mmol, 76% yield). MS (ESI) m/z 144.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[S:18][C:19]([C:25]2[C:30]([F:31])=[CH:29][C:28]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:27][C:26]=2[F:36])=[CH:20][C:21]=1[C:22]([NH2:24])=[O:23]>>[F:36][C:26]1[CH:27]=[C:28]([C:32]([OH:35])([CH3:34])[CH3:33])[CH:29]=[C:30]([F:31])[C:25]=1[C:19]1[S:18][C:17]([NH:16][C:2]2[CH:3]=[CH:4][C:5]([CH2:9][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[C:6]([CH3:8])[N:7]=2)=[C:21]([C:22]([NH2:24])=[O:23])[CH:20]=1
Reactant: Cc1nc(Cl)ccc1CN1CCOCC1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1CN1CCOCC1

Procedure:
The title compound was synthesized from 4-[(6-chloro-2-methylpyridin-3-yl)methyl]morpholine (90 mg, 0.40 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (130 mg, 0.42 mmol) according to the procedure described in Example 1.
Reaction SMILES: COC1C=CC(C2C(C)(C)CC3C(=CC=C(OC)C=3)C=2)=C(N)C=1.Cl.[N:25]1([CH2:32][CH2:33][O:34][C:35]2[CH:43]=[CH:42][C:38]([C:39](O)=O)=[CH:37][CH:36]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.N1(CCOC2C=C[C:57]([CH2:58][NH:59][C:60]3[CH:65]=[C:64]([O:66][CH3:67])[CH:63]=[CH:62][C:61]=3[C:68]3[C:77]([CH3:79])([CH3:78])[CH2:76][C:75]4[C:70](=[CH:71][CH:72]=[C:73]([O:80][CH3:81])[CH:74]=4)[CH:69]=3)=CC=2)CCCCCC1>>[N:25]1([CH2:32][CH2:33][O:34][C:35]2[CH:43]=[CH:42][C:38]([CH2:39][N:59]([CH2:58][CH3:57])[C:60]3[CH:65]=[C:64]([O:66][CH3:67])[CH:63]=[CH:62][C:61]=3[C:68]3[C:77]([CH3:79])([CH3:78])[CH2:76][C:75]4[C:70](=[CH:71][CH:72]=[C:73]([O:80][CH3:81])[CH:74]=4)[CH:69]=3)=[CH:37][CH:36]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Reactant: COc1ccc2c(c1)CC(C)(C)C(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCCC3)cc1)=C2
Agent: COc1ccc(C2=Cc3ccc(OC)cc3CC2(C)C)c(N)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1cc(OC)ccc1C1=Cc2ccc(OC)cc2CC1(C)C

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-3,3-dimethyl-3,4-dihydronaphthalen-2-yl)phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl][5-methoxy-2-(6-methoxy-3,3-dimethyl-3,4-dihydronaphthalen-2-yl)phenyl]amine (454 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl[5-methoxy-2-(6-methoxy-3,3-dimethyl-3,4-dihydronaphthalen-2-yl)phenyl]amine (387 mg). This compound (385 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (345 mg).
Reaction SMILES: [F:1][C:2]([F:32])([CH:8](OC(C(C1NC=CN=1)=O)=S)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[F:1][C:2]([F:32])([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][CH3:21])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCCCCCCCCCCCCC(OC(=S)C(=O)c1ncc[nH]1)C(F)(F)C(=O)OCC
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCC(F)(F)C(=O)OCC
Yield: 87.8 %

Procedure:
Ethyl bromodifluoroacetate (11.2 g) and tetradecyl aldehyde (3.96 g) were mixed with anhydrous tetrahydrofuran (80 ml) under argon atmosphere, and the solution was added dropwise to a suspension of zinc powder (4.1 g) and copper bromide (I) (0.41 g) in anhydrous tetrahydrofuran (80 ml) which was heated to a refluxing temperature. The mixture, after heating under reflux for 5 hours, was cooled and concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 20:1 to 10:1) to give ethyl 2,2-difluoro-3-hydroxyhexadecanoate (1.99 g). After the mixture of ethyl 2,2-difluoro-3-hydroxyhexadecanoate (1.00 g) and 1,1'-thiocarbonyl imidazole (1.18 g) in 1,2-dichloroethane was heated under reflux for 1 hour, it was cooled and concentrated. The residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 30:1 to 10:1) to give ethyl 2,2-difluoro-3-imidazoylthiocarbonyloxyhexadecanoate (1.32 g). To a solution of ethyl 2,2-difluoro-3-imidazoylthiocarbonyloxyhexadecanoate (0.86 g) dissolved in toluene (40 ml) under argon atmosphere, which was heated under reflux, was added dropwise a solution of tri-n-butyltin hydride (1.07 ml) in toluene (80 ml). The mixture, after heating under reflux for 2 hours, was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 300:1 to 50:1) to give ethyl 2,2-difluorohexadecanoate (0.51 g). To a solution of ethyl 2,2-difluorohexadecanoate (300 mg) in N,N-dimethylformamide (30 ml) were added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (300 mg) and triethylamine (1.1 ml). The mixture was stirred for 12 hours. After the solvent was evaporated, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol-water (from 9:1:0.05 to 7:1:0.05) to give SPK193 in the yield of 41 mg.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Na].Cl[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1>[CH2:10]([O:9][CH2:8][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCOCc1ccccc1
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: C1CCOC1
Product: c1ccc(COCn2ccnc2)cc1
Reaction time: 1 h

Procedure:
To 58 g. of imidazole-sodium in 200 ml. of anhydrous tetrahydrofuran 100 g. of benzyl chloromethyl ether were added drop-wise with stirring at a temperature of 0° to 5° C. Cooling was discontinued after one hour. The mixture was left standing overnight and thereafter concentrated. The residue was treated with 2 N hydrochloric acid solution and with diethyl ether. The acidic aqueous layer was made alkaline with potassium carbonate and extracted with chloroform. The chloroform layer was treated with activated carbon, dried and concentrated. The residue was subjected to distillation. Boiling point 147° C./3 mm.Hg.
Reaction SMILES: [CH3:1]N(C)C1C=CN=C2C=1C=CN2.[C:13]1([C:18]2[NH:29][C:21]3=N[CH:23]=[CH:24][C:25](N(C)C)=[C:20]3[CH:19]=2)[CH2:17][CH2:16][CH2:15]C=1.C1(=O)NC(=O)C=C1.[Br-].[Yb+3].[Br-].[Br-]>C1(C)C=CC=CC=1>[CH2:1]1[C:21]2[NH:29][C:18]3[C:19](=[CH:15][CH:16]=[CH:17][CH:13]=3)[C:20]=2[CH2:25][CH2:24][CH2:23]1
Reactant: CN(C)c1ccnc2[nH]ccc12
Reactant: CN(C)c1ccnc2[nH]c(C3=CCCC3)cc12
Agent: O=C1C=CC(=O)N1
Agent: [Br-]
Agent: [Yb+3]
Solvent: Cc1ccccc1
Product: c1ccc2c3c([nH]c2c1)CCCC3
Yield: 88 %

Procedure:
This compound was prepared using the same general procedure as outlined for la starting with 4-dimethylamino-7-azaindole. To a 25 mL round-bottomed flask containing a magnetic stirring bar equipped with a reflux condenser and a three-way stopcock connected to an argon balloon was charged with (2-cyclopent-1-enyl-1H-pyrrolo[2,3-b]pyridine-4-yl)-dimethylamine (12 mg, 0.05 mmol) followed by toluene (2 mL), maleimide (157 mg, 0.79 mmol) and ytterbium(III) bromide (19 mg, 0.04 mmol). The reaction mixture was refluxed for 1 h and the toluene evaporated under vacuum. The crude material was triturated with methanol (10 mL) filtered and washed with methanol. The filtrate was concentrated and purified by silica gel column chromatography to obtain tetrahydrocarbazole (15 mg, 88% yield). An oven dried, 25 mL round-bottomed flask containing a magnetic stirring bar was charged with 7-dimethylamino-1,2,3,3a,3b,6a,11,11b-octahydro-5,10,11-triaza-benzo[a]trindene-4,6-dione (15 mg, 0.04 mmol) followed by acetonitrile (4 mL). DDQ (35 mg, 0.15 mmol) was added at 15° C. and then stirred at rt for 1 h and at reflux for 6 h. Acetonitrile was evaporated under vacuum and dissolved in ethyl acetate then washed with saturated sodium bicarbonate, brine, dried (MgSO4) and concentrated to give a crude material. The crude material was purified by silica gel column chromatography to give Sac (2.3 mg, 15% yield). MS (m/z): 321 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19]Cl)=[CH:7]2.C(N(CC)C(C)C)(C)C.[I-].[Li+].[NH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[CH:7]2
Reactant: NN1CCOCC1
Reactant: ClCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Agent: [I-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccccc1-c1nc2c(Cl)cccc2cc1CNN1CCOCC1
Temperature: 50 °C
Reaction time: 19 h

Procedure:
To a mixture of 8-chloro-3-(chloromethyl)-2-(2-chlorophenyl)quinoline (Prepared in Example 2), N,N-diisopropylethylamine (0.584 mL, 3.35 mmol), and lithium iodide (0.00566 mL, 0.148 mmol) in 7 mL of DMF was added 4-aminomorpholine (0.0647 mL, 0.670 mmol) and the mixture was stirred at 50° C. After 19 h, the mixture was concentrated under reduced pressure to give an yellow oil. The crude mixture was purified by column chromatography on a 40 g of Redi-Sep™ column using 0-100% gradient of EtOAc in hexane over 14 min and then 100% isocratic of EtOAc for 10 min as eluent to give N-((8-chloro-2-(2-chlorophenyl)-quinolin-3-yl)methyl)morpholin-4-amine as a light yellow foam (syrup): 1H NMR (400 MHz, choroform-d) δ ppm 8.39 (1H, s), 7.73-7.88 (2H, m), 7.37-7.53 (5H, m), 3.78-4.07 (2H, m), 3.64 (4H, t, J=4.7 Hz), 2.53 (4H, s); LC-MS (ESI) m/z 388.0 and 390.1 [M+H]+.
Reaction SMILES: C([CH:3]([C@H:7]([NH:14][C:15](=[O:35])[CH2:16][N:17]1[CH2:21][CH2:20][C@H:19]([NH:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[N:25]=2)[C:18]1=[O:34])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:4]([OH:6])=[O:5])C>Cl>[O:34]=[C:18]1[C@@H:19]([NH:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[N:25]=2)[CH2:20][CH2:21][N:17]1[CH2:16][C:15]([NH:14][C@H:7]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH2:3][C:4]([OH:6])=[O:5])=[O:35]
Reactant: CCC(C(=O)O)[C@H](NC(=O)CN1CC[C@H](NCc2ccc3c(n2)NCCC3)C1=O)c1cccnc1
Agent: Cl
Product: O=C(O)C[C@H](NC(=O)CN1CC[C@H](NCc2ccc3c(n2)NCCC3)C1=O)c1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
9-8 (25 mg, 0.043 mmol) was dissolved in 6N HCl (2 mL) and stirred at room temperature for 16 h, then evaporated to afford 9-9 as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[Cl-].Cl[C:15](Cl)=[N+:16]([CH3:18])[CH3:17]>C(Cl)Cl>[CH3:15][N:16]([CH3:18])[C:17]1[O:12][C:3]2[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=2[N:1]=1
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: C[N+](C)=C(Cl)Cl
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(N(C)C)oc2c1
Yield: 102 %

Procedure:
To a solution of methyl 4-amino-3-hydroxybenzoate (1.63 g, 9.8 mmol) in CH2Cl2 (30 mL) was added N-(dichloromethylene)-N-methylmethanaminium chloride (1.63 g, 10.0 mmol, 1.0 eq). The mixture was heated to reflux for 3 h. The reaction was quenched with H2O then extracted with CH2Cl2 (3×30 mL). Solvent was removed under reduced pressure to afford the title compound (2.2 g, ca. 10.0 mmol) which was used in next step without further purification.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=CC=1.C(Cl)(=O)C(C)(C)C.FC(F)(F)C(O)=O.[N+:46]([C:49]1[CH:64]=[CH:63][C:52]([CH2:53][O:54][C:55]([NH:57][C@@H:58]2[CH2:62][CH2:61][NH:60][CH2:59]2)=[O:56])=[CH:51][CH:50]=1)([O-:48])=[O:47]>>[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[C@H:11]([C:27]([N:60]2[CH2:61][CH2:62][C@@H:58]([NH:57][C:55]([O:54][CH2:53][C:52]3[CH:63]=[CH:64][C:49]([N+:46]([O-:48])=[O:47])=[CH:50][CH:51]=3)=[O:56])[CH2:59]2)=[O:29])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: O=C(N[C@@H]1CCNC1)OCc1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)OCc1ccc([N+](=O)[O-])cc1
Yield: 65.8 %

Procedure:
Following a procedure similar to that described in Preparation 18, but using 1.29 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 365 mg of pivaloyl chloride and 1.14 g of (3R)-3-(4-nitrobenzyloxycarbonyl)aminopyrrolidine trifluoroacetate, 1.09 g of the title compound were obtained as a powder.
Reaction SMILES: [H-].[K+].[CH3:3][C:4]([CH3:6])=[O:5].[C:7](Cl)(=[O:11])[CH:8]([CH3:10])[CH3:9].O>O1CCCC1>[C:7]([O:5][C:4]([CH3:6])=[CH2:3])(=[O:11])[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)=O
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)OC(=O)C(C)C
Temperature: -10 °C

Procedure:
Isopropenyl isobutyrate was prepared by the potassium hydride catalyzed condensation of acetone with isobutyryl chloride as follows. A suspension of potassium hydride (100 g, 2.5 mol.) in 1.5 liters of dry tetrahydrofuran was prepared. The suspension was cooled to -10° C. and 200 ml acetone was slowly added maintaining the temperature of the reaction mixture between 0° and -10° C. The resulting solution of acetone enolate was added to a solution of 266 g (2.5 mol.) of isobutyryl chloride in 3 liters of tetrahydrofuran over a 30-minute period. The temperature of the reaction flask was maintained between -30° and -50° C. during the addition. After 16 hours the reaction mixture was poured into water and the resulting mixture was extracted with ether. The ether extracts were combined, dried over sodium sulfate, and the solvent was removed. The residue was distilled through a thin film evaporator (114° to 125° C.) and the distillate was redistilled through a spinning band column. The fraction boiling at 40° to 46° C. (1.5 mm Hg) was collected to give a total of 21 g (7%) of pure isopropenyl isobutyrate. The isopropenyl isobutyrate was polymerized according to the method described in Example 2 to give the corresponding polymer.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27](C#N)[CH:26]=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1.BrCC1C=CC([N:42]2[CH:46]=[CH:45][CH:44]=[N:43]2)=CC=1>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([N:42]4[CH:46]=[CH:45][CH:44]=[N:43]4)=[CH:29][CH:30]=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1
Reactant: N#Cc1cccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)c1
Reactant: BrCc1ccc(-n2cccn2)cc1
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)cc(=O)n(Cc2ccc(-n3cccn3)cc2)c1=O

Procedure:
Title compound 21 was prepared by the methods used in the preparation of compound 17, except that 1-(4-bromomethyl-phenyl)-1H-pyrazole was used in the place of m-cyano-benzyl bromide. 1H-NMR (400 MHz, CDCl3—CD3OD 10:1) δ 7.90 (d, J=2.5 Hz, 1H), 7.71 (d, J=1.8 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.51-7.58 (m, 3H), 7.43-7.37 (m, 3H), 7.22 (d, J=7.8 Hz, 1H), 6.47 (t, J=2.1 Hz, 1H), 5.43 (s, 1H), 5.14-5.30 (ABq, J=41.2, 16.4 Hz, 2H), 5.05 (s, 2H), 3.32-3.40 (m, 2H), 2.96 (m, 1H), 2.89 (m, 1H), 2.70 (m, 1H), 2.10 (m, 1H), 1.88 (m, 1H), 1.66 (s, 2H). MS (ES) [m+H] calc'd for C27H28N7O2, 482.2; found 482.2.
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:13][C:14]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:22]1[O:24][CH2:23]1.O>CCCCCC.C1COCC1.O1CCOCC1>[CH2:6]([NH:13][C:14]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[CH2:22][CH2:23][OH:24])=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(NCc1ccccc1)c1ccncc1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: O=C(NCc1ccccc1)c1ccncc1CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.1 %

Procedure:
Butyl lithium (61.5 mL of a 1.6 M solution in hexane, 98.5 mmol) was added dropwise over 10 min to a stirred solution of N-benzyl-4-pyridinecarboxamide (9.94 g, 46.9 mmol) in THF (200 mL) at −78° C. under N2. The reaction mixture immediately turned dark blue, and was stirred for 1 h. A solution of ethylene oxide (2.27 g, 51.6 mmol) in dioxane (10 mL) was then added and the resulting mixture stirred at −78° C. for 3 h, after which time it was warmed to room temperature and quenched with MeOH (40 mL). The quenched reaction mixture was poured into H2O (200 mL) and extracted with EtOAc (3×150 mL). The combined organic extracts were washed with brine (150 mL), dried (MgSO4) and concentrated under reduced pressure. The crude material was purified by column chromatography on silica using 5–10% MeOH in DCM as the eluent to yield the desired alcohol (2.9 g, 24%). MS (ES+) 257 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[CH3:14][C:15]([CH3:19])([CH3:18])[CH2:16][NH2:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:14][C:15]([CH3:19])([CH3:18])[CH2:16][NH:17][C:11]([CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)=[O:13]
Reactant: CC(C)(C)CN
Reactant: N#Cc1ccc(CCC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CNC(=O)CCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.8 %

Procedure:
Combine 3-(4-cyanophenyl)-propionic acid (870 mg, 4.9 mmol), 2,2-dimethylpropylamine (0.6 mL, 5.4 mmol), EDCI (1.0 g, 5.4 mmol), HOBT (804 mg, 5.9 mmol), triethylamine (2 mL, 14.8 mmol) and DMAP (60.5 mg, 0.5 mmol) in anhydrous DCM (50 mL). Stir at room temperature for 1 day under nitrogen. Concentrate the mixture in vacuo and purify by chromatography on silica gel eluting with hexane/EtOAc (1:1) to obtain the desired intermediate as a white solid (740 mg, 61%). MS (ES+) m/z: 245 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3]OS(C1C=CC(C)=CC=1)(=O)=O.[CH:15]1[C:28]2[C:27](=[O:29])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C:19]=2[CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CCOCC>CN(C)C=O>[CH:25]1[C:26]2[C:21](=[CH:20][C:19]3[C:28]([C:27]=2[O:29][CH2:3][CH2:2][Cl:1])=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:22]=[CH:23][CH:24]=1
Reactant: O=C1c2ccccc2Cc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: ClCCOc1c2ccccc2cc2ccccc12
Temperature: 70 °C
Reaction time: 24 h

Procedure:
2-Chloroethyl-p-toluenesulphonate (6.0 g) was added to a mixture of anthrone (5 g) and potassium carbonate (5 g) in dimethylformamide (130 ml). After stirring for 24 hours at 70° C., the reaction mixture was added to ether. The resultant solution was washed with dilute aqueous potassium hydroxide, dried with magnesium sulphate, and evaporated to yield a crude product which was chromatographed on silica gel, eluting with 4:1 hexane:ethyl acetate, to give 2-(9-anthryloxy)ethyl chloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:9]1=[O:20])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25]Br.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:25][C:24]3[C:23]([F:22])=[CH:30][CH:29]=[CH:28][C:27]=3[F:31])=[CH:17][CH:18]=2)[C:9]1=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cccc(F)c1CBr
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(O)cc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(OCc3c(F)cccc3F)cc2)C1=O

Procedure:
In an analogous manner to that described in Example 2c), the alkylation of the (S)-[1-(4-hydroxy-phenyl)-2-oxo-pyrrolidin-3-yl]-carbamic acid tert-butyl ester [Example 16 a)] with 2,6-difluorobenzylbromide in presence of potassium carbonate yields the title compound as a white solid; MS: m/e=419 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=C[N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=N[NH:38]C(=O)C=1)C1C=CC=CC=1.BrCC(C1C=CC(CO)=CC=1)=O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[N:38][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)cn[nH]1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Agent: O=C(CBr)c1ccc(CO)cc1
Solvent: CS(C)=O
Product: O=C(Cn1ncc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1

Procedure:
5-Benzyloxy-2-[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one is prepared following preparation 15b from 5.20 g (25.7 mmol) 5-benzyloxy-2H-pyridazin-3-one (preparation 5c) and 7.70 g (28.6 mmol) 2-bromo-1-(4-hydroxymethyl-phenyl)-ethanone (preparation 15a) using DMSO as solvent.
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][CH2:6][CH2:7][CH2:8][P:9]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:11])[OH:10].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[CH:23]=O.C(O)(=O)C>CO>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[CH2:23][NH:5][CH2:6][CH2:7][CH2:8][P:9]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:10])[OH:11]
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: NCCCP(=O)(O)CC1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=P(O)(CCCNCc1cc(Cl)cc(Cl)c1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
2.0 g of sodium cyanoborohydride are added in portions to a solution of 6.27 g of 3-aminopropyl-(cyclohexylmethyl)-phosphinic acid and 5.0 g of 3,5-dichlorobenzaldehyde and 1.91 g of glacial acetic acid in 50 ml of anhydrous methanol and the mixture is stirred at room temperature for 4 days. The solvent is removed, the white residue is taken up in 2.0M hydrochloric acid and filtered. The filtrate is concentrated to dryness by evaporation and the white solid that remains behind is suspended in ethyl acetate, filtered off and crystallised from propanol, yielding 3-[(3,5-dichlorobenzyl)amino]-propyl-(cyclohexylmethyl)-phosphinic acid, m.p. 231°-233°.