Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[CH:5]=[O:6].[CH3:14][N:15](C=O)C.Cl>CCOC(C)=O>[CH:5]([C:4]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH3:13])=[C:2]([CH:3]=1)[C:14]#[N:15])=[O:6]
Reactant: CCCOc1ccc(C=O)cc1Br
Reactant: CN(C)C=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCOc1ccc(C=O)cc1C#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.7 %

Procedure:
To a stirred solution of 3-bromo-4-propoxybenzaldehyde (0.6 g, 2.47 mmol) in anhydrous DMF (5 ml) CuCN (0.67 g; 7.4 mmol) was added and the mixture was stirred for 4 h at reflux. After cooling to room temperature, the mixture was treated with EtOAc (50 ml) and 1M HCl (10 ml) and stirred for 15 min. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give 5-formyl-2-propoxybenzonitrile (0.41 g; 88%), as yellow oil 1H NMR (CDCl3) 9.87 (s, 1H); 8.07 (d, 1H, J=1.95 Hz); 8.03 (dd, 1H, J=8.67, 2.1 Hz); 7.06 (d, 1H, J=8.7 Hz); 4.13 (t, 2H, J=6.45 Hz); 1.97-1.85 (m, 2H); 1.1 (t, 3H, J=7.35 Hz). The above benzaldehyde was oxidised via a similar procedure as described in Example 47 Step A, to give the title compound (0.29 g; 68%), as white solid. 1H NMR (CDCl3) 8.3 (d, 1H, J=1.71 Hz); 8.23 (dd, 1H, J=8.88, 2.1 Hz); 7.00 (d, 1H, J=7.62 Hz); 4.12 (t, 2H, J=6.48 Hz); 1.97-1.85 (m, 2H); 1.09 (t, 3H, J=7.38 Hz).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C@@H:7]1[CH2:9][C@H:8]1[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:19]=3[S:20][CH:21]=2)[CH2:13][CH2:12]1)=[O:6]>O1CCOCC1.CO>[F:28][C:26]([F:27])([F:29])[C:23]1[CH:24]=[CH:25][C:18]2[C:17]([N:14]3[CH2:15][CH2:16][N:11]([CH2:10][C@@H:8]4[CH2:9][C@H:7]4[C:5]([OH:6])=[O:4])[CH2:12][CH2:13]3)=[CH:21][S:20][C:19]=2[CH:22]=1
Reactant: COC(=O)[C@@H]1C[C@H]1CN1CCN(c2csc3cc(C(F)(F)F)ccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)[C@@H]1C[C@H]1CN1CCN(c2csc3cc(C(F)(F)F)ccc23)CC1
Yield: 81 %

Procedure:
Add 5N NaOH solution (425 mL, 226 mmol) to a solution of trans-2-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropanecarboxylic acid methyl ester, Example 6a, (18.0 g, 45.1 mmol) in dioxane/methanol (400 mL, 3:1) and heat the reaction at 60° C. for 6 h. Selectively remove most of the methanol and acidify the remaining dioxane solution to pH 5-6 with 2N acetic acid. Collect the desired compound, which precipitates from solution, to obtain 14.08 g (81%) of colorless crystals, m/z=385 (M+H)+
Reaction SMILES: [Cl:1][CH:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]([N:5]1[CH2:14][C:13]2[CH:12]=[N:11][C:10]3[NH:15][N:16]=[CH:17][C:9]=3[C:8]=2[CH2:7][CH2:6]1)=[O:4].[Br:24]N1C(=O)CCC1=O>ClCCl>[Br:24][C:17]1[C:9]2[C:8]3[CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH:2]([Cl:1])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:14][C:13]=3[CH:12]=[N:11][C:10]=2[NH:15][N:16]=1
Reactant: O=C(C(Cl)c1ccccc1)N1CCc2c(cnc3[nH]ncc23)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: O=C(C(Cl)c1ccccc1)N1CCc2c(cnc3[nH]nc(Br)c23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.1 %

Procedure:
To a solution of 2-chloro-1-(8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-phenylethanone (0.340 g, 1.04 mmol) in dichloromethane (20 mL) was added N-bromosuccinimide (NBS, 0.195 g, 1.09 mmol). The reaction mixture was stirred for 16 hours at room temperature. During the reaction a yellow solid crashed out. The reaction was quenched by addition of aqueous NaHCO3. The aqueous layer was extracted with EtOAc (2×200 mL). The combined organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to give crude 1-(1-bromo-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-chloro-2-phenylethanone as a pale yellow solid (0.38 g, 90%). 1H NMR (400 MHz, DMSO-d6) δ11.08 (brs, 1H), 8.43 (s, 1H), 7.52-7.39 (m, 5H), 6.52 (s, 1H), 4.80 (m, 2H), 3.85 (m, 2H), 3.28 (m, 2H); LCMS [M+H]: 405. The product was used in the next step without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[CH:12]([CH3:16])[C:13]([OH:15])=[O:14].[CH3:17]O>Cl>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[CH:12]([CH3:16])[C:13]([O:15][CH3:17])=[O:14]
Reactant: CC(C(=O)O)c1c(F)cc([N+](=O)[O-])cc1F
Reactant: CO
Agent: Cl
Product: COC(=O)C(C)c1c(F)cc([N+](=O)[O-])cc1F
Yield: 89 %

Procedure:
Compound (27b) (3.6 g, 15.6 mmol) was dissolved in a solution of a catalytic amount of concentrated hydrochloric acid (0.14 mL) in methanol (72 mL) and treated in the same manner as in (c) in Production Example 1 to give 3.4 g (89%) of compound (28b) as pale yellow oil.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:33](=[O:34])[N:15]2[C:16]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:17]=3[N:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19](=[O:21])[CH:20]=[C:14]2[NH:13]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:33](=[O:34])[N:15]2[C:16]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:17]=3[N:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19](=[O:21])[CH:20]=[C:14]2[NH:13]1
Reactant: CC(C)(C)OC(=O)NCCCN1NC2=CC(=O)N(c3ccccc3)c3cc(Cl)ccc3N2C1=O
Solvent: O=C(O)C(F)(F)F
Product: NCCCN1NC2=CC(=O)N(c3ccccc3)c3cc(Cl)ccc3N2C1=O

Procedure:
2.5 g of 2-[3-(t-butoxycarbonylamino)propyl]-8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione in 50 ml of trifluoroacetic acid is stirred at room temperature for 2 hours. The reaction is evaporated and the residue is stirred with a solution of 1.9 g of sodium bicarbonate in 400 ml of methanol-water (10:1). After 3 hours the reaction is evaporated and the residue is partitioned between methylene chloride and water. The methylene chloride is washed with water, dried and evaporated to give the title compound.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[I:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.N1C=CN=C1>ClCCl>[Si:1]([O:16][C:13]1[CH:14]=[CH:15][C:10]([I:9])=[CH:11][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Oc1ccc(I)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.2 %

Procedure:
A solution of t-butyl-dimethylsilyl chloride (3.0 g) in dichloromethane (10 ml) was added dropwise to a stirred solution of 4-iodophenol (4.4 g) and imidazole (1.4 g) in dichloromethane (90 ml) whilst maintaining the temperature between 10° C. and 5° C. After the addition was complete, the reaction mixture was stirred for a further 4 hours at ambient temperature. The reaction mixture was washed with water, dried (MgSO4), and evaporated to give 4-(t-butyldimethylsilyloxy)iodobenzene as a colourless oil (6.4 g) NMR(DMSO-d6): 0.0(6H,s), 0.8(9H,s), 6.49-6.58(2H,d), 7.35-7.44(2H,d); m/z=334 (M).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([NH:20]S(C(C)(C)C)=O)[CH2:12][CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl.O1CCOCC1>CO>[NH2:20][CH:11]([C:4]1[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH2:12][CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(C)CC(NS(=O)C(C)(C)C)c1c(OC)cccc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) orange solution of ethyl 4-(2,6-dimethoxyphenyl)-4-(1,1-dimethylethylsulfinamido)-2-methylbutanoate (9.210 g; 23.89 mmol) in MeOH (100 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (11.95 ml; 47.80 mmol). The resulting orange mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 3 h. The reaction mixture was then concentrated to dryness under reduced pressure and the oily residue was further dried under HV to give the chlorhydrate salt of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate as an orange oil. LC-MS (conditions B): tR=0.62 min. and [M+H]+: 282.42 g/mol; tR=0.64 min. and [M+H]+: 282.42 g/mol (mixture of diastereoisomers). Due to transesterification, a reduced amount of methyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate was also detected: tR=0.57 min. and [M+H]+: 268.40 g/mol.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:21][OH:22])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:32][O:33][CH2:34]Cl.Cl.[Cl-].[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:21][O:22][CH2:32][O:33][CH3:34])[CH2:13][C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: CC(C)(C)OC(=O)C[C@@H](CO)NC(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 100.7 %

Procedure:
To a solution of tert-butyl (3S)-3-{[(benzyloxy)carbonyl]amino}-4-hydroxybutanoate (14.26 g, 46.1 mmol) in dichloromethane (190 ml) were added under ice cooling 4-dimethylaminopyridine (0.28 g, 2.3 mmol), diisopropylethylamine (24 ml, 138 mmol) and chloromethyl methyl ether (105 ml, 138 mmol). The mixture was raised to room temperature. Twelve hours later, to the mixture were added ice water and 1N hydrochloric acid under cooling in an ice bath to adjust pH to about 3. To the mixture was added a saturated aqueous sodium chloride solution and the solution was separated with a separating funnel. The organic layer was washed once with water and twice with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed in vacuo to give tert-butyl(3S)-3-{[(benzyloxy)carbonyl]amino}-4-(methoxymethoxy)butanoate (16.4 g, 100%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]2[N:12]=[N:13][N:14]=[C:10]2[C:9]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[N:8][CH:7]=1.C1COCC1.[ClH:33]>CO.C(Cl)Cl>[ClH:33].[N:15]1([C:9]2[C:10]3[N:11]([N:12]=[N:13][N:14]=3)[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[CH:7][N:8]=2)[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccs3)n3nnnc23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: c1csc(-c2cnc(N3CCNCC3)c3nnnn23)c1
Yield: 79 %

Procedure:
A 1 L round bottom flask was charged with tert-butyl 4-(5-(thiophen-2-yl)tetrazolo[1,5-a]pyrazin-8-yl)piperazine-1-carboxylate (210 g, 0.54 mol) and THF (400 mL). To this solution was added concentrated HCl (40 mL) dropwise in an ice-water bath. The resulting solution was stirred at reflux for 0.5 h. Reaction progress was monitored by TLC (MeOH/CH2Cl2=1:10). Work-up: the resulting crystalline solid was collected by filtration, washed with EtOH (200 mL), and dried to afford 139 g (79%) of the product as a yellow solid. MS m/z: 288 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[O:12]([NH2:14])[CH3:13].C(N(CC)CC)C>ClCCl>[CH3:13][O:12][NH:14][C:8](=[O:10])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: CON
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CONC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Introduce into a round-bottomed flask 6.8 g (50 mmol) of phenylacetic acid and 4.6 g (55 mmol) of methoxylamine hydrochloride, 5.55 g (55 mmol) of triethylamine and finally 10.83 g (52.5 mmol) of N,N-dicyclohexylcarbodiimide. Dissolve in 150 cm3 of dichloromethane. Stir for 16 hours at room temperature. Remove the precipitate by means of filtration and wash it with dichloromethane. Treat the filtrate with 100 cm3 of 3% HCl, then with 100 cm3 of water and finally with 100 cm3 of 5% NaHCO3.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:12]=[C:11]([C:13]2[S:14][C:15]3[CH2:16][CH2:17][O:18][C:19]4[CH:26]=[C:25](Br)[CH:24]=[CH:23][C:20]=4[C:21]=3[N:22]=2)[N:10]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:9]=1)(C)(C)C.O.C([O-])(=O)C.[K+].CC1(C)C(C)(C)OB([C:47]2[CH:48]=[N:49][NH:50][CH:51]=2)O1>CC#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:28]([N:10]1[C:11]([C:13]2[S:14][C:15]3[CH2:16][CH2:17][O:18][C:19]4[CH:26]=[C:25]([C:47]5[CH:48]=[N:49][NH:50][CH:51]=5)[CH:24]=[CH:23][C:20]=4[C:21]=3[N:22]=2)=[N:12][C:8]([NH2:7])=[N:9]1)([CH3:30])([CH3:31])[CH3:29]
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n(C(C)(C)C)n1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)n1nc(N)nc1-c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.9 %

Procedure:
[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-tert-butyl-1H-[1,2,4]triazol-3-yl]-carbamic acid tert-butyl ester (0.94 g, 1.8 mmol) was dissolved in MeCN (20 mL) and H2O (20 mL) and added potassium acetate (601 mg, 6.12 mmol). The reaction flask was degassed by bubbling N2 for 5 min. Charged with 4,4,5,5-tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (456 mg, 2.53 mmol) and then tetrakis(triphenylphosphine)palladium(0) (280 mg, 0.24 mmol). The reaction was subjected to microwave irradiation at 140° C. for 20 min. The reaction was cooled to r.t., filtered through a plug of Celite and diluted with water. Extracted three times with EtOAc and the combined organic portions were dried over MgSO4, filtered and concentrated. The crude residue was taken up in DCM (10 mL) and treated with trifluoroacetic acid (5 mL). Stirred at room temperature for 1 h and concentrated in vacuo. The resultant residue was taken up in a minimal amount of DMF/DMSO (1:1) and purified by rp-HPLC to provide 58 mg (10% yield) of 122. LC/MS (ESI+): m/z 408 (M+H). 1H NMR (400 MHz, DMSO) δ 12.96 (bs, 1H), 8.31 (m, 2H), 7.99 (bs, 1H), 7.50-7.39 (m, 2H), 7.34 (d, J=1.5, 2H), 5.47 (s, 2H), 4.47-4.24 (m, 4H), 3.39 (dd, J=15.8, 10.7, 4H), 1.78 (s, J=18.7, 9H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:13]([O:17]C)(=[O:16])[CH:14]=[CH2:15]>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:15][CH2:14][C:13]([OH:17])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCc1ccccc1
Reactant: C=CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCOCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To a stirred solution of 3-phenyl-1-propanol (1.36 g, 10 mmol) in THF (50 mL) at room temperature was added sodium hydride dispersion in oil (60%, 400 mg) portonwise. The cloudy solution warmed sightly and was stirred at room temperature for 30 minutes, and cooled to 0° in an ice-salt bath. Methyl acrylate (1.1 equivalents) was added, the ice bath was removed and stirring was continued for 30 minutes. The mixture was then cautiously treated with water (10 mL) and stirring was continued at room temperature overnight. The solvents were removed under reduced pressure and the residue was partitioned between water (100 mL) and ether (100 mL). The aqueous portion was made acidic to <pH 1 with concentrated HCl, and extracted with ether(2×50 ml). The ether extract was dried (MgSO4), filtered and evaporated under educed pressure to yield the title compound as a mobile colourless oil (0.684 g, 33%). 1H NMR (CDCl3) δ 9.19 (br s, 1H), 7.4-7.0 (5H, m, ArH), 3.60 (2H, t, J 6.2 Hz, OCH2), 3.36 (2H, t, J 6.2 Hz, OCH2), 2.54 (4H, m, 2×CH2), 1.79 (2H, m, CH2). 13C (CDCl3) δ 177.4, 141.7, 128.4, 128.3, 125.7, 70.1, 65.7, 34.8, 31.4, 32.1, 31.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.Cl.[NH2:15][C@@H:16]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:17]([N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1)=[O:18]>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C@H:16]([NH:15][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])[C:17]([N:19]2[CH2:20][CH2:21][CH:22]([OH:25])[CH2:23][CH2:24]2)=[O:18])=[CH:28][CH:29]=1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
Route B: The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-(S)-amino-3-(4-fluorophenyl)-1-(4-hydroxypiperidin-1-yl)propan-1-one hydrochloride (Preparation 20). The product was purified by chromatography on silica gel eluting with methanol/dichloromethane (1:19) to give the title compound as a pale yellow solid. δH (CD3OD): 1.08–1.19 (0.5H, m), 1.29–1.51 (1.5H, m), 1.54–1.62 (0.5H, m), 1.73–1.84 (1.5H, m), 3.06–3.36 (4H, m), 3.67–3.95 (2.5H, m), 4.03–4.10 (0.5H, m), 5.32 (1H, t), 6.97–7.04 (2H, m), 7.14 (1H, s), 7.26–7.33 (2H, m), 7.66 (1H, s), 8.55 (1H, s); m/z (ES+)=445 [M+H]+; RT=3.27 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[H-].[Na+].[C:13](Cl)(=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>O1CCCC1>[C:13]([NH:6][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[F:1])(=[O:22])/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(=O)c1ccccc1F
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccccc1)NC(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
Under an argon atmosphere, 2-fluorobenzamide (1.41 g, 10.0 mmol), sodium hydride (60% dispersion in mineral oil, 1.04 g, 25.0 mmol) and tetrahydrofuran (3 mL) were stirred under ice-cooling. A solution of cinnamoyl chloride (1.68 g, 10.0 mmol) in tetrahydrofuran (3 mL) was added thereto, and the mixture was warmed to room temperature. After stirring for 1 hr, to the mixture was added diluted hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogencarbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane to give the title compound (1.91 g) as a white solid. The yield was 70%.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[C:7]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]#[N:32])=[CH:21][CH:20]=2)=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:33]([O-])([O-])([O-])[O:34][CH2:35][CH3:36]>>[C:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:17]2[C:7]3[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][CH:15]=[CH:16][C:6]=3[N:5]=[C:33]2[O:34][CH2:35][CH3:36])=[CH:20][CH:21]=1)#[N:32]
Reactant: CCOC([O-])([O-])[O-]
Reactant: CCOC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cccc2nc(OCC)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Acetic acid (0.2 g) was added to a solution of ethyl 3-amino-2[(2′-cyanobiphenyl-4-yl)methyl]aminobenzoate (1.0 g) in ethyl orthocarbonate (5 ml).. The mixture was stirred at 80° C. for one hour. The reaction mixture was concentrated, and the concentrate was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium hydrogen carbonate and water. The solvent was evaporated to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals (0.79 g, 69%), m.p. 131-132° C. Elemental Analysis for C26,H23N3O3:
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:14])([CH3:13])[C:6]1[CH:10]=[C:9]([OH:11])[N:8]([CH3:12])[N:7]=1)([CH3:4])[CH3:3].Cl[C:16]1[N:17]=[N:18][CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.N1C(C)=CC=CC=1C>C1(C)C(C)=CC=CC=1>[CH3:4][C:2]([Si:5]([CH3:14])([CH3:13])[C:6]1[CH:10]=[C:9]([O:11][C:16]2[N:17]=[N:18][CH:19]=[C:20]([O:22][CH3:23])[CH:21]=2)[N:8]([CH3:12])[N:7]=1)([CH3:1])[CH3:3]
Reactant: COc1cnnc(Cl)c1
Reactant: Cn1nc([Si](C)(C)C(C)(C)C)cc1O
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1C
Product: COc1cnnc(Oc2cc([Si](C)(C)C(C)(C)C)nn2C)c1
Yield: 25.8 %

Procedure:
3-[(1,1-Dimethylethyl)dimethylsilyl]-1-methyl-1H-pyrazol-5-ol (0.48 g, 0.0023 mole), 3-chloro-5-methoxypyridazine (0.36 g, 0.00249 mole) and 2,6-lutidine (0.396 mL, 0.003396 moles) were refluxed under N2 in xylene (20 mL) for 18 hours. The mixture was then filtered through silica gel with ethyl acetate and evaporated in vacuo. The crude compound was purified by reverse phase chromatography to give 3-[[3-[(1,1-dimethylethyl)dimethylsilyl]-1-methyl-1H-pyrazol-5-yl]oxy]-5-methoxypyridazine (0.19 g, 26% yield) as a brown solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([O:23]C)[CH:17]=3)[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br>C(O)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([OH:23])[CH:17]=3)[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(C2CCCN(CCCc3ccccc3)C2)ccc1F
Agent: Br
Solvent: CC(=O)O
Product: Oc1cc(C2CCCN(CCCc3ccccc3)C2)ccc1F
Yield: 72 %

Procedure:
The 1-(3-phenylpropyl)-3-(4-fluoro-3-methoxyphenyl)piperidine from Preparation 6 was reacted with 48% aqueous hydrobromic acid in glacial acetic acid using the procedure of Example 3. The product was chromatographed on silica gel, eluting with ethyl acetate/hexane/triethylamine (5:5:3). This afforded a 72% yield of the title compound, [alpha]D25 =+20.2° (c=1; C2H5OH).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:33])[O:11][C@@H:12]([CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=1[OH:14])C1C=CC=CC=1>[Pd].CO>[OH:8][C:9]1[C:10](=[O:33])[O:11][C@@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=1[OH:14]
Reactant: CCCCCCCCCCCCCC/C=C\CC[C@@H]1OC(=O)C(OCc2ccccc2)=C1O
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCC[C@@H]1OC(=O)C(O)=C1O

Procedure:
To a 250 mL hydrogenation bottle was added 0.02 g of 10% palladium on carbon in 5 mL methanol. To this suspension was added 0.1 g (0,219 mmol) of (S)-3-benzyloxy-4-hydroxy-5-[(Z)-3-octadecenyl]-2(5H)-furanone dissolved in 15 mL methanol. Hydrogenation was initiated at 40 psi and at room temperature. The reaction was monitored for completion by TLC (approximately 5-6 hours), filtered (Celite) and evaporated under reduced pressure. The residue was purified over silica gel using 10% methanol in chloroform as eluant to generate 58 mg (72%) of white solid: mp 110°-112° C.; [α]D25 -6.8° (c=0.3, CH3OH); IR (Kbr, cm-1) 3380 (br), 2917, 2848, 1741, 1668; 1H NMR (CD3COCD3) δ 4.67 (dd, J=3.5, 7.3 Hz, 1H), 2.01-1.88 (m, 1H), 1.57-1.47 (m, 1H), 1.42-1.23 (m, 322), 0.87 (t, J=6.8 Hz, 3H); HRMS calculated for C22H40O4 (M+), 368.2927, found 368.2928; analysis calculated for C22H40O4 +0.5 H2O: C, 69.99; H, 10.95; Found: C, 70.27; H, 11.22.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:19])[CH:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]1[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:19])[CH:10]=1
Reactant: CCOC(=O)c1sc(NC(=O)OC(C)(C)C)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1sc(N)cc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
A mixture of ethyl 5-(tert-butoxycarbonylamino)-3-methylthiophene-2-carboxylate (25.00 g, 87.61 mmol) and trifluoroacetic acid (50 mL) in dichloromethane (100 mL) was stirred at 0° C. for 2 h, then concentrated in vacuo. The residue was partitioned between ethyl acetate (300 mL) and 1 N aqueous sodium hydroxide (300 mL). The aqueous layer was extracted with ethyl acetate (200 mL), and the combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 40% ethyl acetate in hexanes to afford ethyl 5-amino-3-methylthiophene-2-carboxylate as a beige solid (14.44 g, 89%): 1H NMR (300 MHz, CDCl3) δ 5.95 (s, 1H), 4.25 (q, J=7.1 Hz, 2H), 2.41 (s, 3H), 1.32 (t, J=7.1 Hz, 3H); MS (ES+) m/z 186.2 (M+1).