Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.[CH:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]C>N1C=CC=CC=1>[C:1]([OH:7])(=[O:6])/[CH:2]=[CH:3]/[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=C(O)CC(=O)O
Reactant: CCCCCCC=O
Solvent: c1ccncc1
Product: CCCCCC/C=C/C(=O)O
Temperature: 0 °C
Reaction time: 60 h
Yield: 64 %

Procedure:
Malonic acid (342 g, 3.3 mole) is dissolved in 555 ml of dry pyridine (slightly exothermic). The mixture is cooled in ice water and n-heptaldehyde (342 g, 3.0 mole) is added with stirring. After the addition is complete, the ice bath is removed and the mixture allowed to stand at room temperature for 60 hours, and then heated on a steam bath for 8 hours. The reaction mixture is poured onto an equal volume of water. The organic layer is separated, washed with 900 ml 25% HCl, taken up in benzene, washed with water and dried. Distillation under vacuum gave trans-2-nonenoic acid, b.p. 123°C/2 mm, 297 g, 64% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.[H-].[Na+].[CH2:26](I)[CH3:27]>O>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[N:10]([CH2:26][CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCN(c2cccc(F)c2)c2ncccc21
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CN(c2cccc(F)c2)c2ncccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a solution of 2.4 g of 1-(m-fluorophenyl)-4-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine and 40 ml of dimethylformamide was added 0.6 g of 50% sodium hydride and the mixture was stirred for one hour at room temperature. To this was further added 4.6 g of ethyl iodide and the resulting mixture was stirred at 60° C for 1.5 hours. After the reaction was finished, the solvent was distilled off from the mixture to leave a residue, to which was added water to precipitate a crude product. Recrystallization of this product from ether gave 2.2 g of 1-(m-fluorophenyl)-3-ethyl-4-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as pale yellow prisms, melting at 123° - 124° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Li].BrCCCC1C=CC=CC=1.[CH2:22]([N:24]1[C:30]2[N:31]=[CH:32]C(I)=[CH:34][C:29]=2[C:28](=[O:36])[N:27]([CH3:37])[C:26]2[CH:38]=[CH:39][CH:40]=[N:41][C:25]1=2)[CH3:23]>O1CCCC1.[Cl-].[Zn+2].[Cl-].[Zn].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>[CH2:22]([N:24]1[C:30]2[N:31]=[CH:32][C:6]([CH2:7][CH2:8][CH2:9][C:10]3[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=3)=[CH:34][C:29]=2[C:28](=[O:36])[N:27]([CH3:37])[C:26]2[CH:38]=[CH:39][CH:40]=[N:41][C:25]1=2)[CH3:23]
Reactant: CCN1c2ncc(I)cc2C(=O)N(C)c2cccnc21
Reactant: c1ccc2ccccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: BrCCCc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCN1c2ncc(CCCc3ccccc3)cc2C(=O)N(C)c2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.4 %

Procedure:
A solution of naphthalene (0.65 g, 5.07 mmol) in 2 mL of tetrahydrofuran was added to lithium wire (35 mg, 5.04 mmol), and the mixture was stirred overnight at room temperature under argon. A solution of zinc chloride in tetrahydrofuran (0.5M, 5.25 mL, 2.63 mmol) was then added. After 20 min, 1-bromo-3-phenylpropane (0.18 mL, 1.15 mmol) was added, and the reaction mixture was stirred at room temperature for 4.5 hours. Unreacted zinc was allowed to settle, and the supernatant was added by cannula to a solution of 5,11-dihydro-11-ethyl-8-iodo-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.22 g, 0.58 mmol) and tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.06 mmol) in 3 mL of tetrahydrofuran. The reaction mixture was allowed to stir overnight at room temperature under argon. The reaction was quenched by the addition of saturated aqueous ammonium chloride, and the product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated. Purification by flash chromatography, eluting with ethyl acetate/dichloromethane, and recrystallization from ethyl acetate/hexanes afforded 16 mg of the title compound as off-white crystals, m.p. 100°-102° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[OH:25][C@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>CN1C(=O)CCC1.C(Cl)Cl.CO>[F:22][C:21]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[CH2:11][C:8]1[N:6]2[N:7]=[C:2]([N:28]3[CH2:29][CH2:30][C@H:26]([OH:25])[CH2:27]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: O[C@H]1CCNC1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: O[C@H]1CCN(c2ccc3ncc(Cc4cc5cccnc5cc4F)n3n2)C1
Temperature: 170 °C
Reaction time: 1 h

Procedure:
6-(6-Chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (Stage 173.1, 100 mg, 0.316 mmol), KF (92 mg, 1.581 mmol) and (S)-3-hydroxypyrrolidine (83 mg, 0.949 mmol) were suspended in NMP (1.5 mL). The RM was stirred at 170° C. for 1 h. The mixture was diluted with DCM/MeOH (95:5) and washed with water (2×). The aqueous phases were further extracted with DCM/MeOH (95:5) (2×). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was crystallized in DCM to afford the title compound as a beige solid (tR 2.63 min (conditions 13), MH+=364).
Reaction SMILES: [N:1]1([CH:6]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18](C(OCC)=O)[C:19]([O:21]CC)=[O:20])[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>CO.O>[N:1]1([CH:6]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCCC(CCCCCCCCCCCC(C(=O)OCC)C(=O)OCC)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCC(CCCCCCCCCCCCC(=O)O)n1ccnc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
Diethyl 2-(12-(1H-imidazol-1-yl)hexadecyl)malonate (415 mg, 0.9209 mmol) was dissolved in a 3:1 mixture of methanol (9 ml) and water (3 ml), cooled to 0° C. then NaOH (147 mg, 3.684 mmol) was added and the reaction mixture stirred at room temperature for 3 h. The reaction mixture was then concentrated under reduced pressure to remove MeOH, cooled to 0° C. to 5° C., the pH adjusted to 5, extracted with DCM (3×25 ml), dried on dry MgSO4, and concentrated under reduced pressure. The crude compound was obtained as a light yellow color liquid. This crude compound was heated at 170° C. to remove one carboxyl acid group from the di-carboxylic acid by the evolution of CO2. The crude product was then purified by silica gel column (3 to 5% of MeOH in DCM) to give 14-(1H-imidazol-1-yl)octadecanoic acid (221 mg, 68%) as a pale yellow gummy liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([I:12])[C:5](N)=[C:6]2[C:10]=1[S:9][N:8]=[N:7]2.N(OC(C)(C)C)=O>C1COCC1>[Br:1][C:2]1[C:10]2[S:9][N:8]=[N:7][C:6]=2[CH:5]=[C:4]([I:12])[CH:3]=1
Reactant: Nc1c(I)cc(Br)c2snnc12
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: Brc1cc(I)cc2nnsc12
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
To a solution of 7-bromo-5-iodo-1,2,3-benzothiadiazol-4-amine (95 mg, 0.267 mmol) in THF (6 mL) was added tert-butyl nitrite (0.127 mL, 1.067 mmol) at RT, and the reaction was stirred for 30 min. The solution was adsorbed onto silica gel and purified by ISCO chromatography (1% EtOAc:heptane) to afford 55 mg (60%) of the title compound as a brown solid. 1H NMR (400 MHz, CDCl3): δ 8.09 (d, J=1.0 Hz, 1 H), 8.94 (d, J=1.3 Hz, 1 H).
Reaction SMILES: [N+:1]([C:4]1C(=O)[O:6][C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[C:9]([O:15][CH3:16])[CH:8]=2)([O-:3])=[O:2].Cl>[OH-].[Na+]>[OH:6][C:7]1[CH:8]=[C:9]([O:15][CH3:16])[CH:10]=[CH:11][C:12]=1[C:13](=[O:14])[CH2:4][N+:1]([O-:3])=[O:2]
Reactant: COc1ccc2c(O)c([N+](=O)[O-])c(=O)oc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(=O)C[N+](=O)[O-])c(O)c1
Yield: 55.9 %

Procedure:
3-Nitro-4-hydroxy-7-methoxy coumarin (1.85 g, 0.078 m), prepared as described in D. R. Buckle, et al., J. Med. Chem., 18, 391 (1975), was stirred at room temperature in 5% aqueous sodium hydroxide (60 ml) for 20 hours. The mixture was slowly acidified with 5N HCl. The product was filtered off and sucked dry. Recrystallization from absolute ethanol gave pale yellow crystals (0.92 g, 56%), m.p. 138°-40° C.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:21]>C(Cl)Cl>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([O:12][C:20](=[O:21])[O:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
A solution of 4-pentylphenol (20.1 g, 0.13 mol) and pyridine (10 ml, 0.13 mol) in 300 ml of methylene chloride was added under nitrogen dropwise over 45 minutes to a solution of 4-nitrophenyl chloroformate (25.28 g, 0.13 mol) in 200 ml of methylene chloride at room temperature. After the addition, the reaction was stirred overnight at room temperature. The reaction was extracted one time with 1N HCl, four times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 36.97 g of a yellow crytstalline solid. Purification of the solid on 450 g of silica gel (230-400 mesh) using 50-60% CH2Cl2 -hexane as the eluent gave 11.58 g (28%) of the title compound as a yellow crystalline solid, mp 67-69° C.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13](C)C(O)=O)=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.C1C=CC=CC=1.FC(F)(F)C([O:32][C:33](=[O:38])[C:34](F)(F)F)=O.C1(C(O)C)C=CC=CC=1>CCOCC.O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][CH2:34][C:33]([OH:32])=[O:38])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: CC(O)c1ccccc1
Solvent: O
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=C(O)CCc1ccc2c(=O)c3ccccc3ccc2c1
Reaction time: 0.5 h

Procedure:
2.78 G. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid is stirred in a mixture of 20 ml. of benzene and 5 ml. of trifluoroacetic anhydride for 15 minutes. The mixture is evaporated to dryness and redissolved in 20 ml. of dry benzene. A mixture of 1.0 g. of pyridine and 2.44 g. (2 moles) of (+) α-phenylethanol is added. The mixture is left for 30 minutes and then water and ether is added. The organic layer is washed with dilute hydrochloric acid and water, then dried and evaporated. The residue is chromatographed on 100 g. silica gel, eluting with hexane:ether (4:1) to afford a 1:1 mixture of diastereomeric esters. Repeated crystallization of this mixture from ether-hexane yields the less soluble isomers. The purity of samples from successive recrystallizations is monitored by gas-liquid chromatography using a 1 meter × 2 mm. column packed with Chromosorb W (Regis Chemical Co., Chicago, Ill.) impregnated with 3% w/w OV101 polymeric material (Applied Sciences Laboratory, Inc., State College, Penn.) as stationary phase, and helium as the carrier gas at 220°C. The less soluble isomer is decomposed by stirring in a mixture of 5 ml. of benzene and 5 ml. of trifluoroacetic acid for 30 minutes. Water and ether are added and the ethereal layer washed with water, and then with dilute aqueous sodium carbonate. The aqueous layer is acidified with dilute hydrochloric acid and then extracted with ether. The ethereal layer is washed, dried and evaporated to give d 3-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid. 1 2-(5-Oxo-5H-dibenzo[a,d]cyclohepten-2yl)propionic acid [m.p. 105°-107°C; [α]D -47.4° (chloroform)] can be obtained in similar manner using (-) α-phenylethanol.
Reaction SMILES: C(C1C=CC(C2C=CC=C(C(N)=O)C=2)=CC=1)=O.[C:18]([C@@H:22]1[CH2:27][CH2:26][C@H:25]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([NH2:44])=[O:43])[CH:37]=3)=[C:32]([F:45])[CH:31]=2)[CH2:24][CH2:23]1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C@H:22]1[CH2:23][CH2:24][C@H:25]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([NH2:44])=[O:43])[CH:37]=3)=[C:32]([F:45])[CH:31]=2)[CH2:26][CH2:27]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)[C@H]1CC[C@@H](NCc2ccc(-c3cccc(C(N)=O)c3)c(F)c2)CC1
Agent: NC(=O)c1cccc(-c2ccc(C=O)cc2)c1
Product: CC(C)(C)[C@H]1CC[C@H](NCc2ccc(-c3cccc(C(N)=O)c3)c(F)c2)CC1

Procedure:
The procedure described in Example 56/57 was used to prepare Examples 58 and 59 from 4′-formylbiphenyl-3-carboxylic acid amide (Preparation 1) and the appropriate amine:
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:12][CH:11]2[CH:7]([N:8](C(C3C=CC=CC=3)C)[CH2:9][CH2:10]2)[CH2:6]1)=[O:4].C([O-])=O.[NH4+].Cl>CO.[Pd]>[CH3:1][O:2][C:3]([N:5]1[CH2:12][C@@H:11]2[C@@H:7]([NH:8][CH2:9][CH2:10]2)[CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC2CCN(C(C)c3ccccc3)C2C1
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: CO
Product: COC(=O)N1C[C@H]2CCN[C@H]2C1
Yield: 88.6 %

Procedure:
10% Pd/C (1 g) was added to a solution of 1-(1-phenyl-ethyl)-hexahydro-pyrrolo[3,4-b]pyrrole-5-carboxylic acid methyl ester (Diastereomer B, 4.9 g, 17.9 mmol), ammonium formate (5.6 g, 89 mmol) and 5N hydrochloric acid (4.0 ml, 20 mmol) in methanol (180 ml) at room temperature under nitrogen. The mixture was stirred and heated at reflux for 1 hour. Upon cooling the catalyst was removed by filtration through celite (washing with methanol). The filtrate was evaporated and the residue was partitioned between dichloromethane and saturated aqueous potassium carbonate. The aqueous layer was further extracted with dichloromethane (×1) and n-butanol (×1). The combined extracts were evaporated, and the residue was purified by chromatography on silica gel eluting with CH2Cl2 /MeOH/NH3 (80:8:1) to give the title amine (2.7 g, 89%) as a pale yellow oil; δ (360 MHz, d6 -DMSO) 1.50-1.58 (1H, m), 1.76-1.86 (1H, m), 2.66 (1H, br s), 2.76-2.88 (2H, m), 3.04-3.08 (1H, m), 3.10 (1H, br s, NH), 3.18 (1H, dd, J=11.4, 2.5 Hz), 3.40-3.52 (2H, m), 3.56 (3H, s, CO2Me), 3.66 (1H, br s).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([S:14](Cl)(=[O:16])=[O:15])=[CH:11][C:10]=2[CH3:18])=[CH:5][CH:4]=1.[OH-].[NH4+:20]>CC(C)=O>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([S:14]([NH2:20])(=[O:16])=[O:15])=[CH:11][C:10]=2[CH3:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2sc(S(=O)(=O)Cl)cc2C)cn1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1ccc(-c2sc(S(N)(=O)=O)cc2C)cn1

Procedure:
5-(6-Methoxy-pyridin-3-yl)-4-methyl-thiophene-2-sulfonyl chloride (0.19 g, 0.63 mmol) was dissolved in acetone (6 ml) and added dropwise to an aqueous ammonium hydroxide solution (25%, 1.2 ml). After 1 hour the solvent was removed under reduced pressure, the residue diluted with water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water, brine, dried (MgSO4.2H2O), filtered and concentrated under reduced pressure to yield a crude that was purified over silica gel (n-heptane-ethyl acetate 1:2 to 2:1 v/v) to yield a beige solid: 0.12 g (62%), MS: m/e 283.0 (MH−).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1O)=[C:10]([O:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[CH:9]=[C:8]([O:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[CH:7]=2)#[N:2].P(Cl)(Cl)([Cl:33])=O>C(#N)C>[Cl:33][C:12]1[C:11]2[C:6](=[CH:7][C:8]([O:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:9][C:10]=2[O:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:5]=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cnc2cc(OCCCN3CCOCC3)cc(OC3CCOCC3)c2c1O
Solvent: CC#N
Product: N#Cc1cnc2cc(OCCCN3CCOCC3)cc(OC3CCOCC3)c2c1Cl
Reaction time: 4 h

Procedure:
A mixture of 3-cyano-4-hydroxy-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinoline (500 mg) and phosphoryl chloride (2.5 ml) in acetonitrile (1.5 ml) was refluxed and stirred for 4 hours. After cooling, the solution was evaporated to dryness. The flask containing the residue was filled with ice chips and excess concentrated aqueous ammonia (25 ml) was added. This mixture was allowed to warm up while stirring overnight. The product was filtered off and air-dried. The title compound was obtained as a white solid (480 mg, 92%); Mass spectrum: M+H+ 432.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:5]([O:7][CH3:8])=[O:6].[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21]>CN(C=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:11]3[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=3[NH:1][C:20]2=[O:21])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(Nc2ccc(F)cc2)c(N)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)[nH]c(=O)n2-c1ccc(F)cc1
Temperature: 90 °C

Procedure:
A mixture of 60d (0.20 g, 0.826 mmol) and 1,1′-carbonyldiimidazole (0.535 g, 3.3 mmol) in DMF (8 mL) was heated at 90° C. for 2 h. The solvent was removed and the residue was triturated with water (15 mL). The resulting precipitate was collected by filtration and washed several times with water. The crude product 60i was used in the next reaction without further purification. MS m/z (M+H+) 287.1.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=1)([O-:22])=[O:21].CCN=C=NCCCN(C)C.Cl.[C:44]([NH:47][NH2:48])(=[O:46])[CH3:45]>CN(C=O)C.O>[C:44]([NH:47][NH:48][C:27](=[O:29])[C:26]1[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:31][CH:30]=1)(=[O:46])[CH3:45]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
HOBt (972 mg, 7.2 mmol) and DIEA (1.14 g, 8.9 mmol) were added to a stirred solution of 4-nitro-benzoic acid (1 g, 5.96 mmol) in DMF (6 mL). The reaction mixture was cooled to 10° C. EDCI.HCl (1.38 g, 7.2 mmol) followed by acetic acid hydrazide (490 mg, 6.6 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water and the product extracted with ethyl acetate. The organics were washed with saturated sodium bicarbonate solution followed by brine solution, dried over Na2SO4 and evaporated to afford 700 mg (55%) of 4-nitro-benzoic acid N′-acetyl-hydrazide. 1H NMR: (DMSO-d6): δ 10.7 (s, 1H), 10.0 (s, 1H), 8.4 (d, 2H), 8.1 (d, 2H), 1.9 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:23]=[CH:22][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[BH4-].[Na+].C(O)(=O)C(O)=O>CO.C(O)C>[OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:23]=[CH:22][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCC(c2ccc(OCCCN3CCCCC3)cc2)CC1
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: OC1CCC(c2ccc(OCCCN3CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.5 %

Procedure:
To a solution of 1-{3-[4-(4-oxocyclohexyl)phenoxy]propyl}piperidine (250 mg) in methanol (3 mL) is added sodium borohydride (15 mg). The mixture is stirred for two days at room temperature, then concentrated under reduced pressure and purified by column chromatography on silica gel (eluent dichloromethane/methanol/ammonia from 99.5/0.5/0.05 to 99/1/0.1) to give 179 mg of crude base which is dissolved in ethanol (2 mL). A solution of oxalic acid (50 g) in ethanol (1 mL) is added. A white precipitate appears which is filtered, rinsed with diethyl ether and dried under reduced pressure to give 127 mg of 1-{3-[4-(4-hydroxycyclohexyl)phenoxy]propyl}piperidine as a white solid
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:24])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:20]=[C:19]([C:21](O)=[O:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:26][O:27][C:28](=[O:34])[C@@H:29]([NH2:33])[CH:30]([CH3:32])[CH3:31].[K+].[Br-]>>[CH3:26][O:27][C:28](=[O:34])[C@@H:29]([NH:33][C:21]([C:19]1[O:18][N:17]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:24])=[CH:15][CH:14]=2)[CH:20]=1)=[O:22])[CH:30]([CH3:32])[CH3:31]
Reactant: O=C(Nc1ccc(-c2cc(C(=O)O)on2)cc1)NC1CCCCC1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: COC(=O)[C@@H](NC(=O)c1cc(-c2ccc(NC(=O)NC3CCCCC3)cc2)no1)C(C)C
Yield: 68 %

Procedure:
The title compound was prepared from 3-[4-(3-cyclohexyl-ureido)-phenyl]-isoxazole-5-carboxylic acid and (S)-2-amino-3-methyl-butyric acid methyl ester hydrochloride as set forth in Example 5 and was obtained in 68% yield. Mass (ES+): 443 (M++1); IR (KBr): 3382, 3345, 3290, 2932, 1746, 1665, 1652, 1543; 1H NMR (DMSO-d6) δ: 0.91 (2×d, 6H), 1.08-1.78 (4×m, 10H), 2.16 (m, 1H), 3.42 (br, 1H), 3.53 (s, 3H), 4.26 (t, 1H), 6.14 (d, 1H), 7.48 (d, 2H), 7.60 (s, 1H), 7.72 (d, 2H), 8.56 (s, 1H), 9.12 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[Br:1][C:2]1[C:3]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: Cc1cc(N)n[nH]1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(Cl)ncc2Br)n[nH]1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
A solution of 5-bromo-2,4-dichloropyrimidine (10.0 g, 44 mmol), 3-amino-5-methyl-1H-pyrazole (6.0 g, 62 mmol) and N,N-diisopropylethylamine (9.20 ml, 53 mmol) in 1-butanol (80 ml) was heated at 85° C. for 12 hours. The mixture was allowed to cool to ambient temperature and the resulting precipitate collected by filtration. The solid product was washed with ethanol and dried to give the sub-titled compound (10.8 g, 85%). 1H NMR (DMSO): δ 2.23 (s, 3H), 6.23 (s, 1H), 8.39 (s, 1H), 9.21 (s, 1H), 12.27 (s, 1H); MS: m/z 290 (MH)+.