Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(OC(C)(C)C)=O.[C:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH2:21]C=[CH:19]2)#[N:15].Cl>>[N:8]1([CH:1]2[CH2:19][C:18]3[C:22](=[CH:23][CH:24]=[C:16]([C:14]#[N:15])[CH:17]=3)[CH2:21]2)[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: N#Cc1ccc2c(c1)C=CC2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Product: N#Cc1ccc2c(c1)CC(N1CCNCC1)C2
Reaction time: 2 h

Procedure:
To a flask containing 5-cyano-inden bocpiperazine (0.025 g, 0.076 mmol) and a stir bar was added 4M HCl (2 mL). The resulting mixture was then stirred for 2 h; LC indicated completion of the reaction. The solution was concentrated in vacuo, pumped under reduced pressure and gave the title product (LC/MS: [(M+1)]+=228.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[P:14]([OH:17])([OH:16])[OH:15].P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH3:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:9][CH2:10][C:11]([P:14]([OH:17])([OH:16])=[O:15])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:2]
Reactant: OP(O)O
Reactant: CCCCCN(C)CCC(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClP(Cl)Cl
Product: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Temperature: 57.5 °C
Reaction time: 10 h

Procedure:
3-(N-Methyl-N-pentylamino)propanoic acid hydrochloride (100 g) was suspended in toluene (300 mL) and polyethylene glycol 400 (120 mL). Phosphorous acid (43.01 g 1.1 eq.) was added to the mixture. The mixture was warmed and phosphorous trichloride (98.22 g, 1.5 eq.) was added at a rate such that the temperature remained below 60° C. The mixture was stirred for 10 hours at 55-60° C. whereupon it was quenched by adding water (450 mL). The water addition was controlled to maintain a reaction temperature below 70° C. The layers were separated and the aqueous layer was refluxed for 6 hours. The mixture was cooled to 40-45° C. to provide Ibandronic acid in solution and the pH was adjusted to 4.3-4.5 using 50% aqueous sodium hydroxide. Propylene glycol (150 mL) was then added to the reaction mixture at 60-65° C. and stirred for 4-5 hours. The mixture was cooled to 20-25° C. over a period of 2-3 hours and then for 3-4 hours at 0-5° C., filtered, washed with acetone (2×150 mL) and dried in vacuo.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[CH:11]=[N:12][N:13]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28]C)=[O:27])=[CH:21][CH:20]=3)[C:14]=2[S:15][CH2:16][CH2:17][CH3:18])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([NH:7][C:8]([C:10]2[CH:11]=[N:12][N:13]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:21][CH:20]=3)[C:14]=2[S:15][CH2:16][CH2:17][CH3:18])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCSc1c(C(=O)NC2CCCCC2)cnn1-c1ccc(CC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCSc1c(C(=O)NC2CCCCC2)cnn1-c1ccc(CC(=O)O)cc1
Reaction time: 8 h

Procedure:
Methyl 2-[4-[4-(cyclohexylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]phenyl]acetate (Intermediate#33) (210 mg, 0.51 mmol) was dissolved in methanol (10 mL) and treated at ambient temperature with a 2M solution of sodium hydroxide (1.27 mL, 2.53 mmol). The mixture was stiffed overnight and then methanol was removed by evaporation under reduced pressure. The clear aqueous solution was diluted with water (20 mL) and acidified to pH3 with 2M HCl. The resulting white precipitate was extracted into ethyl acetate (2×20 mL). The combined extracts were washed with brine (10 mL), dried (MgSO4) and evaporated to give the crude product. The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-[4-[4-(cyclohexylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]phenyl]acetic acid. (84 mg, 41%).
Reaction SMILES: O[C:2]1([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([CH3:13])[C:7]=2[CH2:6][C:5]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:4]=2[CH2:3]1.OC1(CC(OCC)=O)C2C=CC=CC=2CC2C=C(OC)C=CC=2C1>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:4]2[CH2:3][CH:2]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([CH3:13])[C:7]=3[CH2:6][C:5]=2[CH:14]=1
Reactant: CCOC(=O)CC1(O)Cc2ccc(OC)cc2Cc2c(C)cccc21
Agent: CCOC(=O)CC1(O)Cc2ccc(OC)cc2Cc2ccccc21
Product: CCOC(=O)CC1Cc2ccc(OC)cc2Cc2c(C)cccc21

Procedure:
According to the procedure of Preparation 10 (f), except substituting ethyl (±)-10,11-dihydro-10-hydroxy-3-methoxy-6-methyl-5H-dibenzo[a,d]cycloheptene-10-acetate for the ethyl (±)-10,11-dihydro-10-hydroxy-3-methoxy-5H-dibenzo[a,d]cycloheptene-10-acetate, the title compound was obtained as a colorless oil following silica gel chromatography (5% EtOAc/hexanes): MS (ES) m/e 325.3 (M+H)+.
Reaction SMILES: [C:1]1([C@H:7]([CH3:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl.C(O)(=O)C.CCCCCC>[Cl:11][C:12]1[C:19]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][NH:9][CH2:8][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:10]
Reactant: C[C@H](CN)c1ccccc1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCCCCC
Product: C[C@H](CNCc1cccc(C(F)(F)F)c1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.4 %

Procedure:
To a solution of (S)-(−)-2-phenyl propylamine (0.5 g, 3.7 mmol) in dry dichloromethane (100 ml) was added acetic acid (2 drops) followed by 2-chloro-3-trifluoromethylbenzaldehyde (1.1 g, 5.5 mmol) and sodium triacetoxyborohydride (1.5 g, 7.4 mmol). After the resulting mixture was stirred for 1.5 h at room temperature, water was added to quench the reaction. The aqueous layer was extracted with ethyl acetate. The combined organic layers was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude mixture was purified by silica gel column chromatograph using EtOAc:Hexane/25:75 as the eluant to give 0.55 g (45% yield) of the title compound as an oil. MS m/e327.6 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O.O.[OH-].[Al+3:17].[OH-].[OH-]>CC(C)=O>[CH2:7]([O:6][P:4]([CH2:9][CH2:10][C:11]([O-:13])=[O:12])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8].[CH2:7]([O:6][P:4]([CH2:9][CH2:10][C:11]([O-:13])=[O:12])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8].[CH2:7]([O:6][P:4]([CH2:9][CH2:10][C:11]([O-:13])=[O:12])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8].[Al+3:17]
Reactant: CCOP(=O)(CCC(=O)O)OCC
Agent: [Al+3]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCOP(=O)(CCC(=O)[O-])OCC
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Use as a reaction vessel a 500 milliliter (mL) single neck round bottomed flask fitted with a condenser with a nitrogen inlet. Charge the vessel with 3-(diethyoxyphosphoryl)propanoic acid (20.30 g) followed by the addition of water (150 mL) and aluminum hydroxide monohydrate (2.709 g). Heat the resulting solution to 90° C. and hold at that temperature for eight hours. Remove the water using a rotovap to leave behind a solid material. Add 100 mL of acetone and isolate the solid by vacuum filtration using a Buchner funnel and wash with acetone (100 mL). Transfer the solid product to a glass bottle and place in a vacuum oven to dry overnight. The yield of the solid product, aluminum tris(3-(diethoxyphosphoryl)propanoate), is 12.45 g.
Reaction SMILES: CS([O:5][C@@H:6]1[CH2:10][CH2:9][O:8][CH2:7]1)(=O)=O.[OH:11][CH2:12][C:13]1[CH:14]=[C:15]([C:19]2[C:24]([CH3:25])=[CH:23][C:22](O)=[CH:21][C:20]=2[CH3:27])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:25][C:24]1[CH:23]=[C:22]([O:5][C@H:6]2[CH2:10][CH2:9][O:8][CH2:7]2)[CH:21]=[C:20]([CH3:27])[C:19]=1[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][OH:11])[CH:14]=1
Reactant: Cc1cc(O)cc(C)c1-c1cccc(CO)c1
Reactant: CS(=O)(=O)O[C@@H]1CCOC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(O[C@H]2CCOC2)cc(C)c1-c1cccc(CO)c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 54 %

Procedure:
The crude (R)-tetrahydrofuran-3-yl methanesulfonate 1b (520 mg, 3.13 mmol), 3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-ol (714 mg, 3.13 mmol, prepared by a method disclosed in Chinese patent application CN101616913) and cesium carbonate (3.10 g, 9.39 mmol) were dissolved in 30 mL of N,N-dimethylformamide. The reaction mixture was heated to 80° C. and stirred for 7 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound (S)-(2′,6′-dimethyl-4′-((tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methanol 1c (500 mg, yield 54.0%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([C:13]([OH:15])=O)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([CH2:30][NH2:31])=[C:25]([CH3:32])[N:24]=1)([CH3:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:16]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([CH2:30][NH:31][C:13]([C:11]2[O:12][C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:9][N:10]=2)=[O:15])=[C:25]([CH3:32])[N:24]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C(O)c1nnc(Cc2ccccc2)o1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1nnc(Cc2ccccc2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of Benzyl-[1,3,4]oxadiazole-2-carboxylic acid (2.4 g, 11 mmol), (5-Aminomethyl-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (2.8 g, 11 mmol), HATU (5.5 g, 15 mmol) and DIPEA (7.8 mL, 45 mmol) in 20 mL DMF was stirred at room temperature for 16 h. The mixture was evaporated and the residue was partitioned between ethyl acetate and 1 N aq. HCl. The organic layer was dried over MgSO4 and evaporated in vacuo. The crude product was purified by preparative HPLC (Waters Sunfire Prep C18 PBD 5 um, 30×100 mm, 5 to 100% ACN and 0.1% TFA, flow 40 ml/min). HPLC (method C) RtA=3.114.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[S:3]([C:6]1[CH:7]=[C:8]([CH:22]=[CH:23][CH:24]=1)[NH:9][C:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=1)=[O:11])(=[O:5])=[O:4].O.[NH2:28][NH2:29]>CCO>[NH:28]([C:16]([C:15]1[CH:20]=[CH:21][C:12]([C:10]([NH:9][C:8]2[CH:22]=[CH:23][CH:24]=[C:6]([S:3]([C:2]([F:26])([F:25])[F:1])(=[O:5])=[O:4])[CH:7]=2)=[O:11])=[CH:13][CH:14]=1)=[O:17])[NH2:29]
Reactant: COC(=O)c1ccc(C(=O)Nc2cccc(S(=O)(=O)C(F)(F)F)c2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(C(=O)Nc2cccc(S(=O)(=O)C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63 %

Procedure:
To a suspension of methyl 4-({3-[(trifluoromethyl)sulfonyl]anilino}carbonyl)benzoate (390 mg, 1.1 mmol) in EtOH (6 mL) was added hydrazine hydrate (1 mL). After stirring for 15 hrs at reflux, the reaction mixture was cooled to rt and a white solid precipitated out Filtration, washing with EtOH (1×1 mL) and water (3×1 mL), and drying under vacuo at 60° C. for 2 hrs gave 247 mg of the title compound (63%) as a white solid in 95% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH:4]([N:7]1[CH:11]=[C:10]([CH2:12][CH2:13][NH:14][C:15]([NH:17][C:18]2[S:19][C:20]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26](S(C)(=O)=O)[N:25]=3)=[C:21]([CH3:23])[N:22]=2)=[O:16])[N:9]=[CH:8]1)([CH3:6])[CH3:5]>CS(C)=O>[C:1]([C:26]1[N:25]=[C:24]([C:20]2[S:19][C:18]([NH:17][C:15]([NH:14][CH2:13][CH2:12][C:10]3[N:9]=[CH:8][N:7]([CH:4]([CH3:6])[CH3:5])[CH:11]=3)=[O:16])=[N:22][C:21]=2[CH3:23])[CH:29]=[C:28]([CH3:30])[N:27]=1)#[N:2]
Reactant: [C-]#N
Reactant: Cc1cc(-c2sc(NC(=O)NCCc3cn(C(C)C)cn3)nc2C)nc(S(C)(=O)=O)n1
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(-c2sc(NC(=O)NCCc3cn(C(C)C)cn3)nc2C)nc(C#N)n1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Sodium cyanide (0.069 g, 1.4 mmol) is added to a stirred solution of 1-[2-(1-isopropyl-1H-imidazol-4-yl)-ethyl]-3-[5-(2-methanesulfonyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-urea (0.21 g, 0.47 mmol) in dry DMSO (10 ml). The reaction is stirred at 50° C. under argon for 3 hours then the solvent is removed. The residue is dissolved in DCM and washed with water. The organic extract is dried (MgSO4) and the solvent removed to give the titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH:13]([CH3:15])[CH3:14].[C:16]1([CH:22](Br)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:16]1([CH:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[CH2:12][CH:13]([CH3:15])[CH3:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(O)c(CC(C)C)c1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(c2ccccc2)c2ccccc2)c(CC(C)C)c1
Temperature: 0 °C
Yield: 31.3 %

Procedure:
A solution of methyl 4-hydroxy-3-isobutylbenzoate (0.80 g, 3.84 mmol), diphenylmethyl bromide (1.05 g, 4.25 mmol) and potassium carbonate (0.69 g, 4.99 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 3 days. The reaction solution was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous citric acid solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/hexane=3/97-15/85) to give the title compound (450 mg, yield 31%) as a colorless oil.
Reaction SMILES: C([O:8][C:9]1[C:10]([C:27]([O:29][CH3:30])=[O:28])=[N:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:14](=[O:26])[C:13]=12)C1C=CC=CC=1>CO.[Pd]>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:15]2[CH2:16][CH2:17][N:12]3[N:11]=[C:10]([C:27]([O:29][CH3:30])=[O:28])[C:9]([OH:8])=[C:13]3[C:14]2=[O:26])=[CH:24][CH:23]=1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(Cc1ccc(F)cc1)CC2
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1nn2c(c1O)C(=O)N(Cc1ccc(F)cc1)CC2
Reaction time: 8 h

Procedure:
Nitrogen gas was bubbled through a solution of methyl 3-benzyloxy-5-(4-fluorobenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (37 mg, 0.09 mmol) in MeOH. To the solution was added a small amount of 10% Pd on carbon, and the mixture was stirred under an atmosphere of hydrogen gas overnight. The reaction mixture was filtered through celite, and the filter cake was washed with MeOH. The resulting filtrate was concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 9.20 (s, 1H), 7.41-7.37 (m, 2H), 7.21-7.16 (m, 2H), 4.65 (s, 2H), 4.32 (t, J=6.0 Hz, 2H), 3.79 (s, 3H), 3.69 (t, J=6.0H, 2H). HRMS (FT-ICR) C15H14FN3O4+H=320.1047; calculated 320.1041.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([O:24]CC)=[O:23])[CH:5]=[CH:6][CH:7]=1.[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]Br>>[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:19])([F:20])[F:21])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([OH:24])=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccccc1CBr
Reactant: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: O=C(O)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccccc2F)c1

Procedure:
The title compound was prepared from ethyl 4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinoline-3-carboxylate and 2-fluorobenzyl bromide according to the procedure of Example 41. MS (ES) m/z 439.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:10]([N+:23]([O-])=O)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]>CO.[Pd]>[NH2:23][C:10]1[C:11]([NH:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[CH:12][C:3]([O:2][CH3:1])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(NCc2ccc(OC)cc2)cc1OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)c(NCc2ccc(OC)cc2)cc1OC
Yield: 65.7 %

Procedure:
To a solution of methyl 2-methoxy-4-(4-methoxybenzylamino)-5-nitrobenzoate (544 g, 144.37 mmol) in methanol (1500 mL) was added palladium on carbon (15 g). The solution was allowed to react for 2 h at room temperature under an atmosphere of H2 (g). The solids were filtered from the resulting solution, and the filtrate was concentrated in vacuo to afford methyl 5-amino-2-methoxy-4-(4-methoxybenzylamino)benzoate as a white solid (30.0 g, 75%).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH:14]1[CH2:18][CH2:17][O:16][CH2:15]1.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][CH:28]=2)=[N:25][CH:26]=1>>[CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([NH:11][C:33](=[O:34])[C:30]3[CH:29]=[CH:28][C:27]([C:24]4[CH:23]=[CH:22][C:21]([C:20]([F:37])([F:19])[F:36])=[CH:26][N:25]=4)=[CH:32][CH:31]=3)[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH:14]1[CH2:18][CH2:17][O:16][CH2:15]1
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Reactant: Cc1c(C2CCOC2)nc2ccc([N+](=O)[O-])cn12
Product: Cc1c(C2CCOC2)nc2ccc(NC(=O)c3ccc(-c4ccc(C(F)(F)F)cn4)cc3)cn12

Procedure:
Conducting the operations similar to those of Example 1 using 3-methyl-6-nitro-2-tetrahydro-3-furanylimidazo[1,2-a]pyridine and 4-[5-(trifluoromethyl)-2-pyridyl]benzenecarboxylic acid, the title compound was obtained as white solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[C:7]1([C:13]2([CH3:20])[O:19][CH:14]2[C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO>[N:1]([C:13]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)([CH3:20])[CH:14]([OH:19])[C:15]([O:17][CH3:18])=[O:16])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)C1OC1(C)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(O)C(C)(N=[N+]=[N-])c1ccccc1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
19.5 g (300 mmol) of sodium azide and 16.0 g (300 mmol) of ammonium chloride are suspended in 400 ml of methanol and treated with 19.2 g (100 mmol) of methyl 3-phenyl-2,3-epoxybutyrate. The mixture is stirred for 9 hours under reflux and for 12 hours at room temperature, the majority of the methanol is distilled off and the residue is treated with 200 ml of water. It is then extracted with ethyl acetate, and the organic phases are dried and concentrated. The residual oil is treated with a little diethyl ether and the crystals formed are filtered off with suction.
Reaction SMILES: [C:1]1([CH:7]2[CH2:9][CH:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]1(C)[O:19]C(=O)[CH2:17][C:16](=O)[O:15]1.N1C=CC=CC=1.OS(O)(=O)=O>ClCCCl.O>[C:1]1([CH:7]2[CH2:9][CH:8]2[C:10](=[O:11])[CH2:13][C:14]([O:15][CH2:16][CH3:17])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C1CC1c1ccccc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)CC(=O)C1CC1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.9 %

Procedure:
A solution of 2-phenyl-1-cyclopropanecarboxylic acid chloride (15 g) in 1,2-dichloroethane (70 ml) is added at 0° C. to a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid, 12 g) and pyridine (13.2 g) in 1,2-dichloroethane (70 ml) and the solution is stirred at room temperature for one hour. A 2N water solution of H2SO4 (20 ml) is then added, the two layers are separated and the organic phase is washed twice with water (50 ml), dryed on Na2SO4 and evaporated in vacuum. The residue is dissolved in EtOH (150 ml), heated to the reflux temperature for two hours and evaporated to dryness to give almost pure ethyl 3-(2-phenyl-1-cyclopropyl)-3-oxo-propanoate (21 g).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.[F-].[K+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.O.CS(C)=O.[Pd](Cl)Cl>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: N#Cc1ccccc1Cl
Reactant: Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Agent: [F-]
Solvent: O
Solvent: CS(C)=O
Solvent: Cc1ccc(C)cc1
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 89.4 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 15.8 g of potassium fluoride in 50 ml of p-xylene, 40 ml of glycol and 10 ml of water were heated to 120° C. At 80° C., a mixture of 38.66 mg of palladium(II) chloride and 1.1 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 18.8 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: [C:1](OCC)(=[O:5])[C@H:2]([CH3:4])[OH:3].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[OH:3][C@@H:2]([CH3:4])[C:1]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:5]
Reactant: C1COCCN1
Reactant: CCOC(=O)[C@H](C)O
Product: C[C@H](O)C(=O)N1CCOCC1
Temperature: 80 °C
Yield: 68.7 %

Procedure:
A mixture of (S)-ethyl lactate (75 g) and morpholine (164 g) was heated at 80° C. for 64 hours. The reaction solution was concentrated and the residue was subjected to silica gel chromatography (eluent: hexane/ethyl acetate=4/1 to ethyl acetate) to give 4-[(S)-2-hydroxypropionyl]-morpholine (69.4 g) as a pale yellow oily substance. p-Toluenesulfonic acid monohydrate (0.82 g) was added to a solution of 4-[(S)-2-hydroxypropionyl]morpholine (69.4 g) in dichloromethane (300 ml), to which 3,4-dihydro-2H-pyran (40.3 g) was added dropwise at ice-bath temperature. The reaction solution was stirred at 0° C. for 30 minutes and washed with a 5% aqueous solution of sodium bicarbonate. After the organic layer was dried over anhydrous magnesium sulfate and concentrated, the residue was subjected to silica gel chromatography (eluent: hexane/ethyl acetate=8/1 to ethyl acetate) to give 4-[(2S)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (89.1 g) as a pale yellow oily substance.