Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:14]1([NH:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Yield: 97.5 %

Procedure:
50 g (0.247 mol) of 1-chloro-2,4-dinitrobenzene, 73.5 g (0.74 mol) of cyclohexylamine, 68 g (0.5 mol) of potassium carbonate and 20 ml of water were heated in 400 ml of dimethylformamide at 80°-90° C. for 3 h. The mixture was then concentrated under reduced pressure, and the residue was partitioned between water and ethyl acetate. The organic phase was dried and concentrated under reduced pressure to yield 63.9 g (98%) of the product. Melting point 155° C.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][P:7]([CH2:27][NH2:28])([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[N+:29]([C:32]1[CH:42]=[CH:41][CH:40]=[C:34]2[C:35]([O:37][C:38](=O)[C:33]=12)=[O:36])([O-:31])=[O:30]>>[CH3:5][O:6][P:7]([CH2:9][CH:10]([C:15](=[O:26])[NH:16][CH:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])([CH2:27][N:28]1[C:38](=[O:37])[C:33]2=[C:32]([N+:29]([O-:31])=[O:30])[CH:42]=[CH:41][CH:40]=[C:34]2[C:35]1=[O:36])=[O:8]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN)OC
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: CC(=O)O
Product: CNC(=O)C(CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN1C(=O)c2cccc([N+](=O)[O-])c2C1=O)OC
Yield: 35.9 %

Procedure:
In a manner analogous to that described in Example 3(A), from 0.23 g of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester acetate and 0.105 g of 3-nitrophthalic anhydride, there was obtained 0.105 g of [4-methyl-2-[[3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl][(3-nitrophthalimido)methyl]phosphinic acid methyl ester in the form of a pale yellow foam.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].[Br:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]Br)=[CH:28][CH:27]=1>C(C(C)=O)C>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][Br:23])=[CH:27][CH:28]=2)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]
Reactant: BrCCc1ccc(CBr)cc1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCc1c(OCc2ccc(CCBr)cc2)ccc(C(C)=O)c1O

Procedure:
To a solution of 1-(2,4-dihydroxy-3-propylphenyl)ethanone (10.0 g; 0.051 m) in dry methyl ethyl ketone (100 ml) was added dried anhydrous sodium carbonate (27 g; 5 mol eq) and sodium iodide (0.5 g). To the stirred suspension was added 4-(2-bromoethyl)phenylmethylbromide (14.2 g; 0.051 m) (literature preparation) and the suspension gently heated at reflux overnight. The cooled suspension was evaporated under reduced pressure, the residue taken up in water and extracted with dichloromethane (×2). The organic extract was washed with aqueous sodium hydroxide (2N), then water, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a yellow oil. The oil was chromatographed on a U30 Sorbsil column using dichloromethane to give a pale yellow oil which crystallised on standing to a white crystalline solid; recrystallised from ethanol m.p. 66°-70° C.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:10](Cl)(=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14]>C(OCC)C>[CH2:1]([N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(=O)Cl
Reactant: CCCCNCCCC
Solvent: CCOCC
Product: CCCCC(=O)N(CCCC)CCCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
a round-bottom flask containing a magnetic stirring bar, diethyl ether (400 mL) and N,N-dibutylamine (37 mL, 0.22 mol, 2.2 equiv.) was cooled in ice for 30 minutes. Valeroyl chloride (12.0 mL, 0.099 mol, 1.0 equiv.) was combined with diethyl ether (75 mL) and added dropwise over 30 minutes to the stirring dibutylamine solution on ice. A white precipitate, likely the amine's chloride salt, was observed. The flask was removed from ice and stirred at room temperature for 3 h. Two 500 mL extractions were performed with dilute HCl (10 mL conc. HCl per 500 mL extraction) to remove the excess amine and ammonium chloride byproduct. The diethyl ether layer was retained and dried with MgSO4. Diethyl ether was removed under rotary evaporation and high vacuum, leaving crude N,N-dibutylpentanamide.
Reaction SMILES: [BH4-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[OH:12])[CH:7]=[O:8].Cl>O>[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[OH:12])[CH2:7][OH:8]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(CO)cc(O)c1O
Temperature: 25 °C

Procedure:
To a solution containing 6.0 g of sodium borohydride in 50 ml of water 9.15 g of 3,4-dihydroxy-5-nitrobenzaldehyde was gradually added with stirring at room temperature. The mixture was stirred for 1 h more after which it was acidified with hydrochloric acid. The solution was filtered to remove tarry impurities and extracted 4 times with ether. The ether extract was dried over anhydrous sodium sulfate, filtered and concentrated to a volyme of about 100 ml.
Reaction SMILES: [Mg].BrCCBr.Br[CH:7]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:8]([O:10][C@H:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][C:13]([O:15]C)=O)=[O:9]>C1COCC1>[CH2:28]([C:7]1[C:8](=[O:9])[O:10][C@H:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][C:13]=1[OH:15])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCC[C@H](CC(=O)OC)OC(=O)C(Br)CCCCCC
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CCCCCCCCCCC[C@@H]1CC(O)=C(CCCCCC)C(=O)O1
Temperature: 80 °C
Reaction time: 14 h
Yield: 45 %

Procedure:
To a 1-L, 3-necked, round-bottomed flask fitted with a Claisen adapter with N2 inlet, a West condenser and a thermocouple-J-KEM controller and a rubber septum was added 13.9 g (0.572 g-atom, 3.2 equiv.) of magnesium (from Chromasco) was added. A small flake of 12 (about 45 mg) was added and the mixture was heated to about 80° C. 1,2-Dibromoethane (3.4 g, 18 mmol) and 350 mL of THF were added to the hot Mg/I2 mixture to activate the metal surface. Methyl (3R)-3-[(2-bromo-1-oxooctyl)oxy]-tetradecanoate (82.9 g, 179 mmol) from Example 2, 1,2-dibromoethane (33.6 g, 179 mmol) and 400 mL of THF were added to the addition funnel. This mixture was slowly added to the Mg/THF mixture at reflux over about 1 h. The reaction mixture was stirred overnight (14 h) at about 60° C. The resulting yellow solution was decanted away from the metal into a 1-L, round-bottomed flask. The residual Mg metal was rinsed twice with 60 mL of THF. The combined THF solution was concentrated on a rotary evaporator. The syrupy mixture was taken up in 1750 mL of methylene chloride and added to a mixture of 500 mL of water, 200 mL of ice and 98 mL of 10% HCl in a separatory funnel. The aqueous layer was removed, the organic layer washed once with 200 mL of saturated sodium chloride, dried (NaSO4), filtered, and the solvent removed on a rotary evaporator. The crude white solid (66.7 g) was slurried in 100 mL of hexane, cooled to 0° C., filtered, and rinsed twice with 50 mL of cold hexane. The isolated white solid was dried in an oven at 40° C. under reduced pressure (10 mm Hg) overnight resulting in 28.4 g of (6R)-3-hexyl-4-hydroxy-6-undecyl-5,6-dihydropyran-2-one (45-50% yield based on methyl (R)-3-hydroxytetradecanoate).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH:10]=2)O1.Br[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1.C(Cl)Cl>COCCOC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[O:13]1[C:12]2([CH2:17][CH2:18][C:9]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=3)=[CH:10][CH2:11]2)[O:16][CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C2=CCC3(CC2)OCCO3)nc1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dioxaspiro[4.5]dec-7-ene prepared as above (8.40 g, 31.56 mmol), 2-bromo-5-nitropyridine (6.0 g, 29.55 mmol) in DME (200 mL), degassed 2M potassium carbonate (40 mL) was added palladium tetrakis(triphenylphosphine) (Pd(PPh3)4; 1.8 g, 1.58 mmol). The reaction mixture was evacuated with nitrogen (3 cycles) and allowed to stir under vacuum for 5 minutes, then heated to 80° C. overnight. The reaction mixture was allowed to cool to ambient temperature, EtOAc (200 mL) was added followed by water (200 mL), the suspension was filtered and the organic phase was separated and the aqueous layer re-extracted into EtOAc (200 mL). The organic extracts were combined, washed with brine (200 mL), dried (MgSO4) and concentrated to leave crude product. DCM was added and the suspension was filtered and dried to leave the title compound (1.64 g). The filtrate was concentrated after the addition of DCM a further 1.51 g of product was obtained, the filtrate was purified on a 120 g SiliCycle cartridge eluting 20-50-70% EtOAc in isohexane to provide 1.72 g of product. Total yield is 4.85 g (18.51 mmol, 58%);
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([CH3:12])[C:9]=1[C:10]#[N:11])(=[O:3])[CH3:2].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:16]([O:15][C:13]([C:7]1[S:6][C:5]2[N:4]([C:1](=[O:3])[CH3:2])[C:19]([C:20](=[O:21])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:10]([NH2:11])[C:9]=2[C:8]=1[CH3:12])=[O:14])[CH3:17]
Reactant: CCOC(=O)c1sc(NC(C)=O)c(C#N)c1C
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1sc2c(c1C)c(N)c(C(=O)c1ccccc1)n2C(C)=O
Yield: 80.4 %

Procedure:
250 g of 2-acetamido-3-cyano-4-methyl-5-ethoxycarbonylthiophene, prepared in accordance with the method of K. Gewald, are refluxed for 24 hours in 1500 ml of acetone with 250 g of α-bromoacetophenone and 220 g of potassium carbonate; the whole is then precipitated in 4000 ml of ice-water. The resulting precipitate is filtered, washed with 1000 ml of an iced mixture of water/ethanol (1/1), then dried and finally washed with 1000 ml of a cold mixture of cyclohexane/benzene (9/1). In this manner 295 g of 2-ethoxycarbonyl-3-methyl-4-amino-5-benzoyl-6-acetylthieno[2,3-b]pyrrole are obtained, m.p.: 188° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]2[O:11][CH2:12][C:13]3[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=3[CH:15]([C:16]([OH:18])=O)[C:9]=2[CH:8]=[C:7]([CH3:23])[CH:6]=1)=[O:4].[CH:24]([C:27]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:36])[CH3:35])[C:28]=1[NH2:29])([CH3:26])[CH3:25]>>[CH:34]([C:30]1[CH:31]=[CH:32][CH:33]=[C:27]([CH:24]([CH3:26])[CH3:25])[C:28]=1[NH:29][C:16]([CH:15]1[C:14]2[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=2[CH2:12][O:11][C:10]2[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]([CH3:23])=[CH:8][C:9]1=2)=[O:18])([CH3:36])[CH3:35]
Reactant: COC(=O)c1cc(C)cc2c1OCc1ccccc1C2C(=O)O
Reactant: CC(C)c1cccc(C(C)C)c1N
Product: COC(=O)c1cc(C)cc2c1OCc1ccccc1C2C(=O)Nc1c(C(C)C)cccc1C(C)C
Yield: 8.5 %

Procedure:
The similar procedures as in Example 1 were repeated except using 6.73 g of 6,11-dihydro-4-methoxycarbonyl-2-methyldibenz[b,e]oxepin-11-carboxylic acid obtained in Example 65 (Compound AD) in place of Compound A and 3.82 g of 2,6-diisopropylaniline in place of aniline to obtain 0.86 g of Compound 51.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([CH:18]([O:23][CH2:24][C:25]3([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[C:19](OC)=[O:20])[CH:17]=1)[NH:14][N:13]=[CH:12]2.ClC1C=C2C(=C(C(OCC3(C4C=CC(F)=CC=4)CCN(C(OC(C)(C)C)=O)CC3)CO)C=1)NN=C2>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([CH:18]([O:23][CH2:24][C:25]3([C:32]4[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=4)[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]3)[CH2:19][OH:20])[CH:17]=1)[NH:14][N:13]=[CH:12]2
Reactant: COC(=O)C(OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(Cl)cc2cn[nH]c12
Agent: CC(C)(C)OC(=O)N1CCC(COC(CO)c2cc(Cl)cc3cn[nH]c23)(c2ccc(F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(COC(CO)c2cc(Cl)cc3cn[nH]c23)(c2ccc(F)cc2)CC1

Procedure:
Prepared according to the procedure used to prepare methyl 2-(5-chloro-1H-indazol-7-yl)-2-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)acetate trifluoroacetic acid salt using tert-butyl 4-((1-(5-chloro-1H-indazol-7-yl)-2-hydroxyethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate as the starting material. 1H-NMR (CD3OD, 500 MHz) 6 8.05 (m, 1H), 7.73 (m, 1H), 7.40 (m, 2H), 6.85-7.20 (m, 3H), 4.65 (m, 1H), 3.77 (m, 1.6H), 3.49 (m, 3.8H), 2.40-3.00 (m, 7H), 2.13 (m, 2H). Mass spec.: 418.24 (MH)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[N:5][N:4]=[N:3]1.[NH2:16][C:17]([NH2:19])=[S:18].[OH-].[Na+]>ClCCCl.CCOCC>[CH3:1][N:2]1[C:6]([C:7]2[S:18][C:17]([NH2:19])=[N:16][C:8]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][N:4]=[N:3]1
Reactant: NC(N)=S
Reactant: Cn1nnnc1CC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCCl
Product: Cn1nnnc1-c1sc(N)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
2-(1-Methyl-1H-tetrazol-5-yl)-1-phenyl-ethanone (4.9 g, 24.2 mmol) was dissolved in 1,2-dichloroethane (150 mL) and ether (100 mL). Brom (1.24 mL, 24.2 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. the solvent was removed in vacuo. The remenance was dissolved in ethanol (250 mL). Thiourea (3.67 g, 48.5 mmol) was added and the reaction mixture was heated at reflux for 20 min. The reaction mixture was poured into water/ice. Concentrated NaOH (aq) was added until pH=10. The mixture was filtered and the solid product was recrystallised from ethylacetate/hexane. Yield: 58%.
Reaction SMILES: [CH:1](NC1CCCCC1)(C)C.[CH3:11][C:12]([CH3:26])=[C:13]([N:18]1[C@H:21]([CH2:22][CH:23]=[CH2:24])[CH2:20][C:19]1=[O:25])[C:14]([O:16][CH3:17])=[O:15].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:11][C:12]([CH3:26])=[C:13]([N:18]1[C@H:21]([CH2:22][CH:23]=[CH2:24])[C@H:20]([CH3:1])[C:19]1=[O:25])[C:14]([O:16][CH3:17])=[O:15]
Reactant: CC(C)NC1CCCCC1
Reactant: C=CC[C@@H]1CC(=O)N1C(C(=O)OC)=C(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC[C@@H]1[C@H](C)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
1.55 M Butyl lithium-hexane solution (1.66 ml) was added to a solution of N-isopropylcyclohexylamine (0.29 ml) in tetrahydrofuran (3 ml) at -70° C., and the mixture was stirred for 20 minutes at -70° C. and allowed to warm up to 0° C. This mixture was added to a solution of methyl 3-methyl-2-[(4R)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (100 mg) in tetrahydrofuran (3 ml) at -70° C., and the mixture was stirred for 1 hour at -70° C. and allowed to warm up to -30° C. during 30 minutes. 1 N Hydrochloric acid (3.6 ml) was added to the reaction mixture at -70° C., and the mixture was diluted with ethyl acetate (30 ml). The solution was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (5:1-2:1) to give methyl 3-methyl-2-[(3S,4R)-3-methyl-2-oxo-4-allylazetidin-1-yl]but-2-enoate (20 mg); IR (CH2Cl2): 1740, 1715 cm-1 ; NMR (CDCl3) δ: 1.23 (d, 3H, J=8 Hz), 1.95 (s, 3H), 2.19 (s, 3H), 1.36 (t, 2H, J=7 Hz), 3.36 (dq, 1H, J=6, 8 Hz), 3.75 (s, 3H), 4.04 (dt, 1H, J=6, 7 Hz), 4.9-5.2 (m, 2H), 5.4-5.9 (m, 2H); and methyl 3-methyl-2-[(3R,4R)-3-methyl-2-oxo-4-allylazetidin-1-yl]but-3-enoate (28 mg); IR (CH2Cl2): 1740 cm-1 ; NMR (CDCl3) δ: 1.27 and 1.29 (a pair of d, 3H, J=8 Hz), 1.83 (broad s, 3H), 2.1-2.9 (m, 2H), 2.85 (dq, 1H, J=2, 8 Hz), 3.2-3.4 (m, 1H), 3.74 and 3.76 (a pair of s, 3H), 4.8-5.2 (m, 5H), 5.5-6.0 (m, 1H); and a mixture of methyl 3-methyl-2-[(3R,4R)-3-methyl-2-oxo- 4-allylazetidin-1-yl]but-2-enoate and methyl 3-methyl-2-[(3S,4R)-3-methyl-2-oxo-4-allylazetidin-1-yl]but-3-enoate (36 mg): IR (CH2Cl2): 1740 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.[Cl:20]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][C:19]=1[Cl:20])[CH2:16][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Nc1cc2c(cc1Cl)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.50 g (2.0 mmol) 5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one in 20 ml DCM were combined with 0.27 g (2 mmol) N-chlorosuccinimide versetzt and stirred for 5 h at RT. The mixture was evaporated down and the residue was purified by HPLC.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:48]([O:50][C:51](=[O:54])[CH2:52][NH2:53])[CH3:49]>CN(C=O)C.O>[CH2:48]([O:50][C:51](=[O:54])[CH2:52][NH:53][C:7]([C:4]1[CH:3]=[CH:2][C:1]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:9])[CH3:49]
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a stirred solution of biphenyl-4-carboxylic acid (10 g, 0.05044 mole) in DMF (50 mL), was added DIPEA (22.82 g, 0.176 mol), HOBt (7.496 g, 0.0554 mol) and EDCI.HCl (17.4 g, 0.09 mol) at ambient temperature. After 2 minutes glycine ethyl ester hydrochloride (8.45 g, 0.06 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was diluted with cold water and the resulting precipitate was isolated by filtration and dried to afford 14.26 g (99.8%) of [(biphenyl-4-carbonyl)-amino]-acetic acid ethyl ester. 1H NMR (DMSO-d6): δ9.0 (t, 1H), 8.0-7.9 (d, 2H), 7.84-7.7 (dd, 4H), 7.5 (t, 2H), 7.46-7.36 (m, 1H), 4.2-4.1 (q, 2H), 4.0 (d, 2H), 1.25 (t, 3H). To a stirred solution of [(biphenyl-4-carbonyl)-amino]-acetic acid ethyl ester (14.26 g, 0.05 mol) in a mixture of THF (60 mL), methanol (60 mL) and H2O (30 mL) was added LiOH.H2O (12.68 g, 0.3023 mol) and the resulting mixture was stirred at ambient temperature for 1 hour. The volatiles were then evaporated and the residue was acidified with 10% aqueous HCl solution. The resulting precipitate was isolated by filtration washed with water followed by hexane and dried to afford 12.8 g (99%) of [(biphenyl-4-carbonyl)-amino]-acetic acid. 1H NMR (DMSO-d6): δ 8.0-7.85 (m, 3H), 7.8-7.7 (m, 4H), 7.55-7.45 (t, 2H), 7.45-7.35 (t, 1H), 3.5 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:16]1[N:21]=[C:20](SC#N)[C:19]([N+:25]([O-:27])=[O:26])=[CH:18][N:17]=1.[NH2:34][CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(N(CC)C(C)C)(C)C>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:16]1[N:21]=[C:20]([NH:34][CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[C:19]([N+:25]([O-:27])=[O:26])=[CH:18][N:17]=1
Reactant: NC1CCOCC1
Reactant: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc([N+](=O)[O-])c(SC#N)n2)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc([N+](=O)[O-])c(NC3CCOCC3)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
To the suspension of 0.92 g (2.0 mmol) of 4-(2,4-dimethoxybenzylamino)-3-(5-nitro-4-thiocyanatopyrimidin-2-ylamino)benzonitrile in 40 mL anhydrous THF was added 0.22 g (2.2 mmol) 4-amino-tetrahydropyran, then 0.7 mL (4.0 mmol) N,N-diisopropylethylamine. The mixture was stirred at room temperature under Argon balloon for 16 hrs till HPLC showed the completion of reaction. The mixture became clear then. The orange-red solution was diluted with EtOAc, washed with brine twice, and then dried over Na2SO4. Solvents were removed under vacuum to give 1.0 g orange-yellow solid as the crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:56]=[CH:55][CH:54]=[CH:53][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40][CH2:41]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[NH:57]1[CH:61]=[CH:60][N:59]=[CH:58]1>>[N:57]1([CH2:41][CH2:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[O:33][CH2:32][CH2:31][O:30][CH:18]2[CH:17]([C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]4[CH:53]=[CH:54][CH:55]=[CH:56][C:3]=4[O:2][CH3:1])=[CH:16][CH:15]=3)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:19]2)[CH:61]=[CH:60][N:59]=[CH:58]1
Reactant: c1c[nH]cn1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCn2ccnc2)cc1

Procedure:
Analogously to Example 27a, 0.20 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-(2-{2-[2-(toluene-4-sulphonyloxy)ethyl]phenoxy}ethoxy)piperidine-1-carboxylate (Example 26b) and 0.34 g of 1H-imidazole are reacted. The title compound is obtained as a colourless oil. Rf=0.55 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=5.37.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]=[C:9]=[O:10].[CH2:11]([C:13]1[C:14]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=2[C:29]([F:32])([F:31])[F:30])=[N:15][NH:16][C:17]=1[CH3:18])[CH3:12].Cl>C(OCC)(=O)C>[CH3:7][NH:8][C:9]([N:16]1[C:17]([CH3:18])=[C:13]([CH2:11][CH3:12])[C:14]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=2[C:29]([F:30])([F:31])[F:32])=[N:15]1)=[O:10]
Reactant: CN=C=O
Reactant: CCc1c(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)n[nH]c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCc1c(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)nn(C(=O)NC)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
Potassium carbonate (0.50 g, 3.6 mmol) and methyl isocyanate (0.17 g, 3.0 mmol) were added to a solution of 4-ethyl-5-methyl-3-(4-nitro-2-trifluoromethylphenyloxy)pyrazole (1.13 g, 3.6 mmol) in ethyl acetate (15 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with diethyl ether (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/3), to give a yellow solid of N-methyl-4-ethyl-5-methyl-3-(4-nitro-2-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.71 g, yield: 63.6%). mp: 96-97° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.08 (t, J=7.6 Hz, 3H), 2.35 (q, J=7.6 Hz, 2H), 2.59 (s, 3H), 2.94 (d, J=5.0 Hz, 3H), 6.70-6.90 (m, 1H), 7.48 (d, J=9.2 Hz, 1H), 8.40 (dd, J=2.7 and 9.2 Hz, 1H), 8.60 (d, J=2.7 Hz, 1H).