Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:17](=[N:16][CH:15]=[CH:14][CH:13]=4)[N:12]([S:29]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: c1cc2[nH]cc(C3CCN4CCCC4C3)c2cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)n1cc(C2CCN3CCCC3C2)c2cccnc21

Procedure:
from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (more polar isomer) (8 mg, 0.033 mmol), 1-naphthalenesulfonyl chloride (15 mg, 0.072 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16](Br)[CH:15]=2)[CH:7]=1)[CH3:2].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:14]2[CH:15]=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=[C:18]([F:20])[CH:19]=2)=[O:22])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2cc(F)cc(Br)c2)c1
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cc(F)cc(-c3ccccc3)c2)c1
Temperature: 80 °C

Procedure:
[3-(3-Bromo-5-fluoro-benzoylamino)-phenyl]-acetic acid ethyl ester (209 mg, 0.55 mmol) was coupled to phenylboronic acid using Method E, except that the reaction mixture was heated at 80° C. The crude residue was purified by column chromatography using 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:18][C:5]2[N:6]=[C:7]([O:14][CH2:15][CH2:16][CH3:17])[N:8]([CH2:11][CH2:12][CH3:13])[C:9](=O)[C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>O1CCOCC1>[Cl:1][C:2]1[S:18][C:5]2[N:6]=[C:7]([O:14][CH2:15][CH2:16][CH3:17])[N:8]([CH2:11][CH2:12][CH3:13])[C:9](=[S:28])[C:4]=2[CH:3]=1
Reactant: CCCOc1nc2sc(Cl)cc2c(=O)n1CCC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CCCOc1nc2sc(Cl)cc2c(=S)n1CCC

Procedure:
In a sulfonation flask, a mixture of 1.15 g 6-chloro-2-propoxy-3-propyl-4-oxo-thieno[2,3-d]pyrimidine, 0.97g Lawesson reagent and 50 ml of dioxane is heated at reflux temperature for 3.5 hours. After removal of the solvent in the water jet vacuum, the residue is taken up in ethylacetate and the organic phase is washed twice with water. The organic phase is dried over sodium sulfate and the solvent removed in the water jet vacuum. The crude material is purified twice by column chromatography over silica gel (eluant: tert. butylmethylether/hexane 1:9). Yield: 0.3 g pure 6-chloro-2-propoxy-3-propyl-4thioxo-thieno[2,3-d]pyrimidine in the form of a yellow powder; m.p. 81-83° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].O.[CH:15]([C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)([CH3:17])[CH3:16]>C1COCC1>[CH:15]([C:18]1[CH:19]=[C:20]([NH:24][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[CH:21]=[CH:22][CH:23]=1)([CH3:17])[CH3:16]
Reactant: CC(C)c1cccc(N)c1
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-3-nitro-benzoyl chloride (2.00 g, 0.010 mol) in THF (30 mL), in a water bath-cooled 100 mL round bottom flask, was added 3-isopropyl-phenylamine (1.35 g, 0.010 mol) dropwise. The reaction was allowed to stir at room temperature for 1 hour before being concentrated. The mixture was taken up in EtOAc and washed with NaHCO3 (aq., conc.) and then brine. The solution was dried over MgSO4, filtered, and concentrated to yield the title compound as an orange oil that solidifies upon standing. MS m/z 299=[M+H]+. Calc'd for C17H18N2O3: 298.34.
Reaction SMILES: C([O:9][CH2:10][C:11]#[C:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)C1C=CC=CC=1.[CH3:21][NH:22][NH2:23].[OH-].[Li+]>C(O)C.O>[CH3:21][N:22]1[C:11]([CH2:10][OH:9])=[CH:12][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:23]1
Reactant: CNN
Reactant: O=C(C#CCOC(=O)c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1nc(-c2ccccc2)cc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
A solution of 4-oxo-4-phenylbut-2-yn-1-yl benzoate (1a) (750 mg, 2.84 mmol) and methylhydrazine (0.30 mL, 5.68 mmol) in ethanol (25 mL) was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue was taken in a mixture of ethanol (3 mL) and tetrahydrofuran (9 mL). Lithium hydroxide (204 mg, 8.51 mmol), previously dissolved in water (3 mL) was added and the mixture was stirred at room temperature for 2 hours. Ethanol and tetrahydrofuran were removed under reduced pressure and the resulting aqueous layer was extracted with ethyl acetate (2×5 mL). The organic layer was successively washed with a saturated solution of sodium hydrogenocarbonate (5 mL) and brine (5 mL) before being dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100/0 to 50/50) to provide (1-methyl-3-phenyl-1H-pyrazol-5-yl)methanol (1b) (341 mg, 1.81 mmol, 64%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1.[CH3:22][C:23]1[CH:32]=[C:31]([NH:33][C:34](NC2C3C(=CC=CC=3)N=C(C)C=2)=[O:35])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>C1COCC1>[CH2:15]([C:9]1([C:12]([OH:14])=[O:13])[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][NH:3][C:34]([NH:33][C:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[C:23]([CH3:22])[CH:32]=2)=[O:35])[CH2:7][CH2:8]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCCN1CCC(Cc2ccccc2)(C(=O)O)CC1
Reactant: Cc1cc(NC(=O)Nc2cc(C)nc3ccccc23)c2ccccc2n1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)NCCN2CCC(Cc3ccccc3)(C(=O)O)CC2)c2ccccc2n1

Procedure:
1-(2-Amino-ethyl)-4-benzyl-piperidine-4-carboxylic acid dihydrochloride (3.35 g, 10 mmol), 1,3-bis-(2-methyl-quinolin-4-yl)-urea (3.43 g, 10 mmol) and TEA (5 mL, 36 mmol) are suspended in THF (50 mL) and heated at reflux for 48 h. The solvent is evaporated and the residue purified by HPLC to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[CH:30]=[CH:31][N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:41])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[C:30]([Br:41])=[CH:31][N:32]=[C:20]4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nccn4cc3-c3ccccc3)cc2)CCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ncc(Br)n4cc3-c3ccccc3)cc2)CCC1
Yield: 127.2 %

Procedure:
To a solution of compound 4-1 (100 mg, 0.227 mmol) in CHCl3 (5 mL) was added NBS (40 mg 0.227 mmol.) and the mixture was heated to reflux for 2 hrs. After cooling, the mixture was diluted with 15 mL of DCM, the combined organic phase was washed with 0.1N HCl(aq) and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 150 mg of 4-3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH3:10][C:11]1([CH3:19])[CH2:16][CH2:15][CH2:14][C:13]([CH3:18])([CH3:17])[NH:12]1>CCCCCC>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([N:12]2[C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][CH2:16][C:11]2([CH3:19])[CH3:10])[N:3]=1
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: CCCCCC
Product: CC1(C)CCCC(C)(C)N1c1nc(Cl)cc(Cl)n1

Procedure:
The mixture of 25 g (136.3 mmoles) of 2,4,6-trichloropyrimidine and 46.3 ml (272.6 mmoles) of 2,2,6,6-tetramethylpiperidine is boiled under reflux for 50 hours, then cooled down and suspended in 250 ml of hexane. The insoluble material is filtered off, the filtrate is evaporated and the evaporation residue is distributed between 300 ml of chloroform and 50 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 100 ml of water each, then dried and evaporated. The evaporation residue is purified by chromatography by using hexane as eluent. After recrystallization of the obtained product from hexane, the title compound is obtained in a yield of 8.04 g (20.47%), m.p.: 89°-90° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24]>>[CH:23]([NH:26][C:27]([NH:19][NH:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)=[O:17])=[O:28])([CH3:25])[CH3:24]
Reactant: NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CC(C)N=C=O
Product: CC(C)NC(=O)NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1

Procedure:
The compound is prepared by a method analogous to that of Example 20 from N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-hydrazine carboxamide and isopropyl isocyanate. The analytical values are summarized in Table I.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[CH2:13]([C:15]1[S:19][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[N:17][C:16]=1[CH2:30][CH2:31]OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:31][CH2:30][C:16]2[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[S:19][C:15]=2[CH2:13][CH3:14])[CH:6]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: CCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCOc1cccc(CC(=O)OC)c1
Temperature: 25 °C
Yield: 32.7 %

Procedure:
(3-Hydroxy-phenyl)-acetic acid methyl ester (166 mg, 1.0 mmol) is dissolved into anhydrous acetonitrile (ACN) (5 mL). Toluene-4-sulfonic acid 2-[5-ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethyl ester (432 mg, 0.950 mmol) is added to the reaction, followed by the addition of cesium carbonate (652 mg, 2.00 mmol). The reaction is allowed to stir under nitrogen at room temperature and monitored by TLC and HPLC. Upon complete consumption of the tosylate, the reaction is diluted with diethyl ether and quenched with 0.1N NaOH. The two phases are separated, then the organic layer washed with water and brine. The organic phase is dried over anhydrous sodium sulfate and concentrated under vacuum. The residue is further purified using either EtOAc/Hexanes (1:9) or Acetone/Hexanes (1:9) gradients on silica gel chromatography to yield (3-{2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-acetic acid methyl ester (140 mg, 0.311 mmol) or 33%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[CH:4][CH:3]=1.C[Si]([C:13]#[N:14])(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:13]#[N:14])[CH:3]=1
Reactant: [O-][n+]1ccc(Cl)cc1
Reactant: C[Si](C)(C)C#N
Product: N#Cc1cc(Cl)ccn1
Yield: 92 %

Procedure:
The general procedure of Referential Example 15 was repeated through use of 4-chloropyridine-N-oxide (6.00 g) and trimethylsilyl cyanide (17.5 mL), to thereby give the title compound as a solid (5.89 g, 92%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:11]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:12]1[O:14][CH2:13]1>CS(C)=O>[OH:14][CH:12]([CH2:11][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:13][NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: NCCc1ccc(O)cc1
Solvent: CS(C)=O
Product: Oc1ccc(CCNCC(O)COc2ccccc2)cc1
Yield: 50.1 %

Procedure:
A mixture of 4.0 g of tyramine and 5.25 g of phenyl glycidyl ether in 100 ml of dimethylsulfoxide was heated to 100° for 17 hours. The solvent was evaporated in vacuo and the residue was chromatographed on 400 g of silica gel. 4.3 g of p-[2-[bis[(RS)-2-hydroxy-3-phenoxypropyl]amino]ethyl]phenol was firstly eluted with chloroform/npropanol/concentrated ammonia (1000:10:1) as an amorphous substance, ε218 =20710. The further fractions yielded 4.2 g of pure (RS)-p-[2-[(2-hydroxy-3-phenoxypropyl) amino]ethyl]phenol of m.p. 122°-124°, ε221 =15310.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)([OH:3])=[O:2].[C:14]1([CH3:24])[CH:19]=CC(S(Cl)(=O)=O)=C[CH:15]=1.C(O)(C)(C)C>N1C=CC=CC=1>[C:14]([O:2][C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3])([CH3:24])([CH3:19])[CH3:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)c1ccc2c(c1)COC2=O
Solvent: c1ccncc1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1ccc2c(c1)COC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Carboxyphthalid (100 g, 0.56 mole) is suspended in pyridine (1200 mL). p-toluenesulfonyl chloride (211 g, 1.12 mole) is added and the mixture is stirred for 30 minutes at room temperature. Tert.Butanol (54 g, 0.73 mole) is added and the reaction mixture is left at room temperature with efficient stirring for 3 days. The clear solution is poured into ice water and the precipitated crystals are filtered off. The product is recrystallized from 2-propanol (500 mL). Yield: 123 g, 94%. DSC onset: 151.5° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].[I-].C([N+]1(C)[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1)C>C(O)C.O>[O:31]=[C:28]1[CH2:29][CH2:30][N:1]([CH2:2][C:3]2([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)C1(CN)CCOCC1
Reactant: CC[N+]1(C)CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)C1(CN2CCC(=O)CC2)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a refluxing mixture of tert-butyl 4-(aminomethyl)tetrahydro-2H-pyran-4-carboxylate (8.00 g, 0.0372 mol, step 2) and K2CO3 (0.51 g, 0.0372 mol) in EtOH—H2O (2:1, 240 mL) was added dropwise 1-ethyl-1-methyl-4-oxopiperidinium iodide (12.0 g, 0.0445 mol, J. Org. Chem. 1995, 60, 4324-4330) in EtOH—H2O (2:1, 150 mL), and the resulting mixture was stirred at the same temperature (reflux) for 1 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was poured into sat. NaHCO3 aq. (200 mL), and the mixture was extracted with CH2Cl2 (200 mL×three times). The extracts were dried over Na2SO4 and concentrated. The residue was chromatographed on a column of silica gel eluting with hexane/ethyl acetate (3:1 to 2:1) to give 10.77 g (98%) of the title compound as a colorless syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[OH-].[NH4+:18]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH2:18])=[O:10])[CH2:6]1
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)cc2Cl)C1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)N1CC(Oc2ccc(Cl)cc2Cl)C1
Reaction time: 5 h
Yield: 87.9 %

Procedure:
A stirred solution of 4.8 g (0.017 mole) of 3-(2,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated with 3.0 mL (0.05 mole) of 57% ammonium hydroxide. After stirring for 5 h, the reaction mixture was diluted with 200 mL of water and the precipitated solid collected by filtration (4.1 g). The crude product was recrystallized from acetonitrile/water to yield 3.9 g (87.9%) of white crystals, mp 169°-170° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[NH2:20][NH2:21]>C(O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:4]2[CH:5]([C:6]3[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=3)[NH:21][NH:20][C:3]2=[O:2])=[CH:13][CH:14]=1
Reactant: NN
Reactant: COC(=O)C(=Cc1ccncc1)c1ccc(Cl)cc1
Solvent: CCO
Product: O=C1NNC(c2ccncc2)C1c1ccc(Cl)cc1
Temperature: 50 °C

Procedure:
To a solution of 2-(4-Chloro-phenyl)-3-pyridin-4-yl-acrylic acid methyl ester 2.02 g in ethyl alcohol 25 mL was added hydrazine 2.37 g. The reaction was heated to 50° C. for 135 minutes. All solvent was removed after under reduced pressure to afford the title compound as light yellow solid. MS (ES+): 274 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][C:5]1([NH:8][C:9]([C:11]2[C:12]([OH:41])=[C:13]3[C:18](=[C:19]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[N:20]=2)[N:17]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:16](=[O:34])[C:15]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:14]3)=[O:10])[CH2:7][CH2:6]1.[OH-].[Na+].CO.C1COCC1>C([O-])(O)=O.[Na+]>[CH2:27]([N:17]1[C:18]2[C:13](=[C:12]([OH:41])[C:11]([C:9]([NH:8][C:5]3([CH2:4][C:3]([OH:42])=[O:2])[CH2:6][CH2:7]3)=[O:10])=[N:20][C:19]=2[C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:14]=[C:15]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:16]1=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)CC1(NC(=O)c2nc(-c3cccnc3)c3c(cc(-c4ccccc4)c(=O)n3Cc3ccccc3)c2O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC1(NC(=O)c2nc(-c3cccnc3)c3c(cc(-c4ccccc4)c(=O)n3Cc3ccccc3)c2O)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.3 %

Procedure:
A mixture of {1-[(1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carbonyl)-amino]-cyclopropyl}-acetic acid methyl ester (5 mg, 0.0089 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 2 days, then concentrated to approximately one-third of its original volume. 1 M HCl was added until pH was about 3, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-90% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting suspension was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated to give 2.3 mg of the title compound as a yellow solid. MS: (+) m/z 547.35 (M+1).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C([N:25]([CH:28]([CH3:30])[CH3:29])CC)(C)C>C(O)CCC>[OH:19][CH:15]1[CH2:16][CH2:29][CH:28]([NH:25][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:21])[C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:30][CH2:14]1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cccc(C(=O)Nc2nc3cccc(Br)n3n2)c1
Solvent: CCCCO
Product: COc1cccc(C(=O)Nc2nc3cccc(NC4CCC(O)CC4)n3n2)c1
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
A sealed vessel containing N-(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-3-methoxybenzamide (69 mg, 0.20 mmol, 1 mol eq.), trans-aminocyclohexanol (35 mg, 0.30 mmol, 1.5 mol eq.), di-iso-propylethylamine (60 μL, 0.32 mmol, 1.6 mol eq.) and n-butanol (0.75 mL) was irradiated at 220° C., with stirring, for 20 minutes. The solvent was removed in vacuo and the residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give the title compound as a beige solid (27.5 mg, 36%). HPLC, Rt: 1.86 min (purity: 100%). LC/MS M+(ESI): 382.3, M−(ESI) 380.3.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[N:4]([CH3:8])[C:3]1=[NH:9].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[N:18]=[C:19]=[O:20]>O1CCCC1>[CH3:1][N:2]1[CH2:6][C:5](=[O:7])[N:4]([CH3:8])[C:3]1=[N:9][C:19]([NH:18][C:12]1[C:11]([CH3:10])=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:17])=[O:20]
Reactant: CN1CC(=O)N(C)C1=N
Reactant: Cc1cccc(C)c1N=C=O
Solvent: C1CCOC1
Product: Cc1cccc(C)c1NC(=O)N=C1N(C)CC(=O)N1C

Procedure:
A mixture of 6.35 g (0.050 mole) of 1,3-dimethyl-2-iminoimidazolidin-4-one and 7.25 g (0.050 mole) of 2,6-dimethylphenylisocyanate in 75 ml. of dry tetrahydrofuran is stirred at room temperature for two hours followed by refluxing it for thirty minutes. The reaction mixture is evaporated in vacuo to give a solid, which is crystallized from tetrahydrofuran-ether. Two more recrystallizations from the same solvent mixture gives pure product, 1-(1,3-dimethyl-4-oxo-2-imidazolidinylidene)-3-(2,6-dimethylphenyl) urea; m.p. 115.5°-118.5°C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:38]([O:45][C:46]1[CH:47]=[N:48][C:49]([CH2:52]Cl)=[CH:50][CH:51]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:52][C:49]2[CH:50]=[CH:51][C:46]([O:45][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:47][N:48]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: ClCc1ccc(OCc2ccccc2)cn1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccc(OCc4ccccc4)cn3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 73.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 3-(benzyloxy)-6-(chloromethyl)pyridine (0.81 g) as starting materials, 5-benzyloxy-N-({1-[(5-(benzyloxy)pyridin-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.75 g) was obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:9]=[C:10]([CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[C:11]([C:13]1[O:14][C:15]2[C:20]([C:21](=[O:23])[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12].[Br:29][CH2:30][CH2:31][CH2:32]Br>CN(C)C=O>[Br:29][CH2:30][CH2:31][CH2:32][O:27][C:26]1[C:25]([CH3:28])=[CH:24][C:10]([C:11]([C:13]2[O:14][C:15]3[C:20]([C:21](=[O:23])[CH:22]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])=[CH:9][C:8]=1[CH3:7]
Reactant: BrCCCBr
Reactant: Cc1cc(C(=O)c2cc(=O)c3ccccc3o2)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(=O)c3ccccc3o2)cc(C)c1OCCCBr
Reaction time: 15 h

Procedure:
27.6 g (0.2 mol) of potassium carbonate was added to a solution of 29.4 g (0.1 mol) of 2-(3,5-dimethyl 4-hydroxy benzoyl) chromone in 150 ml of dimethyl formamide, 101 g (0.5 mol) of 1,3-dibromo propane was added and the admixture left at ambient temperature for 15 hours with constant agitation. The potassium bromide precipitate was filtered, the dimethyl formamide was concentrated in vacuo and the residue dissolved in 300 ml of water. Extraction was effected with 200 ml of methylene chloride, and precipitation was then effected by adding 200 ml of ether. The product was 36 g of 2-[4-(3-bromo propoxy) 3,5-dimethyl benzoyl] chromone.