Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([CH3:18])[CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]1[C:25]([CH2:26]O)=[CH:24][C:23]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)=[N:22]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([CH3:18])[CH:13]=[C:14]([O:17][CH2:26][C:25]3[N:21]([CH3:20])[N:22]=[C:23]([C:28]4[CH:29]=[CH:30][C:31]([O:34][C:35]([F:37])([F:36])[F:38])=[CH:32][CH:33]=4)[CH:24]=3)[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CO
Reactant: Cc1cc(O)cc2c1ccn2CC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: Cc1cc(OCc2cc(-c3ccc(OC(F)(F)F)cc3)nn2C)cc2c1ccn2CC(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-4-methyl-indol-1-yl)-acetic acid tert-butyl ester was reacted with [2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {4-methyl-6-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester as colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:32])[NH:11][C:12]1[N:16]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:18]=2)[N:15]=[C:14]([C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[CH:13]=1.[CH2:33]1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO.O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:32])[NH:11][C:12]1[N:16]([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][C:24]([O:26][CH3:33])=[O:25])=[CH:21][CH:22]=2)[N:15]=[C:14]([C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[CH:13]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)Cc1ccc(-n2nc(-c3ccsc3)cc2NC(=O)Nc2cccc(Cl)c2Cl)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC(=O)Cc1ccc(-n2nc(-c3ccsc3)cc2NC(=O)Nc2cccc(Cl)c2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(4-(5-(3-(2,3-dichlorophenyl)ureido)-3-(thiophen-3-yl)-1H-pyrazol-1-yl)phenyl)acetic acid (0.073 g, 0.15 mmol) in DMF (1 ml) were added PyBop (0.18 mmol) and MeOH (0.1 g, 0.45 mmol) and stirred for 4 h at RT. The reaction mixture was poured into cold H2O and the product was extracted with EtOAc (3×20 ml). The combined organic extracts were washed with 3M HCl, brine, dried (Na2SO4) and concentrated to yield a crude product. To the crude product was added CH2Cl2 (2 ml) and stirred for 10 min and the resultant solid was filtered and dried to afford pure methyl 2-(4-(5-(3-(2,3-dichlorophenyl)ureido)-3-(thiophen-3-yl)-1H-pyrazol-1-yl)phenyl)acetate. 1H NMR (400 MHz, DMSO-d6): δ 9.40 (s, 1H), 8.87 (s, 1H), 8.10 (dd, J=6.8 Hz, 2.4 Hz, 1H), 7.87-7.86 (m, 1H), 7.60 (dd, J=4.8 Hz, 2.8 Hz, 1H), 7.57 (d, J=8.0 Hz, 2H), 7.52-7.49 (m, 1H), 7.48 (d, J=8.0 Hz, 2H), 7.34-7.32 (m, 2H), 6.85 (s, 1H), 3.80 (s, 2H), 3.65 (s, 3H); MS (ESI) m/z: 501.0 (M+H+).
Reaction SMILES: [CH3:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]2[C:16]([CH3:21])=[CH:17][C:18]([CH3:20])=[CH:19][C:5]=2[NH:4][C:3]1=S.[C:23]([NH:26][NH2:27])(=O)[CH3:24]>C(O)C>[CH3:24][C:23]1[N:4]2[C:5]3[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:6]=3[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])=[N:8][CH:2]([CH3:1])[C:3]2=[N:27][N:26]=1
Reactant: CC(=O)NN
Reactant: Cc1cc(C)c2c(c1)NC(=S)C(C)N=C2c1ccccc1Cl
Solvent: CCO
Product: Cc1cc(C)c2c(c1)-n1c(C)nnc1C(C)N=C2c1ccccc1Cl
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 3,6,8-trimethyl-1,3-dihydro-5-(o-chlorophenyl)- 2H-1,4-benzodiazepine-2-thione is heated in ethanol with acetic acid hydrazide and the resulting product heated to 250° C. to give 1,4,7,9-tetramethyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][O:24][C:25](=[O:27])[N:26]=3)=[CH:12][CH:11]=2)[C:7]2[C:28]([C:32]([O:34]C)=[O:33])=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH3:2].[OH-].[Na+].Cl>CO>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][O:24][C:25](=[O:27])[N:26]=3)=[CH:14][CH:15]=2)[C:7]2[C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2nc(=O)o[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nc(=O)o[nH]2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 54.8 %

Procedure:
A mixture of the compound (0.47 g) obtained in Example (54h) and 1N NaOH (3 ml) in methanol (3 ml) was heated for 30 minutes under reflux. The reaction mixture was adjusted to pH 3-4 with 1N HCl. Resulting crystalline precipitates were collected by filtration and recrystallized from ethyl acetate-hexane. The crystals were suspended in water (2 ml), and the suspension was stirred for 2 hours at 60° C. Insoluble materials were collected by filtration and dried to afford colorless crystals (0.25 g, 54%). This product was in agreement with that obtained in Example 1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])[CH:5]=[C:4]([Cl:14])[N:3]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:11][CH2:10][C:9]([NH:8][C:6]1[CH:5]=[C:4]([Cl:14])[N:3]=[C:2]([Cl:1])[N:7]=1)([CH3:12])[CH3:13])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CO)Nc1cc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(COS(C)(=O)=O)Nc1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-((2,6-dichloropyrimidin-4-yl)amino)-2-methylpropan-1-ol (6.67 g, 28.3 mmol) and triethylamine (11.59 mL, 85 mmol) in dichloromethane (DCM) (100 mL) was added dropwise MsCl (4.40 mL, 56.5 mmol) at 0° C. The reaction mixture was stirred at rt for 2 h, diluted with DCM (100 mL), washed with water (50 mL×3) then brine (50 mL×2), dried over Na2SO4, filtered and concentrated to give the residue as a yellow solid, which was used for the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[O:10]1[C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1>>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:17]1([OH:20])[CH2:18][CH2:19][C:14]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:15][CH2:16]1
Reactant: COc1ccccc1Br
Reactant: O=C1CCC2(CC1)OCCO2
Product: COc1ccccc1C1(O)CCC2(CC1)OCCO2

Procedure:
The title compound was prepared as a white solid from 2-bromoanisole (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].[H-].[Na+].[C:32]12([C:42](Cl)=[O:43])[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH2:35]3)[CH2:33]1)[CH2:39]2.Cl>O1CCOCC1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:42]([C:32]45[CH2:41][CH:36]6[CH2:35][CH:34]([CH2:40][CH:38]([CH2:37]6)[CH2:39]4)[CH2:33]5)=[O:43])=[C:3]([N+:27]([O-:29])=[O:28])[CH:4]=3)(=[O:10])=[O:9])=[O:13])=[CH:19][CH:18]=2)=[CH:21][CH:22]=1
Reactant: Nc1ccc(S(=O)(=O)NC(=O)c2ccc(-c3ccc(F)cc3)cc2)cc1[N+](=O)[O-]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NS(=O)(=O)c1ccc(NC(=O)C23CC4CC(CC(C4)C2)C3)c([N+](=O)[O-])c1)c1ccc(-c2ccc(F)cc2)cc1
Reaction time: 0.5 h

Procedure:
A solution of Example 380A (101 mg, 0.25 mmol) in TBF (3 mL) was treated with 60% sodium hydride in oil (40 mg, 1.0 mmol), stirred for 30 minutes, treated with 1-adamantanecarbonyl chloride (60 mg, 0.30 mmol), stirred for 30 minutes, adjusted to pH<7 with 4M HCl in dioxane (0.5 mL), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 30-100% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)) m/e 576 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.52 (d, 1H), 8.23 (dd, 1H), 8.19 (d, 1H), 7.95 (d, 2H, 7.75 (m, 4H), 7.31 (tt, 2H), 2.05 (3s, 3H), 1.90 (m, 6H), 1.70 (m, 6H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:11](Cl)([Cl:13])=[O:12]>>[N:1]1([C:11]([Cl:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)Cl
Reactant: c1ccc2c(c1)CCCN2
Product: O=C(Cl)N1CCCc2ccccc21
Yield: 90 %

Procedure:
By the procedure of Example 7, Step A, 1,2,3,4-tetrahydroquinoline was reacted with phosgene to give a 90% yield of the title compound as a dark orange oil, homogeneous by TLC (3:1 hexane-EtOAc) but Rf identical to that of starting material; IR spectrum νCO 1740 cm-1 ; FAB-MS m/e 196 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1.Cl[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[CH2:14]2)=[O:10])=[CH:4][CH:3]=1
Reactant: ClCc1cccc2ccccc12
Reactant: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: O=C(NCC1CN(Cc2cccc3ccccc23)CCO1)Nc1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
To a stirred solution of Intermediate 9 (0.01 g) in N,N-dimethylformamide (1 ml) was added 1-(chloromethyl)naphthalene (6.1 μl). The mixture was stirred at 22° C. for 24 h before tris-(2-aminoethyl)amine polystyrene (Argonaut Technologies, 0.01 g @ 4.46 mmol/g) and polystyrene methyl isocyanate (Argonaut Technologies, 0.033 g @ 1.39 mmol/g) was added. Stirring was continued for a further 2 h before the mixture was purified by solid phase extraction (Isolute SCX sulphonic acid column), eluting with methanol followed by 10% 0.880 ammonia solution in methanol. The basic fraction was evaporated in vacuo to give the title compound (0.003 g). LC/MS (System A) Rt 2.82 min, Mass Spectrum m/z 4140 [MH+].
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH:34]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:30]3[S:29][CH:33]=[CH:32][CH:31]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cccs1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4cccs4)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and thiophene-2-carbaldehyde according to the procedure of Example 66. MS (ES) m/z 475.2.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1([C:18]([F:21])([F:20])[F:19])[CH2:10][NH:9][C:8]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:7]=2[O:6]1)[CH3:4].Cl.Cl[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N+:25]=1[O-:30]>CS(C)=O>[CH2:3]([C:5]1([C:18]([F:21])([F:20])[F:19])[CH2:10][N:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N+:25]=2[O-:30])[C:8]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:7]=2[O:6]1)[CH3:4]
Reactant: [O-][n+]1ccccc1Cl
Reactant: CCC1(C(F)(F)F)CNc2cc([N+](=O)[O-])ccc2O1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC1(C(F)(F)F)CN(c2cccc[n+]2[O-])c2cc([N+](=O)[O-])ccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
Sodium hydride (0.68 g, 60% in mineral oil) was added to a solution of 2-ethyl-2-trifluoromethyl-6-nitro-3,4-dihydro-2H-1,4-benzoxazine (0.235 g), 2-chloropyridine-N-oxide hydrochloride (0.142 g), and dimethylsulfoxide (10 mL) and stirred at room temperature overnight. The mixture was quenched with saturated ammonium chloride/water and extracted into ethyl acetate. The organic extract was washed (water, brine) dried, decolorized (charcoal), filtered (celite) and evaporated. Chromatography, eluting successively with dichloromethane, ethyl acetate, and then methanol, gave the title compound as a yellow solid (0.11 g); mp 59°-62 ° C.; NMR: 0.95 (t,3), 2.04 (q), 4.05 (d,d), 7.01 (s,1), 7.25 (d) 7.45 (m, 2), 7.63 (d), 7.76 (d), 8.41 (d,1); MS: m/z=370(M+1). Analysis for C16H14F3N3O4 : Calculated: C, 52.04; H, 3.82; N, 11.38; Found: C, 51.95; 3.98; N, 11.10.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([OH:23])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1.O>[C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([O:23][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OS(C)(=O)=O)CC[C@@H]12

Procedure:
3-Acetoxy-oestra-1,3,5(10)-trien-17β-ol (500 mg., 1.6 mmole) in pyridine (2 ml.) was treated at room temperature for 16 hr. with methanesulphonyl chloride (1 ml.). The solution was diluted slowly with water (25 ml.) then the product was extracted into ether (50 ml.). The extract was washed with 2N-sulphuric acid (25 ml.) then water (50 ml.) and the solvent was evaporated in vacuo. Crystallisation of the residue from slightly aqueous methanol gave the title compound in two crops (total 519 mg., 93%), m.p. 120°-122°.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:7]#[N:8])([O-])=O.[Cl:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[N:20][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([O:22][C:4]2[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=2)[C:7]#[N:8])[CH:19]=[N:20][CH:21]=1
Reactant: Oc1cncc(Cl)c1
Reactant: N#Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Oc2cncc(Cl)c2)cc([N+](=O)[O-])c1
Yield: 0 %

Procedure:
A solution of 3,5-dinitro-benzonitrile (5 g, 25.9 mol), 5-chloro-pyridin-3-ol (3.35 g, 25.9 mol) and K2CO3 (7.2 g, 52 mol) in DMF (150 mL) was heated at 100° C. overnight. The mixture was concentrated in vacuo and the residue was poured into water. The aqueous layer was extracted with ethyl acetate (3×150 mL) and the combined organics were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by silica gel chromatography to afford 3-(5-chloro-pyridin-3-yloxy)-5-nitro-benzonitrile (3.1 g, 44% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.51 (s, 1H), 8.47 (s, 1H), 8.22 (s, 1H), 8.19 (s, 1H), 7.87 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1)#[N:2].C(=O)([O-])[O-].[Na+].[Na+].[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][C:22]=1[S:30](=[O:33])(=[O:32])[NH2:31]>O1CCOCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([Cl:20])=[C:22]([S:30](=[O:32])(=[O:33])[NH2:31])[CH:23]=2)[NH2:10])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1)#[N:2]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: N#Cc1ccc(NN)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1ccc(N(N)C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)c([N+](=O)[O-])c1
Yield: 20.8 %

Procedure:
The process described in Example 1(B) was followed and 8.1 g of 4-cyano-2-nitrophenylhydrazine (prepared as described in: Beilst. 9 Vol. II page 289), 114 ml of dioxane, 46 ml aqueous solution of 2.4 g of crystalline sodium carbonate and 11.6 g of 4-chloro-3-sulfamoylbenzoyl chloride dissolved in 53 ml of dioxane were used as starting materials. After evaporating the reaction mixture, the residue was thoroughly mixed with water, the yellow precipitate was filtered by suction, washed with water and dried at 80° C. Thus, 3.75 g (65%) of 4-cyano-2-nitro-N-(4'-chloro-3'-sulfamoylbenzoyl)-phenylhydrazine were obtained, m.p.: 292°-295° C. (with decomposition) after recrystallization from acetic acid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([O:42][CH2:43][O:44][CH:45]([Si:47]([CH3:50])([CH3:49])[CH3:48])[CH3:46])[C:7]([C:10]2([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=3[O:35][CH2:36][C:37]([O:39]CC)=[O:38])S[C:11]2([CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[C:13]([O:15]C)=[O:14])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].P(OC)(OC)OC.CN1C=CN=C1>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[N:6]([O:42][CH2:43][O:44][CH:45]([Si:47]([CH3:48])([CH3:49])[CH3:50])[CH3:46])[C:7](/[C:10](/[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[O:35][CH2:36][C:37]([OH:39])=[O:38])=[C:11](\[CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)/[C:13]([OH:15])=[O:14])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C2(c3ccc(OC)cc3OCC(=O)OCC)SC2(Cc2ccc3c(c2)OCO3)C(=O)OC)n1OCOC(C)[Si](C)(C)C
Agent: COP(OC)OC
Agent: Cn1ccnc1
Solvent: ClC(Cl)Cl
Product: CCCCc1ncc(/C(=C(\Cc2ccc3c(c2)OCO3)C(=O)O)c2ccc(OC)cc2OCC(=O)O)n1OCOC(C)[Si](C)(C)C

Procedure:
Methyl (2RS,3RS)-3-(2-n-Butyl-1-trimethylsilylethyloxymethoxy-1H-imidazol-5-yl)-3-(2-ethoxycarbonylmethoxy-4-methoxyphenyl)-2-(3,4-methylenedioxybenzyl)thiirane-2-carboxylate (411 mg, 0.58 mmol) and trimethyl phosphite, freshly distilled from Na (2 ml, 6 mmol) with 1-methylimidazole (100 μl) in CHCl3 (4 ml) were kept at reflux temperature for 48 h under argon. The solvent and excess trimethyl phosphite were removed under reduced pressure (high vacuum) and the residue chromatographed on silica gel (80% EtOAc/hexanes) to give the title compound. (256 mg, 65%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:17]=[CH:16][CH:15]=[C:4]([CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=2)=[CH:22][CH:21]=1)=[O:19]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CN(Cc1cccc(Br)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)OC(C)(C)C
Temperature: 90 °C

Procedure:
61.5 g (205 mmol) of tert-butyl (3-bromobenzyl)-N-methylcarbamate, 40 g (260 mmol) of 4-formylbenzeneboronic acid and 800 ml of toluene are introduced into a three-necked flask and under argon. 205 ml of an aqueous potassium carbonate solution (2 M) are added dropwise, the reaction medium is degassed with argon and 7 g of tetrakis(triphenylphosphine)-palladium(0) chloride are added and the mixture is heated at 90° C. for 24 hours. The reaction medium is poured into water, extracted with dichloromethane, the organic phase decanted off, dried over magnesium sulphate and evaporated off. The residue obtained is purified by chromatography on a silica column eluted with a heptane and ethyl acetate (70–30) mixture. After evaporation of the solvents, 38 g (57%) of the expected product are recovered.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].Br[CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6])[CH2:13][CH3:14]
Reactant: CCCBr
Reactant: OCCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccccc1CCO
Temperature: 60 °C
Reaction time: 64 h

Procedure:
A mixture of 2-hydroxyphenethyl alcohol (1.5 g), 1-bromopropane (1.3 ml), potassium carbonate (2.25 g) and acetone (50 ml) was stirred at 60° C. for 64 hours. After concentration under reduced pressure, the residue was mixed with water and was extracted with ethyl acetate. The organic layer was washed with a 1 N aqueous solution of sodium hydroxide and an aqueous saturated solution of sodium chloride, and was dried with magnesium sulfate. The resulting organic layer was concentrated under reduced pressure to obtain 2-propoxyphenethyl alcohol (2.02 g) as a yellow oily substance.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH:4]([N:12]=[CH:13][B:14]=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:20][CH2:19]1>C(O)(C)C>[OH:1][CH:2]([CH:4]([N:12]=[CH:13][B:14]=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][NH:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25])[CH2:20][CH2:19]1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=BC=NC(Cc1ccccc1)C1CO1
Solvent: CC(C)O
Product: O=BC=NC(Cc1ccccc1)C(O)CNCC1CCN(C(=O)OCc2ccccc2)CC1
Yield: 121.6 %

Procedure:
1-(oxiran-2-yl)-N-((oxoboryl)methylene)-2-phenylethanamine (1.61 mmol, 424 mg) and benzyl 4-(aminomethyl)piperidine-1-carboxylate (1.94 nmnol, 480 mg) in isopropanol (20 mL) was heated at 80° C. for overnight. Evaporated the solvent and purified by flash chromatography to get benzyl 4-((2-hydroxy-3-((oxoboryl)methyleneamino)-4-phenylbutylamino)methyl)piperidine-1-carboxylate (880 mg). 1H NMR (300 MHz, CDCl3), δ: 7.363-7.174 (m, 10H), 5.118 (s, 2H), 4.767 (br, 1H), 4.187 (m, 2H), 3.786 (m, 1H), 3.458 (m, 1H), 3.023-2.671 (m, 6H), 2.484 (d, J=6.6 Hz, 2H), 1.733 (m, 2H), 1.600 (m, 1H), 1.347 (s, 9H), 1.135 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=O)=[CH:5][CH:4]=1.[H-].[Na+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=[CH:32][C:33]#[N:34])=CC=2OCC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:32][C:33]#[N:34])=[CH:5][CH:4]=1
Reactant: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=CC#N)c2ccc(OC)cc2)cc1
Yield: 69 %

Procedure:
Bis-(4-methoxy-phenyl)-methanone (2.42 g, 10 mmol), cyano-methylphosphonic acid diethyl ester (1.6 ml, 10 mmol) in anhydrous THF (10 ml), and sodium hydride (0.48 g, 10 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified by flash column chromatography to give 3,3-bis-(4-methoxy-phenyl)-acrylonitrile as a solid (1.84 g, 69%): 1H NMR (CDCl3) δ 7.39 (d, J=8.7 Hz, 1H, Ar), 7.25 (d, J=8.7 Hz, 1H, Ar), 6.95 (d, j=8.7 Hz, 1H, Ar), 6.88 (d, J=8.7 Hz, 1H, Ar), 5.54 (s, 1H, CH), 3.86, 3.83 (2s, 6H, CH3); 13C NMR (CDCl3) δ 162.3, 161.4, 160.9, 131.7, 131.3, 130.1, 129.5, 118.7, 113.9, 113.8, 91.5, 55.4, 55.3; Anal. Calcd. For C17H15NO2: C, 76.94; H, 5.70; N, 5.27. Found: C, 76.83; H, 5.64; N, 5.17.