Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:32][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)([CH2:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[C:7](=[O:24])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH:45]([C:47]1[CH:52]=[CH:51][C:50](B(O)O)=[CH:49][CH:48]=1)=[O:46]>C1(C)C=CC=CC=1.CCO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:45]([C:47]1[CH:52]=[CH:51][C:50]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH2:25][C:26]4[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=4)([CH2:32][C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[C:7](=[O:24])[N:8]3[CH2:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=3)=[CH:4][CH:3]=2)=[CH:49][CH:48]=1)=[O:46]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CN(C)S(=O)(=O)c1ccc(CN2C(=O)C(Cc3ccncc3)(Cc3ccncc3)c3ccc(Br)cc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(C)S(=O)(=O)c1ccc(CN2C(=O)C(Cc3ccncc3)(Cc3ccncc3)c3ccc(-c4ccc(C=O)cc4)cc32)cc1
Temperature: 100 °C
Yield: 80.9 %

Procedure:
4-(6-Bromo-2-oxo-3,3-bis-pyridin-4-ylmethyl-2,3-dihydro-indol-1-ylmethyl)-N,N-dimethyl-benzenesulfonamide (306 mg, 0.517 mmol) was dissolved in a solution of 6 ml of toluene and 1 ml of EtOH under an atmosphere of dry N2. To this solution was added tetrakis(triphenylphosphine)palladium (0) (34 mg, 0.029 mmol) followed by a solution of Na2CO3 (126 mg, 1.19 mmol) dissolved in 1 ml of water and 4-formylbezeneboronic acid (116 mg, 0.776 mmol). The reaction mixture was heated to 100° C. and reacted at this temperature overnight. The reaction mixture was cooled to ambient temperature and then partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was washed two more times with EtOAc. The combined EtOAc layers were dried over Na2SO4, filtered and concentrated under vacuum to give a dark oil. The oil was purified using radial chromatography eluting with MeOH/DCM (5:95) to give 258 mg of the titled compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([I:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.Cl[C:21](=[O:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl>[Cl:12][C:10]1[C:9]([I:13])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:1][C:21](=[O:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:11]=1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: COC(=O)c1cc(I)c(Cl)cc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Nc1cc(Cl)c(I)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a solution of methyl 2-amino-4-chloro-5-iodobenzoate (Intermediate 2) (8 g, 25.7 mmol) and pyridine (2.18 mL, 27 mmol) in dichloromethane (200 mL) was added ethyl 3-chloro-3-oxopropanoate (Aldrich, 3.45 mL, 27 mmol) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness, diluted with ethyl acetate, washed successively with water and brine. The organic layer was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated in pentane, filtered and dried to give the title compound methyl 4-chloro-2-{[3-(ethyloxy)-3-oxopropanoyl]amino}-5-iodobenzoate (8.24 g, 19.36 mmol, 75% yield) as beige solid. LCMS: (M+H)+=426; Rt=3.78 min.
Reaction SMILES: [Na].[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][OH:11])[CH2:4][CH2:3]1.[Br:12][C:13]1[CH:14]=[C:15]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26](F)=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH:16]=[CH:17][CH:18]=1>C1COCC1.O>[Br:12][C:13]1[CH:14]=[C:15]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:11][CH2:10][CH2:9][CH2:8][N:5]4[CH2:6][CH2:7][O:2][CH2:3][CH2:4]4)=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3cccc(Br)c3)ncnc2cc1F
Reactant: OCCCN1CCOCC1
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc2c(Nc3cccc(Br)c3)ncnc2cc1OCCCN1CCOCC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Sodium metal (27.6 mmol, 0.63 g) was added to a solution of 3-morpholinopropan-1-ol (22.0 mmol, 3.20 g) in THF (60 mL) under N2. The resulting suspension was stirred at 20° C. for 2 hours and then cannulated into a solution of 4-[(3-bromophenyl)amino]-7-fluoro-6-nitroquinazoline, J Med Chem, 1996(39):918) (2.0 g, 5.51 mmol) in THF (50 mL) under N2. The solution was then heated at reflux for 24 hours before being diluted with water and extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, concentrated under reduced pressure and chromatographed on alumina eluting with EtOAc/hexane (1:1) to MeOH/CH2Cl2/EtOAc (2:3:5) to give 4-[(3-bromophenyl)amino]7-[(3-morpholino)propyloxy]-6-nitroquinazoline (1.75 g, 65%) as a yellow powder, mp (MeOH) 216-220° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([Br:20])=[CH:9][N:8]=1)(=O)=O.C(O)(=O)C.[OH:27][C@H:28]1[C@H:32]([OH:33])[CH2:31][NH:30][CH2:29]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH2:13]([C:11]1[C:10]([Br:20])=[CH:9][N:8]=[C:7]([N:30]2[CH2:31][C@@H:32]([OH:33])[C@H:28]([OH:27])[CH2:29]2)[CH:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Oc1cc(Cc2ccccc2)c(Br)cn1)C(F)(F)F
Reactant: O[C@@H]1CNC[C@H]1O
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O[C@@H]1CN(c2cc(Cc3ccccc3)c(Br)cn2)C[C@H]1O
Reaction time: 3 h
Yield: 47.4 %

Procedure:
A mixture of 4.0 g of 4-benzyl-5-bromo-2-pyridyl trifluoromethanesulfonate, 1.8 g of (3R,4R)-3,4-dihydroxypyrrolidine acetate, 3 ml of 1,8-diazabicyclo[5.4.0]-7-undecene and 5 ml of tetrahydrofuran was heated under stirring for 3 hours in an oil bath kept at 70° C. in a nitrogen atmosphere. After cooling as it was, the reaction mixture was extracted with ethyl acetate-water. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to silica gel column chromatography and eluted with 10% methanol/ethyl acetate, to give 1.67 g of the target compound.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[N:5]([C:17]2[CH:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[N:4]=1.CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[CH3:33][S:34]([O:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]([C:17]3[CH:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[N:4]=[C:3]([CH:2]([F:1])[F:25])[CH:7]=2)=[CH:9][CH:10]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-n2nc(C(F)F)cc2-c2ccc(CCO)cc2)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(C(F)F)cc2-c2ccc(CCOS(C)(=O)=O)cc2)cn1
Reaction time: 1 h

Procedure:
To a solution of 2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenyl}ethanol (7.4 g) and Et3N (4.5 ml) in CH2Cl2 (75 ml) was added MsCl (2.5 ml) under ice-cooling. After stirring for 1 hour, the reaction mixture was quenched with water, separated. The aqueous layer was extracted with CH2Cl2 and combined organic layer was washed with water and brine, dried over MgSO4, filtered and evaporated under reduced pressure to give 10.5 g (quant) of 2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenyl}ethyl methanesulfonate as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl-].[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[C:35]12[CH2:44][CH:39]3[CH2:40][CH:41]([CH2:43][CH:37]([CH2:38]3)[CH2:36]1)[CH2:42]2)[C:29](O)=[O:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)(=O)C.CCCCCC>[CH2:10]([O:9][C:7]1[CH:6]=[CH:5][C:3]([NH:4][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:34]([C:35]34[CH2:36][CH:37]5[CH2:38][CH:39]([CH2:40][CH:41]([CH2:43]5)[CH2:42]3)[CH2:44]4)=[C:26]([O:25][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:27]=2)=[C:2]([NH2:1])[CH:8]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1N
Reactant: O=C(O)c1ccc(C23CC4CC(CC(C4)C2)C3)c(OCc2ccccc2)c1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1cc(OCc2ccccc2)ccc1NC(=O)c1ccc(C23CC4CC(CC(C4)C2)C3)c(OCc2ccccc2)c1

Procedure:
2.7 g (12.7 mM) of 2-amino-4-(benzyloxy)aniline and 5 g (12.7 mM) of the chloride of 3-benzyloxy-4-(1-adamantyl)benzoic acid are treated under the conditions described in Example 1(f) to lead, after the same treatment andchromatography on silica in the ethyl acetate/hexane (30/70) eluent, to 4.2g (59.3%) of the expected derivative, of melting point 178° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=2)[CH:25]=[CH:26][CH:27]=1)=[O:21].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:9]([C:8]3[C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=4)=[N:15][CH:14]=[CH:13][CH:12]=3)=[O:11])=[CH:30][CH:29]=2)[CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: O=C(O)c1cccnc1Oc1ccc(F)cc1
Reactant: COC(=O)c1cccc(-c2ccc(CN)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(-c2ccc(CNC(=O)c3cccnc3Oc3ccc(F)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.8 %

Procedure:
To a stirred solution of 290 mg (1.24 mmol.) 2-[4-fluoro-phenoxy]-nicotinic acid, 300 mg (1.24 mmol.) 4′-aminomethyl-biphenyl-3-carboxylic acid methyl ester and 184 mg (1.36 mmol.) 1-hydroxybenzotriazole hydrate in 10 mL dimethylformamide at ambient temperature was added 285 mg (1.49 mmol.) 1-[3-[dimethylamino]propyl]-3-ethylcarbodiimide hydrochloride. The mixture was stirred at ambient temperature for 18 hours then poured into water and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed successively with 1N NaOH, water, brine then dried (MgSO4 ) and concentrated in vacuo to give an oil. Chromatography on silica Gel eluting with ethyl acetate/hexanes (1:1) gave 310 mg 4′-[[[2-[4-Fluorophenoxy]-pyridine-3-carbonyl]-amino]-methyl]-biphenyl-3-carboxylic acid methyl ester as an oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])O[CH2:12][CH2:11]2.[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH2:26][C@@H:25]([NH2:30])[CH2:24][CH2:23]2>>[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH2:26][C@@H:25]([N:30]1[CH2:12][CH2:11][C:10]3[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH2:6][C@@H:2]4[CH2:3][CH2:4][CH2:5][O:1]4)[CH:9]=3)[C:14]1=[O:18])[CH2:24][CH2:23]2
Reactant: N[C@H]1CCc2cc(Br)ccc2C1
Reactant: O=C1OCCc2cc(OC[C@@H]3CCCO3)ccc21
Product: O=C1c2ccc(OC[C@@H]3CCCO3)cc2CCN1[C@H]1CCc2cc(Br)ccc2C1

Procedure:
According to method O, 6-[(S)-1-(tetrahydrofuran-2-yl)methoxy]isochroman-1-one was reacted with (S)-6-bromo-1,2,3,4-tetrahydronaphthalen-2-ylamine (J. Org. Chem. 1995, 60, 4324). The product was thus obtained with the molecular weight of 456.38 (C24H26BrNO3); MS (ESI): 456 (M+H+).
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[C:27]1([CH:33]2[CH2:38][CH2:37][CH:36]([CH2:39]O)[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl.CCCCC>[C:27]1([CH:33]2[CH2:38][CH2:37][CH:36]([CH2:39][I:25])[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OCC1CCC(c2ccccc2)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: ClCCl
Product: ICC1CCC(c2ccccc2)CC1
Reaction time: 0.17 h
Yield: 88.4 %

Procedure:
Imidazole (4.4 g, 0.065 mol) is added in one portion to a solution of triphenylphosphine (17.0 g, 0.065 mol) in dichloromethane (300 mL) at 25° C. After all of the solids dissolved, iodine (16.5 g, 0.065 mol) is added in four portions. The mixture is stirred for 10 min. then a solution of 4-phenylcyclohexylmethanol (10.5 g, 0.055 mol) is added dropwise and the mixture is stirred at 25° C. for 18 h. The reaction mixture is poured into pentane and the resulting solids filtered. The filtrate is concentrated in vacuo and the residue is dissolved in dichloromethane. This solution is poured into hexanes, the solids were filtered, and the filtrate is concentrated in vacuo. The residue is passed through a pad of silica gel using hexanes as eluent to afford 14.6 g (89%) of 4-phenylcyclohexylmethyl iodide as an oil.
Reaction SMILES: [C:1]1(/[C:7](/[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[C:8](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)\[CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:25][CH:26](Br)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:1]1([C:7]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:27][CH2:26][Br:25])=[CH:22][CH:23]=2)=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC/C(=C(\c1ccccc1)c1ccc(O)cc1)c1ccccc1
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: OCCC(=C(c1ccccc1)c1ccc(OCCBr)cc1)c1ccccc1

Procedure:
A mixture containing 31.6 g of (Z)-1,2-diphenyl-1-(4-hydroxyphenyl)-1-buten-4-ol, 93.9 g of dibromoethane, 20.7 g of anhydrous potassium carbonate and 250 ml of methyl ethyl ketone is refluxed for 24 h. The inorganic salts are removed by filtration followed by evaporating the solvent and recrystallizing from methanol. The yield is 17.3 g (41%) and m.p. 133°-7° C.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:16]([O-])=[O:17].[Na+]>C(O)(=O)C.O>[CH3:14][C:12]1[CH:11]=[C:10]([CH3:15])[N:9]=[C:8]([N:1]([N:16]=[O:17])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:13]=1
Reactant: O=N[O-]
Reactant: Cc1cc(C)nc(Nc2ccccc2)n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C)nc(N(N=O)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a solution of 2.0 g of 2-anilino-4,6-dimethylpyrimidine in 15 ml of acetic acid was added dropwise a solution of 1.4 g of sodium nitrite in 10 ml of water. After 30 minute's stirring, 50 ml of water was added to the mixture. The resulting crystals were collected by filtration and dried. Recrystallization from ethanol afforded 1.7 g (yield: 74%) of 4,6-dimethyl-2-(N-nitrosoanilino)pyrimidine having a melting point of 117°-121° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[N:8][OH:9])=[CH:3][CH:2]=1.C(Cl)(Cl)[Cl:11]>>[OH:9][N:8]=[C:7]([Cl:11])[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: ClC(Cl)Cl
Reactant: ON=Cc1ccncc1
Product: ON=C(Cl)c1ccncc1

Procedure:
4-Pyridinecarboxaldehyde oxime (30.6 g, 0.25 mol) was chlorinated in chloroform (350 ml) as described in Example 1 to produce N-hydroxy-4-pyridine-carboximidoyl chloride which was suspended in ether (500 ml) containing 2-chloroethanethiol (26.9 g, 0.25 mol). With ice bath cooling, triethylamine (5.1 g, 0.5 mol) was added dropwise. After the addition, water was made, the suspended solid, crude 2-chloroethyl N-hydroxy-4-pyridinecarboximidothioate was collected on a filter and dried. This crude ester was added to a solution of sodium ethoxide (from 5.75 g sodium in 500 ml ethanol), and the reaction mixture stirred for 4 hours. Water was added and the product was extracted with ether to give 5,6-dihydro-3-(4-pyridinyl)-1,4,2-oxathiazine, mp 80°-82° C., (found: C, 53.16; H, 4.56; N, 15.07. C8H8N2OS requires C, 53.33; H, 4.48; N, 15.55).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:64]([NH2:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CN(C)C=O>[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([NH:71][CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[O:18])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1
Reactant: NCc1ccccc1
Reactant: O=C1COc2ccc(C(=O)c3ccccc3C(=O)O)cc2N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C1COc2ccc(C(=O)c3ccccc3C(=O)NCc3ccccc3)cc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 211.7 %

Procedure:
To a solution of 2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-yl)carbonylbenzoic acid (100 mg, 033 mmol) in N,N-dimethylformamide (2.00 mL) was added N-methylmorpholine (0.14 mL 1.32 mmol) followed by addition of HOAt (55 mg, 0.40 mmol) and HATU (130 mg, 0.33 mmol). The mixture was stirred for 30 minutes at room temperature followed by the addition of benzylamine (36 uL, 0.33 mmol). The reaction mixture was then heated to 60° C. for 18 h. The mixture was cooled to room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate the organic layer was washed with brine, 1.0 M aq. hydrochloric acid, brine, saturated aq. sodium-hydrogencarbonate and brine. The organic layer was separated dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexanes/ethyl acetate) to afford the title compound (0.27 g, 80%). MS (EI) for C23H18N2O4: 387 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:9][C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:7][C:6]=2[CH:23]=1.B([O-])([O-])O[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][CH3:38])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:15]([O:14][C:12]([N:11]1[C:5]2[CH:4]=[CH:3][C:2]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][CH3:38])=[CH:28][CH:27]=3)=[CH:23][C:6]=2[CH:7]=[C:8]([C:19]([O:21][CH3:22])=[O:20])[CH2:9][CH2:10]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOCCCOc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C(=O)OC(C)(C)C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
A mixture of methyl 7-bromo-1-(t-butoxycarbonyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.0 g), 4-(3-ethoxypropoxy)phenyl borate (0.62 g), 1M potassium carbonate solution (8 ml), ethanol (8 ml) and toluene (50 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.12 g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-(t-butoxycarbonyl)-7-[4-(3-ethoxypropoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.2 g) as colorless crystals.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[Br:14]Br.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26](=[C:5]([Br:14])[C:3]#[N:4])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: BrBr
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=C(Br)C#N)CC1
Reaction time: 2 h
Yield: 73.2 %

Procedure:
A slurry of sodium hydride (0.76 g, 19.0 mmol) in THF (75 mL) at 0° C. under nitrogen was carefully treated with diethyl cyanomethylphosphonate (3.4 g, 19.0 mmol) via a syringe. After gas evolution ceased, the reaction mixture was treated with bromine (3.04 g, 19.0 mmol) via a dropping funnel over 10 min., and the resulting mixture was allowed to stir for 2 h. The reaction mixture was treated with sodium hydride (0.76 g, 19.0 mmol) and the resulting slurry was allowed to stir for 30 min. at 0° C. A solution of 1-(tert-butoxycarbonyl)-4-piperidinone (2.52 g, 12.7 mmol) in THF (10 mL) was added dropwise over 10 min. and the resulting solution was allowed to stir at room temperature overnight. The reaction was quenched by the addition of water (50 mL) and the resulting mixture was diluted with ethyl acetate (100 mL), washed with sat. NH4Cl (100 mL), brine (100 mL), and concentrated in vacuo. Purification by chromatography (EtOAc/hexanes=1:4) yielded the title compound (2.8 g, 74%) as a white solid. MS 301 (M+H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:20])[CH:13]=2)[CH:9]=[N:8][CH:7]=1.Br[CH2:22][CH2:23][O:24][CH2:25][CH2:26]Br>C(#N)C.C(N(CC)CC)C>[F:20][C:14]1[CH:13]=[C:12]([CH2:11][N:10]2[C:6]([CH2:5][CH2:4][N:3]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:7][N:8]=[CH:9]2)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: BrCCOCCBr
Reactant: N#Cc1ccc(Cn2cncc2CCN)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccc(Cn2cncc2CCN2CCOCC2)cc1F

Procedure:
To a solution of 4-[5-(2-amino-ethyl)-imidazol-1-ylmethyl]-2-fluoro-benzonitrile dihydrochloride (0.92 g, 0.0029 mmol) in acetonitrile (150 mL) and triethylamine (3.2 mL) was added 2-bromoethyl ether (0.839 mL, 0.0067 mmol) and the mixture was refluxed for 48 hr. The solvents were removed in vacuo and the residue was dissolved in EtOAc which was washed twice with 1M HCl (100 mL). The HCl layers were combined and adjusted to pH=9 with solid Na2CO3 and extraxcted 3 times with EtOAc. The EtOAc layers were combined and dried with brine and MgSO4. Removal of the EtOAc in vacuo yielded the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13]2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc([N+](=O)[O-])cc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(c2ccc(N)cc2)C1
Reaction time: 18 h

Procedure:
A suspension of tert-butyl 3-(4-nitrophenyl)azetidine-1-carboxylate (A76) (2.14 g, 7.68 mmol) and 10% Pd/C (0.320 g) in EtOAc (16 mL) was stirred under a hydrogen atmosphere for 18 hours. Additional 10% Pd/C (1.00 g) was added and the mixture stirred under a hydrogen atmosphere for a further 20 hours. The resulting mixture was filtered through a pad of Celite, washing with EtOAc and the filtrate concentrated in vacuo to give the title compound A77 as a light yellow/cream solid (1.80 g, 94%); 1H NMR (300 MHz, CDCl3) δ 7.12 (d, J=8.3 Hz, 2H), 6.69 (dd, J=6.5, 1.9 Hz, 2H), 4.29 (t, J=8.7 Hz, 2H), 3.93 (dd, J=8.4, 6.1 Hz, 2H), 3.69-3.61 (s, 2H), 1.55-1.68 (m, 1H), 1.48 (s, 9H). LCMS-B: rt 4.964 min; m/z 249 [M+H]+.