Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:17]=[CH:16][C:8]([CH2:9]P(=O)(OC)OC)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[H-].[Na+].C([O:23][CH2:24][CH2:25][N:26]([CH3:35])[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1)(=O)C>COCCOC>[OH:23][CH2:24][CH2:25][N:26]([CH3:35])[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[CH:9][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:17][CH:16]=2)=[CH:29][CH:28]=1
Reactant: COP(=O)(Cc1ccc(S(C)(=O)=O)cc1)OC
Reactant: CC(=O)OCCN(C)c1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CN(CCO)c1ccc(C=Cc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 0 °C

Procedure:
A solution of dimethyl 4-methylsulfonylbenzylphosphonate prepared as described in Ulman et al U.S. Pat. No. 4,792,208 (6.29 g, 22.6 mmol), 60% sodium hydride dispersion (1.35 g, 33.9 mmol) and 50 mL of dry 1,2-dimethoxyethane (DME) under nitrogen was treated with a solution of 4-[(2-acetoxyethyl)methylamino]benzaldehyde (5.00 g, 22.6 mmol, Example 5) in 50 mL of DME. The resulting mixture was heated at reflux for 16 hr, then cooled and poured onto 300 g of ice. The resulting yellow solid was filtered, washed with water and air-dried. The solid was heated at reflux in a mixture of 10 g of NaOH, 90 mL of ethanol and 90 mL of water for 24 hr, then cooled and poured onto 200 mL of water. The resulting brown solid was filtered and air-dried. The product was recrystallized twice from a mixture of ethanol and pyridine to produce 4.46 g (60%) of yellow plates, m.p. 201°-204° C.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:28][O:29][CH2:30][C:31](Cl)=[O:32].O>CN(C)C=O>[NH2:19][C:18](=[N:17][C:14]1[S:15][CH:16]=[C:12]([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:5][NH:4][C:31](=[O:32])[CH2:30][O:29][CH3:28])[N:11]=2)[N:13]=1)[NH2:20]
Reactant: COCC(=O)Cl
Reactant: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC(=O)NCc1cccc(-c2csc(N=C(N)N)n2)n1
Reaction time: 2.5 h

Procedure:
To a mixture of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole trihydrochloride (3.0 g) and triethylamine (4.7 ml) in N,N-dimethylformamide (60 ml) was added a methoxyacetyl chloride (0.9 ml) under ice-cooling and the mixture was stirred for 2.5 hours at the same temperature. The reaction mixture was added to water and the mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 2-(diaminomethyleneamino)-4-(6-methoxyacetylaminomethylpyridin-2-yl)thiazole (0.86 g).
Reaction SMILES: [OH-].[K+].[C:3]1([CH2:8][OH:9])[S:7][CH:6]=[CH:5][CH:4]=1.[C:10]1([CH2:15][O:16][CH2:17][C:18]2SC=C[CH:19]=2)SC=CC=1>CCOCC>[C:3]1([CH2:8][O:9][CH2:10][C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[S:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1csc(COCc2cccs2)c1
Reactant: OCc1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: c1coc(COCc2cccs2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diethyl ether. To a suspension of 1.32 g. (0.01 mole) of cloromethylthiophene [obtained by the method of F. F. BLICKE, J.A.C.S. 64, 477 (1942)] and 1.2 g. (0.02 mole) of powdered potassium hydroxide in 10 ml. of ether there is added a solution of 3.5 g. (0.03 mole) of thenyl alcohol in 10 ml. of ether. The reaction mixture is stirred for 1 hour at room temperature, then refluxed for 30 minutes and finally allowed to stand over night. After filtration the ethereal solution is concentrated and the residue fractionally distilled. There is obtained 0.22 g. (10%) of dithenyl ether having a b.p. of 99°C./0.01 mm. Hg. and a m.p. of 36.5°. 1c. Furfuryl thenyl ether is obtained by the same method as used for preparing compound (1) b., but using furfuryl alcohol instead of thenyl alcohol. The product thus obtained had a b.p. of 50°C./0.01 mm. Hg.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=O>C1C=CC=CC=1.C(O)(=O)C.N1CCCCC1>[CH3:3][CH:2]([CH3:4])[C:1](=[O:5])[C:6](=[CH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=Cc1ccccn1
Reactant: CCOC(=O)CC(=O)C(C)C
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1ccccn1)C(=O)C(C)C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a solution of ethyl isobutyrylacetate (15.78 g, 99.7 mmol) and pyridine-2-carboxaldehyde (10.7 g, 99.9 mmol) in dry benzene (100 mL) at room temperature under argon was added acetic acid (0.30 mL, 5.2 mmol) and piperidine (0.80 mL, 8.1 mmol). After stirring at room tempertaure for 1 hour and at reflux for 3 hours, the cooled mixture was washed with water, saturated NaHCO3 and saturated NaCl solutions, dried (Na2SO4) ) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate (EtOAc)-hexane (1:9) to give title compound (20.61 g, 83%) as an orange, viscous oil which crystallized on standing to a semi-solid mass, mp 53°-55° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:5]=2[N:4]=[C:3]1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1SC.Cl[C:24]1C=CC=C(C(OO)=O)C=1.C(=O)([O-])O.[Na+].[S:39]([O-:43])([O-])(=[O:41])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:24][S:39]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[C:3]1[N:2]([CH3:1])[C:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:12])[F:13])=[CH:10][C:5]=2[N:4]=1)(=[O:43])=[O:41]
Reactant: CSc1cnccc1-c1nc2cc(C(F)(F)F)ccc2n1C
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1c(-c2ccncc2S(C)(=O)=O)nc2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 0.60 g of 1-methyl-2-(3-methylthiopyridin-4-yl)-5-trifluoromethyl-1H-benzimidazole and 9 ml of chloroform was added 1.40 g of 69% m-chloroperbenzoic acid under ice cool, then, the mixture was stirred for 2 hours at room temperature. Thereafter, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium thiosulfate aqueous solution were poured, and the mixture was extracted three times with chloroform. The combined organic layers were dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.52 g of 2-(3-methanesulfonylpyridin-4-yl)-1-methyl-5-trifluoromethyl-1H-benzimidazole (hereinafter, referred to as present active compound 19).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:35]=[CH:36][N:37]=[CH:38][CH:39]=2)[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) according to the general procedure M. Obtained as a white solid (275 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.ON1C(=O)CC[C:11]1=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:29][CH2:30][CH2:31][CH2:32][S:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH3:11][C:5]1[S:1][C:2]([C:6]([NH:29][CH2:30][CH2:31][CH2:32][S:33][C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)=[O:8])=[CH:3][CH:4]=1
Reactant: NCCCSc1ccncc1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCCCSc2ccncc2)s1
Yield: 64.5 %

Procedure:
To a solution of 1.27 g (8.91 mmol) of 5-methyl-2=thiophenecarboxylic acid and 1.33 g (11.6 mmol) of N-hydroxysuccinimide in 90 ml of methylene chloride, 2.05 g (10.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1 hour. Further, 1.50 g (8.91 mmol) of 4-(3-aminopropylthio)pyridine was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain powder. The powder thus obtained was washed with ether and dried to obtain 1.68 g of the desired compound (yield: 64.5% colorless powder)
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[N:36](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=2)[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[N:9]=1)[CH3:2].C(O)(=O)C.C(O)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=2)[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:10]([OH:13])([CH3:11])[CH3:12])[N:9]=1)[CH3:2]
Reactant: CCOCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCOCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 99.6 %

Procedure:
A solution of 600 mg of ethyl 2-ethoxymethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] in 10 ml of a 25% v/v aqueous solution of acetic acid was stirred at 60° C. for 2 hours. 10 ml of water were then added, and the mixture was then cooled with ice. The trityl alcohol which appeared as crystals was filtered off. The filtrate was concentrated by distillation under reduced pressure, and then acetic acid and water were distilled off as azeotropic mixtures with toluene, to give 400 mg of the title compound in an amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.P(=O)(O)(O)O.CO>O.S(N(C1C=C(C(O)=O)C(N(S(=O)(=O)N)C2C=CC=CC=2)=CC=1C(O)=O)C1C=CC=CC=1)(=O)(=O)N.C(N(CC)S(C1C=CC(NC2C=C(C(O)=O)C(NC3C=CC(S(=O)(=O)N(CC)CC)=CC=3)=CC=2C(O)=O)=CC=1)(=O)=O)C>[CH:3]1[C:2]([Cl:1])=[CH:28][C:27]2[C:9]([C:8]3[C:7]([NH:6][C:5]=2[CH:4]=1)=[CH:15][C:14]1[C:16]([C:21]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=2[NH:19][C:13]=1[CH:12]=3)=[O:18])=[O:11]
Reactant: O=C(O)c1cc(Nc2ccc(Cl)cc2)c(C(=O)O)cc1Nc1ccc(Cl)cc1
Agent: CCN(CC)S(=O)(=O)c1ccc(Nc2cc(C(=O)O)c(Nc3ccc(S(=O)(=O)N(CC)CC)cc3)cc2C(=O)O)cc1
Agent: NS(=O)(=O)N(c1ccccc1)c1cc(C(=O)O)c(N(c2ccccc2)S(N)(=O)=O)cc1C(=O)O
Agent: O=P(O)(O)O
Solvent: CO
Solvent: O
Product: O=c1c2cc(Cl)ccc2[nH]c2cc3c(=O)c4cc(Cl)ccc4[nH]c3cc12
Temperature: 95 °C
Reaction time: 0.08 h
Yield: 101.2 %

Procedure:
To 720 g of polyphosphoric acid (116.5%) heated at 90° C. were added 0.6 g of 2,5-di(sulfamoylanilino)terephthalic acid followed by 12.0 g of 2,5-di[4-(N,N-diethylsulfamoyl)anilino]terephthalic acid. The mixture was stirred for five minutes, after which 120 g of 2,5-di(4-chloroanilino)terephthalic acid were added over a period of approximately 45 minutes, the temperature being maintained below 110° C. by adjustment of the addition rate. The reaction mixture was held at 113° C. for five hours and then cooled to 95° C. To this mixture was added 89.4 g of phosphoric acid (75%) dropwise over a period of 20 minutes. The resultant melt was allowed to stir for 15 minutes at 92° C. and then poured slowly into 1240 g of methanol, the temperature being maintained below reflux by adjustment of the addition rate. The slurry was allowed to cool to room temperature and stand for 16 hours. The pigment slurry was heated at reflux for one hour, cooled below 65° C., diluted with water, collected by filtration, and washed with water until free of acid. The resultant wet cake can be dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give approximately 111 g of 2,9-dichloroquinacridone as a magenta pigment.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:25]1(B(O)O)[CH2:27][CH2:26]1>>[ClH:20].[CH:25]1([C:19]2[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:15][CH:16]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:18]=2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(F)(F)F)cc2Cl)CC1
Reactant: OB(O)C1CC1
Product: Cl
Product: FC(F)(F)c1cnc(N2CCNCC2)c(C2CC2)c1
Yield: 94.4 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 49 and using 4-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (7.3 g), which is the intermediate described in Preparation Example 51, and cyclopropylboronic acid (4.2 g), the title compound (5.8 g) was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]2[N:21]=[CH:22][S:23][C:17]=2[CH:16]1[C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[O:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:14])(C)(C)C.C(N(CC)CC)C.ClC(O[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=O>C(Cl)Cl>[CH2:49]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]2[N:21]=[CH:22][S:23][C:17]=2[CH:16]1[C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[O:31][CH2:32][C:33]([OH:35])=[O:34])=[O:14])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CCOC(=O)COc1ccc(F)cc1C1c2scnc2CCN1C(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)COc1ccc(F)cc1C1c2scnc2CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Trifluoroacetic acid (8.2 mL) was added to a solution of (±)-4-(2-ethoxycarbonylmethoxy-5-fluoro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester (237 mg, 0.52 mmol, 1.0 eq.) in DCM (12 mL). The resulting mixture was stirred at r.t. for 5 hours. The solvent was removed in vacuo. To an-ice cooled suspension of the residue and triethylamine (0.11 mL, 0.79 mmol, 1.5 eq.) in DCM (5 mL), benzyl chloroformate (79 μL, 0.52 mmol, 1.0 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the suspension was stirred at r.t. for 18 hours. Triethylamine (0.11 mL, 0.79 mmol, 1.5 eq.) and benzyl chloroformate (39 μL, 0.26 mmol, 0.5 eq.) were added again. The mixture was stirred at r.t. for 18 hours. The reaction was quenched with 1M aq. citric acid soln. (12 mL). The layers were separated. The aq. phase was extracted with DCM (3×6 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. To a solution of the crude ester in THF (2.3 mL), 1M aq. NaOH soln. (0.7 mL) was added. The solution was stirred at r.t. for 18 hours. The solution was diluted with water (2 mL), 1M aq. HCl soln. (0.7 mL), and DCM. The layers were separated and the aq. phase was extracted with DCM (2×). The comb. org. phases were concentrated in vacuo. The residue was dissolved in DMF (1.2 mL), purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions), and concentrated in vacuo to give the title compound as a pale yellow foam.
Reaction SMILES: C1OC1.C1C2C=CC=CC=2CCON1.[OH:15][CH2:16][CH2:17][N:18]1[O:24][CH2:23][CH2:22][C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[CH2:19]1.[O-:29][C:30]#[N:31].[Na+]>C(Cl)(Cl)Cl.CO>[C:30]([O:15][CH2:16][CH2:17][N:18]1[O:24][CH2:23][CH2:22][C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[CH2:19]1)(=[O:29])[NH2:31]
Reactant: OCCN1Cc2ccccc2CCO1
Reactant: N#C[O-]
Agent: [Na+]
Agent: c1ccc2c(c1)CCONC2
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CO1
Product: NC(=O)OCCN1Cc2ccccc2CCO1
Reaction time: 8 h

Procedure:
8 Grams of ethylene oxide was dissolved at room temperature in 80 ml. of methanol. To this solution, 8 mg. of 1,2,4,5-tetrahydro-3,2-benzoxazepine were added. After standing overnight, the reaction mixture was refluxed for one hour and then evaporated in vacuo. The residue was distilled at 120° C./0.1 mm Hg. giving 9.3 g. of 2-(2-hydroxyethyl)-1,2,4,5-tetrahydro-3,2-benzoxazepine. To 2.9 g. of the latter compound in 160 ml. of chloroform, 2.47 g. of sodium cyanate was added, then hydrogen chloride was bubbled therethrough for about 30 minutes under stirring. The reaction mixture was then transferred to a separatory funnel and treated with 90 ml. aqueous of 5 percent sodium hydroxide. The organic layer was separated, washed with a saturated solution of sodium chloride and dried over sodium sulfate. After evaporation of the chloroform solution, the residue was crystallized from diisopropyl ether giving 1.82 g. of 2-(2-carbamyloxyethyl)-1,2,4,5-tetrahydro-3,2-benzoxazepine, m.p. 110°-111° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[OH-].[K+].[O:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13]>CS(C)=O.CCOCC.O>[Br:1][CH2:2][CH2:3][CH2:4][N:10]1[CH2:11][CH2:12][O:8][C:9]1=[O:13]
Reactant: BrCCCBr
Reactant: O=C1NCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: O=C1OCCN1CCCBr
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a cooled solution (15-20° C.) of 1,3-dibromopropane (6.4 mL, 63.05 mmol) in dry DMSO (5 mL) was added ground KOH (0.920 g, 16.40 mmol). 2-Oxazolidinone (1.100 g, 12.63 mmol) was added in small amounts over 5 min, and the reaction was stirred for 4 hr at 20° C. The mixture was diluted with ether (100 mL) and H2O (20 mL), and the aqueous phase was extracted with ether (3×50 mL). After drying with MgSO4, the crude product was purified by flash chromatography using a step gradient (25% EtOAc/75% hexanes to 50% EtOAc/50% hexanes) to give N-(3′-bromopropyl)-2-oxazolidinone, 17 (1.48 g, 56%). IR (neat) 1747 cm−1; 1H NMR (CDCl3) δ 4.30 (2H, t, J=7.2 Hz), 3.57 (2H, t, J=8.2 Hz), 3.33-3.43 (4H, q), 2.03-2.17 (2H, m); 13C NMR (CDCl3) δ 158.4, 61.7, 45.0, 43.0, 30.4, 29.9; HRMS (FAB+) m/z: calcd for C6H10NO2Br, 207.9972; found, 207.9957.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:5].[S:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(O)(=O)C>[CH2:23]([O:22][C:19]1[CH:20]=[CH:21][C:2]([NH:1][CH:33]2[CH2:34][CH2:35][S:30][CH2:31][CH2:32]2)=[C:3]([CH:18]=1)[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:5])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(CNC(=O)c2cc(OCc3ccccc3)ccc2N)cc1OC
Reactant: O=C1CCSCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(CNC(=O)c2cc(OCc3ccccc3)ccc2NC2CCSCC2)cc1OC
Yield: 67.8 %

Procedure:
A mixture of 0.235 g of 2-amino-5-(benzyloxy)-N-(3,4-dimethoxybenzyl)benzamide, 0.090 g of tetrahydro-4H-thiopyran-4-one and 0.78 g of sodium triacetoxyborohydride in 0.5 ml of acetic acid is irradiated in a microwave field for 5 minutes at 130° C. 1N HCl is added and the mixture is extracted with EtOAc. The organic phase is dried over MgSO4 and filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a heptane/EtOAc mixture from (90/10, v/v) to (20/80, v/v) to give 0.2 g of the expected product.
Reaction SMILES: OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[N:15]1([CH2:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH2:28][CH:27]([NH2:32])[CH2:26][CH2:25]3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[S:43]([NH:46][CH:47]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:48][C:49](O)=[O:50])(=[O:45])=[O:44].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[S:43]([NH:46][CH:47]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:48][C:49]([NH:32][CH:27]1[CH2:26][CH2:25][C:24]2[C:29](=[CH:30][CH:31]=[C:22]([CH2:21][N:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[CH:23]=2)[CH2:28]1)=[O:50])(=[O:45])=[O:44]
Reactant: O=C(O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Reactant: NC1CCc2cc(CN3CCCCC3)ccc2C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1)NC1CCc2cc(CN3CCCCC3)ccc2C1
Temperature: 25 °C

Procedure:
6-Piperidin-1-ylmethyl-1,2,3,4-tetrahydro-naphthalen-2-ylamine bis-TFA salt (Step F) (0.143 g, 0.327 mmol), 3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionic acid (0.128 g, 0.360 mmol), HOBt (0.057 g, 0.425 mmol) and EDC (0.081 g, 0.425 mmol) were dissolved in CH2Cl2 (25 mL) and stirred at RT. TEA (0.228 mL, 1.64 mmol) was added drop-wise to the mixture and the reaction was stirred at RT until HPLC analysis showed complete consumption of starting material. The reaction mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the crude material. The crude was purified by flash column chromatography to furnish the title compound. MS (APCI pos) 582 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.[F:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1>>[F:23][C:24]1[C:29]([C:2]2[CH:3]=[C:4]3[C@@:15]4([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]4)[C:14]4[CH:13]=[C:12]([C:38]5[CH:37]=[CH:36][N:35]=[C:34]([F:33])[CH:39]=5)[N:11]=[CH:10][C:9]=4[O:8][C:5]3=[CH:6][CH:7]=2)=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: OB(O)c1cccnc1F
Reactant: OB(O)c1ccnc(F)c1
Reactant: NC1=N[C@@]2(CCO1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Product: NC1=N[C@@]2(CCO1)c1cc(-c3cccnc3F)ccc1Oc1cnc(-c3ccnc(F)c3)cc12

Procedure:
The titled compound was synthesized by steps analogous to those described in method A1 above, but using intermediate 18B, 2-fluoropyridin-3-ylboronic acid and 2-fluoropyridin-4-ylboronic acid. MS m/z=458.0 [M+H]+. Calculated for C25H17F2N5O2: 457.43
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH2:16][CH2:15][CH2:14][N:13]=1.[CH2:17]([O:19][CH2:20]C)C.C[OH:23]>>[ClH:1].[CH3:3][C:4]1[CH:9]=[C:8]([NH:10][C:17]([O:19][CH3:20])=[O:23])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH2:16][CH2:15][CH2:14][N:13]=1
Reactant: CO
Reactant: Cc1cc(N)ccc1NC1=NCCC1
Reactant: CCOCC
Agent: Cl
Product: COC(=O)Nc1ccc(NC2=NCCC2)c(C)c1

Procedure:
The title compound was prepared by the method of Example 26 using the product compound of Example 9 and excess methanol. The crude product was dissolved in the minimum amount of methanol and treated with diethyl ether to point of cloudiness, then cooled. Insolubles were removed by filtration and the product forced out of the filtrate by addition of ether, giving the title compound as a solid. Structure assignment was supported by the nmr spectrum and by elemental analysis.