Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[N:18]1([C:24]2[C:32]3[O:31][C:30](=[O:33])[NH:29][C:28]=3[CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.N1CCNCC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl.CO.CCOCC.CN(C=O)C>[O:33]=[C:30]1[NH:29][C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([N:18]3[CH2:23][CH2:22][N:21]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]4[N:9]=[C:10]5[C:5]([CH2:4][CH2:3][C:2](=[O:1])[NH:11]5)=[CH:6][CH:7]=4)[CH2:20][CH2:19]3)[C:32]=2[O:31]1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Reactant: O=c1[nH]c2cccc(N3CCNCC3)c2o1
Agent: C1CNCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5[nH]c(=O)oc45)CC3)nc2N1
Reaction time: 0.17 h
Yield: 64 %

Procedure:
To a solution of 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (300 mg, 1.28 mmol) in DCE (6 mL) was added 7-piperazin-1-yl-3H-benzooxazol-2-one (309 mg, 1.41 mmol, prepared according to EP 0189612 and/or EP 0138280; Drugs of the Future, 2001, 26,128). The piperazine did not dissolve so DMF (1 mL) was added. The reaction was stirred for 10 min and NaBH(OAc)3 (380 mg, 1.79 mmol) was added. The reaction was stirred for 2 h at RT. Saturated NaHCO3 was added and the mixture was extracted with EtOAc (along with a little MeOH). The organic layer was washed with H2O and brine, and concentrated to give a light brown solid. The solid was dissolved in CH2Cl2/MeOH, absorbed onto SiO2 and purified by liquid chromatography (AnaLogix, RS-40, 0–5% MeOH/CH2Cl2) to give a white solid. Et2O was added and the solid was collected by filtration and dried to give the product as a white solid (360 mg, 0.823 mmol, 64%). MS: APCI: M+1: 438.2 (Exact Mass: 437.21).
Reaction SMILES: [N:1]1[C:6]([C:7]([O-])=[O:8])=[CH:5][CH:4]=[CH:3][C:2]=1[C:10]([O:12]CC1C=CC=CC=1)=[O:11].[NH3:20]>>[C:7]([C:6]1[N:1]=[C:2]([C:10]([OH:12])=[O:11])[CH:3]=[CH:4][CH:5]=1)(=[O:8])[NH2:20]
Reactant: N
Reactant: O=C([O-])c1cccc(C(=O)OCc2ccccc2)n1
Product: NC(=O)c1cccc(C(=O)O)n1

Procedure:
Monobenzyl pyridine-2,6-dicarboxylate (compound H1) (1 g, 3.8 mmol) and aqueous 25-% ammonia solution (40 mL) are heated to 90° C. for 6 h. After cooling the mixture is evaporated and washed with ether.
Reaction SMILES: C([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2([C:21]#[N:22])[CH2:20][CH2:19][CH2:18]2)=[C:11]([N+:23]([O-:25])=[O:24])[CH:10]=1)C1C=CC=CC=1.[H][H]>CCO.[Pd]>[OH:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2([C:21]#[N:22])[CH2:18][CH2:19][CH2:20]2)=[C:11]([N+:23]([O-:25])=[O:24])[CH:10]=1
Reactant: [H][H]
Reactant: COc1cc(C2(C#N)CCC2)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(C2(C#N)CCC2)c([N+](=O)[O-])cc1O
Temperature: 70 °C
Yield: 98 %

Procedure:
A solution of 1-(4-(benzyloxy)-5-methoxy-2-nitrophenyl)cyclobutanecarbonitrile (2.78 g, 8.22 mmol), from Step 2, in EtOH (30 mL) was treated with 10% Pd/C (0.87 g, 0.822 mmol), fitted with hydrogen filled balloon and heated to 70° C. for 3 hours under hydrogen atmosphere. The catalyst was filtered off and washed with EtOH. Solvent was concentrated to provide 1-(4-(hydroxyl)-5-methoxy-2-nitrophenyl)cyclobutanecarbonitrile (2 g, 99%). MS (ESI) m/z 249 (M+H)+.
Reaction SMILES: CC(C)=[O:3].S(=O)(=O)(O)O.[O:10]1[CH2:20][C:11]1([CH3:21])[CH:12]1[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH:13]1[OH:19]>>[CH:15]1([CH3:18])[CH2:16][CH2:17][CH:12]([C:11]([OH:3])([CH3:21])[CH2:20][OH:10])[CH:13]([OH:19])[CH2:14]1
Reactant: CC(C)=O
Reactant: CC1CCC(C2(C)CO2)C(O)C1
Agent: O=S(=O)(O)O
Product: CC1CCC(C(C)(O)CO)C(O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Into a solution of acetone (116 g; 2 mol) and a 3% aqueous solution of sulfuric acid (35 g) was added 8,9-epoxy-p-menthan-3-ol (17 g; 0.1 mol), and the mixture was stirred at room temperature for 16 hours. Then, the acetone was distilled and recovered, and the concentrated solution was mixed with water (40 ml) and heated to within 80° C. of the distilling temperature to completely recover the acetone. The remaining aqueous solution was cooled, neutralized with a 10% aqueous solution of sodium carbonate, and saturated with sodium chloride. The reaction product was extracted with THF, dried over anhydrous magnesium sulfate, and concentrated to give a crude product (19 g). The crude product was purified by column chromatography on silica gel. That is, the crude product was eluted with 50% ethyl acetate-n-hexane, then eluted with ethyl acetate only, and the eluate was concentrated to give a highly pure title compound (4) (7 g; a mixture of diastereomers). This was a mixture of solid and liquid, and the mixing ratio of diastereomers was calculated as 7:3 by measuring with NMR. Analytical results on the title compound are given below. Optical rotation [α]D25=+15.6 (c=1, EtOH)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:33][CH2:32][C:14]2([C:18](=[O:19])[N:17]([O:20]C(OCC3C=CC=CC=3)=O)[C:16](=[O:31])[CH2:15]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCCN.Cl>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:33][CH2:32][C:14]2([C:18](=[O:19])[N:17]([OH:20])[C:16](=[O:31])[CH2:15]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CC2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Agent: CN(C)CCCN
Agent: Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2(CC1)CC(=O)N(O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a solution of 8-benzyloxycarbonyl-2-benzyloxycarbonyloxy-2,8-diazaspiro[4,5]decane-1,3-dione (5.6 g) in dichloromethane (50 ml) was added N,N-dimethyl-1,3-propanediamine (1.9 ml), and the mixture was stirred overnight at room temperature, to which was then added 1N hydrochloric acid (50 ml). The organic layer was washed with water, dried over anhydrous magnesium sulfate. The solvent was then evaporated off. The residual solid was recrystallized from ethyl ether-n-hexane to obtain 3.8 g of a colorless solid, m.p. 131° to 132° C.
Reaction SMILES: C(OC([N:8]1[C@@H:12](/[CH:13]=[C:14](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)\[CH3:15])[CH2:11][O:10]C1(C)C)=O)(C)(C)C>CCO.C(Cl)(Cl)Cl.[Pd]>[NH2:8][C@@H:12]([CH2:13][CH:14]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:15])[CH2:11][OH:10]
Reactant: C/C(=C\[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccccc1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(C[C@H](N)CO)c1ccccc1
Yield: 86.5 %

Procedure:
A solution of (S)-2,2-dimethyl-4-((E)-2-phenyl-propenyl)-oxazolidine-3-carboxylic acid tert-butyl ester (700 mg) in EtOH (30 ml) and CHCl3 (15 ml) was treated with 10% Pd/C (200 mg) and hydrogenated with a balloon overnight. The catalyst was filtered off, washed with EtOH and concentrated. The residue was dissolved in EtOH (10 ml) and treated with 2N HCl (15 ml). The mixture was heated for 90 min to 100° C., then concentrated. The residue was taken up in 1N NaOH and extracted with CH2Cl2/MeOH 4:1. The organic layer was dried over MgSO4, filtrated and concentrated. The crude product was purified by column chromatography (SiO2; gradient: CH2Cl2->CH2Cl2/MeOH 9:1) to give (S)-2-amino-4-phenyl-pentan-1-ol (342 mg) as off-white waxy solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:15]C.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[OH:15]
Reactant: COc1cc(Oc2ccccc2)ccc1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(Oc2ccccc2)ccc1Br
Reaction time: 2 h

Procedure:
To a solution of 1-bromo-2-methoxy-4-phenoxy-benzene (100.00 mg, 0.35 mmol) in DCM (5 mL) was slowly added boron tribromide (0.16 mL, 1.53 mmol) at −20° C. The reaction was stirred at that temperature for 2 h. The reaction mixture was concentrated in vacuo and dried on the pump. The crude reaction mixture was used for next step without further purification.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:16])[N:8]([CH2:17][O:18][CH3:19])[C:7]=2[CH:20]=1.S(Cl)([Cl:23])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:23][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:16])[N:8]([CH2:17][O:18][CH3:19])[C:7]=2[CH:20]=1
Reactant: O=S(Cl)Cl
Reactant: COCn1c(=O)c2c(c3ccc(CO)cc31)NCCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCn1c(=O)c2c(c3ccc(CCl)cc31)NCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
Anhydrous dichloromethane (10 ml) was added to the compound (50.0 mg, 0.182 mmol) prepared in step 5, and thionyl chloride (0.016 ml, 0.219 mmol) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 hours and poured into sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (51.4 mg, yield: 96%, white solid). The compound was used in the following reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[C:12](OCC)(OCC)(OCC)[CH2:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.NC1C=CC=CC=1O>C1(C)C=CC=CC=1>[CH2:13]([C:14]1[O:11][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[N:1]=1)[CH3:12]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: CCOC(CC)(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Nc1ccccc1O
Solvent: Cc1ccccc1
Product: CCc1nc2c([N+](=O)[O-])cccc2o1

Procedure:
A mixture of 2-amino-3-nitrophenol (1 eq.), triethyl orthopropionate (2 eq.) and p-toluene sulphonic acid (in a catalytic quantity) is stirred at 110° C. until disappearance of the aminophenol is verified by thin layer chromatography (2 hours). After cooling down, the reaction mixture is taken up in toluene followed by evaporating under vacuum then treating with isopropanol. The resulting precipitate is collected by filtration, followed by washing with isopropanol and isopentane, then drying under reduced pressure in order to produce a violet-brown solid.
Reaction SMILES: Cl[CH:2]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:3]1[O:4][C:5]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=1>>[CH:14]1([CH:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:3]2[O:4][C:5]3[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:6]=3[CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: COc1cccc2cc(C(Cl)C3CCCCC3)oc12
Product: COc1cccc2cc(C(Nc3ccc(C(=O)NCCC(=O)O)cc3)C3CCCCC3)oc12

Procedure:
Using 2-[chloro(cyclohexyl)methyl]-7-methoxy-1-benzofuran (422 mg) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (357 mg) synthesized in Example 1(2) and in the same manner as in Example A7(3), the title object compound (64.3 mg, 9%) was obtained as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([N:10]=[S:11]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[O:9])[CH:5]=[N:6][CH:7]=1.[OH:25][C:26]1[CH:27]=[C:28]([C:32]#[CH:33])[CH:29]=[CH:30][CH:31]=1.C(N(CC)CC)C>CN(C=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:25][C:26]1[CH:27]=[C:28]([C:32]#[C:33][C:2]2[CH:3]=[C:4]([C:8]([N:10]=[S@:11]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])=[O:9])[CH:5]=[N:6][CH:7]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: C#Cc1cccc(O)c1
Reactant: CCOC(=O)CS(=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Temperature: 60 °C
Yield: 94.3 %

Procedure:
A solution ethyl {N-[(5-bromopyridin-3-yl)carbonyl]-S-phenylsulfonimidoyl}acetate (216 mg, 0.52 mmol) and 3-hydroxyphenylacetylene (0.052 mL, 0.79 mmol) in anhydrous DMF (3 mL) was treated with triethylamine (0.22 mL, 1.58 mmol). The reaction mixture was degassed (alternating vacuum and argon) and PdCl2(Ph3P)2 (36.9 mg, 0.052 mmol) and triphenylphosphine (3.4 mg, 0.013 mmol) were added. The reaction mixture was degassed (alternating vacuum and argon) and placed under an atmosphere of 1:3 Argon/hydrogen atmosphere. Copper(1+) iodide was added and the reaction mixture was heated at 60° C. for 50 min. The brown reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc. The organic layer was collected and washed further with saturated aqueous NaHCO3 (1×), brine (1×), and dried over anhydrous Na2SO4. The residue was purified by chromatography (silica gel, 50:1 CHCl3:MeOH). The product containing fractions were concentrated to give the title compound as a light yellow solid (220 mg, 94%).
Reaction SMILES: COC1C2C=NCC3C4C=CC=CC=4CCC(C=23)=CC=1OC.[CH3:23][O:24][C:25]1[C:26]([O:43][CH3:44])=[C:27]2[CH2:38][CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=3[CH:29]3[CH2:30][N:31]=[CH:32][C:33]([CH:34]=1)=[C:28]23>>[CH3:23][O:24][C:25]1[C:26]([O:43][CH3:44])=[C:27]2[CH2:38][CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=3[CH:29]3[CH2:30][NH:31][CH2:32][C:33]([CH:34]=1)=[C:28]23
Reactant: COc1cc2c3c(c1OC)CCc1ccccc1C3CN=C2
Agent: COc1cc2c3c(c1OC)C=NCC3c1ccccc1CC2
Product: COc1cc2c3c(c1OC)CCc1ccccc1C3CNC2

Procedure:
By following the procedure of example 3, but replacing 4,5-dimethoxy-1,7,8,12b-tetrahydrobenzo[6,7]cyclohepta[1,2,3-de]isoquinoline with an equivalent amount of 5,6-dimethoxy-1,7,8,12b-tetrahydrobenzo[6,7]cyclohepta[1,2,3-de]isoquinoline, described in example 2; 5,6-dimethoxy-1,2,3,7,8,12b-hexahydrobenzo[6,7]cyclohepta[1,2,3-de]isoquinoline, NMR (CDCl3)δ 1.9 (s, 1H), 3.8 (2s, 6H), 4.4 (m, 1H), 6.6 (s, 1H), 7.15 (m, 4H), was obtained. The corresponding hydrochloride of the latter compound had mp>250° C., IR (white mineral oil) 2600 cm-1 ; Anal Calcd for C19H21NO2.HCl: C, 68.77% H, 6.68% N, 4.22%; Found: C, 68.25% H, 6.75% N, 3.98%.
Reaction SMILES: C(N(CC)CC)C.[N:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]=[O:10].[OH:17][C:18]1[C:23](=[O:24])[CH:22]=[CH:21][N:20]([CH3:25])[C:19]=1[CH3:26]>C(#N)C.C(Cl)Cl>[CH2:15]([O:14][C:12]([CH2:11][NH:8][C:9]([O:17][C:18]1[C:23](=[O:24])[CH:22]=[CH:21][N:20]([CH3:25])[C:19]=1[CH3:26])=[O:10])=[O:13])[CH3:16]
Reactant: CCOC(=O)CN=C=O
Reactant: Cc1c(O)c(=O)ccn1C
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)Oc1c(C)n(C)ccc1=O
Reaction time: 0.25 h

Procedure:
With stirring, 1.4 ml of triethylamine 1.7 ml of ethyl isocyanatoacetate are added at room temperature to a suspension of 1.39 g of 3-hydroxy-1,2-dimethyl-4(1H)-pyridinone in 100 ml of acetonitrile and 100 ml of methylene chloride, followed by the addition of 1.7 ml of ethyl isocyanatoacetate. The ensuing reaction is slightly exothermic. The solution that forms after about 15 minutes is concentrated by evaporation under reduced pressure after a further 45 minutes. The residue is dried under a high vacuum and crystallized from a mixture of methylene chloride and ethyl acetate. The crude crystalline product is taken up in 10 ml of methanol, insoluble material is removed by filtration, and the filtrate is concentrated by evaporation under reduced pressure. The residue is crystallised from a mixture of methylene chloride/ethyl acetate, affording 3-(ethoxycarbonylmethylaminocarbonyloxy)-1,2-dimethyl-4(1H)-pyridinone with a melting point of 132°-135° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1(O)[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1.C(N(S(F)(F)[F:23])CC)C>C(Cl)Cl>[F:23][C:6]1([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC1(c2nccs2)CCC2(CC1)OCCO2
Solvent: ClCCl
Product: FC1(c2nccs2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 4 h
Yield: 82.1 %

Procedure:
To a −78° C. solution of the product of Example 27A (4.53 g, 17.77 mmol) in methylene chloride (50 mL) was added diethylaminosulfur trifluoride (DAST) (4.18 g, 3.97 mL, 30.0 mmol). The reaction mixture was stirred at −78° C. for four hours, then allowed to warm to ambient temperature, and stirred overnight. The reaction mixture was then cooled to 0° C., quenched with saturated aqueous sodium bicarbonate, and extracted with methylene chloride. The organic layer was separated and concentrated. The resulting residue was chromatographed on silica gel, eluting with 0%-15% ethyl acetate-hexane to obtain the title compound (3.55 g, 78%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.83 (m, 1H), 7.79 (m, 1H), 3.92 (s, 4H), 2.41-2.07 (m, 4H), 1.91-1.63 (m, 4H). MS (DCI) m/z 244 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1)[CH3:2].Br[CH2:13][C:14]1[CH:33]=[CH:32][C:17]2/[C:18](=[C:28](/[CH3:31])\[C:29]#[N:30])/[C:19]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=3[O:21][CH2:22][C:16]=2[CH:15]=1>>[CH2:1]([C:3]1[N:4]([CH2:13][C:14]2[CH:33]=[CH:32][C:17]3/[C:18](=[C:28](/[CH3:31])\[C:29]#[N:30])/[C:19]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=4[O:21][CH2:22][C:16]=3[CH:15]=2)[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2]
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: CCc1nc2ccccc2[nH]1
Product: CCc1nc2ccccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 95.8 %

Procedure:
Using 2-ethyl-1H-benzo[d]imidazole (61 mg, 0.419 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (150 mg, 0.419 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (170 mg, 96%) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)#[N:14]>C1COCC1>[CH2:19]([C:18]1[CH:21]=[CH:22][C:15]([C:13]#[N:14])=[CH:16][CH:17]=1)[O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(CO)cc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(COCc2ccc(C#N)cc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a cooled (0° C.), stirred solution of 4-cyanobenzyl alcohol (637 mg, 4.8 mmol) in dry THF (15 mL) was added a dispersion of sodium hydride in mineral oil (60%; 192 mg, 4.8 mmol), portionwise over five minutes under an argon atmosphere. The resulting milky white solution was allowed to warm to room temperature and stirred for three hours (bubbling was observed). To the resulting light green mixture was added dry dimethylformamide (3 mL) to improve homogeneity. After stirring for an additional hour, the 4-cyanobenzyl bromide (930 mg, 4.8 mmol) was added. The resulting yellow, cloudy mixture was stirred at room temperature overnight. The reaction was then carefully quenched with the addition of 1 N aqueous HCl (15 mL) and extracted with ether (3×30 mL). The combined ethereal extracts were washed with water and brine then dried (MgSO4), filtered and concentrated in vacuo to provide the desired ether as a light yellow solid (1.06 g, 89%). No further purification was necessary.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])[C:28]=4[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])[CH:19]=3)[C:14](O)=[O:15])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH:49]1([NH2:52])[CH2:51][CH2:50]1>>[C:44]([CH2:43][CH2:42][C:28]1[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:18]2[CH:19]=[C:11]([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)[CH:12]=[C:13]([C:14](=[O:15])[NH:52][CH:49]3[CH2:51][CH2:50]3)[CH:17]=2)=[CH:32][CH:31]=[CH:30][C:29]=1[O:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])([OH:46])=[O:45]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)OCC
Reactant: NC1CC1
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NC3CC3)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)O

Procedure:
The title compound was prepared according to the general procedure described in Example 74 starting from 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoic acid and cyclopropylamine.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[S:13][CH:14]=[C:15]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:16]=2)=[N:4][CH:3]=1.[NH:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1.CC(C)([O-])C.[Na+]>CN(C=O)C.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[Pd].[Pd].[Pd]>[NH:24]1[CH:28]=[C:27]([C:2]2[N:7]3[N:8]=[CH:9][N:10]=[C:6]3[C:5]([NH:11][C:12]3[S:13][CH:14]=[C:15]([CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:16]=3)=[N:4][CH:3]=2)[CH:26]=[N:25]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Brc1cnc(Nc2nc(CN3CCOCC3)cs2)c2ncnn12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1nc2c(Nc3nc(CN4CCOCC4)cs3)ncc(-c3cn[nH]c3)n2n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 28.5 %

Procedure:
The product of Step 1 (43 mg, 0.11 mmol), 4-pyrazole boronic acid pinacol ester (32 mg, 0.16 mmol), tetrakis palladium triphenylphosphine (13 mg, 0.11 mmol) and sodium tert-butoxide are suspended in a mixture of DMF (2 mL) and water (0.66 mL). The reaction is degassed with nitrogen for 10 min before being sealed and stirred at 90° C. for 16 h. The reaction is condensed in vacuo and the residue purified by column chromatography, eluting with 3% methanolic ammonia (7 N) in dichloromethane to give the title compound as a pale yellow powder (12 mg, 29%). 1H NMR (400 MHz, d6-DMSO) δ 2.48 (s, 4H, CH2CH2), 3.35 (s, 2H, CH2), 3.63 (t, 4H, J=6 Hz, CH2CH2), 6.97 (s, 1H, H), 8.43 (s, 1H, H), 8.61 (brs, 2H), 8.81 (s, 1H, H), 12.9-12.4 (brs, 2H, NH×2). MS (MH+, m/z) 384.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>ClCCl.N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:11]([CH3:10])(=[O:13])=[O:12])=[C:4]([F:9])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Br)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Procedure MM: To a stirring solution of 4-bromo-2-fluoroaniline (1.0 mmol) in 3:1 dichloromethane/pyridine, add methanesulfonyl chloride (1.5 mmol) and stir at room temperature for 18 hours. After this time, wash the reaction with 1N hydrochloric acid while extracting with dichoromethane. Purify the title compound via radial chromatography eluting with ethyl acetate and hexane.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([N+:19]([O-])=O)=[C:7]([C:15]([O:17][CH3:18])=[O:16])[C:8](=[CH:13][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10])(=O)[CH3:2]>CO.[Pt].C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:2][C:1]1[NH:19][C:6]2[C:5](=[CH:14][CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]=2[C:15]([O:17][CH3:18])=[O:16])[N:4]=1
Reactant: COC(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1C(=O)OC
Agent: [Pt]
Solvent: CO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2nc(C)[nH]c2c1C(=O)OC
Yield: 60.1 %

Procedure:
A mixture of dimethyl 4-acetamido-3-nitrophthalate (142.1 g, 0.480 mol) in methanol with 5% platinum on carbon catalyst is hydrogenated on a Parr hydrogenator at room temperature. The reaction mixtures is filtered through diatomaceous earth and concentrated in vacuo to afford a solid residue. This solid is dispersed in glacial acetic acid and toluene, and heated with stirring at reflux temperatures for 4 hours with azeotropic removal of water. The resultant hot reaction mixture is slowly added to a saturated sodium bicarbonate solution with vigorous stirring, filtered and the filter cake dried to give the title product as a white solid (71.6 g, 60.1%), mp 97°-103° C.