Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[N:5]=[C:4]([C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])[N:3]=1.[F-:25].[K+].C1OCCOCCOCCOCCOCCOC1>S1(CCCC1)(=O)=O>[Cl:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[C:4]1[N:3]=[C:2]([F:25])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[N:5]=1
Reactant: [F-]
Reactant: Fc1cccc(Cl)c1-c1nc(Cl)n(-c2ccccc2C(F)(F)F)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: Fc1cccc(Cl)c1-c1nc(F)n(-c2ccccc2C(F)(F)F)n1
Temperature: 140 °C

Procedure:
A mixture of 2.61 g (6.9 mmol) of 5-chloro-3-(2-chloro-6-fluorophenyl)-1-(α,α,α-trifluoro-o-tolyl)-1H-1,2,4-triazole, 0.84 g (14.5 mmol) of dry potassium fluoride and 0.23 g (0.9 mmol) of 18-crown-6 in 15 ml of dry sulfolane is heated at 140° C. for 65 hours. The reaction mixture is subsequently cooled and eluted on silica gel (φ 40-63 μm, column: 0 7 cm, height 20 cm) with ethyl acetate/n-hexane (7:13). There is obtained 3-(2-chloro-6-fluorophenyl)-5-fluoro-1-(α,α,α-trifluoro-o-tolyl)-1H-1,2,4-triazole as white crystals, m.p. 68°-70° C.; mass spectrum: 359(100).
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11](O)=[CH:12][CH:13]=2)=[CH:5][CH:4]=[C:3](O)[CH:2]=1.CC1C([N:26]2[C:30](=[O:31])[CH:29]=[CH:28][C:27]2=[O:32])=C(C=CC=1)C(Cl)=O>C(N(CC)CC)C.ClCCCl>[CH:1]1[C:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([N:26]3[C:30](=[O:31])[CH:29]=[CH:28][C:27]3=[O:32])=[CH:12][CH:13]=2)=[CH:5][CH:4]=[C:3]([N:26]2[C:27](=[O:32])[CH:28]=[CH:29][C:30]2=[O:31])[CH:2]=1
Reactant: Cc1cccc(C(=O)Cl)c1N1C(=O)C=CC1=O
Reactant: Oc1ccc(Cc2ccc(O)cc2)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C1C=CC(=O)N1c1ccc(Cc2ccc(N3C(=O)C=CC3=O)cc2)cc1

Procedure:
A 6.0 g quantity of 4,4′-dihydroxydiphenylmethane is dissolved in a solution of 12.6 ml of triethylamine in 50 ml of 1,2-dichloroethane in a 250 ml flask. To the solution is slowly added a solution of 15.5 g of methyl maleimidobenzoyl chloride in 50 ml of 1,2-dichloroethane. The mixture is allowed to react at room temperature for 16 hr. The reaction mixture is precipitated in water, filtered under reduced pressure, washed sequentially with water and ethanol, and dried at 60° C. under vacuum for 48 hr, yielding the bismaleimide compound of Formula 20m.
Reaction SMILES: [Na].[C:2]([O:8][CH3:9])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[CH2:10]([C:15]1[C:16](=[O:20])[CH2:17][CH2:18][CH:19]=1)[CH2:11][CH2:12][CH2:13][CH3:14].[Cl-].[Na+]>C(O)(=O)C.CO>[CH2:10]([C:15]1([CH:3]([C:2]([O:8][CH3:9])=[O:7])[C:4](=[O:5])[CH3:6])[CH2:19][CH2:18][CH2:17][C:16]1=[O:20])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC1=CCCC1=O
Reactant: COC(=O)CC(C)=O
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCCC1(C(C(C)=O)C(=O)OC)CCCC1=O
Reaction time: 48 h
Yield: 70.5 %

Procedure:
750 ml of absolute methanol was introduced into a 2 liter flask. Then 17.3 g of sodium were added thereto, and 580 g of methyl acetoacetate were then added after which 456 g of 2-n-pentyl-cyclopent-2-en-1-one were added and the mixture was allowed to stand for 48 hours at the ambient temperature. The reaction product was neutralised with 45 g of acetic acid and then poured into 3 liters of a 10% aqueous sodium chloride solution. The product was then worked up as described in Example 1 (a). There were thus obtained 567 g (yield=70%) of 2-n-pentyl-(1-carbomethoxy-2-oxopropyl)-1-cyclopentanone having: nD20 =1.4702, d420 =1.0545.
Reaction SMILES: [CH2:1]([CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:21][C:22]1[CH:35]=[CH:34][C:25]([C:26]([O:28][CH2:29][P:30]([CH3:33])([CH3:32])=[O:31])=[O:27])=[CH:24][CH:23]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:33][P:30]([CH2:29][O:28][C:26]([C:25]1[CH:24]=[CH:23][C:22]([N:21]2[C:11]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[CH2:18][CH2:19][C:10]=3[CH:1]=[C:2]2[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:35][CH:34]=1)=[O:27])([CH3:32])=[O:31]
Reactant: O=C(CC1CCc2ccccc2C1=O)c1ccccc1
Reactant: CP(C)(=O)COC(=O)c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CP(C)(=O)COC(=O)c1ccc(-n2c(-c3ccccc3)cc3c2-c2ccccc2CC3)cc1

Procedure:
A mixture of 2.6 g. (0.01 mole) of 2-phenacyl-1-tetralone, 2.3 g. (0.01 mole) of dimethylphosphinylmethyl p-aminobenzoate, 0.4 g. of p-toluenesulfonic acid, and 250 ml. of dry toluene was heated under reflux for 73 hours, concentrated to about 100 ml., diluted with 25 ml. of cyclohexane, and cooled. The solid which separated was collected to provide 2.6 g. (57%) of solid, m.p. 171°-173°. Recrystallization from cyclohexane-benzene gave pale yellow crystals, m.p. 180°-181°.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([CH:9]2[CH2:11][CH2:10]2)[C:7]2[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:3].Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([NH2:27])[C:22]=1[I:28].CCN(C(C)C)C(C)C>C(O)CCC>[NH2:27][C:23]1[N:24]=[CH:25][N:26]=[C:21]([NH:1][C@H:2]([C:4]2[N:8]([CH:9]3[CH2:10][CH2:11]3)[C:7]3[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=3[N:5]=2)[CH3:3])[C:22]=1[I:28]
Reactant: CNC(=O)c1cccc2nc([C@H](C)N)n(C3CC3)c12
Reactant: Nc1ncnc(Cl)c1I
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3I)n(C3CC3)c12
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-2-(1-aminoethyl)-1-cyclopropyl-N-methyl-1H-benzo[d]imidazole-7-carboxamide (Prepared in Example 20, 190 mg, 0.74 mmol), 6-chloro-5-iodopyrimidin-4-amine (188 mg, 0.736 mmol) and 1,1′-dimethyltriethylamine (256 μL, 1.47 mmol) in n-butanol (2 mL) was stirred at 120° C. After 18 h, the mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using 0 to 10% gradient of MeOH in DCM-EtOAc (1:1) as eluent to give (S)-2-(1-(6-amino-5-iodopyrimidin-4-ylamino)ethyl)-1-cyclopropyl-N-methyl-1H-benzo-[d]imidazole-7-carboxamide: 1H NMR (400 MHz, DMSO-d6) δ 8.46-8.40 (m, 1H), 7.87 (s, 1H), 7.67 (d, J=8 Hz, 1H), 7.24 (d, J=8 Hz, 1H), 7.20 (dd, J=8, 8 Hz, 1H), 6.46 (m, 1H), 6.37 (d, J=8 Hz, 1H), 5.82-5.75 (m, 1H), 2.84 (d, J=4 Hz, 3H), 1.60 (d, J=8 Hz, 3H), 1.14-1.04 (m, 2H), 0.93-0.90 (m, 1H), 0.85-0.76 (m, 1H); LC-MS (ESI) m/z 478.0 [M+H]+.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][S:8][CH2:9][CH:10]([C:17](=[O:24])[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:2][CH2:3][CH3:4].[CH:25]1([N:31]=[C:32]=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH2:1]([N:5]([C:32]([NH:31][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:33])[CH2:6][CH2:7][S:8][CH2:9][CH:10]([C:17](=[O:24])[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: O=C=NC1CCCCC1
Reactant: CCCCNCCSCC(CC(=O)OCC)C(=O)c1cccnc1
Product: CCCCN(CCSCC(CC(=O)OCC)C(=O)c1cccnc1)C(=O)NC1CCCCC1
Yield: 48 %

Procedure:
The title compound was prepared from ethyl 3 {[2-(butylamino)ethylthio] methyl}-4-oxo-4-(3-pyridyl)butanoate and cyclohexylisocyanate as described in the above Example 35 in 48% yield; ESMS (M+1+) 478.
Reaction SMILES: O=[C:2]1[C:7]([O:8]B(O)O)=[CH:6][CH2:5][CH2:4][CH2:3]1.Br[C:13]1[N:17]([CH3:18])[CH:16]=[N:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>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.O>[CH3:18][N:17]1[C:13]([C:2]2[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH:3]=2)=[CH:14][N:15]=[CH:16]1
Reactant: Cn1cncc1Br
Reactant: O=C1CCCC=C1OB(O)O
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cncc1C1=CCCCC1=O
Yield: 8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 39a by using (6-oxocyclohex-1-en-1-yl)boric acid (J. Org. Chem. 2011, 76, 3946-3959; 790 mg, 5.65 mmol), 5-bromo-1-methyl-1H-imidazole (910 mg, 5.65 mmol), tetrakis(triphenylphosphine)palladium (0) (326 mg, 0.282 mmol), cesium carbonate (4.00 g, 12.3 mmol), 1,4-dioxane (10 mL) and water (5 mL), to yield the title compound (80 mg, 8%) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:29])=[CH:7][C:8]([CH3:28])=[C:9]([C:11]2[NH:27][C:14]3[CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH2:19][C:13]=3[N:12]=2)[CH:10]=1)=[O:4].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[NH:12]1[C:13]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15][C:14]=2[N:27]=[C:11]1[C:9]1[C:8]([CH3:28])=[CH:7][C:6]([CH3:29])=[C:5]([CH:10]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cc(-c2nc3c([nH]2)CCN(C(=O)OC(C)(C)C)CC3)c(C)cc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(-c2nc3c([nH]2)CCNCC3)c(C)cc1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of tert-butyl 2-(5-(methoxycarbonyl)-2,4-dimethylphenyl)-4,5,7,8-tetrahydroimidazo[4,5-d]azepine-6(1H)-carboxylate (compound 83.3, 800 mg, 2.00 mmol) in dichloromethane (16 mL). Trifluoroacetic acid (4 mL) was added drop-wise and the resulting solution was stirred for 5 h at room temperature. The pH of the solution was carefully adjusted to 8-9 with NaHCO3 (sat.) and the aqueous phase was extracted with DCM (3×30 mL), and the combined organics were dried (Na2SO4), filtered, and concentrated under reduced pressure to yield 0.60 mg (crude) of the title compound as brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=[O:10])=[C:4]([N+:12]([O-])=O)[CH:3]=1.C(OCC)(=O)C>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][C:9](=[O:10])[NH:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1Cc2ccc(Br)cc2N1
Temperature: 100 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
Iron (40.0 g, 700 mmol) was added slowly to a stirred solution of 2-(4-bromo-2-nitrophenyl)acetic acid (preparation 1b, 46.6 g, 200 mmol) in acetic acid (390 mL) at 75° C., and then mixture was stirred for 1 hour at 100° C. The mixture was cooled and ethyl acetate was added. The mixture was filtered through Celite® and the solvent evaporated. The crude product was washed with 0.1M aqueous hydrochloric acid, water, diethyl ether and dried to give the title compound (22.0 g, 58%) as a solid.
Reaction SMILES: O=[C:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][O:4][C:5](=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].C([NH2:26])(=O)C.B(F)(F)F.CCOCC>C([O-])(O)=O.[Na+]>[CH3:15][O:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1[O:4][CH:3]=[C:2]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: CC(N)=O
Reactant: COC(=O)CCCCCCC(=O)OCC(=O)c1ccccc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: COC(=O)CCCCCCc1nc(-c2ccccc2)co1
Yield: 87.8 %

Procedure:
Heat a mixture of octanedioic acid methyl ester 2-oxo-2-phenylethyl ester (6.93 g, 22.6 mmol), acetamide (6.75 g, 114 mmol) and boron trifluoride diethyl etherate (3.0 mL, 23.7 mmol) at 135-140° C. under nitrogen for 4 hours. Cool the mixture, dilute with saturated NaHCO3 solution (100 mL), and extract with ethyl acetate (250 mL). Wash the organic extract with 100 mL of saturated aqueous sodium chloride (brine) and dry over sodium sulfate. Remove the solvent under reduced pressure and purify the residue by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (85:15), to provide 7-(4-phenyloxazol-2-yl)heptanoic acid methyl ester (5.7 g, 88%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[NH:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[NH:7][C:8](=[O:10])[CH3:9])=[O:3]
Reactant: BrBr
Reactant: CC(=O)Nc1cccc(C(C)=O)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cccc(C(=O)CBr)c1
Reaction time: 1 h

Procedure:
To a stirred solution of 110.0 g. (0.62 mole) of 3'-acetylacetanilide in 2400 ml. of chloroform is added dropwise a solution of 33.0 ml. (102.9 g; 0.644 mole) of bromine in 240 ml. of chloroform. The solution is stirred one hour and the resultant precipitate is then filtered, washed with ether and dried. The solid is stirred in a large volume of water to give an oily precipitate which crystallizes on further stirring. The solid is filtered, washed with water and then 2-propanol. The dried product weighs 148.34 g., and is recrystallized from 2-propanol to give the product, melting point 108.5°-110°C. Analysis: Calcd. for C10H10BrNO2 : Calcd: C, 46.90; H, 3.94; Br, 31.20; N, 5.47. Found: C, 47.12; H, 3.94; Br, 31.21; N, 5.47.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.Cl.[NH2:12][C@H:13]([CH:28]1[CH2:30][CH2:29]1)[C:14]1([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>C(C#N)(C)=O.CCOC(C)=O>[CH2:20]([O:19][C:18](=[O:27])[NH:17][C:14]1([C@H:13]([NH:12][C:6]2[CH:5]=[N:4][C:3]([C:9]#[N:10])=[C:2]([Cl:1])[N:7]=2)[CH:28]2[CH2:29][CH2:30]2)[CH2:15][CH2:16]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: N#Cc1ncc(Cl)nc1Cl
Reactant: N[C@H](C1CC1)C1(NC(=O)OCc2ccccc2)CC1
Agent: CC(=O)C#N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ncc(N[C@H](C2CC2)C2(NC(=O)OCc3ccccc3)CC2)nc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.4 %

Procedure:
To a mixture of 3,5-dichloropyrazine-2-carbonitrile (208 mg, 1.19 mmol) and (R)-benzyl 1-(amino(cyclopropyl)methyl)cyclopropylcarbamate HCl salt (350 mg, 1.19 mmol) in AcCN (2 mL) was added DIPEA (0.467 mL, 2.62 mmol). After stirring at room temperature for 3 h, it was diluted with EtOAc, washed with sat. NaHCO3, organic layer was separated and washed with brine, dried and concentrated to give (R)-benzyl-1-((6-chloro-5-cyanopyrazin-2-ylamino)(cyclopropyl)methyl)cyclopropylcarbamate (480 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]([CH3:22])[CH:11]=2)=[S:9])=[CH:4][CH:3]=1.[CH2:25]([OH:28])[C:26]#[CH:27]>C(NCC)C.[Cu](I)I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:27]#[C:26][CH2:25][OH:28])[CH:17]=3)[N:12]([CH3:22])[CH:11]=2)=[S:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=S)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Reactant: C#CCO
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: Cn1cc(C(=S)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21

Procedure:
A suspension of N-(4-chlorobenzyl)-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbothioamide (0.20 g) from Preparation No. 44, propargyl alcohol (0.030 mL), copper iodide (0.028 g), and bis(triphenylphosphine)palladium(II)chloride (0.0095 g) in diethylamine (10 mL) is stirred at room temperature for 18 h. The solid in the reaction mixture is filtered, then dissolved in CH2Cl2/MeOH, and adsorbed onto silica. Purification by chromatography (eluent 1% MeOH:CH2Cl2 (1 L), 2% MeOH:CH2Cl2 (1 L)) affords the title compound as a yellow solid (0.12 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][C:7](=[O:21])[C:6]=2[CH:22]=1.[CH3:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:26](=[O:27])[C:25]4[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=4[CH3:23])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][C:7](=[O:21])[C:6]=2[CH:22]=1
Reactant: Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)cn1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of 7-chloro-5-oxo-1-(6-aminonicotinoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.25 g) in pyridine (2 ml) is added with stirring 2-methylbenzoyl chloride (0.18 g) under ice-cooling, and the mixture is stirred at room temperature for one hour. To the reaction solution is added water, and the mixture is extracted with ethyl acetate. The extract is washed successively with 0.1N aqueous hydrochloric acid solution and water, and dried over magnesium sulfate. The resultant is evaporated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography to give 7-chloro-5-oxo-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.3 g) as colorless amorphous.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2(CC3C=CC=CC=3[O:11]2)[CH2:3][NH:2]1.[H][H].FC1C=CC=CC=1CCl.FC1C=CC=CC=1CBr>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([OH:11])[CH2:3][NH:2]1
Reactant: [H][H]
Reactant: c1ccc2c(c1)CC1(CNCc3ccccc31)O2
Agent: Fc1ccccc1CBr
Agent: Fc1ccccc1CCl
Product: OC1CNCc2ccccc21

Procedure:
To prepare the parent ring system 7, i.e., the spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] 1 wherein R is hydrogen, a 2,3-dihydro-4(1H)isoquinoline 3 wherein R is loweralkyl or benzyl is treated with a Grignard reagent 4, prepared from a 2-fluorobenzyl chloride or 2-fluorobenzyl bromide by conventional methods, to afford the 1,2,3,4-tetrahydro-4-isoquinolinol 2, which is cyclized to the spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] 5, wherein R is loweralkyl or benzyl and dealkylated or debenzylated to spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] 7, via the alkoxycarbonyl or phenoxycarbonyl derivative 6 wherein R1 is loweralkyl or phenyl, respectively. (See Reaction Scheme I).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23].C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>CN(C)C=O>[C:19]([C:4]1[C:3]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[C:2]([NH:1][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:20]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)C(F)(F)F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(NCc2ccccc2)c1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoroacetylpyrazole (1 g) in anhydrous N,N-dimethylformamide (4 ml) at room temperature was added potassium carbonate (0.7 g), then benzyl bromide (228 μl). The mixture was stirred at room temperature for 40 minutes. Water (50 ml) was then added, and the mixture was extracted with ether (50 ml, ×2). The combined organic layers were washed with water (50 ml), dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography on silica gel (50 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p 75-76° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:21]([NH:23][NH2:24])=O.Cl.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]2[N:4]([C:21]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][N:15]=3)=[N:23][N:24]=2)[N:3]=1
Reactant: Clc1cc(-c2ccccc2)c(Cl)nn1
Reactant: NNC(=O)c1cnccn1
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: Clc1nn2c(-c3cnccn3)nnc2cc1-c1ccccc1

Procedure:
The product from Example 1 step b) (1 g, 4.46 mmol) was suspended in xylene (25 ml) with pyrazine-2-hydrazide (0.74 g, 5.35 mmol) and triethylamine hydrochloride (0.61 g, 4.46 mmol) and the reaction mixture was heated at reflux for 2 days. The solvent was removed under high vacuum, and the residue was dissolved in dichloromethane, basified with sodium bicarbonate and the aqueous extracted with dichloromethane (2×150 ml). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by silica gel chromatography using 0-40% ethyl acetate in dichloromethane as eluent to give the required product (0.249 g). 1H NMR (250 MHz, DMSO) δ 7.56 (5H, m), 8.43 (1H, s), 8.87 (1H, d, J=2.5 Hz), 8.96 (1H, d, J=2.5 Hz), 9.49 (1H, d, J=2.5 Hz); MS (ES+) m/e 309 [MH+].
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[Cl:21][C:22]1[CH:34]=[CH:33][C:25]([CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:24][CH:23]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:21][C:22]1[CH:34]=[CH:33][C:25]([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([C:15](=[O:17])[CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)[CH2:29][CH2:28]2)=[CH:24][CH:23]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N2CCN(Cc3ccc(Cl)cc3)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1-(4-chloro-benzyl)-piperazine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C23H27ClN2O5 [M+H]+: 447.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1

Procedure:
61.2 g of 3-hydroxy-4-nitrotoluene, 66.3 g of potassium carbonate, and 54.7 ml of benzyl chloride are heated in 800 ml of dimethylformamide to 100° C. for 1.5 hours; after cooling, the mixture is poured into water, and the thus-precipitated material is recrystallized from ethanol, yielding 82.0 g of 3-benzyloxy-4-nitrotoluene, mp 49°-51° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.O=C1[N:15]2[CH2:16][CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH:14]2[CH2:13]O1.O>CN(C=O)C>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:13][C@@H:14]2[NH:15][CH2:16][CH2:17][N:18]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:19]2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)OCC2C1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN[C@@H](COc2cccnc2)C1
Temperature: 120 °C
Yield: 41.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 4.50 g, 113 mmol) was added portionwise to a solution of 3-hydroxypyridine (13.2 g, 139 mmol) and tert-butyl tetrahydro-3-oxo-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylate (3.37 g, 13.9 mmol) in DMF (100 mL). Upon complete addition, the reaction mixture was heated to 120° C. for 60 h. Upon cooling to rt, water (10 mL) was added and the reaction mixture was concentrated under reduced pressure. The material was dissolved in H2O (150 mL) and EtOAc (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organics were concentrated under reduced pressure. The material was dissolved in EtOAc (150 mL) and washed with 1 N NaOH (3×50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (0 to 5% MeOH in CH2Cl2 gradient) gave 1.7096 g (42%) of the desired product as a white solid. LC-MS: RT=3.81 min, [M+H]+=294.2.