Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([C:5]1[C:25](=[O:26])[C:24](C(C)(C)C)=[CH:23][C:7](=[C:8]2[CH:14]=[C:13](C(C)(C)C)[C:11](=[O:12])[C:10](C(C)(C)C)=[CH:9]2)[CH:6]=1)(C)C>[Pd]>[C:11]1([OH:12])[CH:10]=[CH:9][C:8]([C:7]2[CH:23]=[CH:24][C:25]([OH:26])=[CH:5][CH:6]=2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)C1=CC(=C2C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C2)C=C(C(C)(C)C)C1=O
Agent: [Pd]
Product: Oc1ccc(-c2ccc(O)cc2)cc1
Reaction time: 3 h
Yield: 85.4 %

Procedure:
10 g (24.5 mmol) of 3,3',5,5'-tetra-tert-butyl-diphenoquinone in 40 ml of ethylbenzene was hydrogenated as in Example 9. The filtered reaction mixture containing 4,4'-bis(2,6-di-tert-butylphenol) was transferred to a heavy walled bottle containing a magnetic stirring bar and as strong solid acid 9 g Nafion® 117, which was obtained from the Du Pont Company as a film, which was cut into small pieces, treated with conc. HCl at 70° C. for one hour, washed with water and acetone and dried in an oven at 70° C. over night. The reactor was placed in an oil bath at 170° C. with stirring. The dealkylation was completed within 30 minutes. 3.8 g (20.4 mmol) of 4,4'-biphenol was obtained in the same way as described in Example 9 (83.3% yield). The filtrate containing 14.3 g p- and m-tert-butyl-ethylbenzene was placed in a popbottle containing 0.2 g 5% Pd/C, 10 g 3,3',5,5'-tetra-tert-butyl-diphenoquinone, and magnetic stirring bar. The hydrogenation was completed after 3 hours at 130° C. under 25 psi H2 pressure. The removal and washing of the catalyst was done as described above. The filtrate was transferred to a popbottle containing a magnetic stirring bar and the catalyst from the previous dealkylation, which had been treated with conc. HNO3, washed with acetone and water and dried at 70° C. overnight. The reaction mixture was kept at 170° C. for 45 minutes, cooled and worked up in the same way as above. 3.9 g (20.9 mmole) of 4,4'-biphenol was obtained (85.5% yield). The filtrate contained 22.2 g of p- and m-tert-butyl-ethylbenzene (69.9% yield).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:33])[CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:10][O:11][C:12](=[O:33])[CH:13]=[CH:8][C:5]1[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)nc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1ccc(Br)nc1
Yield: 97.5 %

Procedure:
To 6-bromo-pyridine-3-carboxaldehyde (300 mg, 1.61 mmol) in toluene was added methyl(triphenylphosphoranylidene)acetate (647 mg, 1.94 mmol) and the solution was refluxed for 6 hrs. The reaction mixture was diluted with EtOAc and then washed three times with H2O, brine, dried. Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was column-chromatographed to yield 3-(6-bromo-pyridin-3-yl)-acrylic acid methyl ester (380 mg, 97%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=4)[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:30]([O:32][C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([C:40]#[CH:41])=[CH:36][CH:35]=1)[CH3:31].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:30]([O:32][C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([C:40]#[C:41][C:12]2[C:13]3[C:14](=[N:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=4)[CH:18]=3)[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:11]=2)=[CH:36][CH:35]=1)[CH3:31]
Reactant: COc1ccc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccccc2)cc1OC
Reactant: C#Cc1ccc(C(=O)OCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(-c4ccc(OC)c(OC)c4)cc23)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
1-Benzenesulfonyl-5-(3,4-dimethoxy-phenyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine (0.0800 g, 0.000151 mol), 4-Ethynyl-benzoic acid ethyl ester (0.0321 g, 0.000181 mol), Bis(triphenylphosphine)palladium(II) chloride (0.0048 g, 0.0000069 mol), and Copper(I) iodide (0.00024 g, 0.0000013 mol) were dissolved in Triethylamine (0.8 mL, 0.005 mol) under an atmosphere of Nitrogen. The resulting mixture was heated to 60° C. and stirred under an atmosphere of Nitrogen for 2 hours. The reaction mixture was was concentrated under reduced pressure and water (30 mL) was added to the residue. This slurry was extracted with ether. (20 mL 2×). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by chromatography (Silica gel, ethyl acetate/hexanes to give 85 mg of the titled product as a pale orange solid. MS(ESI) [M+H+]+=567.10
Reaction SMILES: [N+:1]([CH2:4][CH:5]([OH:20])[CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)([O-])=O.[C:21]([OH:24])(=[O:23])[CH3:22].CCOCC>C(O)C.[Ni]>[NH2:1][CH2:4][CH:5]([OH:20])[CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1.[C:21]([O-:24])(=[O:23])[CH3:22]
Reactant: O=[N+]([O-])CC(O)C(c1ccccc1)c1cccc(Cl)c1
Reactant: CC(=O)O
Agent: [Ni]
Solvent: CCO
Solvent: CCOCC
Product: CC(=O)[O-]
Product: NCC(O)C(c1ccccc1)c1cccc(Cl)c1
Reaction time: 4 h
Yield: 72 %

Procedure:
Crude 3-nitro-1-phenyl-1-(m-chlorophenyl)propan-2-ol (43 g; 0.15 M) in ethanol (600 ml) containing acetic acid (9.3 ml:l equiv.) and RaNi (approx. 20 g.,) was hydrogenated at 250 p.s.i. H2 pressure for 4 hours. The mixture was filtered and evaporated to give a greenish oil. Trituration with ether (250 ml) gave the required product (34 g; 72%) as an off-white solid M.pt. 132°-137° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH:18]([NH2:27])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([OH:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:29][C:30](Cl)=[O:31].[Na+].[I-].[I-].CC(C)([O-])C>>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C:14]2([O:17][CH2:29][C:30](=[O:31])[NH:27][CH:18]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: NC(Cc1ccc(F)cc1)C1(O)CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [Na+]
Product: O=C1COC2(CCN(C(=O)OCc3ccccc3)CC2)C(Cc2ccc(F)cc2)N1
Yield: 19 %

Procedure:
The title compound was prepared from aminoalcohol 103NLS28 (303 mg, 0.81 mmol) according to literature procedures (Clark et al., J. Med. Chem. 26:855-861 (1983)), by acylation of the amino function with chloroacetylchloride, followed by halogen exchange with NaI and ring closure of the iodide derivative in presence of tert-butoxide. Purification of the crude product by silica gel column chromatography, eluting with a stepwise gradient of 0-100% ethyl acetate in n-heptane, afforded the title compound (64 mg, 19% overall yield) as a colourless solid.
Reaction SMILES: [BH4-].[Na+].CSC.B(F)(F)F.CCOCC.[CH:15]1([CH2:20][CH2:21][C:22](O)=[O:23])[CH2:19][CH2:18][CH2:17][CH2:16]1>O1CCCC1>[CH:15]1([CH2:20][CH2:21][CH2:22][OH:23])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(O)CCC1CCCC1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CSC
Product: OCCCC1CCCC1
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
A 12-liter, 4-necked glass reaction vessel equipped as described in Example 1 was charged with 180 grams (4.75 moles) of sodium borohydride, 4 liters of tetrahydrofuran, 0.485 liter (6.6 moles) of dimethyl sulfide, and 0.74 liter (6.0 moles) of boron trifluoride diethyl etherate at 0°-5°C using essentially the same procedure as described in Example 1. After stirring for a additional 0.5 hour at 20°-25°C, 780 grams (5.5 moles) of 3-cyclopentylpropionic acid was added dropwise over a 3 hour period while maintaining a temperature of 35°-40°C. After standing overnight at room temperature, hydrolysis of the reaction mixture followed by distillation of the crude product gave 613 grams (87.5% yield) of 3-cyclopentyl-1-propanol, bp 93°-95°C at 8 mm, n20D 1.4595.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[S:10][C:11]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16]Cl)=[CH:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1.C(O)(=O)C(O)=O.S1C2C=CC=CC=2C(N2CCN(CCCC(C3SC4SCCNC(=O)C=4C=3)=O)CC2)=N1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[S:10][C:11]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][N:31]3[CH2:30][CH2:29][CH:28]([C:25]4[C:24]5[CH:34]=[CH:35][C:21]([F:20])=[CH:22][C:23]=5[O:27][N:26]=4)[CH2:33][CH2:32]3)=[CH:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)N1CCc2sc(C(=O)CCCCl)cc2C1
Agent: Cl
Agent: O=C(CCCN1CCN(c2nsc3ccccc23)CC1)c1cc2c(s1)SCCNC2=O
Agent: O=C(O)C(=O)O
Product: CC(=O)N1CCc2sc(C(=O)CCCN3CCC(c4noc5cc(F)ccc45)CC3)cc2C1
Yield: 34.2 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.8 g of 5-acetyl-2-(4-chlorobutyryl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and 1.6 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 1.0 g of 5-acetyl-2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine as an oil, m.p. 235° C. as hydrochloride 1/2 hydrate thereof.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:17]=1[CH:18]=[CH:19][CH:20]=O.C(O)=O.Cl>C(O)C>[ClH:1].[ClH:15].[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:20][CH:19]=[CH:18][C:17]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:16]=3[Cl:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=CC=Cc1ccc(Cl)cc1Cl
Reactant: Clc1ccc(CN2CCNCC2)cc1
Agent: Cl
Solvent: CCO
Solvent: O=CO
Product: Clc1ccc(CN2CCN(CC=Cc3ccc(Cl)cc3Cl)CC2)cc1
Temperature: 130 °C
Yield: 81.4 %

Procedure:
N-(4-Chlorobenzyl)piperazine (4.2 g, 19.93 mmole) (which is prepared by the process as disclosed in Yoshiaki Ikeda et al., Yakugaku Zasshi, Vol. 89, 669-676, 1969) and 2,4-dichlorocinnamaldehyde (4.1 g, 20.39 mmole) (which is prepared by the process as disclosed in U.S. Pat. No. 3,094,561) are mixed and heated on an oil bath at 130° C. to melt them, and thereto is added dropwise formic acid (2.0 ml, 52.6 mmole), and the mixture is stirred under heating for 30 minutes. The reaction mixture is allowed to cool and is dissolved in ethanol (30 ml), and to the solution is added an ethanol solution (90 ml) of conc. hydrochloric acid (4.5 ml). The precipitated crystals are separated by filtration. The crystals are recrystallized from water-ethanol to give the title compound (3.8 g). The product shows the same physical properties as those of the compound prepared in Example 1-(1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:21])=[CH:5][C:6]([OH:20])=[C:7]2[C:12](=[O:13])[CH:11]=[C:10]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:9][C:8]=12.[CH2:22]=O.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CO>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:22][C:5]2[C:6]([OH:20])=[C:7]3[C:8](=[C:3]([O:2][CH3:1])[C:4]=2[OH:21])[O:9][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][C:12]3=[O:13])[CH2:27][CH2:26]1
Reactant: CN1CCNCC1
Reactant: COc1c(O)cc(O)c2c(=O)cc(-c3ccccc3)oc12
Reactant: C=O
Solvent: CO
Product: COc1c(O)c(CN2CCN(C)CC2)c(O)c2c(=O)cc(-c3ccccc3)oc12
Temperature: 51 °C
Reaction time: 4 h

Procedure:
The mixture of Wogonin (28.4 g), methanol (350 ml), 37% formaldehyde solution (8.04 ml), 4-N-methyl-piperazine (10.1 g) was stirred under for 4 hours at 51° C., then precipitates were removed by filtration and washed several times with methanol, after drying under reduced pressure at 55° C. to get the product as orange red solid 38.6 g of purity 99.7%. m.p.: 179° C. MS: (API-ES) m/z 397.5 [M+H]+, 419.5 [M+Na]+, 1H NMR (DMSO-d6/CF3COOD, 400 MHz): δ 8.12˜8.14 (m, 2H, Ar-2′,6′-H), 7.64˜7.66 (m, 3H, Ar-3′,4′,5′-H), 7.15 (s, 1H, 3-H), 4.44 (s, 2H, CH2), 3.96 (s, 3H, 8-OCH3), 3.43-3.74 (m, 8H, CH2), 2.93 (s, 3H, N—CH3).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([N:20]([CH2:25][C:26]([OH:28])=O)[CH2:21][C:22]([OH:24])=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)=O.[NH2:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:43][CH3:44])[CH:41]=2)[CH:36]=[CH:35][CH:34]=1>O1CCCC1.C(O)C>[CH3:44][O:43][C:40]1[CH:41]=[C:42]2[C:37]([CH:36]=[CH:35][CH:34]=[C:33]2[N:32]2[C:22](=[O:24])[CH2:21][N:20]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:25][C:26]2=[O:28])=[CH:38][CH:39]=1
Reactant: O=C(O)CN(CC(=O)O)Cc1ccccc1
Reactant: COc1ccc2cccc(N)c2c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2cccc(N3C(=O)CN(Cc4ccccc4)CC3=O)c2c1
Yield: 82 %

Procedure:
126 mmol (2.2 equivalents) of carbonyldiimidazole are added to a suspension containing 58 mmol (1 equivalent) of N-benzyliminodiacetic acid in 200 ml of anhydrous tetrahydrofuran. The mixture is brought to reflux until the evolution of CO2 has ceased. A solution containing 58 mmol (1 equivalent) of 1-amino-7-methoxynaphthalene in 40 ml of anhydrous tetrahydrofuran is then added to the above mixture. The resulting mixture is brought to reflux for 20 hours, the solvent is evaporated off and the residue obtained is taken up with 300 ml of anhydrous ethanol. The precipitate formed is filtered off and then dissolved in 200 ml of dichloromethane. The insoluble matter is filtered off and the filtrate concentrated. The expected product is then obtained after taking up in isopropyl ether followed by filtration.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH:3]=[CH:4][C:5]#[N:6].C(N(CC)CC)C.[Cl:15][C:16]1[CH:24]=[C:23]([Cl:25])[C:22]([F:26])=[CH:21][C:17]=1[C:18](Cl)=[O:19]>O1CCOCC1>[CH3:1][N:2]([CH3:7])[CH:3]=[C:4]([C:18](=[O:19])[C:17]1[CH:21]=[C:22]([F:26])[C:23]([Cl:25])=[CH:24][C:16]=1[Cl:15])[C:5]#[N:6]
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1Cl
Reactant: CN(C)C=CC#N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(C)C=C(C#N)C(=O)c1cc(F)c(Cl)cc1Cl
Yield: 77.4 %

Procedure:
9.6 g of 3-dimethylaminoacrylonitrile and 10.5 g of triethylamine are added dropwise to a solution of 22.75 g of 2,4-dichloro-5-fluorobenzoyl chloride in 100 ml of anhydrous dioxane, while cooling in ice and stirring. The mixture is stirred at room temperature for 1 hour and then heated to boiling under reflux for 4 hours. The solvent is removed by distillation in vacuo, and the residue is taken up in methylene chloride/water. The methylene chloride phase is washed with water, dried with sodium sulphate, and evaporated in vacuo. The crystalline residue is recrystallized from ethanol. 22.2 g of 3-dimethylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylonitrile of melting point 138°-139° C. are obtained.
Reaction SMILES: [CH2:1]([N:17]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[N:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:24][Cl:25]>S1(CCCC1)(=O)=O>[Cl-:25].[CH2:1]([N+:17]1[N:18]([CH3:24])[C:19]([CH3:23])=[CH:20][C:21]=1[CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCl
Reactant: CCCCCCCCCCCCCCCCn1nc(C)cc1C
Solvent: O=S1(=O)CCCC1
Product: CCCCCCCCCCCCCCCC[n+]1c(C)cc(C)n1C
Product: [Cl-]
Temperature: -40 °C
Reaction time: 60 h

Procedure:
A mixture of 16. g (0.05 mol) of 1-hexadecyl-3,5-dimethylpyrazole and 50 ml of sulfolane is cooled down to -30° C. in a rotary autoclave and 9 g (0.18 mol) of liquid methyl-chloride cooled down to -40° C. are added. Upon sealing the autoclave, the reaction mixture is heated to 120° C. and kept at this temperature for 60 hrs. After cooling, the sulfolane is distilled off under high vacuum. 50 Ml of ether are added to the residue and the mixture shaken thoroughly. The crystalate is then filtered off and recrystallized first from 100 ml of acetone and then from 60 ml of acetone, filtered off, and vacuum dried at 40° C./12 Torr to yield about 10.1 g of 1-hexadecyl-2,3,5-trimethyl-pyrazolium chloride; m.p. 92°-94° C. The same compound is obtained by appropriate anion exchange of the product obtained in Example I.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].C([O-])([O-])=O.[K+].[K+].O>COCCOC>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:10]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: Nc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: O=C(O)c1cc(Cl)ccc1Nc1ccc(Br)nc1
Temperature: 130 °C
Yield: 34.5 %

Procedure:
A mixture of 6-bromopyridin-3-amine (27.27 mmol, 4.70 g), 2,5-dichlorobenzoic acid (54.34 mmol, 10.38 g), Cu (2.71 mmol, 0.2 g), Cu2O (1.36 mmol, 0.2 g) and K2CO3 (54.27 mmol, 7.5 g) in 1,2-dimethoxiethane (40 ml) was heated in a microwave oven at 130° C. for 14 hours, under nitrogen atmosphere. Water was added and the mixture was filtered through celite and extracted with AcOEt. The organic phase was washed with saturated K2CO3 aqueous solution and brine. The solvent was evaporated to afford 3.08 g (yield 31%) of the expected product.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][NH:7][C:8](=[O:27])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH:18]=[CH:17][C:16]=2[NH2:26])[CH:10]=1.[CH3:33][N:34]([CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)[C:35]([C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](O)=[O:41])=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:22]([N:21]([CH2:24][CH3:25])[C:19]1[CH:18]=[CH:17][C:16]([NH:26][C:40](=[O:41])[C:39]2[CH:43]=[CH:44][CH:45]=[C:37]([C:35]([N:34]([CH3:33])[CH2:46][CH2:47][N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[O:36])[CH:38]=2)=[C:15]([C:11]2[CH:10]=[C:9]([C:8](=[O:27])[NH:7][CH2:6][C:5]3[CH:28]=[CH:29][CH:30]=[C:3]([C:2]([F:31])([F:1])[F:32])[CH:4]=3)[CH:14]=[CH:13][N:12]=2)[CH:20]=1)[CH3:23]
Reactant: CCN(CC)c1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCOCC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 13.6 %

Procedure:
A mixture of 80 mg of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(diethylamino)phenyl)isonicotinamide, 64 mg of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid, 83 mg of HATU, and 190 μL of diisopropylethylamine in 0.5 mL of DMF was stirred at 60° C. for 2 h. The product was isolated by reverse phase chromatography eluting with 0.05% TFA in a water/acetonitrile gradient. This procedure gave 17.6 mg of product. 1H NMR (400 MHz, CD3OD, ppm): δ 9.54 (t, J=5.9 Hz, 1H), 8.98 (dd, J=5.2, 0.6 Hz, 1H), 8.88 (d, J=9.0 Hz, 1H), 8.49 (s, 1H), 8.26 (d, J=2.6 Hz, 1H), 8.20 (s, 1H), 8.16-8.10 (m, 1H), 7.90 (dd, J=5.2, 1.5 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.75-7.63 (m, 4H), 7.63-7.50 (m, 2H), 4.74-4.67 (m, 2H), 4.21-4.03 (m, 2H), 3.99 (t, J=5.7 Hz, 2H), 3.90-3.69 (m, 4H), 3.76 (q, J=7.2 Hz, 4H), 3.54 (t, J=5.9 Hz, 2H), 3.34-3.18 (m, 2H), 3.10 (s, 3H), 1.22 (t, J=7.2 Hz, 6H). MS (ESI, m/z) 717.24 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:33][C:34]1[CH:48]=[CH:47][C:37]([C:38]([NH:40][CH:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[O:39])=[CH:36][C:35]=1[O:49][CH3:50]>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:34]4[CH:48]=[CH:47][C:37]([C:38]([NH:40][CH:41]5[CH2:42][CH2:43][O:44][CH2:45][CH2:46]5)=[O:39])=[CH:36][C:35]=4[O:49][CH3:50])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)NC2CCOCC2)ccc1N
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2CCOCC2)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Yield: 43.8 %

Procedure:
A mixture of 0.0605 g (0.20 mmole) 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 0.0571 g (0.30 mmole) of toluenesulfonic acid monohydrate, 0.0501 g (0.20 mmole) of 4-amino-3-methoxy-N-(tetrahydro-2H-pyran-4-yl) benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 19.5 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from acetonitrile-methanol to give 0.0452 g 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(tetrahydro-pyran-4-yl)-benzamide (I-7).
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][CH2:10][C@H:2]1[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].Cl.[N:14]1(C(OCC2C=CC=CC=2)=O)[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16](O)=[O:17]>>[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([N:1]1[CH2:12][CH2:11][CH2:10][C@H:2]1[C:3]([O:5][C:6]([CH3:8])([CH3:9])[CH3:7])=[O:4])=[O:17]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: Cl
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1
Yield: 99.4 %

Procedure:
A] Starting from H-Pro-OtBu.HCl (0.315 g, 1.5 mmoles) and Z-Pro-OH (0.397 g, 1.59 mmoles) the procedure of Example 1, C-D] was substantially applied. There was obtained 0.4 g of H-Pro-Pro-OtBu.
Reaction SMILES: [CH2:1]([C:3]12[CH2:9][C:7]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=3)([CH2:8]1)[C:6](=[O:19])[N:5]([CH2:20][CH2:21][CH3:22])[C:4]2=[O:23])[CH3:2].CCOCC>C(OCC)(=O)C.[Pd]>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]23[CH2:9][C:3]([CH2:1][CH3:2])([CH2:8]2)[C:4](=[O:23])[N:5]([CH2:20][CH2:21][CH3:22])[C:6]3=[O:19])=[CH:15][CH:14]=1
Reactant: CCCN1C(=O)C2(CC)CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCN1C(=O)C2(CC)CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 12a, 6.3 g of 5-ethyl-1-(4-nitrophenyl)-3-n-propyl-3-azabicyclo[3.1.1]-heptane-2,4-dione are dissolved in 120 ml of ethyl acetate, hydrogenated in the presence of 0.6 g of 5% palladium-on-carbon and worked up. Melting point 124.5°-125° (from ether).
Reaction SMILES: C(OC([N:11]1[CH2:22][CH2:21][C:14]2([O:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH3:32]>CS(C)=O>[CH2:30]([N:16]1[C:15](=[O:20])[C:14]2([CH2:13][CH2:12][NH:11][CH2:22][CH2:21]2)[O:18][C:17]1=[O:19])[CH2:31][CH3:32]
Reactant: O=C1NC(=O)C2(CCN(C(=O)OCc3ccccc3)CC2)O1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCN1C(=O)OC2(CCNCC2)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 124.9 %

Procedure:
To a solution of 2,4-dioxo-1-oxa-3,8-diaza-spiro[4.5]decane-8-carboxylic acid benzyl ester (24.4 g, 80 mmol) in DMSO (240 ml), potassium carbonate (16.5 g, 120 mmol) and bromopropane (11 ml, 120 mmol) are added to the mixture at ambient temperature. The reaction mixture is stirred at ambient temperature for 12 h, quenched with water and extracted with AcOEt:ether (1:1 (v/v)). The combined extracts are washed with brine, dried over magnesium sulfate, filtrated and concentrated. The residue is purified by column chromatography on silica gel using n-hexane:AcOEt=2:1 (v/v). to give 21.2 g of desired product in 76% yield. Rf=0.8 (n-hexane:AcOEt=1:1). To white solid (21.2 g) and 10% Pd/C (3 g), MeOH (300 ml) is added. The reaction mixture is stirred at ambient temperature for 18 h under H2. After the filtration, the solvent is evaporated down to give the desired product.