Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[C:21]([O:20][CH3:19])[CH:22]=1)=[O:14]
Reactant: COc1cccc(N)c1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: COc1cccc(NC(=O)c2ccncc2Nc2ccc(I)cc2F)c1

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-(3-methoxyphenyl)isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.31 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.46 mmol of 3-methoxyaniline. LC/MS [6.40 min; 464 (M+1)]
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.[BH4-].[Na+].C(=O)(O)[O-].[Na+].[Cl-].[Na+]>C(O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=1
Reactant: CCCCCCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(C)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCCC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(C)c1
Yield: 96.4 %

Procedure:
Dissolve 1-(2-methyl-4′-trifluoromethyl-biphenyl-4-yl)-heptan-1-one (0.516 g, 1.48 mmol) in ethanol (5 mL). Add sodium borohydride (0.224 g, 5.93 mmol) at 0° C. under inert atmosphere and stir three hours. Quench reaction with saturated solution of ammonium chloride, dilute with ethyl acetate. Wash organic phase with saturated sodium bicarbonate solution, then saturated sodium chloride solution. Dry organic fraction with Na2SO4, filter and concentrate under reduced pressure. Purify on silica gel chromatography (0-30% Ethyl acetate/hexanes gradient) to provide 0.5 g of title compound (97%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:12]3[C:28]([F:29])=[CH:27][C:15]([O:16]CC4NC5C=CC=CC=5N=4)=[C:14]([F:30])[CH:13]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1>C(#N)C.C(=O)([O-])[O-].[K+].[K+].O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:30][C:14]1[CH:13]=[C:12]([CH2:11][C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:35]4[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=4)[CH:3]=3)[NH:8][CH:9]=2)[C:28]([F:29])=[CH:27][C:15]=1[OH:16]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Fc1cc(OCc2nc3ccccc3[nH]2)c(F)cc1Cc1c[nH]c2ncc(Br)cc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cn1cc(-c2cnc3[nH]cc(Cc4cc(F)c(O)cc4F)c3c2)cn1
Temperature: 160 °C

Procedure:
To 2-[4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,5-difluoro-phenoxymethyl]-1H-benzoimidazole (P-2107, 25.0 m g, 0.053 mmol, prepared as described in Example 41) in acetonitrile (4.00 mL) and 1M potassium carbonate in water (2.00 mL), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (13.3 mg, 0.064 mmol) and tetrakis(triphenylphosphine)-palladium(0) (10.0 mg, 8.65E-3 mmol) were added. The reaction was heated to 160° C. for 20 minutes in a CEM Discover microwave instrument. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (P-2161, 5.4 mg, 29.8%). MS (ESI) [M+H+]+=341.2.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[F:10][C:11]([F:23])([F:22])[O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1>>[F:9][C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][C:11]([F:10])([F:22])[F:23])[CH:14]=2)[CH:8]=[CH:7][C:5]=1[NH2:6]
Reactant: Nc1ccc(Br)cc1F
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: Nc1ccc(-c2cccc(OC(F)(F)F)c2)cc1F
Yield: 34.8 %

Procedure:
The title compound (0.5 g) was prepared from 4-Bromo-2-fluoroaniline (1 g, 5.3 mmol) and 3-(trifluoromethoxy)phenylboronic acid (1.4 g, 6.8 mmol) as a yellow liquid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.62 (d, J 8, 1H), 7.53 (s, 1H), 7.48 (t, J 8, 1H), 7.42 (dd, J 2, 9.1, 1H), 7.28 (dd, J 2, 8.3, 1H), 7.23 (d, J 11, 1H), 6.82 (t, J 8.5, 1H), 5.40 (s, 2H).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][N:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=3[CH:20]=2)[C:7](=[O:21])[CH2:6]1)=[N+]=[N-].O1CCCC1>CO.[Pd]>[NH2:1][CH2:4][C@@H:5]1[CH2:9][N:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=3[CH:20]=2)[C:7](=[O:21])[CH2:6]1
Reactant: [N-]=[N+]=NC[C@H]1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: NC[C@H]1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a solution of 6-[(4S)-4-(azidomethyl)-2-oxopyrrolidin-1-yl]-2H-1,4-benzoxazin-3(4H)-one (430 mg, 1.50 mmol) in methanol (40 ml)/tetrahydrofuran (40 ml) was added 10% palladium on carbon catalyst (53% aqueous, 100 mg) at room temperature and the mixture was stirred at the same temperature for 2 hours under a hydrogen atmosphere. The catalyst was removed by filtration and the residue obtained by concentrating the filtrate was purified by silica gel column chromatography (NH silica gel, dichloromethane/methanol) to yield 336 mg (86%) of the title compound in the form of a light yellow amorphous solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][CH2:22][S:23]([C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1)(=[O:25])=[O:24].C(Br)(Br)(Br)[Br:35]>ClCCl>[Br:35][CH2:21][CH2:22][S:23]([C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1)(=[O:25])=[O:24]
Reactant: N#Cc1ccc(S(=O)(=O)CCO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)CCBr)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4 g of 4-(2-hydroxyethylthio)benzonitrile was reacted via Procedure R to yield 4-(2-hydroxyethylsulfonyl)benzonitrile. 3.0 g of triphenylphosphine was added to a solution of 2 g of 4-(2-hydroxyethylsulfonyl)benzonitrile and 4.7 g of carbon tetrabromide in dichloromethane at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was diluted with dichloromethane, washed with H2O, dried (MgSO4) and evaporated. Purified by silica gel chromatography (0-70% ethyl acetate/hexane) to afford 4-(2-bromoethylsulfonyl)benzonitrile. 250 mg of 4-(2-bromoethylsulfonyl)benzonitrile was used in Procedure P with imidazole to give 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)benzonitrile. 300 mg of 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)benzonitrile was reacted via Procedure T to give 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 467.1 (M)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:11]([CH2:14][CH2:15][NH2:16])([CH3:13])[CH3:12]>C(O)C>[CH3:12][N:11]([CH3:13])[CH2:14][CH2:15][NH:16][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CN(C)CCN
Solvent: CCO
Product: CN(C)CCNc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 61 %

Procedure:
A solution of 2-chloro-3-nitropyridine (1.76 g, 20.0 mmol) in ethanol is treated with Me2NCH2CH2NH2 (3.17 g, 20.0 mmol), stirred at ambient temperature for 17 h, heated to reflux temperature for 7 h, cooled to room temperature and concentrated in vacuo. The resulting solid residue is triturated with ethanol and suction filtered. The filtercake is air-dried to give the title compound as a yellow solid, 3.20 g (61% yield),. mp 202-203° C., identified by NMR and mass spectral analyses.
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]([CH3:16])([S:7]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)(=[O:9])=[O:8])[CH3:6])C.O.[OH-].[Li+]>C1COCC1.O.O>[CH3:16][C:5]([S:7]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)(=[O:9])=[O:8])([CH3:6])[C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)S(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
To a solution of 240 mg (0.93 mmol) of 2-methyl-2-(pyridine-3-sulfonyl)-propionic acid ethyl ester in THF/water (4/1, 10 mL) were added 76 mg (1.8 mmol) of lithium hydroxide monohydrate. The reaction was stirred at room temperature for 18 h. The reaction was further diluted with water (20 mL) and then washed with DCM (2×15 mL). The basic aqueous layer was cooled in an ice bath and acidified with 1M aqueous HCl solution to pH 2. The acidic aqueous layer was extracted with isopropanol/chloroform (1/1, 3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and filtered. Concentration of the filtrate under reduced pressure afforded 213 mg of 2-methyl-2-(pyridine-3-sulfonyl)-propionic acid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[CH3:12][C:13]1([CH3:23])[CH2:19][CH2:18][CH2:17][CH2:16][C:15]([CH3:21])([CH3:20])[C:14]1=[O:22].S(=O)(=O)(O)O>O>[CH3:12][C:13]1([CH3:23])[CH2:19][CH2:18][CH2:17][CH2:16][C:15]([CH3:21])([CH3:20])[CH:14]1[OH:22]
Reactant: CC1(C)CCCCC(C)(C)C1=O
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CC1(C)CCCCC(C)(C)C1O
Temperature: 25 °C
Yield: 98.2 %

Procedure:
Lithium aluminium hydride (3.80 g, 0.1 mole) and dried diethyl ether (100 ml) were added to a one liter four-necked flask equipped with a mechanical stirrer, a dropping funnel, a thermometer, a reflux condenser and a calcium chloride tube and stirred at room temperature. A mixed solution of 2,2,7,7-tetramethylcycloheptanone (33.66 g, 0.2 moles)/dried diethyl ether (60 ml) was dropped into the mixture in 1 hour while stirring at room temperature. The mixture was stirred at room temperature for 1 hour. Subsequently, water (40 ml) and a 10% sulfuric acid aqueous solution (250 ml) were added in this order to the resulting reaction mixture to separate it into two layers. The resulting organic layer was washed twice with saturated saline solution (100 ml). The organic layer was dried over anhydrous magnesium sulfate and separated by filtration, followed by concentration and fractionation to obtain 33.45 g (yield 98.2%) of the captioned compound. This compound was a white solid having a woody, earthy, camphoraceous and hay-like odor.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1.[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1B(O)O>>[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3ccc(C(F)(F)F)cc3Cl)cc3c1N2CC3

Procedure:
The title compound was prepared by the method of Example 90 from tert-butyl(±)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (136 mg, 0.30 mmol) and corresponding 2-chloro-4-trifluoromethylphenylboronic acid (128 mg, 0.60 mmol), to afford after chromatographic purification the title compound (160 mg, 99%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 7.70 (br, 1H), 7.51 (dd, 1H, J=1.1 Hz, 8.0 Hz), 7.42 (d, 1H, J=8.0 Hz), 7.03 (s, 1H), 6.99 (s, 1H), 3.80–3.90 (m, 1H), 3.60–3.80 (m, 1H), 3.10–3.50 (m, 7H), 2.80–3.00 (m, 1H), 1.70–1.90 (m, 2H), 1.48 (s, 9H) ppm. MS (CI, NH3): 479 (base, M+H).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[C:15]([CH3:21])=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:16]([N:17]=[C:5]=[O:11])[C:15]=1[CH3:21]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1c(N)cccc1Br
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Br)cccc1N=C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 229 %

Procedure:
A solution of triphosgene (2.25 g, 7.58 mmol) in toluene (27 mL), cooled in an ice-water bath, was treated slowly with a solution of 3-bromo-2-methylaniline (3.00 g, 16.1 mmol) and DIEA (5.6 mL, 32.2 mmol) in toluene (5.4 mL). The resulting suspension was stirred at room temperature for 2 h. The precipitate was removed by filtration and washed with EtOAc. The combined filtrates were diluted with EtOAc, washed with brine, dried and concentrated to provide 1-bromo-3-isocyanato-2-methylbenzene as a brown oil (3.68 g, 98% yield), used without purification. 1H NMR (400 MHz, DMSO-d6) δ 7.49 (dd, J=8.1, 0.9 Hz, 1H), 7.31 (dd, J=7.9, 0.7 Hz, 1H), 7.15 (td, J=8.0, 0.7 Hz, 1H), 2.38 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:8](=[O:9])[C:7]([CH3:11])([CH3:10])[CH2:6][C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH3:1][C:2]1([CH3:16])[CH:8]([OH:9])[C:7]([CH3:10])([CH3:11])[CH2:6][C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[CH2:3]1
Reactant: CC1(C)Cc2ccccc2CC(C)(C)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC1(C)Cc2ccccc2CC(C)(C)C1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.57 g of 5,6,8,9-tetrahydro-6,6,8,8-tetramethyl-7H-benzocycloheptene-7-one are dissolved in 50 ml of absolute diethyl ether and treated cautiously at 0° with 460 mg of lithium aluminum hydride. The cooling bath is removed and the mixture is stirred at room temperature for an additional 2 hours. Then, 1.2 g of sodium hydroxide, dissolved in a small amount of water, are added portionwise, whereupon the reaction mixture is stirred until a filterable precipitate has formed. After filtration and evaporation of the filtrate, there is obtained 6,7,8,9-tetrahydro-6,6,8,8-tetramethyl-5H -benzocycloheptene-7-ol as a crude product which melts at 66°-68° after recrystallization from petroleum ether (low-boiling).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:9]=3[CH2:8][CH:7](O)[C:6]=2[CH:20]=1.S(=O)(=O)(O)O.O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:20]=1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccc(F)cc1C(O)C2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc2c(c1)Sc1ccc(F)cc1C=C2

Procedure:
Suspend 14.8 gm of the crude alcohol from Step C in 300 ml of glacial acetic acid and heat the mixture with stirring in an oil-bath at 110°-115° C. Add 50 ml of sulfuric acid in a thin stream. Continue stirring and heating for 15 minutes. Cool and pour into 500 ml of water. Separate the solids by filtration and stir at room temperature in 125 ml of ethylacetate overnight. Separate the solids by filtration to obtain the title product. (m.p. 273°-275° C.)
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:13]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])(=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[Cl:3][C:5]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][C:21]=2[N+:22]([O-:24])=[O:23])[C:15](=[O:17])[O:16]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)c1ccccc1
Product: O=C1OC(Cl)(c2ccccc2)c2c1cccc2[N+](=O)[O-]
Reaction time: 4 h

Procedure:
To 37 ml of thionyl chloride was added 40 g of 2-benzoyl-3-nitrobenzoic acid. The mixture was heated and stirred for 4 hours on an oil bath kept at a temperature of 50° to 60° C. Excess thionyl chloride was distilled away under reduced pressure, and 40.2 g of 3-chloro-3-phenyl-4-nitrophthalide was obtained as a brown oily substance. Separately, 9.0 g (0.08 mol.) of potassium tert-butoxide and 9.3 g (0.07 mol.) of 5-methylbenzotriazole were added to 300 ml of dried dimethylformamide, and stirred for 20 minutes at room temperature. The resulting mixture was cooled to 5° C. and thereto, was added dropwise gradually the previously prepared solution containing 20 g (0.07 mol.) of 3-chloro-3-phenyl-4-nitrophthalide in 100 ml of dried dimethylformamide as the mixture was kept at 5° C. After the dropwise addition, the cooling bath was removed, and the stirring was further continued for 5 hours at room temperature. Thereto, 300 ml of a saturated aqueous solution of ammonium chloride was added subsequently. The reaction mixture was extracted with ethyl acetate repeatedly, and the extract was washed with water. The rsulting organic layer was dried over anhydrous sodium sulfate, and the sodium sulfate was filtered off with suction. The filtrate was concentrated to obtain 27.5 g of oily substance. This oily substance was separated and purified by flash column chromatography (silica gel: 1 Kg, eluate: hexane-ethyl acetate (2:1 by volume) mixture) to obtain the intended compound, 3-phenyl-3-(5-methyl-1-benzotriazolyl)-4-nitrophthalide, in the form of white crystals. Yield 6.9 g, Melting Point 240° to 248° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:62]=[CH:61][C:28]([CH2:29][N:30]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)[C:31]2[N:36]=[CH:35][C:34]([C:37]3[C:38]4[CH2:51][CH2:50][NH:49][C:39]=4[N:40]=[C:41]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[N:42]=3)=[CH:33][N:32]=2)=[CH:27][CH:26]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[C:20]([N:49]3[C:39]4[N:40]=[C:41]([N:43]5[CH2:44][CH2:45][O:46][CH2:47][CH2:48]5)[N:42]=[C:37]([C:34]5[CH:35]=[N:36][C:31]([N:30]([CH2:52][C:53]6[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=6)[CH2:29][C:28]6[CH:61]=[CH:62][C:25]([O:24][CH3:23])=[CH:26][CH:27]=6)=[N:32][CH:33]=5)[C:38]=4[CH2:51][CH2:50]3)[CH:19]=[CH:18][N:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cl)ccn2)CC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)c3)cn2)cc1
Yield: 57.7 %

Procedure:
Using 4-(4-chloro-pyridine-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (163 mg, 0.500 mmol) obtained in Step A instead of 4-chloropicolinic acid t-butylamide, and bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (245 mg, 445 mmol), in the same manner as Example 1-D-07, amination was carried out, to obtain a crude product of 4-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridine-2-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (239 mg), and further PMB group and BOC group were removed according to the above Deprotection method 2, to obtain the desired compound (D-199) as a yellow powder (67 mg, 49%).
Reaction SMILES: [OH-].[Na+].CO.[C:5]([NH:13][C:14]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCCC1>[C:5]([NH:13][C:14]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cc(OCc2ccccc2)ccc1C(=O)O)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
0.11 mL of 2.0 mol/L aqueous sodium hydroxide was added dropwise to a mixed solution of 1 mL of methanol and 2 mL of tetrahydrofuran containing 70 mg of methyl 2-(benzamido)-4-(benzyloxy)benzoate at room temperature, and stirred at the same temperature for 6 hours and 30 minutes, at 40° C. for 1 hour and 30 minutes and at 50° C. for 2 hours. After the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure and water and diethyl ether were added. The aqueous layer was separated and pH was adjusted to pH 4.0 with 1.0 mol/L hydrochloric acid. A solid substance was separated by filtration to obtain 35 mg of 2-(benzamido)-4-(benzyloxy)benzoic acid as white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:24]([O:28][C:29](Cl)=[O:30])[CH2:25][CH2:26][CH3:27]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:29]([O:28][CH2:24][CH2:25][CH2:26][CH3:27])=[O:30])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOC(=O)Cl
Reactant: NC1CCN(C(=O)OCc2ccccc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)NC1CCN(C(=O)OCc2ccccc2)C1
Reaction time: 12 h

Procedure:
To a solution of 3.00 g 3-amino-pyrrolidine-1-carboxylic acid benzyl ester hydrotrifluoroacetate in 50 ml dichloromethane were added dropwise 3.7 ml triethylamine and 1.3 ml butylchloroformate at 0° C. After stirring for 12 h the reaction mixture was diluted with dichloromethane, washed with 0.1 M HCl, saturated aqueous NaHCO3 and brine. The crude product thus obtained was purified by flash chromatography on silica using ethyl acetate/heptane 2:3 as eluent. Yield: 648 mg.
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21](CN4CCOCC4)=[CH:20][CH:19]=3)[NH:15][C:12]2=[N:13][CH:14]=1.NC1C(N)=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.COC1C=C(C=CC=1)C=O>>[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:4][CH3:3])[CH:19]=3)[NH:15][C:12]2=[N:13][CH:14]=1
Reactant: O=C(O)C(F)(F)F
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Agent: COc1cccc(C=O)c1
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: COc1cccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)c1
Yield: 34 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 3-methoxybenzaldehyde were reacted to produce the title compound (34%). 1H NMR (d-chloroform): 15.77 (br s, 1H) 8.43 (d, J=8 Hz, 1H), 7.80 (s, 1H), 7.67 (s, 1H), 7.66 (m, 1H), 7.44 (t, J=8 Hz, 1H), 7.04 (d, J=8 Hz, 1H), 6.51 (m, 1H), 6.42 (m, 1H), 5.93 (br s, 1H), 5.55 (br s, 1H), 5.36 (t, J=8 Hz, 1H), 3.93 (s, 3H), 3.17 (s, 1H), 3.05 (s, 1H), 2.69 (d, J=8 Hz, 1H), 2.32 (d, J=9 Hz, 1H), 1.67 (d, J=9 Hz, 1H). MS: 466.07 (M+H). HPLC retention time: 2.42 minutes (G Method).