Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])([CH3:14])[O:13][C:9]=2[CH:8]=[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:6]=1[OH:27])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[C].[Pd]>[C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])([CH3:14])[O:13][C:9]=2[CH:8]=[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:6]=1[OH:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C=CCCCC(=O)O)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(CCCCCC(=O)O)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Reaction time: 24 h
Yield: 90.4 %

Procedure:
To a solution of 0.11 g of 6-(4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl)-5-hexenoic acid synthesized in Example 77 in 10 ml of ethyl acetate was added a catalytic amount of 10% palladium-carbon, and the mixture was stirred for 24 hours under a hydrogen atmosphere. After the catalyst was filtered off, the filtrate was concentrated to give 0.10 g of 6-(4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl)hexanoic acid as a colorless viscous liquid (yield 90%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:16][CH:17]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:16]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:13](=[O:15])[CH3:14])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)[CH3:17]
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CCN(c2ccc(C(C)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
A mixture of 1-(4-piperazin-1-yl-phenyl)-ethanone (500 mg, 2.45 mmol), CH3CHO (161 mg, 3.67 mmol) and NaBH(OAc)3 (778 mg, 3.67 mmol) in DCM (15 ml) was stirred at room temperature overnight. The resulting solution was partitioned between water and DCM and the organic phase was extracted with 1 M HCl. The aqueous layer was brought to basic conditions with NH4OH, extracted with AcOEt and then the organic phase was dried over Na2SO4 and evaporated in vacuo to give 250 mg of 1-[4-(4-ethyl-piperazin-1-yl)-phenyl]-ethanone.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:9][C:10]2[N:15]=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[N:13]=[C:12]([NH:22][C:23]3[CH:35]=[CH:34][C:26]([C:27]([O:29]C(C)(C)C)=[O:28])=[CH:25][CH:24]=3)[N:11]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1([NH:9][C:10]2[N:15]=[C:14]([O:16][CH2:17][C:18]([F:21])([F:19])[F:20])[N:13]=[C:12]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:34][CH:35]=3)[N:11]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(Nc2nc(Nc3ccc(C(=O)OC(C)(C)C)cc3)nc(OCC(F)(F)F)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(Nc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
To a suspension of tert-butyl 4-(4-(1-(ethoxycarbonyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (1.6 g) in dichloromethane (15 mL) was added TFA (4.96 mL). The mixture was stirred at r.t. for 16 hours. All solvents were removed under vacuum to give product 4-(4-(1-(ethoxycarbonyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (1.35 g).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[F:5][C:6]([F:16])([F:15])[C:7]1[N:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][CH:8]=1>C(O)C>[F:16][C:6]([F:15])([F:5])[C:7]1[N:12]=[C:11]([C:13](=[NH:14])[O:1][CH2:2][CH3:3])[CH:10]=[CH:9][CH:8]=1
Reactant: CC[O-]
Reactant: N#Cc1cccc(C(F)(F)F)n1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=N)c1cccc(C(F)(F)F)n1
Reaction time: 2 h
Yield: 92 %

Procedure:
Sodium ethoxide (197 mg, 2.9 mmol) was added to a solution of 6-(trifluoromethyl)picolinonitrile (250 mg, 1.45 mmol) in ethanol (10 mL) at room temperature. The reaction mixture was stirred for 2 h. The solvent was removed under reduced pressure and the resulting residue was dissolved in dichloromethane, washed with water, dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound (291 mg) which was used without further purification. MS (ES+) (M+H) 219.16
Reaction SMILES: N[C:2]1[C:3]([C:13]#[N:14])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[I:15]CI.N(OCCC(C)C)=O>C1COCC1.[Cu](I)I>[C:13]([C:3]1[C:2]([I:15])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:12])[CH:4]=1)#[N:14]
Reactant: COC(=O)c1cc(N)c(C#N)cc1C
Reactant: ICI
Agent: I[Cu]I
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(I)c(C#N)cc1C
Temperature: 85 °C
Reaction time: 3 h
Yield: 46.9 %

Procedure:
To a solution of methyl 5-amino-4-cyano-2-methylbenzoate (5.0 g, 0.0262 mol) in THF (100 mL) was added copper iodide (5.0 g, 0.0262 mol), diiodomethane (10.5 mL, 0.131 mol) and isoamyl nitrite (10.5 mL, 0.0786 mol). The reaction mixture was heated to 85° C. and stirred for 3 h, at which time it was cooled to room temperature. The heterogeneous mixture was filtered through a bed of celite, and the filter cake rinsed with ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography (100% hexanes to 2% diethyl ether in hexanes), then triturated with hexanes to afford methyl 4-cyano-5-iodo-2-methylbenzoate (3.7 g, 76%) as a white powder. 1H NMR (400 MHz, CDCl3): 8.39 (s, 1H), 7.50 (s, 1H), 3.94 (s, 3H), 2.56 (s, 3H).
Reaction SMILES: B(Br)(Br)[Br:2].[Cl:5][C:6]1[C:7]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:8][C:9]([O:15]C)=[C:10]([CH2:12][CH2:13]O)[CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br:2][CH2:13][CH2:12][C:10]1[CH:11]=[C:6]([Cl:5])[C:7]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:8][C:9]=1[OH:15]
Reactant: COc1cc(N2CCCCC2)c(Cl)cc1CCO
Reactant: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cc(N2CCCCC2)c(Cl)cc1CCBr
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5.0 ml of boron tribromide are added dropwise over a period of approximately 5 minutes to a solution, cooled to 0°, of 2.70 g (10 mmole) of 2-[5-chloro-2-methoxy-4-(piperidin-1-yl)-phenyl]-ethanol in 70 ml of absolute methylene chloride. The reaction mixture is then stirred for a further 5 hours at room temperature, poured onto ice and the resulting suspension is adjusted to pH 6-7 with solid sodium carbonate and extracted with methylene chloride. The organic extracts are washed with water, combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. Recrystallisation from petroleum ether yields 1-bromo-2-[5-chloro-2-hydroxy-4-(piperidin-1-yl)-phenyl]-ethane, melting point 115°-116°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O-:16])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1.[C:26]1([C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:33][CH2:34]O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC.O>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH2:34][CH:33]=[C:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: OCC=C(c1ccccc1)c1ccccc1
Reactant: CC1=C(C(=O)[O-])C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC1=C(C(=O)OCC=C(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1

Procedure:
308 mg (0.85 mmol) of mono(2-cyanoethyl) 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, 348 mg (1.65 mmol) of 3,3-diphenyl-2-propene-1-ol, 260 mg (1.36 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 26 mg (0.21 mmol) of 4-dimethylaminopyridine were stirred together in 10 ml of dichloromethane at room temperature for one hour. Water was added to the reaction liquid. After the extraction with dichloromethane, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (hexane/ethyl acetate=2/1) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]([NH2:17])[CH:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]2=[O:23].[C:24](OC(=O)C)(=[O:26])C>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16]1)[N:8]([NH:17][CH:24]=[O:26])[CH:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]2=[O:23]
Reactant: CCOC(=O)c1cn(N)c2cc(-n3cccc3)c(F)cc2c1=O
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CCOC(=O)c1cn(NC=O)c2cc(-n3cccc3)c(F)cc2c1=O
Temperature: 0 °C

Procedure:
A solution of 3.15 g (0.01 mol) of ethyl 6-fluoro-7-(pyrrol-1-yl)-1-amino-4-oxo-1,4-dihydroquinoline-3-carboxylate in 25 ml of formic acid is added dropwise to a mixture of 9.5 ml (0.01 mol) of acetic anhydride and 4 ml (0.01 mol) of formic acid, cooled to 0° C., the addition being carried out so as to maintain room temperature ±5° C. The mixture is kept at room temperature for48 hours and poured into a water/ice mixture, and the precipitate formed is filtered off, washed with water and recrystallized from a dimethylformamide/water mixture (1:1) to give a solid melting at 254°-257° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.[H-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[O:21][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(O)C1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
200 mg (0.68 mmol) of tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-hydroxy-piperidine-1-carboxylate and 159 mg (1.01 mmol) of 4-methoxybenzyl chloride were dissolved in 3 ml of dimethylformamide. 40 mg (1.01 mmol) of a 60% sodium hydride suspension were added and the mixture was stirred at room temperature for 3 hours. Subsequently, the reaction mixture was partitioned between ethyl acetate and water, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel with a 1:3 mixture of ethyl acetate and hexane as the eluent. There were obtained 250 mg (90% of theory) of tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-(4-methoxy-benzyloxy)-piperidine-1-carboxylate as a light yellow oil; MS: 358 (M-C4H9)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:32][CH3:33])[C:9](=[O:31])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25]C)=[O:24])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O>[CH2:1]([N:8]([CH2:32][CH3:33])[C:9](=[O:31])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([OH:25])=[O:24])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(Cc1ccccc1)C(=O)COc1ccc(CCOc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(Cc1ccccc1)C(=O)COc1ccc(CCOc2ccccc2C(=O)O)cc1
Yield: 109.3 %

Procedure:
Methyl 2-[2-(4-{2-[benzyl(ethyl)amino]-2-oxoethoxy}phenyl)ethoxy]benzoate (0.138 g, 0.308 mmol) was dissolved in a mixture of THF/water (1/1, 4 ml). Lithium hydroxide (0.015 g, 0.617 mmol) was added. The reaction was performed in an single node microwave oven (14 min, 150 deg). Workup by removing the solvent by evaporation and addition of HCl (2 ml, 1 M). The waterphase was extracted with two portions of EtOAc (20 ml), the organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 0.146 g of 2-[2-(4-{2-[benzyl(ethyl)amino]-2-oxoethoxy}phenyl)ethoxy]benzoic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[N:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[Cl:15][C:16]1[N:21]=[CH:20][C:19]([S:22]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: O=C1CNCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
To a mixture of 2-piperazinone (0.46 g, 4.59 mmol, Sigma-Aldrich, St. Louis, Mo.) and triethylamine (1.5 mL, 10.76 mmol) in CH2Cl2 (20 mL) at 0° C. was added 6-chloropyridine-3-sulfonyl chloride (0.974 g, 4.59 mmol, Organic Process Research & Development 2009, 13, 875). The resulting slurry was stirred at room temperature for 30 min and then was concentrated. The residue was mixed with saturated aqueous NaHCO3 (10 mL) and was stirred at room temperature for 1 d. The slurry was filtered, washed with water (3×5 mL), and dried under reduced pressure to give 4-((6-chloro-3-pyridinyl)sulfonyl)-2-piperazinone as a white solid (1.12 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][S:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=2[O-:20])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(OO)(=[O:23])C>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][S:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=2[O-:20])(=[O:23])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(=O)OO
Reactant: Cc1cc(CS(=O)c2cccc[n+]2[O-])ccc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: Cc1cc(CS(=O)(=O)c2cccc[n+]2[O-])ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a mixture of 9.5 g of 2-[[(3-methyl-4-nitrophenyl)methyl]sulfinyl]-pyridine-1-oxide in 50 ml of acetic acid was added, dropwise with stirring at room temperature, 9.17 g of 40% peracetic acid in acetic acid. After addition, a short period of heating was required to complete the reaction. Excess peracetic acid was then destroyed by the addition of sodium bisulfite and this was followed by the addition of 200 ml of water and potassium carbonate to neutralize the acidic solution. The white solid was filtered off and washed with water. Yield 9.7 g, melting point of 160-162° C. Infrared and NMR spectra supported the proposed structure.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.CCCCCC.[C:32]([C:34]1[CH:35]=[C:36](/[C:40](/[CH:46]([CH3:48])[CH3:47])=[CH:41]\[C:42](OC)=[O:43])[CH:37]=[CH:38][CH:39]=1)#[N:33]>ClCCl>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:42](=[O:43])/[CH:41]=[C:40](\[C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([C:32]#[N:33])[CH:35]=2)/[CH:46]([CH3:48])[CH3:47])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)cc1
Reactant: COC(=O)/C=C(\c1cccc(C#N)c1)C(C)C
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)/C(=C/C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of 2′-tert-butylaminosulfonyl-4-amino-[1,1′]-biphenyl (139 mg, 0.46 mmol) in 4 ml anhydrous dichloromethane was added a solution of 2M trimethylaluminum in hexane (0.69 ml, 1.38 mmol). Reaction was stirred at room temperature for 20 minutes to which a solution of crude methyl (2Z)-3-(3-cyanophenyl)-4-methylpent-2-enoate (105 mg, 0.46 mmol) in 2 ml anhydrous dichloromethane was added. Reaction was stirred at room temperature overnight. Reaction was quenched with 5 ml 1N HCl after which an additional 20 ml dichloromethane was added. Organic was washed with 2×20 ml water, dried over magnesium sulfate, filtered and concentrated to give (2Z)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)-4-methylpent-2-enamide (190 mg, 82%) as an off-white foam which was sufficiently pure to be used without further purification. ES-MS (M+H): 501.2.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:12]3[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=[C:16]([C:17]4[CH:18]=[N:19][C:20]([N:23]([CH2:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=5)[CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)=[N:21][CH:22]=4)[C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:20]2[N:19]=[CH:18][C:17]([C:16]3[C:11]4[CH2:10][CH2:9][N:8]([C:5]5[CH:6]=[N:7][C:2]([N:52]6[CH2:53][CH2:54][N:49]([CH3:48])[CH2:50][CH2:51]6)=[CH:3][CH:4]=5)[C:12]=4[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=3)=[CH:22][N:21]=2)=[CH:26][CH:27]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(Cl)nc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(N4CCN(C)CC4)nc3)cn2)cc1
Yield: 99.3 %

Procedure:
Using {5-[7-(6-chloro-pyridin-3-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine (200 mg, 0.31 mmol) obtained in Step A in Example 1-D-48 and N-methylpiperazine (46 mg, 0.46 mmol) instead of N,N,N′-trimethyl ethylenediamine, in the same manner as Example 1-D-48, amination was carried out, to obtain a crude product of bis-(4-methoxy-benzyl)-(5-{7-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl)-amine as a colorless solid (220 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-71) as a yellow solid (35 mg, 24%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:19]2[CH:18]=[C:17]3[CH:20]([CH2:23][C:24]([OH:26])=O)[CH2:21][O:22][C:16]3=[CH:15][C:14]=2[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([N:29](CC)[CH2:30]C)C.ClC(OCC)=O>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[C:19]2[CH:18]=[C:17]3[CH:20]([CH2:23][C:24]([N:29]([CH3:30])[CH3:27])=[O:26])[CH2:21][O:22][C:16]3=[CH:15][C:14]=2[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC1COc2cc3c(cc21)N(C(=O)OCc1ccccc1)CC3
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: CN(C)C(=O)CC1COc2cc3c(cc21)N(C(=O)OCc1ccccc1)CC3
Reaction time: 2 h
Yield: 46.3 %

Procedure:
5-(Benzyloxycarbonyl)-2,3,6,7-tetrahydrofuro[2,3-f]indol-3-ylacetic acid (D22, 0.89 g, 2.5 mmol) and triethylamine (0.7 ml, 5 mmol) were stirred in dichloromethane (80 ml) under Ar at 0° C. as ethyl chloroformate (0.27 ml, 92.8 mmol) was added. The mixture was stirred for 2 h, and dimethylamine gas was then bubbled through the solution for 10 min. It was then washed with water, K2CO3 solution and brine, dried (Na2SO4) and evaporated. Chromatography of the crude product on silica, eluting with 75% ethyl acetate/petroleum ether (b.p. 60-80° C.) gave the title compound (0.44 g, 46%) as an off-white solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:12]([CH2:13][CH2:14]Cl)=[C:11](Cl)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([CH3:26])[CH:20]=1>C(O)C>[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([N:23]2[C:11]3[C:10]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:4]=[C:3]([CH3:2])[C:12]=3[CH2:13][CH2:14]2)=[C:21]([CH3:26])[CH:20]=1
Reactant: Cc1nc2ccccc2c(Cl)c1CCCl
Reactant: COc1ccc(N)c(C)c1
Agent: Cl
Solvent: CCO
Product: COc1ccc(N2CCc3c(C)nc4ccccc4c32)c(C)c1
Yield: 33.5 %

Procedure:
2-Methyl-3-(2-chloroethyl)-4-chloroquinoline hydrochloride (5.53 g, 20 mmol) and 4-methoxy-2-methylaniline (5.15 ml, 40 mmol) in ethanol (100 ml)were heated at 170° C. in a pressure vessel for 24 hours, then the solvent evaporated, the crude product taken up in dichloromethane, washed with aqueous sodium bicarbonate, dried and evaporated. Chromatography (silica gel, 2% methanolic ammonia in dichloromethane) and recrystallisation from aqueous methanol gave 1-(4-methoxy-2-methylphenyl)-4-methyl-2,3-dihydropyrrolo[3,2-c]quinoline (2.04 g, 22 %), m.p. 115°-117°.
Reaction SMILES: [CH2:1]([NH:10][CH3:11])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:13][C:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH2:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[O:17]1[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:14]([CH2:13][N:10]([CH2:1]/[CH:2]=[CH:3]/[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH3:11])=[CH:15][CH2:16]1
Reactant: ClCC1=CCOc2ccccc21
Reactant: CNC/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C/C=C/c1ccccc1)CC1=CCOc2ccccc21
Reaction time: 24 h

Procedure:
1.15 g of trans-N-cinnamyl-methylamine in 20 ml of dimethylformamide are slowly added dropwise with stirring to 1.4 g of 4-chloromethyl-2H-1-benzopyrane and 0.8 g of sodium carbonate in 40 ml dimethylformamide. Stirring is continued for 24 hours at room temperature, the resulting mixture evaporated under vacuum and the residue taken up in ethylacetate/water. The organic phase is separated, washed with 1% tartaric acid, saturated NaHCO3 and saturated NaCl, dried over MgSO4 and concentrated by evaporation. After purification by chromatography on kieselgel (eluant toluene/ethylacetate 10/1) the title compound is obtained.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][NH:14]C(=O)OC(C)(C)C)=[C:11]([CH2:24][NH:25][C:26]([C@@H:28]2[CH2:33][O:32][CH2:31][CH2:30][N:29]2[C:34](=[O:41])[C@H:35]([OH:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[O:27])[CH:10]=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:14][CH2:13][C:12]1[CH:22]=[CH:23][C:9]([Cl:8])=[CH:10][C:11]=1[CH2:24][NH:25][C:26]([C@@H:28]1[CH2:33][O:32][CH2:31][CH2:30][N:29]1[C:34](=[O:41])[C@H:35]([OH:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[O:27]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1COCCN1C(=O)[C@H](O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@@H](O)C(=O)N1CCOC[C@H]1C(=O)NCc1cc(Cl)ccc1CN
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (50% solution in CH2Cl2, 3 mL) was added to a solution of tert-Butyl 4-chloro-2-[{(S)-4-{(R)-2-hydroxy-3,3-dimethylbutanoyl}morpholine-3-carboxamido}-methyl]-benzylcarbamate (0.25 g, 0.50 mmol) in CH2Cl2 (1 mL) and the reaction was stirred at 0° C. for 30 min. The reaction mixture was concentrated under reduced pressure and residue was triturated with diethyl ether to afford the title compound as a white hygroscopic solid. 1HNMR (400 MHz, CD3CN): 8.37 (t, J=4.0 Hz, 1H), 8.05 (bs, 3H), 7.46-7.43 (m, 2H), 7.34 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 4.78 (d, J=4.0 Hz, 1H), 4.46 (dd, J=15.2, 6.0 Hz, 1H), 4.39-4.43 (m, 3H), 4.22 (d, J=2.8 Hz, 2H), 3.91 (d, J=12.4 Hz, 2H), 3.86 (dd, J=11.6, 2.4 Hz, 1H), 3.58 (dd, J=8.4 Hz, J=4.0 Hz, 1H), 3.53-3.42 (m, 2H), 0.98 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].C(N(C(C)C)CC)(C)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([O:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:8]([C:9]#[N:10])[CH:7]=1)(=[O:26])=[O:25]
Reactant: N#Cc1cccc(COCCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCc1cccc(C#N)c1
Reaction time: 2 h

Procedure:
To a solution of 3-[(2-hydroxyethoxy)methyl]benzonitrile (example 28vi) (6.00 g) and diisopropylethylamine (11.8 ml) in dichloromethane (100 ml) at 0° C. was added methanesulphonyl chloride (3.14 ml) dropwise and the mixture allowed to stir for 2 h. The resultant mixture was partitioned between dichloromethane and saturated sodium hydrogen carbonate. The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (8.5 g). LCMS RT=2.58 min.