Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:5]2.O[C:21]1[N:22]=CC2C(C=1)=CC=CC=2C#N>>[C:21]([C:10]1[CH:11]=[CH:2][CH:3]=[C:4]2[C:9]=1[CH:8]=[N:7][C:6]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:5]2)#[N:22]
Reactant: O=S(=O)(Oc1cc2cc(F)ccc2cn1)C(F)(F)F
Reactant: N#Cc1cccc2cc(O)ncc12
Product: N#Cc1cccc2cc(OS(=O)(=O)C(F)(F)F)ncc12

Procedure:
Following the procedure for trifluoromethanesulfonic acid 6-fluoroisoquinolin-3-yl ester, using 3-hydroxyisoquinoline-8-carbonitrile in place of 6-fluoroisoquinolin-3-ol, the title compound was obtained as a yellow solid. MS (ES+): m/z=303.04 [MH+]. HPLC: tR=3.55 min (ZQ2, polar—5 min).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH2:24]([NH2:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>C(O)(C)C>[CH3:8][C:6]1[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=[C:2]([NH:29][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:7]=1
Reactant: CC(C)(C)CN
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Solvent: CC(C)O
Product: CCCC(C(=O)OC)c1c(C)nc(NCC(C)(C)C)nc1-c1ccc(C)cc1
Yield: 49.5 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.300 mmol), and neopentyl amine (0.177 mL; 1.502 mmol) were placed in a 2 mL reaction tube and dissolved in isopropanol (1.5 mL). The tube was sealed and irradiated in a microwave oven at 180° C. for 1 h. The reaction mixture was partitioned between brine and dichloromethane, filtered over a phase separator filter (1PS) and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-20%) in heptane to give 57 mg (49%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5]>C1COCC1.[Ni]>[NH2:16][C:15]1[C:9]2[S:8][C:7]([NH:6][C:4](=[O:5])[C:3]3[C:19]([CH3:24])=[CH:20][C:21]([CH3:23])=[CH:22][C:2]=3[CH3:1])=[N:11][C:10]=2[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cc(C)c(C(=O)Nc2nc3cccc([N+](=O)[O-])c3s2)c(C)c1
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1cc(C)c(C(=O)Nc2nc3cccc(N)c3s2)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
To 0.200 (0.586 mmol) of 2,4,6-trimethyl-N-(7-nitro-1,3-benzothiazol-2-yl)benzamide in 5 mL of THF was added a pipet tip of Raney nickel. The reaction was kept under a hydrogen atmosphere via a balloon and stirred at room temperature for 90 min. The catalyst was removed via filtration and the filtrate was concentrated in vacuo to give a burnt orange solid. The resulting crude solid was purified by flash chromatography eluting with 25% ethyl acetate/hexanes mixture to give 0.118 g (65%) of the title compound as a light yellow powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:14]2([CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[C:13]([F:21])([F:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:23]1[C:24]2[CH:31]=[CH:30][NH:29][C:25]=2[N:26]=[CH:27][N:28]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[C:14]2([CH2:19][CH2:18][CH2:17][N:16]([C:23]3[C:24]4[CH:31]=[CH:30][NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH2:15]2)[C:13]([F:21])([F:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CC(F)(F)C12CCCNC2
Reactant: Clc1ncnc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CC(F)(F)C12CCCN(c1ncnc3[nH]ccc13)C2
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 106.1 %

Procedure:
An optically-active compound of 3,3-difluoro-1,6-diaza-spiro[3.5]nonane-1-carboxylic acid benzyl ester 1 hydrochloride (11.2 g) was mixed with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4.2 g), potassium carbonate (18.7 g) and water (104 ml), and the mixture was stirred for 16.5 hours with refluxing. The mixture was cooled to room temperature, and thereto were added ethyl acetate and water. The mixture was filtered, and the filtrate was separated and the resulting organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/acetone=3/1). The resulting residue was purified by silica gel column chromatography (eluent: chloroform/acetone=2/1) again to give the titled compound (12.0 g).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:7]=1[CH:8]=O>>[CH:1]1([NH:4][CH2:8][C:7]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:6]=2[Cl:5])[CH2:3][CH2:2]1
Reactant: O=Cc1cc(Cl)ccc1Cl
Reactant: NC1CC1
Product: Clc1ccc(Cl)c(CNC2CC2)c1

Procedure:
prepared by reaction of cyclopropylamine with 2,5-dichloro-benzaldehyde.
Reaction SMILES: [CH2:1]1[CH2:7][CH2:6][CH:5]([C:8]2([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH:32][C:33]4[N:34](C(OC(C)(C)C)=O)[CH:35]=[CH:36][N:37]=4)[CH:26]=3)=[O:23])[N:14]=[CH:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[N:10]([CH3:19])[C:9]2=[O:20])[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH2:2]1[CH2:3][CH2:4][CH:5]([C:8]2([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH:32][C:33]4[NH:37][CH:36]=[CH:35][N:34]=4)[CH:26]=3)=[O:23])[N:14]=[CH:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[N:10]([CH3:19])[C:9]2=[O:20])[CH2:6][CH2:7][CH2:1]1
Reactant: CN1C(=O)C(NC(=O)Nc2cccc(CNc3nccn3C(=O)OC(C)(C)C)c2)(C2CCCCCC2)N=Cc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)C(NC(=O)Nc2cccc(CNc3ncc[nH]3)c2)(C2CCCCCC2)N=Cc2ccccc21
Reaction time: 3 h

Procedure:
To a solution of N-[3(R,S)-5-cycloheptyl-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]N'-[3-[(1-(tert-butyloxycarbonyl)imidazol-2-ylamino]methyl)phenyl] urea in anhydrous dichloromethane (5 ml) at room temperature, under nitrogen, was added trifluoroacetic acid (0.5 ml). After stirring for 3 h the solvent was evaporated in vacuo and the residue azeotroped with toluene (20 ml). The residue was partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was separated, washed with 0.5M sodium carbonate solution (2×20 ml) and water (20 ml), then the organic layer separated and dried (Na2SO4). The solvent was evaporated and the residue chromatographed on silica gel using a gradient elution of dichloromethane:methanol (90:10) followed by methanol to afford the title compound (33 mg) as a white solid. 1H NMR (360 MHz, D6 -DMSO) δ 1.12-1.80 (11H, m), 1.92-1.97 (1H, m), 3.10-3.18 (1H, m), 3.32 (3H, s), 4.25 (2H, d, J=6.2 Hz), 5.04 (1H, d, J=8.4 Hz) 6.42 (1H, m), 6.49 (2H, s), 6.87 (1H, d, J=7.6 Hz), 7.14 (1H, t, J=7.9 Hz), 7.23-7.29 (3H, m), 7.37 (1H, dd, J=7.2 and 7.2 Hz), 7.54 (1H, m), 7.63 (1H, dd, J=7.1 and 7.1 Hz), 7.76 (1H, d, J=6.7 Hz), 8.95 (1H, s). MS (FAB) 500 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([Cl:13])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccnc(F)c1
Product: O=C(Cl)c1ccnc(F)c1

Procedure:
A mixture of the above 2-fluoropyridine-4-carboxylic acid (10 g) and thionyl chloride (70 mL) was heated at reflux for 25 hours. The excess thionyl chloride was removed by distillation at atmospheric pressure and the residue was distilled giving 9.51 grams of 2-fluoropyridine-4-carbonyl chloride having a boiling point of 88° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][C:13](=O)[CH2:14][O:15][CH2:16][CH3:17])=[C:10]([NH:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(O)C.O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:14][O:15][CH2:16][CH3:17])[N:19]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:28])[CH3:26])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCC(=O)Nc1c(Cl)nc2ccccc2c1NCCNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOCc1nc2c(Cl)nc3ccccc3c2n1CCNC(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 70.4 %

Procedure:
To a solution of the hydrochloride salt of tert-butyl 2-({2-chloro-3-[(ethoxyacetyl)amino]quinolin-4-yl}amino)ethylcarbamate (2.50 g, 5.44 mmol) in 9:1 ethanol/water (50 mL) was added a solution of potassium carbonate (1.12 g, 8.16 mmol) in water (5 mL). The solution was heated to 50° C. for five hours. The solution was concentrated under reduced pressure and the residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to a pale yellow solid that was purified by flash chromatography (silica gel, gradient elution from 1:1 to 4:1 ethyl acetate/hexane) to afford the tert-butyl 2-(4-chloro-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate as a white solid (1.55 g).
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].[Br:5][C:6]1[CH:11]=[CH:10][C:9](F)=[C:8]([Cl:13])[CH:7]=1.O>CN(C)C=O>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([S:3][CH2:1][CH3:2])=[C:8]([Cl:13])[CH:7]=1
Reactant: CC[S-]
Reactant: Fc1ccc(Br)cc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1ccc(Br)cc1Cl
Temperature: 65 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
Sodium ethanethiolate (2.0 g) was added to a solution of 4-bromo-2-chloro-1-fluorobenzene (5.0 g) in N,N-dimethylformamide (20 mL), and the mixture was stirred at 65° C. for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:1→0:100) to give the title compound as a colorless oil (4.8 g).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]([NH:19][CH:20]=[O:21])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:22]C1C=CC(C=O)=CC=1>>[Br:22][C:7]1[CH:6]=[CH:5][C:4]([CH:8]([NH:19][CH:20]=[O:21])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2cccc(I)c2)cc1
Reactant: O=Cc1ccc(Br)cc1
Product: Cc1ccc(S(=O)(=O)C(NC=O)c2ccc(Br)cc2)cc1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 52 but using 4-bromobenzaldehyde in place of 3-iodobenzaldehyde. Solid (31 g, 80%);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].[N:13]#[C:14]Br>O.C(#N)C>[NH2:13][C:14]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][C:11]=2[N:12]=1
Reactant: N#CBr
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc2nc(N)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
300 mg (1.8 mmol) of methyl 3,4-diaminobenzoate was stirred in 5 ml of water. 0.5 ml of a solution of 5 M of cyanogen bromide in acetonitrile was added to the obtained mixture, and they were stirred at room temperature for 20 minutes. The mixture was filtered. Aqueous ammonia was added to the filtrate. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]=[O:8].[C:9]1([CH2:15][CH2:16][CH2:17][Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]([OH:8])[CH2:17][CH2:16][CH2:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Br[Mg]CCCc1ccccc1
Reactant: O=Cc1ccsc1Br
Product: OC(CCCc1ccccc1)c1ccsc1Br

Procedure:
Prepared according to the procedure described in Example 5, Step 1, using the following starting materials: 2-bromo-thiophene-3-carbaldehyde and 3-phenyl-propyl magnesium bromide.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.CC(C)([O-])C.[K+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>CS(C)=O.O>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: Cc1cc2ccccc2[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc2ccccc2n1-c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 26.1 %

Procedure:
A solution of 2-methylindol (1 g, 7.6 mmol) and potassium t-butoxide (897 mg, 8 mmol) in DMSO (10 mL) was stirred at room temperature under argon for 30 min. 4-Fluoronitrobenzene (0.81 mL, 7.62 mmol) was added and the reaction mixture was heated to 100° C. in an oil bath for 5 h. The reaction mixture was diluted with water, extracted with EtOAc, the organic extract with washed with water and dried (MgSO4). The oil obtained on concentration was flash chromatographed on silica gel and elution was -carried out with a gradient of 5-8% EtOAc in hexane to give 1-(4-nitrophenyl)-2-methylindol (500 mg).
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[C:8]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[CH:7]=[CH:6][C:5]=2[N:4]1[S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH3:2].C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[C:8]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[CH:7]=[CH:6][C:5]=2[N:4]1[S:23]([C:26]1[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=1)(=[O:25])=[O:24])[CH3:2]
Reactant: CCC1c2cc(F)ccc2-c2cc(-c3ccsc3)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CCC1c2cc(F)ccc2-c2cc(-c3ccsc3)ccc2N1S(=O)(=O)c1ccc(O)cc1
Yield: 63 %

Procedure:
The title compound was prepared from 6-ethyl-8-fluoro-5-[(4-methoxyphenyl)sulfonyl]-2-thien-3-yl-5,6-dihydrophenanthridine (0.28 g, 0.58 mmol), cyclohexene (13 mL, 10.5 mmol), and 1 M boron tribromide in dichloromethane (3.5 mL, 3.5 mmol) according to the procedure and in the same manner as described in Example 47, Step b. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:4) to yield 4-[(6-ethyl-8-fluoro-2-thien-3-ylphenanthridin-5(6H)-yl)sulfonyl]phenol as a homogeneous solid (0.17 g, 63%);
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:19])[CH2:9][C:10]1[NH:14][C:13]2[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=2[N:11]=1.C[O-].[Na+].[C:23](OC)(=[O:26])[C:24]#[CH:25]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:9]1[CH:25]=[CH:24][C:23](=[O:26])[N:14]2[C:13]3[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=3[NH:11][C:10]=12)=[O:19]
Reactant: C#CC(=O)OC
Reactant: Cc1ccccc1C(=O)Cc1nc2c([nH]1)CCCC2
Agent: C[O-]
Agent: [Na+]
Product: Cc1ccccc1C(=O)c1ccc(=O)n2c3c([nH]c12)CCCC3

Procedure:
The compound is prepared as described in example 20 with 1450 mg (5.90 mmol) of 1-(2-Methylphenyl)-2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone (example XXXX), 637.2 mg (11.80 mmol) of sodium methylate and 495.8 mg (5.90 mmol) methyl propiolate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=5[F:38])[CH:33]=O)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:50]([N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)[CH3:51]>>[CH2:50]([N:52]1[CH2:57][CH2:56][N:55]([CH2:33][C:32]2[CH:35]=[CH:36][C:37]([F:38])=[C:30]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:13]=[N:14][C:9]([N:8]([CH2:39][C:40]6[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=6)[CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:49][CH:48]=6)=[N:10][CH:11]=5)[C:16]=4[CH2:29][CH2:28]3)[CH:31]=2)[CH2:54][CH2:53]1)[CH3:51]
Reactant: CCN1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cc(C=O)ccc3F)cn2)cc1
Product: CCN1CCN(Cc2ccc(F)c(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)c2)CC1

Procedure:
In the same manner as Step A in Example 1-D-26, using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (215 mg) and 4-fluoro-3-bromo-benzaldehyde (113 mg) instead of 2-(4-bromo-phenyl)-[1,3]dioxolane, a crude product of 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-4-fluoro-benzaldehyde was obtained as a colorless solid (260 mg). Using a crude product (130 mg) of 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-4-fluoro-benzaldehyde, in the same manner as Step B in Example 1-D-26, using 1-ethylpiperazine (0.05 ml) instead of 1-methylpiperazine, a crude product of 5-{7-[5-(4-ethyl-piperazin-1-ylmethyl)-2-fluoro-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine was obtained as a colorless solid (57 mg). Using a crude product (57 mg) of 5-{7-[5-(4-ethyl-piperazin-1-ylmethyl)-2-fluoro-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine, according to the above Deprotection method 2, 5-{7-[5-(4-ethyl-piperazin-1-ylmethyl)-2-fluoro-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-ylamine was obtained as a colorless powder (26 mg, 68%).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:9][OH:10])(C)(C)C.[CH:19]1(O)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:15]([O:14][C:12](=[O:13])[NH:11][CH:8]1[CH2:7][C:6](=[O:5])[O:18][CH:9]1[O:10][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH:16]=[CH2:17]
Reactant: OC1CCCC1
Reactant: C=CCOC(=O)NC(CO)CC(=O)OC(C)(C)C
Product: C=CCOC(=O)NC1CC(=O)OC1OC1CCCC1

Procedure:
Prepared from 3-allyloxycarbonylamino-4-hydroxy-butyric acid tert-butyl ester as described for 40 using cyclopentanol to afford the title compound as a mixture of diastereomers. Flash column chromatography using hexanes/EtOAc (90/10 to 80/20) afforded the syn diastereomer of the title compound: syn diastereomer 1H NMR (500 MHz, CDCl3) δ 1.5-2.0 (m, 8H), 2.45 (dd, 1H), 2.81 (dd, 0.9H), 3.0 (dd, 0.1H), 4.31 (m, 1H), 4.59 (m, 4H), 5.23 (m, 1H), 5.32 (m, 1H), 5.45 (s, 0.1H), 5.51 (s, 0.9H), 5.92, (m, 1H) ppm; anti diastereomer 1H-NMR (500 MHz, CDCl3) δ 1.50 (m, 2H), 1.67 (m, 6H), 2.36 (d, 1H), 2.8 (dd, 0.08H), 2.96 (dd, 0.92H), 4.13 (m, 1H), 4.25 (m, 1H), 4.55 (br, 2H), 5.20 (d, 1H), 5.30 (m, 2H), 5.43 (s, 0.92H), 5.5 (d, 0.08H), 5.89 (s, 1H) ppm.
Reaction SMILES: C(OC([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19](=[O:37])[C@@H:20]([NH:25][C:26]([C:28]2[O:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[CH:32]=2)=[O:27])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:13]([OH:38])[CH2:12]1)=O)C1C=CC=CC=1.C(OCC)(=O)C.[H][H]>CO.[Pd]>[OH:38][CH:13]1[CH:14]([NH:18][C:19]([C@@H:20]([NH:25][C:26]([C:28]2[O:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[CH:32]=2)=[O:27])[CH2:21][CH:22]([CH3:23])[CH3:24])=[O:37])[CH2:15][CH2:16][CH2:17][NH:11][CH2:12]1
Reactant: [H][H]
Reactant: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CCCN(C(=O)OCc2ccccc2)CC1O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CCCNCC1O
Yield: 97.6 %

Procedure:
To a solution of 4-{(S)-2-[(benzofuran-2-carbonyl)-amino]-4-methyl-pentanoylamino}-3-hydroxy-azepane-1-carboxylic acid benzyl ester of Example 78b (1.6 g) in methanol:ethyl acetate (50 mL: 100 mL) was added 10% Pd/C. The reaction was stirred under a balloon of hydrogen for 2 hours whereupon it was filtered and concentrated to provide the title compound (1.16 g): MS(EI) 387 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])[CH2:29]P(OCC)(OCC)=O)[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[CH3:61][N:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH:63]1[CH:68]=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])/[CH:29]=[CH:68]/[CH:63]4[CH2:64][CH2:65][CH2:66][CH2:67][N:62]4[CH3:61])[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)CP(=O)(OCC)OCC
Reactant: CN1CCCCC1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)/C=C/C1CCCCN1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.9 %

Procedure:
N-[4-[[3-Chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-2-diethoxyphosphoryl-acetamide 1d (300 mg, 0.48 mmol) was dissolved in 10 mL of tetrahydrofuran in a dry ice bath, followed by dropwise addition of a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (530 μL, 0.53 mmol). After stirring for 30 minutes, a solution of l-methylpiperidine-2-carbaldehyde 6b (120 mg, 0.96 mmol) in 5 mL of tetrahydrofuran was added dropwise. The reaction mixture was stirred for another 30 minutes, then warmed up to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-3-(1-methyl-2-piperidyl)prop-2-enamide 6 (14 mg, yield 4.9%) as a yellow solid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH2:21]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(#N)C>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]([N:31]1[CH2:32][CH2:33][CH2:34][C@H:30]1[C:29]([O:28][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:35])=[O:19])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a suspension of N-Boc-L-phenylalanine (1.000 g, 3.77 mmol) in acetonitrile (25 ml) at room temperature was added L-proline benzyl ester HCl (1.002 g, 4.15 mmol), PyBOP (2.060 g, 3.96 mmol) followed by DIPEA (1.382 ml, 7.92 mmol). The reaction turned to clear and was stirred at room temperature for 1 hour. The reaction was quenched by brine and was extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (silica gel, 30 to 50% EtOAc/HEP) and gave the title compound: 1.6 g (yield: 97%). LCMS (condition B): 453.4 (M+1); retention time=1.44 min.