Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)(C)(C)C.Cl>O1CCOCC1>[CH:14]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH2:7])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccccc1C1CCCCC1

Procedure:
The carbamate obtained as above was treated with 4 M HCl in dioxane following the procedure described in Example 80 to afford 2-cyclohexylphenylamine as a hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.Cl[C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:21])[C:11]=1O>COCCOC.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([C:11]3[C:12](=[O:21])[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19](=[O:20])[C:10]=3[N:1]=2)[CH:4]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C1C(O)=C(Cl)C(=O)c2ccccc21
Solvent: COCCOC
Solvent: O
Product: O=C1c2ccccc2C(=O)c2c1nc1ccc(Cl)cn21
Yield: 4 %

Procedure:
1.58 g (12.30 mmol) of 2-amino-5-chloropyridine are added to a suspension of 1.29 g (6.21 mmol) of 3-chloro-1,4-dihydro-1,4-dioxo-2-hydroxynaphthalene in solution in 10 mL of 1,2-dimethoxyethane. The reaction medium is brought to reflux for 23 h. After complete cooling, the medium is diluted in 10 mL of water. The precipitate is filtered, washed with water and heptane, and dried. The precipitate is then diluted in dichloromethane and the organic phase is washed successively with a saturated solution of sodium hydrogen carbonate and sodium chloride. The organic phase is dried on sodium sulfate, filtered, and evaporated under reduced pressure. The raw product obtained is purified on a flash column (support: silica; eluent: dichoromethane/heptane/methanol, 79.5/20.0/0.5) to produce 0.07 g of 2-chloro-6,11-dihydro-6,11-dioxo-naphtho[2',3':4,5]imidazo [1,2-a]pyridine in the form of yellow crystals after decoloration with animal black.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=O)[NH:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([Cl:15])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1cnc2ccc(Br)cc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cnc2ccc(Br)cc2n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
7-bromo-2(1H)-quinoxalinone (47.2 g; 210 mmol) was added to phosphorus oxychloride (470 mL). The reaction mixture was stirred at 100° C. for 2 hours, cooled down to room temperature and evaporated to dryness. The crude product was taken up into DCM and poured onto ice, water and K2CO3 powder. The mixture was filtered over celite. The celite was washed twice with DCM. The organic layer was decanted, dried over MgSO4, filtered and evaporated to dryness to give 49 g (96%) of 7-bromo-2-chloro-quinoxaline (grey solid). MP=146° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=O)[CH2:11][CH:10]([C:14](OC)=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC1CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
First, N-benzyl-pyrrolidine-3-methanol was prepared as follows. Methyl N-benzyl-5-oxo-pyrrolidine-3-carboxylate (11.66 g, 50 mmol) was dissolved in diethyl ether and cooled to 0° C. This solution was added to a 0° C. suspension of lithium aluminum hydride in diethyl ether under nitrogen atmosphere. After addition, the mixture was refluxed for 1 hr, and then cooled with an ice bath. To quench the reaction, sodium sulfate decahydrate was added and the mixture was stirred for 1 hr. After filtration, the filtrate was collected, and concentrated to dryness to give N-Benzyl-pyrrolidine-3-methanol. ESMS (C12H17NO): calcd. 191.13; obsd. 192.2 [M+H]+. Retention time (anal. HPLC: 10-70% MeCN/H2O over 5 min)=0.95 min.
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][C:5]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)=[O:6].[OH-].[Na+]>CCOCC>[CH3:1][NH:2][CH2:4][C:5]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)=[O:6]
Reactant: CN
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CNCC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Methylamine (100 mL of 2M solution in THF) was charged into a 500 mL flask, to which was added 150 mL of Et2O. At −78° C., 15 g of 4-bromoacetyl benzonitrile was added, and the reaction was allowed to warm to rt. After stirring for 5 h, the reaction mixture was poured into a separatory funnel and shaken with 15% aq NaOH (20 mL). The precipitate was collected by filtration, and air-dried to give 4-(N-methylglycyl)benzonitrile.
Reaction SMILES: C([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]2([C:25]3[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:27])[CH:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)=[O:7])(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Cl:26][C:22]1[CH:21]=[C:20]2[NH:19][C:18](=[O:27])[C:10]3([CH:9]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=4)[CH:8]([C:6]([OH:7])=[O:5])[NH:12][CH:11]3[CH2:13][C:14]([CH3:16])([CH3:15])[CH3:17])[C:25]2=[CH:24][CH:23]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester (3.6 g, 7.2 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (7 mL). The reaction mixture was stirred at room temperature for 18 h, then concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried in vacuo to give rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid as a off white solid (3.8 g, 95%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]3[CH:37]=[C:36]([CH2:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH:35]=[CH:34][C:26]=3[C:27]([O:29]C(C)(C)C)=[O:28])=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)=O)(C)(C)C>>[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]3[CH:37]=[C:36]([CH2:38][CH2:39][C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:35]=[CH:34][C:26]=3[C:27]([OH:29])=[O:28])=[CH:21][CH:22]=2)[CH:17]=[CH:16]1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1Nc1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(CCc2ccccc2)cc1Nc1ccc2[nH]ccc2c1

Procedure:
Trifluoroacetic acid 3.0 mL solution of the obtained tert-butyl 2-((1-(tert-butoxycarbonyl)-1H-indol-5-yl)amino)-4-phenethylbenzoate was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 60-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-((1H-indol-5-yl)amino)-4-phenethylbenzoic acid 25 mg of pale yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:18]([NH:20][C@H:21]([C:32]([NH:34][C@H:35]([C:38]([NH:40][C@H:41]([C:50]([NH:52][C@@H:53]([C:60]([NH:62][C@H:63]([C:68]([NH:70][C@H:71]([C:79]([N:81]1[CH2:90][CH2:89][CH2:88][C@H:82]1[C:83]([NH:85][CH2:86][CH3:87])=[O:84])=[O:80])[CH2:72][CH2:73][CH2:74][NH:75][C:76](=[NH:78])[NH2:77])=[O:69])[CH2:64][CH:65]([CH3:67])[CH3:66])=[O:61])[CH2:54][O:55]C(C)(C)C)=[O:51])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1)=[O:39])[CH2:36][OH:37])=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].[CH3:91][C:92]([CH2:94][C:95]([OH:97])=[O:96])=[O:93].SC(O)C>FC(F)(F)C(O)=O>[NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:18]([NH:20][C@H:21]([C:32]([NH:34][C@H:35]([C:38]([NH:40][C@H:41]([C:50]([NH:52][C@@H:53]([C:60]([NH:62][C@H:63]([C:68]([NH:70][C@H:71]([C:79]([N:81]1[CH2:90][CH2:89][CH2:88][C@H:82]1[C:83]([NH:85][CH2:86][CH3:87])=[O:84])=[O:80])[CH2:72][CH2:73][CH2:74][NH:75][C:76](=[NH:77])[NH2:78])=[O:69])[CH2:64][CH:65]([CH3:67])[CH3:66])=[O:61])[CH2:54][OH:55])=[O:51])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1)=[O:39])[CH2:36][OH:37])=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7].[CH3:91][C:92]([CH2:94][C:95]([OH:97])=[O:96])=[O:93]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)CCC(=O)O
Agent: CC(=O)CC(=O)O
Agent: CC(O)S
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CO)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)CCC(=O)O
Reaction time: 1 h

Procedure:
200 mg of Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-NH-C2H5 -diacetate were dissolved with 0.1 ml of mercaptoethanol in 2 ml of trifluoroacetic acid. The solution was allowed to stand for 1 hour at room temperature, it was concentration and the residue was triturated with ether. The substance was suction-filtered and washed with ether, dissolved in water and chromatographed over Dowex 1×2 (acetate form). The eluate was concentrated and the residue was purified in analogy to Example 1 e) on Sephadex LH 20. Yield: 120 mg. The content of peptide base was 77.5% as per UV-spectrum [-α]D20 = -43.7° (c=1, H2O).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([NH:23][CH2:24][CH2:25][CH3:26])=[N:10][C:11]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[N:12][CH:13]=1)=[O:7].[C:27]([NH:34][CH2:35][C:36](O)=[O:37])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(N(CC)CC)C.CN(C)C=O>[O:37]=[C:36]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([NH:23][CH2:24][CH2:25][CH3:26])=[N:10][C:11]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[N:12][CH:13]=1)=[O:7])[CH2:35][NH:34][C:27](=[O:28])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)NCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)NCCCNC(=O)CNC(=O)OC(C)(C)C
Reaction time: 7 h
Yield: 101.1 %

Procedure:
To N-(3-aminopropyl)-4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxamide (B4, 57 mg), N-Boc-glycine (44 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (127 mg) and 1-hydroxybenzotriazole monohydrate (102 mg), N,N-dimethylformamide (2 mL) and triethylamine (46 μL) were added at room temperature, and the mixture was stirred at the same temperature for 7 hours. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent, 95 to 90% ethyl acetate in methanol) to obtain amorphous tert-butyl (2-oxo-2-((3-(4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxamido)propyl)amino)ethyl)carbamate (B5, 83 mg).
Reaction SMILES: Cl.[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[OH:16][CH:17]1[CH2:21][CH:20]([CH3:22])[NH:19][CH2:18]1>>[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([N:19]3[CH:20]([CH3:22])[CH2:21][CH:17]([OH:16])[CH2:18]3)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CC1CC(O)CN1
Agent: Cl
Product: CC1CC(O)CN1S(=O)(=O)c1cccc2cnccc12

Procedure:
In substantially the same manner as in Example 11, 2.64 g of 5-isoquinolinesulfonyl chloride hydrochloride was reacted with 2.0 g of 3-hydroxy-5-methylpyrrolidine to obtain 1-(5-isoquinolinesulfonyl)-3-hydroxy-5-methylpyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 35.9 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 4-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 180° C. for 5 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.028 g (35%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-2-carboxamide as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[Li+].[OH-]>C1COCC1.CO>[N:17]1[CH:16]=[CH:15][C:14]([CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:20])=[O:2])=[CH:7][CH:8]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)CCc1ccc(OCc2ccncc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(OCc2ccncc2)cc1
Reaction time: 8 h

Procedure:
To a solution of 3[4-(Pyridin-4-ylmethoxy)-phenyl]-propionic acid methyl ester (0.28 g, 1.03 mmol) in THF (5 ml) and MeOH (5 ml) at room temperature is added 2 N LiOH (0.52 ml, 1.032 mmol) and the resulting solution is stirred overnight. Further 2 N LiOH (0.103 ml) is added and the reaction mixture stirred for a further 1 hour. The reaction mixture is concentrated in vacuo and the residue is diluted with water (50 ml) followed by EtOAc. The aqueous phase is acidified to pH2 with 1 N HCl, and extracted with DCM. The organic phase is concentrated to a third of its volume in vacuo until a white powder precipitates which is collected by filtration to yield the title compound; [M+H]+ 258.0
Reaction SMILES: [OH:1][CH:2]1[CH2:6][O:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:11]#[N:12].[H-].[Na+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:20]([O:1][CH:2]1[CH2:6][O:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:11]#[N:12])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: COc1ccc(C#N)cc1OC1COCC1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1OC1COCC1OCc1ccccc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
2.5 g (11.0 mmol) of 3-(4-hydroxytetrahydrofuran-3-yloxy)-4-methoxybenzonitrile (A 15) in 12 ml of dimethylformamide are added dropwise under a nitrogen atmosphere to a solution of 350 mg (12.0 mmol) of sodium hydride in 12 ml of dimethylformamide and the mixture is heated at 40° C. for 1 h. 1.6 ml (13.0 mmol) of benzyl chloride, dissolved in 6 ml of dimethylformamide, are then added dropwise at RT. The mixture is stirred at RT for 4 h. concentrated, treated with 50 ml of water and acidified with 2 N hydrochloric acid. After extraction with 3×40 ml of ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. For further purification, the product is chromatographed on silica gel [toluene/ethyl acetate=4:1]. The product-containing fractions are concentrated and the residue is crystallized from isopropanol. 3.05 g of the title compound of m.p. 72-75° C. are obtained.
Reaction SMILES: [F:1][C:2]([F:16])([CH3:15])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][C:6]=1[CH3:14].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[F:1][C:2]([F:16])([CH3:15])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:12])=[CH:7][C:6]=1[CH3:14]
Reactant: CC(=O)c1cnc(OCC(C)(F)F)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OCC(C)(F)F
Yield: 61 %

Procedure:
The title compound is prepared in 61% yield (481 mg, colorless oil) from 1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethanone (545 mg, 2.38 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (346 mg, 2.85 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: N#N.C(OC([NH:10][C@@H:11]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:17])[CH2:12][CH2:13][S:14][CH3:15])=O)(C)(C)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[K+].C(OCC)(=O)C.[ClH:50]>C(O)(=O)C>[ClH:50].[C:22]1([CH2:21][CH2:20][CH2:19][NH:18][C:16](=[O:17])[C@@H:11]([CH2:12][CH2:13][S:14][CH3:15])[NH2:10])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCCCc1ccccc1
Agent: Cl
Agent: N#N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CSCC[C@@H](N)C(=O)NCCCc1ccccc1

Procedure:
A solution of N2 -(tert-butyloxycarbonyl)-N-(3-phenylpropyl)-D-methioninamide (1.75 g.) in acetic acid (10 ml.) and hydrogen chloride-ethyl acetate (4 N, 20 ml.) was stirred at room temperature for one hour, then stripped of volatiles under vacuum. A solution of the residue in ethyl acetate-ether was stripped of volatiles under vacuum, finally over phosphorous pentoxide and potassium hydroxide, affording N-(3-phenylpropyl)-D-methioninamide hydrochloride as a vicous oil (1.50 g.).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:31]=[C:30]([C:32]([N:34]2[CH2:43][C:42]3[CH:41]=[N:40][N:39]([CH3:44])[C:38]=3[NH:37][C:36]3[CH:45]=[CH:46][CH:47]=[CH:48][C:35]2=3)=[O:33])[CH:29]=[CH:28][C:27]=1[CH2:49][CH2:50][C:51]([OH:53])=O.[O:54]1[CH:58]=[CH:57][CH:56]=[C:55]1[C:59]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)=[O:60]>CN(C=O)C.CCN(C(C)C)C(C)C>[O:54]1[CH:58]=[CH:57][CH:56]=[C:55]1[C:59]([N:61]1[CH2:62][CH2:63][N:64]([C:51](=[O:53])[CH2:50][CH2:49][C:27]2[CH:28]=[CH:29][C:30]([C:32]([N:34]3[CH2:43][C:42]4[CH:41]=[N:40][N:39]([CH3:44])[C:38]=4[NH:37][C:36]4[CH:45]=[CH:46][CH:47]=[CH:48][C:35]3=4)=[O:33])=[CH:31][C:26]=2[CH3:25])[CH2:65][CH2:66]1)=[O:60]
Reactant: O=C(c1ccco1)N1CCNCC1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCN(C(=O)c2ccco2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of HBTU (1.90 mg, 0.005 mmol) in DMF (0.05 ml) was added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid from Example E45 (1.95 mg, 0.005 mmol) in DMF (0.05 ml) and DIEA (0.0022 ml). The mixture was stirred at room temperature for 30 min then a solution of 1-(2-furoyl)piperazine (0.90 mg, 0.005 mmol) in DMF (0.05 ml) was added. The mixture was stirred for 18 h at room temperature then sol-vents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=553.4
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@@H:9]1[NH:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:37][C:38]([F:41])([F:40])[F:39])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:20]=[C:19]([C:30]2[CH:31]=[N:32][C:33]([NH2:36])=[N:34][CH:35]=2)[N:18]=3)[CH2:10]1.C([O:45][CH2:46][C:47](Cl)=[O:48])(=O)C.C[O-].[Na+].CO>C(Cl)Cl.CO.O1CCCC1.C(Cl)Cl.CO>[NH2:36][C:33]1[N:34]=[CH:35][C:30]([C:19]2[N:18]=[C:17]3[C:22]([N:23]=[C:15]([N:11]4[CH2:12][CH2:13][N:14]([C:46](=[O:45])[CH2:47][OH:48])[C@@H:9]([CH3:8])[CH2:10]4)[N:16]3[CH2:37][C:38]([F:41])([F:39])[F:40])=[C:21]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:20]=2)=[CH:31][N:32]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: C[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1C(=O)CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
Triethylamine (55.8 μl, 0.40 mmol) was added to a methylene chloride suspension (3.0 ml) of 5-{8-[(3S)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl}pyrimidin-2-amine (87.1 mg, 0.18 mmol) at room temperature followed by the addition of acetoxyacetyl chloride (24.2 μl, 0.22 mmol) with ice cooling. The resulting mixture was stirred at room temperature for 90 minutes, then the reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, a 25% by weight sodium methoxide-methanol solution (83.3 μl, 0.36 mmol) was added to a methanol-tetrahydrofuran (1:1) mixture solution (12.0 ml) of the resulting white solid, and the resulting mixture was stirred at room temperature for 25.5 hours. The reaction mixture was poured into methylene chloride and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (85.0 mg, 87%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[S:11])[CH:5]2[CH3:12].[Cl:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:13][C:5]1([CH3:12])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=2)[NH:7][C:6]1=[S:11]
Reactant: Cc1ccc2c(c1)C(C)C(=S)N2
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc2c(c1)C(C)(Cl)C(=S)N2

Procedure:
A solution of 5-methyl-3-methylthiooxindole (1.00 g, 0.0052 mol) and N-chlorosuccinimide (700 mg, 0.0053 mol) in carbon tetrachloride (100 ml) was stirred at room temperature for 1 hour. The precipitate was removed by filtration and the filtrate was evaporated to give the crude 3-chloro-5-methyl-3-methylthiooxindole, which was dissolved in tetrahydrofuran (20 ml) and added to a vigorously stirred slurry of red mercuric oxide (1.13 g, 0.0052 mol) and boron trifluoride etherate (745 mg, 0.0052 mol) in 70 ml of 20 percent aqueous tetrahydrofuran. After stirring at room temperature for 2 hours, the reaction mixture was filtered through a Celite pad and the filtrate was extracted with two 100-ml portions of chloroform. The chloroform extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed on silica gel. Elution with chloroform gave 5-methylisatin (610 mg, 0.0038 mol, 74%), mp 185°-187° (recrystallized from ethanol) as red needles.