Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:5]=[C:4]([NH2:20])[C:3]=1[NH2:21].[C:22]([CH2:26][C:27](Cl)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(#N)C>[NH2:20][C:4]1[C:3]([NH:21][C:27](=[O:28])[CH2:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:2]([CH3:1])[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:14][CH:15]=2)[N:5]=1
Reactant: Cc1nc(NCc2ccc(C(F)(F)F)cc2)nc(N)c1N
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CC#N
Product: Cc1nc(NCc2ccc(C(F)(F)F)cc2)nc(N)c1NC(=O)CC(C)(C)C
Reaction time: 0.75 h
Yield: 33.6 %

Procedure:
To a cold stirred solution (ice/water bath) of 6-methyl-N*2*-(4-trifluoromethyl-benzyl)-pyrimidine-2,4,5-triamine (341 mg, 1.15 mmol) in acetonitril (7.5 ml), tert-butylacetyl chloride (0.16 ml, 1.15 mmol) was added dropwise in 2 min. Cold bath was removed and stirring continued for 45 min. The obtained reaction mixture was poured into SCX column (10 g, H+ form), washed with acetonitrile (20 ml), methanol (100 ml), and the product was eluted with 4M NH3 in methanol (60 ml). The volatiles were removed in vacuo and the crude product was purified by flash chromatography on silica gel (20 g) with gradient heptane-ethyl acetate to give 153 mg of solid. Yield 33.7%. LC-MS (m/z) 395.9 (MH+); tR=2.00. 1H NMR (500 MHz, DMSO-d6): 1.02 (s, 9H), 1.96 (s, 3H), 2.15 (s, 2H), 4.5 (d, 2H), 5.9 (br, 2H, NH2), 6.97 (br, 1H, NH), 7.5 (d, 2H), 7.65 (d, 2H), 8.57 (s, 1H, NHCO).
Reaction SMILES: [CH2:1]([OH:6])[CH:2]=[CH:3][CH2:4][OH:5].N1C=CN=C1.[C:12]([Si:16](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:15])([CH3:14])[CH3:13].C(OCC)(=O)C>ClCCl.CN(C)C=O>[Si:16]([O:5][CH2:4][CH:3]=[CH:2][CH2:1][OH:6])([C:12]([CH3:15])([CH3:14])[CH3:13])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCC=CCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCC=CCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 41.5 %

Procedure:
In a dichloromethane/N,N-dimethylformamide (200 ml/200 ml) mixture were dissolved 2-buten-1,4-diol (10.0 g, 113 mmol) and imidazole (4.70 g, 69.0 mmol), followed by the dropwise addition of t-butylchlorodiphenylsilane (30.0 ml, 115 mmol) at room temperature. After completion of the dropwise addition, the mixture was stirred at room temperature for 4 days. The residue obtained by concentrating the reaction mixture under reduced pressure was added with diethyl ether. From the resulting mixture, the insoluble matter was filtered off. The diethyl ether layer was washed with water and then, the organic layer was dried over anhydrous magnesium sulfate. After fitration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure, whereby the title compound (15.3 g, 46.9 mmol, 42%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:32])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:29][CH3:30])[C:25]([O:27]C)=[O:26])[C:5]1=[O:31])[CH:2]=[CH2:3].[OH-].[Na+]>C1COCC1.O>[CH2:1]([C@@:4]1([CH3:32])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([CH:24]([CH2:29][CH3:30])[C:25]([OH:27])=[O:26])[C:5]1=[O:31])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OC)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)C(=O)O)C1=O
Temperature: 25 °C

Procedure:
To a stirred solution of methyl 2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate (200 mg, 0.42 mmol; Example 91, Step A) in THF (5 mL) was added sodium hydroxide (506 mg, 12.65 mmol) in water (5 mL) and the reaction was heated at reflux for about 12 h. After this time the reaction was cooled to rt and partitioned between EtOAc (80 mL) and 1.0 M HCl (20 mL). The separated aqueous layer was extracted with EtOAc (30 mL) and the combined organic layers were dried over MgSO4, filtered and the filtrate was evaporated in vacuo to give the title compound as a white solid. Mass Spectrum (ESI) m/z=460.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[N+:10]([O-])([OH:12])=[O:11]>ClCCl.S([O-])([O-])(=O)=O.[Ni+].[NH4+]>[F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Oc1cc(F)cc(F)c1
Reactant: O=[N+]([O-])O
Agent: [Ni+]
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: ClCCl
Product: O=[N+]([O-])c1c(O)cc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a yellow solution of 3,5-difluorophenol (1.50 g, 11.5 mmol) in dichloromethane (20 mL) under a blanket of nitrogen is added ammonium nickel sulfate (4.56 g, 11.54 mmol) with vigorous stirring, followed by the addition of nitric acid (69%, 0.74 mL, 11.54 mmol). The resulting heterogeneous mixture is then stirred at ambient temperature vigorously for 30 minutes. It is filtered and dichloromethane is removed under reduced pressure. The residue is purified by column chromatography to afforded a yellow solid as the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:27][C:26]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]#[N:32])=[CH:25][C:24](=O)[O:23]1>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)=[CH:10][C:9]=1[NH:19][C:24](=[O:23])[CH2:25][C:26]([C:28]1[CH:35]=[CH:34][CH:33]=[C:30]([C:31]#[N:32])[CH:29]=1)=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccsc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccsc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (2-amino-4-thiophen-3-yl-phenyl)-carbamic acid tert.-butyl ester (Example G6) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. Obtained as a brown solid (104 mg) and used crude in the next step (Example 7).
Reaction SMILES: [NH:1]([C:8](OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:9])[C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[N:25]1[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1.[F:33][C:34]([F:46])([F:45])[S:35]([C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1)(=[O:37])=[O:36]>>[F:33][C:34]([F:46])([F:45])[C:5]([OH:7])=[O:6].[CH3:5][C@H:2]1[N:1]([CH2:31][C:28]2[CH:27]=[CH:26][N:25]=[CH:30][CH:29]=2)[C:8](=[O:9])[N:42]([C:41]2[CH:43]=[CH:44][C:38]([S:35]([C:34]([F:45])([F:33])[F:46])(=[O:36])=[O:37])=[CH:39][CH:40]=2)[C:3]1=[O:4]
Reactant: O=C(N[C@H](CO)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: O=Cc1ccncc1
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Product: C[C@@H]1C(=O)N(c2ccc(S(=O)(=O)C(F)(F)F)cc2)C(=O)N1Cc1ccncc1
Product: O=C(O)C(F)(F)F

Procedure:
The compound is prepared from 0.28 mmol of resin, 0.84 mmol of N-Fmoc-D-Ala(OH), 1.4 mmol of 4-pyridinecarboxaldehyde and 0.70 mmol of 4-(trifluoromethanesulfonyl)aniline, in the same way as in Example 1. After purification by preparative LC-MS, 105 mg of expected product are obtained.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[OH:12][C@H:13]1[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[C@H:15]([CH2:31][N:32]2[C:36](=O)[CH:35]([CH3:38])[NH:34][C:33]2=[O:39])[CH2:14]1.CO>O1CCCC1>[OH:12][C@H:13]1[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)=[O:19])[C@H:15]([CH2:31][N:32]2[CH2:36][CH:35]([CH3:38])[NH:34][C:33]2=[O:39])[CH2:14]1
Reactant: CC1NC(=O)N(C[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1=O
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: CC1CN(C[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1
Reaction time: 0.25 h
Yield: 47.7 %

Procedure:
To a suspension of sodium borohydride (1.81 g) in tetrahydrofuran (50 ml) was dropwise added boron trifluoride etherate (23.4 ml) under ice-cooling and the mixture was stirred at the same temperature for 15 minutes. To this solution was added a solution of (2S,4R)-4-hydroxy-2-(4-methyl-2,5-dioxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (9.37 g) in tetrahydrofuran (50 ml) under ice-cooling and the mixture was stirred at ambient temperature overnight. To the reaction mixture was dropwise added methanol (30 ml) and the mixture was filtered. The filtrate was evaporated in vacuo. The resulting residue was dissolved in methanol (100 ml) and concentrated hydrochloric acid (5 ml) and the solution was allowed to stand at ambient temperature for 3 hours. The reaction mixture was evaporated in vacuo and dissolved in ethyl acetate (300 ml). The solution was washed successively with saturated aqueous sodium hydrogen carbonate and aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-hydroxy-2-(4-methyl-2-oxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (4.31 g).
Reaction SMILES: C[O-].[Na+].[SH:4][CH2:5][C:6](=[O:8])[CH3:7].[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](Cl)=[C:15]([CH:20]=O)[CH2:16][O:17]2)=[CH:12][CH:11]=1>CO>[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[S:4][C:5]([C:6](=[O:8])[CH3:7])=[CH:20][C:15]=3[CH2:16][O:17][C:18]=2[CH:19]=1
Reactant: O=CC1=C(Cl)c2ccc(Br)cc2OC1
Reactant: CC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1cc2c(s1)-c1ccc(Br)cc1OC2
Reaction time: 0.25 h

Procedure:
To a solution of sodium methoxide (5.57 g, 103 mmol) in 250 ml of methanol at 0° C., mercaptoacetone (5.11 g, 57 mmol) was added portion-wise, and after 15 min., 7-bromo-4-chloro-2H-chromene-3-carbaldehyde (1a) (14 g, 52 mmol) was added to it portion-wise with stirring. After the addition, the ice bath was removed and the product gradually started precipitating out as a yellow solid. Stirring was continued for another 3 h, after which water was added to quench the reaction and the methanol was removed under vacuum. Addition of more water yielded the title compound as a yellow solid (1b) which was filtered and dried (14.1 g, 78%). m/z 308.9 (79Br) & 310.9 (81Br).
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][N:12]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10][N:9]1NC(CC1C=CC=CC=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][N:12]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)[C@@H]1CN(NC(=O)OC(C)(C)C)CCN1NC(=O)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)NC(=O)[C@@H]1CN(NC(=O)OC(C)(C)C)CCN1
Reaction time: 2 h

Procedure:
To 1.20 g (2.86 mmol) of N-t-butyl-4-(1,1-dimethyl-ethoxy-carbonylamino)-1-(phenylmethylcarbonyl-amino)piperazine-2(S)-carboxamide and 1.1 g (0.086 mmol) of 10% Pd/C was added 15 mL of methanol. The vessel was charged with hydrogen and the reaction stirred for 2 hours, filtered through celite and washed with ethanol. The solvents were removed in vacuo to provide the title product as a foam.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10](C)[CH2:9]1)C1C=CC=CC=1.FC1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27]([OH:29])=O)=CC=1.C1C=CC2N(O)N=[N:36]C=2C=1.CCN(CC)CC>C(Cl)Cl.CCOC(C)=O>[NH2:36][CH:11]1[CH2:12][CH2:13][N:8]([C:27](=[O:29])[CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:9][CH2:10]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: NC1CCN(C(=O)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 4 (Ar2 =3,4-dichlorophenyl) (200 mg, 0.433 mmol) in CH2Cl2 (5 mL) were sequentially added 4-fluoro-1-naphthoic acid (84.8 mg, 0.433 mmol), HOBT (58.5 mg, 0.434 mmol), Et3N (0.634 mL, 0.455 mmol) and DEC (85 mg, 0.434 mmol) at RT. The reaction was stirred at RT under N2 overnight. After completion the reaction was diluted with EtOAc (150 mL) and washed with brine (50 mL, 3×), dried over MgSO4, filtered and concentrated to give a crude product 5 (Ar2 =3,4-dichlorophenyl, Ar1 =4-fluoro-1-naphthyl) which was purified by flash chromatography (50 g flash grade silica gel), eluting with 4% sat'd NH3 --MeOH in CH2Cl2 to give pure compound 5 Fab Mass [M+1]+ 35 Cl 633.2, m.p. 78°-81° C.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].[CH2:14]([NH2:17])[CH2:15][CH3:16].CCCCCC.CCOC(C)=O>C(Cl)Cl.[OH-].[Na+]>[CH2:14]([NH:17][S:9]([C:2]1[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=1[CH3:13])(=[O:11])=[O:10])[CH2:15][CH3:16]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CCCN
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCNS(=O)(=O)c1c(C)cc(C)cc1C
Yield: 69.9 %

Procedure:
Mesitylenesulfonyl chloride (12.0 g, 55 mmol) and propylamine (2.96 g, 50 mmol) in CH2Cl2 (60 mL) and 1 N NaOH (60 mL) were combined and worked up by the method of 31. Column chromatography (3:1 hexane/EtOAc) afforded 8.44 g (85%) of 65 as a crystalline solid: mp 53-54° C.; NMR δ 0.86 (t, 3 H, J=7), 1.44-1.51 (m, 2 H), 2.30 (s, 3 H), 2.64 (s, 6 H), 2.86 (q, 2 H), 4.40 (br t, 1 H), 6.96 (s, 2 H). Anal. (C12H19NO2S) C, H, N.
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH3:13])C.C([Li])(C)(C)C.CCCCC.[F:27][C:28]1[CH:29]=C([CH:33]=[CH:34][C:35]=1[O:36][CH:37]([CH3:39])[CH3:38])C#N>C1COCC1>[F:27][C:28]1[CH:29]=[C:16]([C:15]2[N:3]=[C:4]([OH:14])[C:5]3[C:6]([CH:13]=2)=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=3)[CH:33]=[CH:34][C:35]=1[O:36][CH:37]([CH3:39])[CH3:38]
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Reactant: CC(C)Oc1ccc(C#N)cc1F
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc2c(O)nc(-c3ccc(OC(C)C)c(F)c3)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (500 mg, 2.259 mmol) in THF (5 ml) at −78° C. was added dropwise tert-butyllithium 1.7 M in pentane (1595 μl, 2.71 mmol) and the solution was stirred for 0.5 h before addition of 3-fluoro-4-isopropoxybenzonitrile (405 mg, 2.259 mmol) in THF (5 ml). The resulting solution was warmed to rt and stirred for 16 h. The reaction mixture was quenched with water, neutralized with 1 N HCl. The precipitated solid was collected washing with water to give 3-(3-fluoro-4-isopropoxyphenyl)-6-methoxyisoquinolin-1-ol (520 mg, 70% yield) as a solid after drying. MS: MS m/z 328.1 (M++1).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3](=[O:7])[C:4](O)=[O:5].O.OC1C2N=NNC=2C=CC=1.[N:20]1([C:26]2[N:34]=[C:33]([C:35]3[CH:36]=[N:37][C:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[N:39][CH:40]=3)[N:32]=[C:31]3[C:27]=2[N:28]=[C:29]([N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[N:30]3[CH2:49][C:50]([F:53])([F:52])[F:51])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1>[CH3:1][N:2]([C:3](=[O:7])[C:4]([N:57]1[CH2:56][CH2:55][N:54]([C:29]2[N:30]([CH2:49][C:50]([F:51])([F:52])[F:53])[C:31]3[C:27]([N:28]=2)=[C:26]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[N:34]=[C:33]([C:35]2[CH:40]=[N:39][C:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[N:37][CH:36]=2)[N:32]=3)[CH2:59][CH2:58]1)=[O:5])[CH3:8]
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCNCC4)n(CC(F)(F)F)c3n2)cn1
Reactant: CN(C)C(=O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)C(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(NC(=O)OC(C)(C)C)nc4)nc3n2CC(F)(F)F)CC1
Reaction time: 18 h
Yield: 82.6 %

Procedure:
N,N-Dimethyl-oxalamic acid (34 mg, 0.29 mmol), hydroxybenzotriazole hydrate (45 mg, 0.29 mmol), and tetrahydrofuran (5 ml) were added to tert-butyl {5-[6-morpholin-4-yl-8-piperazin-1-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-yl}carbamate (150 mg, 0.27 mmol). 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (56 mg, 0.29 mmol) and triethylamine (74 μl, 0.53 mmol) were added and the resulting mixture was stirred for 18 hours. The reaction mixture was partitioned with ethyl acetate and water and the organic layer was washed with saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel chromatography (chloroform:methanol=19:1) to give the title compound (148 mg, 84%) as a white solid.
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)=[N:40][C:41]([CH3:49])=[CH:42][C:43]=2[N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:65][C:66]1[O:67][C:68]2[C:69]([N:74]=1)=[N:70][CH:71]=[CH:72][CH:73]=2>>[O:67]1[C:68]2[C:69](=[N:70][CH:71]=[CH:72][CH:73]=2)[N:74]=[C:66]1[S:65][CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:50]3[CH2:51][CH2:52][CH2:53][CH2:54]3)=[N:40][C:41]([CH3:49])=[CH:42][C:43]=2[N:44]2[CH2:45][CH2:46][CH2:47][CH2:48]2)=[O:36])[CH2:32][CH2:33]1
Reactant: Sc1nc2ncccc2o1
Reactant: Cc1cc(N2CCCC2)c(NC(=O)CN2CCN(CCO)CC2)c(N2CCCC2)n1
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(N2CCCC2)c(NC(=O)CN2CCN(CCSc3nc4ncccc4o3)CC2)c(N2CCCC2)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 2-mercaptooxazolo[4,5-b]pyridine, to thereby yield the title compound as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H].[C:30]([O:34][C:35]([N:37]([CH2:48][CH2:49][CH2:50][CH2:51]Cl)[S:38]([C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)(=[O:40])=[O:39])=[O:36])([CH3:33])([CH3:32])[CH3:31]>CN(C)C=O>[C:30]([O:34][C:35]([N:37]([S:38]([C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)(=[O:40])=[O:39])[CH2:48][CH2:49][CH2:50][CH2:51][N:19]([C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:3](=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:51][CH2:50][CH2:49][CH2:48][N:37]([C:35]([O:34][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:36])[S:38]([C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)(=[O:40])=[O:39])=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: Cc1ccc(S(=O)(=O)N(CCCCCl)C(=O)OC(C)(C)C)cc1
Reactant: [H][H]
Reactant: O=C(NCCCCCCCNC(=O)c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(CCCCN(CCCCCCCN(CCCCN(C(=O)OC(C)(C)C)S(=O)(=O)c2ccc(C)cc2)C(=O)c2ccccc2)C(=O)c2ccccc2)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Suspend sodium hydride (4.8 g, 0.2 mol) in anhydrous dimethylformamide (100 mL), cool to 0° C. and place under a nitrogen atmosphere. Add, by dropwise addition, a solution 1,9-bis(benzoyl)-1,9-diazanonane (33.8 g, 0.1 mol) in dimethylformamide. Stir until evolution of hydrogen ceases. Add, by dropwise addition, a solution of N-(tert-butyloxycarbonyl)-N-[(4-methylphenyl)sulfonyl]-4-chlorobutylamine (72.4 g, 0.2 mol) in dimethylformamide (100 mL). Stir overnight at room temperature then carefully quench with saturated ammonium chloride. Extract into ethyl acetate, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatogaphy to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[N:6]=1.[C:19]([N:27]1[CH2:33][CH2:32][CH2:31][CH2:30][C:29]([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=2)([CH2:34][CH2:35][CH2:36]OS(C)(=O)=O)[CH2:28]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(#N)C>[ClH:48].[ClH:48].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9][N:10]([CH2:36][CH2:35][CH2:34][C:29]3([C:42]4[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=4)[CH2:30][CH2:31][CH2:32][CH2:33][N:27]([C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:28]3)[CH2:11][CH2:12]2)[N:6]=1
Reactant: CS(=O)(=O)OCCCC1(c2ccc(Cl)c(Cl)c2)CCCCN(C(=O)c2ccccc2)C1
Reactant: Nc1nc(C2(c3ccccc3)CCNCC2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cl
Product: Nc1nc(C2(c3ccccc3)CCN(CCCC3(c4ccc(Cl)c(Cl)c4)CCCCN(C(=O)c4ccccc4)C3)CC2)cs1

Procedure:
This compound is prepared by the procedure described in step D of EXAMPLE 13, starting from 0.77 g of 4-(2-aminothiazol-4-yl)-4-phenylpiperidine (compound of PREPARATION 1.4 in the form of the free base), 1.2 g of the compound obtained in step C of EXAMPLE 13 and 1.2 g of K2CO3 in 20 ml of a DMF/acetonitrile mixture (50150; v/v). This gives 0.8 g of the expected product after crystallization from AcOEt, m.p.=178° C.
Reaction SMILES: O.[NH2:2][NH2:3].[O:4]=[C:5]1[N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]2=[C:15]([C:18]([O:20]CC)=O)[N:16]=[CH:17][N:8]2[C:7]2[CH:23]=[CH:24][S:25][C:6]1=2>C(O)C>[O:4]=[C:5]1[N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]2=[C:15]([C:18]([NH:2][NH2:3])=[O:20])[N:16]=[CH:17][N:8]2[C:7]2[CH:23]=[CH:24][S:25][C:6]1=2
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1sccc1-2
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1sccc1-2
Yield: 94 %

Procedure:
8 ml of hydrazine hydrate were added to a suspension of 4.0 g (12.6 mmol) of ethyl (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carboxylate in 40 ml of ethanol and the mixture was heated at reflux for 3 hours. After cooling to 0° the crystals obtained were filtered off and there were obtained 3.6 g (94%) of (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carboxylic acid hydrazide as colourless needles of m.p. >260°.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>>[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:19][CH2:18]2)=[CH:15][CH:16]=1
Reactant: ON=C1CCCCCC1
Reactant: CCOC(=O)CCCN1CCC(c2ccc(C)cc2)CC1
Product: Cc1ccc(C2CCN(CCCc3onc4c3CCCCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-methylphenyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(4-methylphenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.