Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[CH2:14][S:15](Cl)(=[O:17])=[O:16])=[O:4].[OH-].[NH4+:20].O>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[CH2:14][S:15]([NH2:20])(=[O:17])=[O:16])=[O:4]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CS(=O)(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc([N+](=O)[O-])c1CS(N)(=O)=O
Temperature: 25 °C

Procedure:
The crude product from Example 3 (15.1 g) was dissolved in 150 ml tetrahydrofuran and this solution was contacted at 0° C. with concentrated aqueous ammonium hydroxide. The resulting suspension was allowed to warm to room temperature over a 15-minute period and the solvent was removed in vacuo to yield an oily solid. Addition of water to this crude material resulted in gradual crystallization. The aqueous layer was extracted with ethyl acetate and the combined extracts were dried and concentrated in vacuo to give a yellow oil which solidified upon scratching. This material was washed with warm n-butyl chloride, filtered and dried to give the title compound as a pale yellow solid, m.p. 119°-123°; IR(nujol): 3490, 3330, 1710 cm-1 ; NMR (CDCl3): δ 4.0 (3H, s, CO2CH3), 5.4 (2H, s, --CH2 --), 6.8 (2H, s, NH2), 7.5-8.25 (3H, m).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH:11]2[CH:18]3[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:20][CH:12]2[CH2:13]4)[CH2:17]3)=[O:9])[CH2:4]1.Cl[C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23]>>[CH2:25]([O:24][C:22]([NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH:11]2[CH:12]3[CH2:13][CH:14]4[CH2:15][CH:16]([CH2:17][CH:18]2[CH2:19]4)[CH2:20]3)=[O:9])[CH2:4]1)=[O:23])[CH2:26][CH3:27]
Reactant: N[C@@H]1CCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1
Reactant: CCCOC(=O)Cl
Agent: Cl
Product: CCCOC(=O)N[C@@H]1CCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1

Procedure:
The title compound was prepared from (R)-2-adamantyl 3-aminopyrrolidine-1-carboxylate HCl salt and propyl chloroformate following a procedure analogous to that described in Example 3 Step 2. LC-MS Method 1 tR=2.00 min, m/z=351; 1H NMR (CDCl3) 0.97 (t, 3H), 1.50-2.05 (16H), 2.19 (m, 1H), 2.42 (1H), 3.29 (dd, 1H), 3.50 (m, 2H), 3.70 (m, 1H), 4.04 (m, 2H), 4.28 (1H), 4.78 (1H), 4.83 (s, 1H)
Reaction SMILES: I.CS[C:4](=[N:19][CH2:20]CCC)[NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:24][NH2:25]>>[CH3:24][NH:25][C:4]([NH:19][CH3:20])=[N:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: CCCCN=C(Nc1cc(Cl)ccc1N1CCOCC1)SC
Reactant: CN
Agent: I
Product: CNC(=Nc1cc(Cl)ccc1N1CCOCC1)NC

Procedure:
A mixture of 2-methyl-1-(5-chloro-2-morpholinophenyl)-3-(n-butyl)-2-thiopseudourea hydroiodide (3.4 g) and a 33% ethanolic solution of methylamine (10 ml) were stored at ambient temperature in a sealed container for 8 months to yield 1,3-dimethyl-2-(5-chloro-2-morpholinophenyl)guanidine (m.p. 145°-146° C.) which was recrystallised from hexane. In this reaction the butylamino and the methylthio group of the starting material are replaced by a methylamino group.
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][C:35]=5[CH3:43])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:44]4[CH2:47][CH:46]([F:48])[CH2:45]4)[N:21]=3)[C@H:14]2[CH3:49])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.O.[NH2:72][C:73]1[NH:77][N:76]=[N:75][N:74]=1>CN(C=O)C.C(Cl)CCl>[F:1][C:2]([F:50])([F:51])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:42]=[CH:41][C:37]([C:38]([NH:72][C:73]6[NH:77][N:76]=[N:75][N:74]=6)=[O:39])=[CH:36][C:35]=5[CH3:43])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:44]4[CH2:45][CH:46]([F:48])[CH2:47]4)[N:21]=3)[C@H:14]2[CH3:49])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: COc1ncc(-c2ccc(C(=O)O)cc2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: Nc1nnn[nH]1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ncc(-c2ccc(C(=O)Nc3nnn[nH]3)cc2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 40 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(3-fluoroazetidin-1-yl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoic acid (EXAMPLE 36, 167 mg, 0.232 m mol), EDC (90 mg, 0.464 m mol), HOBt (60 mg, 0.437 m mol), and DIEA (81 μl, 0.464 m mol) in DMF (2 mL) was added 5-aminotetrazole monohydrate (120 mg, 1.16 mmol). After stirring at 40° C. for 8 hours, the reaction mixture was directly applied to reverse phase HPLC, eluting with 10% to 100% acetonitrile in water, to get the title compound (121 mg, 43% yield), as a white solid after lyophilization. LCMS (M+H)+: 787.2. 1H NMR (DMSO-d6, 500 MHz): δ 12.44 (s, 1H), 8.31 (s, 1H), 8.29 (d, 3.5 Hz, 1H), 8.12 (s, 1H), 8.09 (s, 1H), 8.00 (m, 3H), 7.82 (d, 2.0 Hz, 1H), 7.50 (d, 8.0 Hz, 1H), 5.91 (d, 8.5 Hz, 1H), 5.59 (m, 1H), 4.53 (d, 17.0 Hz, 1H), 4.49-4.38 (m, 3H), 4.22-4.07 (m, 3H), 3.93 (s, 3H), 2.40 (s, 3H), 0.64 (d, 6.5 Hz, 3H). RTA IC50: 10 nM.
Reaction SMILES: [C:1]1([C:11]2[NH:12][C:13]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)=[C:14]([C:16]([NH:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[O:17])[N:15]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Sn](Cl)Cl>CO.Cl>[NH2:30][C:27]1[CH:26]=[CH:25][C:24]([C:13]2[NH:12][C:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)=[N:15][C:14]=2[C:16]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[O:17])=[CH:29][CH:28]=1
Reactant: O=C(Nc1nccs1)c1nc(-c2cccc3ccccc23)[nH]c1-c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Product: Nc1ccc(-c2[nH]c(-c3cccc4ccccc34)nc2C(=O)Nc2nccs2)cc1
Yield: 24.6 %

Procedure:
2-(1-Naphthyl)-5-(4-nitrophenyl)-N-(2-thiazolyl)imidazole-4-carboxamide (1.22 g) obtained in Example 18 was suspended in methanol and ice-cooled. To the suspension was added a solution of tin(II) chloride 6 hydrate (3.0 g) in 6 M hydrochloric acid (30 ml) and the mixture was refluxed under heating for 1.5 hr. The precipitated white crystals were collected by filtration and the crystals were dissolved in ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogencarbonate solution and water, and dried. To the ethyl acetate layer was added 1 M hydrochloric acid—ether and the precipitated crystals were collected by filtration. The obtained crude crystals were recrystallized from methanol to give 5-(4-aminophenyl)-2-(1-naphthyl)-N-(2-thiazolyl)imidazole-4-carboxamide (0.28 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O[CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[O:10][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1
Reactant: OC(c1ccccc1)c1ccc(F)cc1F
Reactant: OC1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(C(OC2CCNCC2)c2ccccc2)c(F)c1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
Molecular sieves, (2,4-difluorophenyl)phenylmethanol (3.69 g, 16.8 mmol), and p-toluenesulfonic acid monohydrate (3.84 g, 20.2 mmol) were added to a suspension of 4-hydroxypiperidine (1.7 g, 16.8 mmol) in toluene, and the mixture was refluxed for 3 hours while removing water using a Dean-Stark condenser. After the completion of the reaction was confirmed by HPLC, the reaction mixture was allowed to cool down to a room temperature. From the reaction mixture, the insoluble matter was removed, and then the solvent was distilled off. The resulting residue was dissolved in ethyl acetate and washed with a 2-N sodium hydroxide solution 3 times. The organic layer was dried over magnesium sulfate, and then the solvent was distilled off. Thus the title compound (2.8 g, 54.9%) was obtained as an oily substance.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C@:9]1([NH2:31])[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:13][C@@H:12]2[C@H:10]1[C@@:11]2([F:30])[C:25]([O:27]CC)=[O:26])=[O:8])C.Cl>O1CCCC1.O>[NH2:31][C@@:9]1([C:7]([OH:8])=[O:6])[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:13][C@@H:12]2[C@H:10]1[C@@:11]2([F:30])[C:25]([OH:27])=[O:26]
Reactant: CCOC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.7 %

Procedure:
5.53 g of lithium hydroxide hydrate was added to 22.9 g of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 480 mL of tetrahydrofuran and 240 mL of water, and the mixture was stirred for three days at room temperature. 443 mg of lithium hydroxide hydrate was further added thereto, and the mixture was stirred for 1 day at room temperature. 169 mL of 1N hydrochloric acid was added dropwise thererto at ice-cooling, and the mixture was stirred for 14 hours at room temperature. The precipitated solids were filtured, and then washed with 200 mL of tetrahydrofuran and 100 mL of water, thereby yielding 12.3 g of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+:14]([O-])=O)[CH:6]=1.[N-:25]=[N+:26]=[N-].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N:14]=[N+:25]=[N-:26])[CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=Nc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene (2.0 g, 5.5 mmol) and sodium azide (1.1 g, 16.6 mmol) in acetone (25 ml) is heated under reflux for 3.5 hours. The reaction is then cooled and filtered, and the filtrate is stripped. The residue is taken up in chloroform, washed with water (2X) and with brine, dried, stripped and purified by preparative thin layer chromatography (prep. TLC) (silica gel, eluting with 15% ethyl acetate/hexane) to give 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrophenyl azide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Cl[CH2:10][C:11]#[N:12]>[OH-].[Na+].C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[NH2:12][C:11]1[CH2:10][S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: N#CCCl
Reactant: Nc1ccccc1S
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NC1=Nc2ccccc2SC1
Yield: 32 %

Procedure:
A mixture of 2-aminothiophenol (1.6 ml, 15 mmol) in 25% NaOH (10 ml) and chloroacetonitrile (0.95 ml, 15 mmol) in CH2Cl2 (20 ml) is stirred at room temperature for 20 hours, in the presence of tetrabutylammonium hydrogensulphate (0.51 g, 1.5 mmol). The organic phase is then separated, washed with H2O, dried over Na2SO4 and concentrated. The residue is taken up with 5% HCl/EtOH (20 ml) and the resulting solution refluxed for 2 hours. The solvent is evaporated under vacuum and the resulting solid taken up in H2O then washed with CHCl3, basified with NH4OH and the precipitate obtained extracted with CHCl3. The organic phase is dried over Na2SO4 and concentrated. The residue is purified by chromatography through silica, eluting with AcOEt/Triethylamine (8:2). The product is obtained as a yellowish solid, with a yield of 32%. Recrystallisation from ethyl acetate gives the product with an m.p. of 168-172° C., 1H-NMR (CDCl3): 3.18 (s, 2H), 4.38 (br s, 2H), 6.89-7.25 (m, 4H). MS (ESI): m/z 165 (M+H+). MS (ESI): m/z 165 (M+H+). The product is more stable as the oxalate salt, white solid m.p. 182-184° C.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[C:8]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([Cl:25])[CH:19]=4)[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].C(OC)(OC)OC.C(O)(=O)C.[CH2:41]1[CH2:45][O:44][CH2:43][CH2:42]1>CO>[Cl:25][C:20]1[CH:19]=[C:18]([C:8]2[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]3[NH:12][C:13]4[C:5]([C:6]=3[CH:7]=2)=[CH:4][CH:3]=[C:2]([N:1]2[CH2:41][CH2:45][O:44][CH2:43][CH2:42]2)[CH:14]=4)[CH:23]=[CH:22][C:21]=1[OH:24]
Reactant: NC(=O)c1cc(-c2ccc(O)c(Cl)c2)cc2c1[nH]c1cc(N)ccc12
Reactant: C1CCOC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: COC(OC)OC
Product: NC(=O)c1cc(-c2ccc(O)c(Cl)c2)cc2c1[nH]c1cc(N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
7-Amino-3-(3-chloro-4-hydroxyphenyl)-9H-carbazole-1-carboxamide (700 mg, 1.094 mmol, Example 406A) and sodium cyanoborohydride (400 mg, 6.37 mmol) were dissolved in methanol (20 mL)+THF (20.00 ml). Trimethyl orthoformate (10 ml, 90 mmol) and acetic acid (100 μl, 1.747 mmol) were added, followed by 28 ml of the crude reaction mixture from Example 406B (contained ˜4 mmol of 2,2′-oxydiacetaldehyde in CH2Cl2). The reaction mixture was stirred at room temperature for 90 minutes, then filtered through a Waters MCX cartridge (18 g adsorbent). The cartridge was washed with water, methanol and dichloromethane, then the product was eluted with 2M NH3 in MeOH. Evaporation of volatiles and purification by prep HPLC gave 149.0 mg 3-(3-chloro-4-hydroxyphenyl)-7-morpholino-9H-carbazole-1-carboxamide. MS (ESI) m/e+=422/424, m/e−=420/422 [1 Cl isotope pattern]. HPLC retention time 7.34 min. (Sunfire C18 3.5 μm, 3.0×150 mm column, 15 min gradient, 10-100% B, 0.5 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA). 1H NMR (DMSO-d6) δ ppm 11.13 (s, 1H), 10.22 (b, 1H), 8.45 (d, 1H, J=1.5), 8.32 (b, 1H), 8.11 (d, 1H, J=1.7), 8.07 (d, 1H, J=8.8), 7.89 (d, 1H, J=2.3), 7.67 (dd, 1H, J=8.5, 2.3), 7.50 (b, 1H), 7.27 (d, 1H, J=1.0), 7.09 (d, 1H, J=8.5), 6.97 (dd, 1H, J=8.7, 1.7), 3.86-3.79 (m, 4H), 3.25-3.19 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N+:6]([O-])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].P(Cl)(Cl)([Cl:24])=O>C(OCC)(=O)C>[Cl:24][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: Cc1cccc2cc([N+](=O)[O-])c[n+]([O-])c12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1cccc2cc([N+](=O)[O-])c(Cl)nc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A suspension of 2.09 g of 3-nitro-8-methyl-quinoline-1-oxide (compound D1) in 15 ml of phosphorus oxychloride is stirred at 100° C. for 1 h. After cooling to room temperature, the reaction mixture is added to 40 ml of ice water and diluted with 50 ml of ethyl acetate. With the aid of solid potassium carbonate the pH value is adjusted to pH 8 and the mixture is extracted two times each with 30 ml of ethyl acetate. The combined organic phases are dried using magnesium sulfate, filtered and evaporated in vacuo. The residue is recrystallized from diethylether to give 1.3 g of the title compound as violet solid.
Reaction SMILES: [C:1]([O:5][P:6]([O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19](C(OCC2C=CC=CC=2)=O)[CH2:18][C:17]1=[O:32])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[P:6]([O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][C:17]1=[O:32])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OP(=O)(OCCN1CCN(C(=O)OCc2ccccc2)CC1=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OP(=O)(OCCN1CCNCC1=O)OC(C)(C)C

Procedure:
Benzyl 4-{2-[(di-tert-butoxyphosphoryl)oxy]ethyl}-3-oxopiperazine-1-carboxylate (1.20 g, 2.55 mmol) and 10% palladium on carbon (100 mg) in methanol (25 ml) were stirred at room temperature under an atmosphere of hydrogen for 2 hours and then filtered through Celite. The filtrate was evaporated to give di-tert-butyl 2-(2-oxopiperazin-1-yl)ethyl phosphate as a colourless oil which was dissolved in dimethylacetamide(4.0 ml) containing 2-(4-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)-N-(2,3-difluorophenyl)acetamide hydrochloride (326 mg, 0.64 mmol) and potassium iodide (213 mg, 1.28 mmol) and the mixture was then heated at 90° C. for 3 hours. The mixture was cooled to room temperature, poured into dilute aqueous sodium hydrogen carbonate solution and then extracted with a solution of 10% isopropanol in dichloromethane. The organic layer was dried over magnesium sulphate and then evaporated to leave an orange oil. The crude product was purified by silica gel chromatography eluting with 5% methanol in dichloromethane containing 0-4% 7N ammonia in methanol to give di-tert-butyl 2-{4-[3-({4-[(1-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-4-yl)amino]quinazolin-7-yl}oxy)propyl]-2-oxopiperazin-1-yl}ethyl phosphate (211 mg, 43% yield) as a pale yellow solid: MS (+ve ESI): 773 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Cl:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[C:34]([N:39]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[CH:33]=[CH:32]2>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:42]2[CH2:43][CH2:44][CH2:45][N:39]([C:34]3[CH:33]=[CH:32][C:31]4[C:36](=[CH:37][CH:38]=[C:29]([Cl:28])[CH:30]=4)[N:35]=3)[CH2:40][CH2:41]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: Clc1ccc2nc(N3CCCNCC3)ccc2c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCCN(c3ccc4cc(Cl)ccc4n3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 6-chloro-2-[1.4]diazepan-1-yl-quinoline
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[CH2:27][CH2:26]3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[C:4]=12>CC(C)=O>[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:27][CH2:26]3)[N:10]=[C:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:16][CH:17]=3)[C:4]=12
Reactant: CC(C)(C)OC(=O)CN1CCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1
Agent: Cl
Solvent: CC(C)=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCN(CC(=O)O)CC1
Temperature: 45 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
2 mL of an 6 N aqueous solution of hydrochloride were added to the mixture of tert-butyl 2-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}acetate (0.10 g, 0.0002 mol) in acetone (5 mL). The mixture was stirred at 45° C. for 2 hours. The solvent was removed under reduced pressure. Water (10 mL) was added into the residue, and the mixture was lyophilized to yield 2-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}acetic acid (0.010 g, 0.0002 mol).
Reaction SMILES: [NH2:1][CH:2]([C:4]([OH:6])=[O:5])[CH3:3].C(N(CC)CC)C.C[Si](Cl)(C)C.[C:19](Cl)(=[O:23])[CH2:20][CH2:21][CH3:22]>ClCCl.O>[C:19]([NH:1][CH:2]([CH3:3])[C:4]([OH:6])=[O:5])(=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(=O)Cl
Reactant: CC(N)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCC(=O)NC(C)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
22.27 g (250 mmol) of D,L-alanine and 55.66 g (550 mmol) of triethylamine are dissolved in 250 ml of dichloromethane, and the solution is cooled to 0° C. 59.75 g (550 mmol) of trimethylsilyl chloride are added dropwise, and the solution is stirred at room temperature for 1 hour and at 40° C. for one hour. After cooling to −10° C., 26.64 g (250 mmol) of butyryl chloride are added dropwise, and the resulting mixture is stirred at −10° C. for 2 hours and at room temperature for one hour. With ice-cooling, 125 ml of water are added dropwise, and the reaction mixture is stirred at room temperature for 15 minutes. The aqueous phase is evaporated to dryness, the residue is triturated with acetone and the mother liquor is filtered off with suction. Following removal of the solvent, the residue is chromatographed. The resulting product is dissolved in 3N aqueous sodium hydroxide solution, and the resulting solution is evaporated to dryness. The residue is taken up in conc. HCl and again evaporated to dryness. The residue is triturated with acetone, the precipitated solid is filtered off with suction and the solvent is removed under reduced pressure. This gives 28.2 g (71%) of a viscous oil which crystallizes after some time.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[CH3:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][NH:26]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: COc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1cccc2c1CCN2C(=O)Cc1nc(N2CCOCC2)cc(=O)n1C
Yield: 27.9 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 298 mg of 4-methoxyindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 161 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 107 mg of 2-[2-(4-methoxy-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a salmon pink powder, the characteristics of which are the following:
Reaction SMILES: ClC1C=CC([N+]([O-])=O)=CN=1.N[C:12]1[N:17]=[C:16]([NH:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[NH:29][CH:30]=[CH:31][N:32]=3)=[C:24]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=3[Cl:40])[N:23]=2)[CH:15]=[CH:14][C:13]=1[N+:41]([O-:43])=[O:42]>>[Cl:40][C:34]1[CH:35]=[C:36]([Cl:39])[CH:37]=[CH:38][C:33]=1[C:24]1[N:23]=[C:22]([NH:21][CH2:20][CH2:19][NH:18][C:16]2[CH:15]=[CH:14][C:13]([N+:41]([O-:43])=[O:42])=[CH:12][N:17]=2)[CH:27]=[CH:26][C:25]=1[C:28]1[NH:32][CH:31]=[CH:30][N:29]=1
Reactant: Nc1nc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: O=[N+]([O-])c1ccc(Cl)nc1
Product: O=[N+]([O-])c1ccc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
[6-(2,4-dichlorophenyl)-5-imidazolyl(2-pyridyl)]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine was prepared from 2-chloro-5-(nitro)pyridine using the general method for {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[6-(2,4-dichlorophenyl)-5-imidazolyl(2-pyridyl)]amine.