Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[O:5]1[CH2:9][CH2:8][C@@H:7]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:6]1.N1C=CC=CC=1>C(Cl)Cl>[O:15]=[C:11]1[N:10]([C@@H:7]2[CH2:8][CH2:9][O:5][CH2:6]2)[CH2:14][CH2:13][N:12]1[C:1]([Cl:4])=[O:2]
Reactant: O=C1NCCN1[C@@H]1CCOC1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cl)N1CCN([C@@H]2CCOC2)C1=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
A 0° C. solution of phosgene (20% in toluene, 1.132 mL, 2.151 mmol) in DCM (9 mL) was treated slowly with a solution of (R)-1-(tetrahydrofuran-3-yl)imidazolidin-2-one (0.28 g, 1.793 mmol) and pyridine (0.290 mL, 3.59 mmol) in DCM (9 mL) and stirred at 0° C. for 45 min. The mixture was concentrated to dryness to afford crude (R)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carbonyl chloride (100% yield assumed) which was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]([N:5]([C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)[CH3:6])=[O:4].C1N2CN3CN(C2)C[N:23]1C3.[Br-].[NH4+].C(O)(C)C>O>[Cl:21][C:18]1[CH:19]=[CH:20][C:7]2[N:5]([CH3:6])[C:3](=[O:4])[CH2:2][N:23]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]=2[CH:17]=1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: CN(C(=O)CBr)c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [Br-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21

Procedure:
Reflux 1.8 g. (0.005 moles) of 2-(2-bromo-N-methylacetamido)-5-chlorobenzophenone, 2.8 g. (0.020 moles) of hexamethylenetetramine and 1.96 g. (0.020 moles) of ammonium bromide together for 2 hours in 14 ml. of 85% (v/v) aqueous isopropyl alcohol. Pour the reaction mixture into water and extract the product with benzene. Wash the benzene solution with water, dry over anhydrous sodium sulfate, filter and evaporate to dryness. After recrystallization, 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one is obtained. The material gives a single spot by thin layer chromatography, and after drying under vacuum at 110° C., shows no depression on mixed melting point with an authentic sample (M.P. 129.5°-130.5° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:17])[CH:9]([NH2:16])[CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl.[CH2:19]([O:21][C:22]1[CH:32]=[C:31]([O:33][CH2:34][CH3:35])[CH:30]=[CH:29][C:23]=1[C:24](=N)OCC)[CH3:20].ClC1C=CC(C2NC(C3C=CC(OC)=CC=3OCC)=NC2CC2CCCC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:17][C:24]([C:23]3[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH3:35])=[CH:32][C:22]=3[O:21][CH2:19][CH3:20])=[N:16][CH:9]2[CH2:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: NC(CC1CCCC1)C(N)c1ccc(Cl)cc1
Reactant: CCOC(=N)c1ccc(OCC)cc1OCC
Agent: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Agent: Cl
Product: CCOc1ccc(C2=NC(CC3CCCC3)C(c3ccc(Cl)cc3)N2)c(OCC)c1

Procedure:
5-(4-Chloro-phenyl)-4-cyclopentylmethyl-2-(2,4-diethoxy-phenyl)-4,5-dihydro-1H-imidazole was prepared from 1-(4-chloro-phenyl)-3-cyclopentyl-propane-1,2-diamine and ethyl 2,4-diethoxy-benzimidate hydrochloride in an analogous manner as described for the preparation of 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 9). HR-MS (ES, m/z) observed 427.2152, calculated for C25H32N2O2Cl [(M+H)+]427.2147.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:10]([OH:14])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[N+](=[CH2:23])=[N-]>C(OCC)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:10]([OH:14])[C:11]([O:13][CH3:23])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(O)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.00 g (3.8 mmole) of 3(S)-t-butoxycarbonylamino-2-hydroxy-5-methylhexanoic acid prepared by the method of R. L. Johnson [J. Med. Chem., 25, 605 (1982)] in 30 ml, of methanol was stirred, whilst cooling with ice, and then a diethyl ether solution of diazomethane was added and the mixture was stirred at room temperature for 1 hour. The solvent was then distilled off and the resulting solid was recrystallized from hexane to give 952 mg of the title product as colorless needles, melting at 84°-85° C.; [α]25 -10.2° (C=1.26, methanol).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6]Br.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26]CC)=O)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C1COCC1>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:24]2([OH:26])[CH2:6][CH2:5][CH2:4][CH2:3]2)=[CH:20][CH:21]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: BrCCCCBr
Reactant: CCOC(=O)CCc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(CCc2ccc(OCc3ccccc3)cc2)CCCC1
Reaction time: 1 h

Procedure:
To a mixture of magnesium (120 mg) and THF (1.5 mL) was added 1,4-dibromobutane (0.2 mL) at room temperature under nitrogen flow, followed by stirring for 1 hour. The reaction solution was ice-cooled, and a solution of ethyl 3-[4-(benzyloxy)phenyl]propanoate (400 mg) in THF (3 mL) was added dropwise thereto while maintaining an internal temperature of 10° C. or less. The reaction mixture was stirred under ice-cooling for 3 hours, and allowed to stand overnight at room temperature. The reaction liquid was ice-cooled and was adjusted to an acidic pH by adding 1M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=20/3-1/1) to obtain 1-{2-[4-(benzyloxy)phenyl]ethyl}cyclopentanol (145 mg).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([NH2:15])[C@H:11]([CH:16]([CH3:18])[CH3:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:19]([NH:29][C@H:30]([C:35](O)=[O:36])[CH2:31][CH2:32][S:33][CH3:34])([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:35](=[O:36])[C@@H:30]([NH:29][C:19](=[O:20])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:31][CH2:32][S:33][CH3:34])[C@H:11]([CH:16]([CH3:18])[CH3:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1N
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 92.4 %

Procedure:
(1S,2S,4R)-4-(tert-Butyldimethylsilyloxy)-2-isopropylcyclohexanamine (2.9 g) was dissolved in DMF (36 mL) and cooled to 0° C. prior to the addition of N-Cbz methionine (5.5 g), 4-methyl morpholine (3.8 g), and BOP (8.7 g). The reaction was stirred for 12 h at rt and then partitioned between EtOAc and 1N HCl solution. The organic phases were combined, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford benzyl (S)-1-((1S,2S,4R)-4-(tert-butyldimethylsilyloxy)-2-isopropylcyclohexylamino)-4-(methylthio)-1-oxobutan-2-ylcarbamate (5.3 g). MS found: (M+H)+=537.3.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:1]([O:5][C:6]([CH:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)C1CCC(NCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(Cc1ccccc1)C1CCC(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h
Yield: 34.1 %

Procedure:
To a solution of 4-benzylamino-cyclohexanecarboxylic acid tert-butyl ester (630 mg, 2.180 mmol) in DMF (20 mL) is added t-butyl bromoacetate (1 mL, 6.856 mmol) and Cs2CO3 (1.0 g, 3.069 mmol). The mixture stirs for 2 h. Then H2O (50 mL) is added the mixture is extracted with EtOAc (2×100 mL), dried with sodium sulfate and concentrated. The resulting solid is purified by flash chromatography (gradient elution: 0-20% EtOAc/Hep) which affords 300 mg of 4-(benzyl-tert-butoxycarbonylmethyl-amino)-cyclohexanecarboxylic acid tert-butyl ester. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.24 (m, 5 H), 1.38 (m, 18 H), 1.86 (m, 4 H), 2.09 (m, 1 H), 3.14 (m, 2 H), 3.71 (m, 2 H), 7.29 (m, 5 H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[C:26](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:25][O:24][C:22]([C:16]1([N:15]([S:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:7][CH:8]=2)(=[O:14])=[O:13])[CH3:26])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:23]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)OC)CCCCC2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C2(C(=O)OC)CCCCC2)cc1
Temperature: 25 °C

Procedure:
A mixture of methyl 1-({[4-(2-butynyloxy)phenyl]sulfonyl}-amino)cyclohexanecarboxylate (4.5 g.,12.3 mmol), anhydrous potassium carbonate (20.0 g, excess) and methyl iodide (2 g, 14.08 mmol) was refluxed in acetone for sixteen hours. The reaction mixture was then cooled to room temperature and filtered. The acetone layer was concentrated and extracted with chloroform. The chloroform layer was washed well with water, dried over anhydrous MgSO4, filtered and concentrated to provide methyl1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]cyclohexanecarboxylate as a yellow oil. Yield: 4.6 g (quantitative) Electrospray Mass Spec 380 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].[CH:13](Br)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH:13]([N:2]([CH3:1])[CH2:3][CH2:4][NH:5][CH3:6])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNCCNC
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNCCN(C)C(c1ccccc1)c1ccccc1

Procedure:
15.1 g (171 mmol) N,N′-dimethylethylenediamine, 35 g (255 mmol) potassium carbonate are placed in 250 ml DMF and 30.9 g (125 mmol) benzhydryl bromide are added dropwise at RT. The mixture is concentrated under vacuum. The residue is taken up in chloroform and washed with water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The purification occurs by chromatography on silica gel with chloroform: Yield 14.5 g (45%).
Reaction SMILES: C1(C2C=CC(C[NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15](F)=[C:14](C(F)(F)F)[CH:13]=3)=CC=2)CC1.[CH3:25][C:26]1([CH3:37])[C:34]2[C:29](=[CH:30][C:31]([CH:35]=O)=[CH:32][CH:33]=2)[CH2:28][CH2:27]1.C(N)CC1C=CC=CC=1.[BH4-].[Na+]>>[CH3:25][C:26]1([CH3:37])[C:34]2[C:29](=[CH:30][C:31]([CH2:35][NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:32][CH:33]=2)[CH2:28][CH2:27]1
Reactant: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Reactant: CC1(C)CCc2cc(C=O)ccc21
Agent: NCCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: CC1(C)CCc2cc(CNCCc3ccccc3)ccc21
Yield: 83 %

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 1,1-dimethylindan-5-carbaldehyde (prepared as described in example S100) (197 mg, 0.56 mmol), phenethylamine (67 mg, 0.56 mmol) and sodium borohydride (32 mg, 0.84 mmol). The desired product (129 mg, 83%) was isolated without further purification as a colorless oil. MS (ISP) 280.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)#[CH:18]>>[Cl:25][C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:24]=[CH:23][CH:22]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: C#Cc1cccc(Cl)c1
Product: O=c1[nH]c2nccc(C#Cc3cccc(Cl)c3)c2c2ccccc12
Yield: 72.4 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using Compound 83 (100 mg, 0.43 mmol) and 1-ethynyl-3-chloro-benzene (88 mg, 0.65 mmol) to provide 165 (103 mg, 72% yield) as a white solid. LC-MS (M+H=331, obsd.=331).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:22]=[C:21]([C:23]([OH:25])=O)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl.[OH:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH2:30][CH2:31][NH:32][CH2:33]2>>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]2[N:22]=[C:21]([C:23]([N:32]3[CH2:31][CH2:30][C:29]4[C:34](=[CH:35][CH:36]=[CH:37][C:28]=4[OH:27])[CH2:33]3)=[O:25])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(-c2nc(C(=O)O)c3ccccc3n2)cc(OC)c1OC
Reactant: Oc1cccc2c1CCNC2
Agent: Cl
Product: COc1cc(-c2nc(C(=O)N3CCc4c(O)cccc4C3)c3ccccc3n2)cc(OC)c1OC
Yield: 18.8 %

Procedure:
Reaction of 2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 93 (18.8% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.74 and 2.87 (2t, 2H), 3.54 and 4.05 (2t, 2H), 3.76-3.78 (2s, 3H), 3.86 and 3.92 (2s, 6H), 4.46 and 4.96 (2s, 2H), 6.30-7.08 (m, 3H), 7.64-8.17 (m, 6H), 9.50 and 9.53 (2s, 1H); MS (ESI) m/z 472 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:21]([OH:23])=O)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C(=O)CCC1=O.[CH2:44]([NH2:47])[CH2:45][NH2:46]>CN(C)C=O.C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:21]([NH:46][CH2:45][CH2:44][NH2:47])=[O:23])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: O=C(O)c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NCCNC(=O)c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
80 mg (0.24 mmol) of N-[3-chloro-phenyl]-4-(2-carboxy-4-pyridyl)-2-pyrimidineamine, 70.8 mg (0.36 mmol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride and 42 mg (0.36 mmol) of N-hydroxysuccinimide are dissolved in 3 ml of dimethylformamide and stirred for 2.5 h at RT. The reaction mixture is then added dropwise at 0° within a period of 30 minutes to a solution of 0.77 ml (11.8 mmol) of ethylenediamine in 2 ml of DMF. After stirring for 14 h at RT, the reaction mixture is poured into 50 ml of ethyl acetate and extracted with 30 ml of water. The organic phase is dried (sodium sulfate) and concentrated. Crystallisation from isopropanol/ethanolic hydrochloric acid gives N-[3-chloro-phenyl]-4-[2-(N-{2-amino-ethyl}-aminocarbonyl)-4-pyridyl]-2-pyrimidineamine hydrochloride; m.p. 161°-163°, FAB-MS: 369 (M+ +H).
Reaction SMILES: Cl[CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.[NH2:8][C:9]([NH2:11])=[S:10]>>[S:10]1[C:3]2[CH2:4][CH2:5][CH2:6][C:2]=2[N:8]=[C:9]1[NH2:11]
Reactant: NC(N)=S
Reactant: O=C1CCCC1Cl
Product: Nc1nc2c(s1)CCC2
Temperature: 70 °C

Procedure:
A mixture of 2-chlorocyclopentanone (5.0 g, 40 mmol) and thiourea (3.0 g, 40 mmol) was heated at 70° C. for 3 hours. After cooling, the solid was triturated with ethanol and collected by filtration to afford the title compound. MS (ESI) m/z 141 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:26])[CH2:23][CH2:24][OH:25])=[C:18]([CH3:27])[CH:17]=2)=[C:12]([CH:28]([CH3:30])[CH3:29])[CH:11]=[N:10]1.C(N(CC)CC)C.[N+:38]([C:41]1[CH:42]=[C:43]([S:47](Cl)(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=1)([O-:40])=[O:39]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:26])[CH2:23][CH2:24][O:25][S:47]([C:43]3[CH:44]=[CH:45][CH:46]=[C:41]([N+:38]([O-:40])=[O:39])[CH:42]=3)(=[O:48])=[O:49])=[C:18]([CH3:27])[CH:17]=2)=[C:12]([CH:28]([CH3:30])[CH3:29])[CH:11]=[N:10]1
Reactant: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1C(C)CCO
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1C(C)CCOS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (+/−)-3-{4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-butan-1-ol (0.245 g, 0.548 mmol) in dichloromethane (10 mL) is added triethylamine (0.15 mL, 1.09 mmol). After 10 minutes, m-nitrobenzene sulfonyl chloride (0.243 g, 1.09 mmol) is added. The reaction is stirred at room temperature for 4 hours and the reaction mixture is concentrated under reduced pressure. The residue is dissolved in ethyl acetate and is washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound. 1H NMR (CDCl3) δ 1.1 (d, 3H), 1.28 (d, 6H), 1.62 (s, 2H), 1.85-1.95 (m, 2H), 2.17 (s, 3H), 2.91-3.039 (m, 2H), 3.85-3.95 (m, 1H), 4.04-4.12 (m, 2H), 4.74 (s, 2H), 6.45 (d, 1H), 6.51 (dd, 1H), 6.86 (d, 1H), 7.26 (t, 1H), 7.38 (d, 2H), 7.65 (t, 3H), 8.1 (d, 1H), 8.39 (d, 1H), 8.63 (s, 1H);
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[N+:7]([C:10]1[CH:24]=[CH:23][C:13]([CH2:14][P:15](=O)([O:19]CC)[O:16][CH2:17][CH3:18])=[CH:12][CH:11]=1)([O-:9])=[O:8]>C(Cl)Cl.C(Cl)(Cl)Cl>[N+:7]([C:10]1[CH:24]=[CH:23][C:13]([CH2:14][P:15]([Cl:4])(=[O:19])[O:16][CH2:17][CH3:18])=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOP(=O)(Cl)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 48 h
Yield: 98.6 %

Procedure:
Oxalyl chloride (4.8 mL, 9.6 mmol, 2 M solution in methylene chloride) was added to a solution of diethyl 4-nitrobenzylphosphonate 298 (546 mg, 2.0 mmol) in methylene chloride (10 mL) at room temperature under nitrogen, and the mixture was stirred for 48 h. The mixture was diluted with chloroform (10 mL), and the solvent was concentrated to provide 520 mg (99% yield) of ethyl 4-nitrobenzylphosphonochloridate 299 as a thick yellow oil that was used in the next step without purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:71]1([CH:77]2[CH2:82][CH2:81][NH:80][CH2:79][CH2:78]2)[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1>CN1C(=O)CCC1>[N:71]1([CH:77]2[CH2:82][CH2:81][N:80]([C:32]([C:31]3[CH:30]=[CH:29][C:28]([NH:27][C:26]([NH:25][C:22]4[CH:21]=[CH:20][C:19]([C:9]5[N:10]=[C:11]([N:13]6[CH2:14][CH2:15][O:16][CH2:17][CH2:18]6)[N:12]=[C:7]([N:4]6[CH2:3][CH2:2][O:1][CH2:6][CH2:5]6)[N:8]=5)=[CH:24][CH:23]=4)=[O:37])=[CH:36][CH:35]=3)=[O:33])[CH2:79][CH2:78]2)[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(C(=O)N2CCC(N3CCCCC3)CC2)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 60.1 %

Procedure:
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with 1,4′-bipiperidine (67 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product as a white solid (39 mg, 60% yield); MS (ESI) m/z=656.8
Reaction SMILES: [ClH:1].O[C@@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[S:8][CH2:9][C:10]([OH:12])=[O:11].[Cl-].[Na+]>O>[Cl:1][C@@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[S:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=C(O)CS[C@@H]1CCC[C@H]1O
Reactant: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CS[C@@H]1CCC[C@H]1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Concentrated hydrochloric acid (50 ml) was added to the product of Example 3 (8.4 g) and stirred for 20 hours at room temperature. The reaction mixture was poured into a solution of water (50 ml) containing sodium chloride and extracted three times with 75 ml of diethyl ether. The combined diethyl ether extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil with a rotary evaporator. The product was purified by silica gel chromatography, and the structure was supported by NMR spectroscopy. The NMR spectrum showed a small amount of the cis-product as well.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1[C:20]2[C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17][C:16]=2[CH:15]=[CH:14][CH:13]=1.C(O)C>C(Cl)(Cl)Cl>[CH:12]1[C:20]2[C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17](=[O:9])[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc2c(c1)sc1ccccc12
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=S1c2ccccc2-c2ccccc21
Temperature: -35 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A solution of mCPBA (8.27 g, 36.9 mmol) in 71 mL chloroform was added dropwise over 30 minutes to a solution of dibenzothiophene in 89 mL chloroform at −35° C. The reaction mixture was stirred at −35° C. for 1 hour and then warmed up to room. The reaction was quenched with saturated sodium bicarbonate aqueous solution. The organic layer was washed with saturated sodium bicarbonate solution twice and dried over MgSO4, concentrated down to give an off-white solid. The solid was dissolved in refluxing ethanol and slowly cooled to room temperature to give a white crystalline solid Dibenzothiophene 5-oxide (5.65 g, 76%). LCMS-ESI−: calc'd for C12H8OS: 200.26. Found: 200.9 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]2[C:8](=[O:11])[NH:9][N:10]=[C:6]2[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:3]=1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>C1COCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:4]2[N:3]=[C:2]([NH:29][CH:26]([CH3:28])[CH3:27])[N:7]3[C:8](=[O:11])[NH:9][N:10]=[C:6]3[C:5]=2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:20][CH:21]=1
Reactant: CC(C)N
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cl)n12
Solvent: C1CCOC1
Product: CC(C)Nc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2n[nH]c(=O)n12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 5-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (39 mg, 0.10 mmol) in 1 mL THF, was added isopropylamine (18 mg, 0.30 mmol). The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The resulting crude title compound was used in the next step without further purification.