Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)=[N:8][CH:7]=[C:6]2[CH2:26]O.S(Cl)([Cl:30])=O>C(Cl)Cl>[Cl:30][CH2:26][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)=[N:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(Cc2ncc(CO)c3cc(OC)c(OC)cc23)cc1OC
Solvent: ClCCl
Product: COc1ccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A cold mixture of 26.8 g of 6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]-4-isoquinoline methanol in 600 ml of methylene chloride was treated dropwise with 27 ml of thionyl chloride over 15 minutes. The cooling bath was removed and the solution was allowed to stir at ambient temperature for 3 hours after which the volatiles were removed in vacuo. The residue was mixed with methylene chloride and water followed by careful addition of excess sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, evaporated, and crystallized from ethyl acetate to give 23.1 g of 4-chloromethyl-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]isoquinoline as a yellow solid, mp 153° dec. Recrystallization from ethyl acetate provided the analytically pure material, mp 153° dec.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:25]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[N:27]=4)=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH3:34][C:35]([CH3:39])([CH3:38])[C:36]#[CH:37]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:34][C:35]([CH3:39])([CH3:38])[C:36]#[C:37][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:25]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[N:27]=4)=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1
Reactant: C#CC(C)(C)C
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(Cl)c4ccccc34)cc2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(C#CC(C)(C)C)c4ccccc34)cc2)n1
Temperature: 90 °C

Procedure:
A resealable pressure tube, purged with argon, was charged with 4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine (150 mg, 0.329 mmol), bis(triphenylphosphine)palladium(II) chloride (14 mg, 0.020 mmol), copper(I) iodide (3.8 mg, 0.020 mmol), and 3,3-dimethyl-1-butyne (0.101 mL, 0.823 mmol). This mixture was purged with argon for 10 minutes, followed by addition of acetonitrile (3.3 ml, 0.1 M). The pressure tube was sealed and the mixture inside heated to 90° C. for 16 hrs. The next day, the reaction was stopped, cooled to RT, diluted with dichloromethane and filtered over a plug of celite. Filtrate was concentrated to afford a brown residue, which was purified by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA). The product-containing fractions were combined, basified by addition of aq. NaHCO3 and extracted with ethyl acetate. The organic portion was dried with Na2SO4, filtered, and concentrated to afford pure 4-(3,3-dimethylbut-1-ynyl)-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine as a yellow solid. MS m/z=502 [M+H]+. Calc'd for C30H27N7O: 501.58.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[C@H:19]2[C@H:23]([OH:24])[C@H:22]([OH:25])[C@@H:21]([CH2:26][O:27][CH3:28])[O:20]2)=[C:12]([NH:29][CH2:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:11]=1)(=O)=O>CN(C)C=O>[OH:24][C@@H:23]1[C@H:22]([OH:25])[C@@H:21]([CH2:26][O:27][CH3:28])[O:20][C@H:19]1[N:16]1[CH:15]=[N:14][C:13]2[C:17]1=[N:18][C:10]([CH2:9][C:1]#[N:2])=[N:11][C:12]=2[NH:29][CH2:30][CH:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O)[C@@H]1O
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CC#N)nc32)[C@H](O)[C@@H]1O
Temperature: 70 °C
Yield: 63.6 %

Procedure:
Potassium cyanide (22 mg, 0.33 mmol) was added to a stirred solution of {9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl methanesulfonate (130 mg, 0.22 mmol) (preparation 25) in N,N-dimethylformamide (3 ml). The reaction mixture was heated to 70° C. for 1.5 hr, allowed to cool to room temperature and then partitioned between diethyl ether and water. The aqueous layer was washed with diethyl ether. The combined organic solutions were washed with brine and dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give a residue that was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol (97:3). This gave the title compound (70 mg) as a powder. MS: 523 (MNa+).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([NH2:12])=[O:11].O[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=1>>[F:1][C:2]1[C:7]([O:8][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([NH2:12])=[O:11]
Reactant: Cc1cc(CO)ccn1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Product: Cc1cc(COc2ccc(F)c(C(N)=O)c2F)ccn1
Yield: 34 %

Procedure:
Synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Method C, scheme 3. The required building block, 4-hydroxymethyl-2-methylpyridine, was synthesised according to the literature method, shown in Scheme 23 (Ragan, J. A., Jones, B. P., Meltz, C. N., Teixeira J. J. Jr.; Synthesis 2002, 483-486. Yield 34%, mp 185-186° C., HPLC-MS (method 1): m/z 279 [M+H]+, Rt=2.50 min.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[CH3:33][N:34]([CH2:36][C:37]1([OH:43])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH3:35]>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:40]5[CH2:41][CH2:42][C:37]([CH2:36][N:34]([CH3:35])[CH3:33])([OH:43])[CH2:38][CH2:39]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:30])([F:31])[F:32])[CH:3]=1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CN(C)CC1(O)CCNCC1
Product: CN(C)CC1(O)CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-dimethylaminomethyl-4-hydroxy-piperidin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and 4-Dimethylaminomethyl-piperidin-4-ol following General Procedure B.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:16]([Cl:17])=[C:15]([Cl:18])[N:14]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:25][CH2:26][C:27]([OH:29])=[O:28]>C[O-].[Na+].CO>[Cl:18][C:15]1[N:14]([CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5])[C:7]([OH:24])=[C:8]2[C:16]=1[Cl:17]
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Cl)c(Cl)n2CCC(C)C
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCn1c(Cl)c(Cl)c2c(O)c(C(=O)NCC(=O)O)nc(C#N)c21

Procedure:
7-Cyano-2,3-dichloro-4-hydroxy-1-(3-methyl-butyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (80 mg, 0.22 mmol) and glycine (324 mg, 4.32 mmol) were suspended in 8.64 mL of 0.5 N sodium methoxide in methanol. The reaction was heated at reflux temperature overnight, cooled, and concentrated. The residue was dissolved in water (15 mL), and the solution was acidified to pH 1-2 with 1 N hydrochloric acid. The title compound (60 mg) was collected by filtration as a light yellow solid. MS: (+) m/z 399.2 (M+1).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[O:18][C@@H:16]([CH3:17])[CH2:15][C@@H:14]2[OH:19])(=O)=O)=CC=1.CN(C)C=O.[N-:25]=[N+:26]=[N-:27].[Na+]>C(OCC)C>[N:25]([CH2:12][C@H:13]1[O:18][C@@H:16]([CH3:17])[CH2:15][C@@H:14]1[OH:19])=[N+:26]=[N-:27]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](C)C[C@@H]2O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C[C@H]1C[C@H](O)[C@@H](CN=[N+]=[N-])O1
Yield: 77.4 %

Procedure:
A mixture, under argon, of 0.560 g of product from Example 337, 2 ml of N,N-dimethylformamide and 0.250 g of sodium azide is stirred at 75° C. for 12 hours. The reaction mixture is diluted with diethyl ether, washed with water and saturated sodium chloride, dried and concentrated in vacuo to give 0.238 g of the desired product.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[S:27](Cl)(=[O:29])=[O:28].C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([N:5]([CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[S:27]([C:23]1[S:22][CH:26]=[CH:25][CH:24]=1)(=[O:29])=[O:28])[CH:2]([CH3:4])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1cccs1

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with 2-thiophenesulfonyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give thiophene-2-sulfonic acid isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amide as a light yellow solid. MS: 487.0 ([M+NH4]+)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1.O>CN(C)C=O>[N+:20]([C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][S:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1])([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: Nc1cccc(S)c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cccc(SCc2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 3-aminobenzenethiol (0.51 mL, 4.8 mmol) and sodium methoxide (0.31 g, 5.8 mmol) in N,N-dimethylformamide (5.3 mL) was stirred at 25° C. for 10 minutes (min). The reaction mixture was treated with a solution of 1-(bromomethyl)-3-nitro-benzene (1.0 g, 4.8 mmol) in N,N-dimethylformamide (4.5 mL) dropwise and stirred at 25° C. for 1 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated and washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude brown oil. This material was purified by flash column chromatography to give the desired product (1.2 g, 95%) as a tan oil. LCMS for C13H13N2O2S (M+H)+: m/z=261.0.
Reaction SMILES: [C:1]([C@@H:4]([NH:13][C@H:14]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2].[C:30]([O:34][CH2:35][CH3:36])(=[O:33])[CH:31]=O>>[C:1]([C@@H:4]([NH:13][C@H:14]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:31][C:30]([O:34][CH2:35][CH3:36])=[O:33])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)C=O
Reactant: NCCCC[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Product: CCOC(=O)CNCCCC[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
The reductive alkylation of N-[N2 (1(S)-carboxy-3-phenylpropyl)-L-lysyl]-L-proline and ethyl glyoxylate was carried out in accordance with the procedures described in Example 1 to give N-[N2 -(1(S)-carboxy-3-phenylpropyl)-N6 -ethoxycarbonylmethyl-L-lysyl]-L-proline. The product was then treated with ammonia at 100° C. followed by absorption on strong acid ion exchange resin and eluting with 2% pyridine in water. Freeze drying of product-rich cuts afforded N-[N2 -(1(S)-carboxy-3-phenylpropyl)-N6 -carbamoylmethyl-L-lysyl]-L-proline. The nmr spectrum was consistent with the structure.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH:10]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12].C(O)C.S(=O)(=O)(O)O.[OH-].[Na+]>O>[C:19]1([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([OH:12])[CH:10]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:9][CH2:8][OH:7])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C(CCOC1CCCCO1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCCC(c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The evaporation residue obtained in step (b) is dissolved in a mixture containing 400 ml of absolute ethanol, 10 g of concentrated sulfuric acid and 75 ml of water. The mixture is stirred for 2 h at room temperature. The solution is neutralized with 2M sodium hydroxide solution, after which the ethanol is evaporated. Water is added to the residue. Then the product is extracted in ethyl acetate. The ethyl acetate solution is dried over sodium sulfate, and the solvent is evaporated. The product is recrystallized from toluene. The yield is 16.5 g (52% from desoxybenzoin) and m.p. 185°-7° C.
Reaction SMILES: C(O[CH:4](OCC)[CH:5]1[C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[O:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=O)C.[NH2:31][NH2:32].Cl>CCO>[N:17]1([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:16][CH2:15][C:14]2([C:5]3[CH:4]=[N:32][NH:31][C:6]=3[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13]2)[CH2:19][CH2:18]1
Reactant: CCOC(OCC)C1C(=O)c2ccccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Reactant: NN
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1-c1[nH]ncc12
Temperature: 60 °C
Yield: 71.5 %

Procedure:
To tert-butyl 3-(diethoxymethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (15.1 g, 35.9 mmol) and hydrazine (1.35 mL, 43.1 mmol) in EtOH (120 mL) was added hydrochloric acid (900 μL of 4.0 M in dioxanes, 3.6 mmol). The mixture was heated at 60° C. for 2 h before it was cooled and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexanes to give tert-butyl spiro[1H-chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (8.76 g, 71%). ESI-MS m/z calc. 341.2, found 342.3 (M+1)+; Retention time: 1.69 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([OH:29])=O)[C:24]3[C:19](=[C:20]([O:30][CH3:31])[CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.[NH:34]1[CH2:38][CH2:37][N:36]=[C:35]1[C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][NH2:47])=[CH:41][CH:40]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([NH:47][CH2:46][CH2:45][C:42]3[CH:43]=[CH:44][C:39]([C:35]4[NH:36][CH2:37][CH2:38][N:34]=4)=[CH:40][CH:41]=3)=[O:29])[C:24]3[C:19](=[C:20]([O:30][CH3:31])[CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NCCc1ccc(C2=NCCN2)cc1
Reactant: COc1cccc2c1-c1ccccc1N(S(=O)(=O)c1ccc(Cl)c(Cl)c1)C2CC(=O)O
Agent: Cl
Product: COc1cccc2c1-c1ccccc1N(S(=O)(=O)c1ccc(Cl)c(Cl)c1)C2CC(=O)NCCc1ccc(C2=NCCN2)cc1

Procedure:
The title compound was prepared from [5-(3,4-dichloro-benzenesulfonyl)-10-methoxy-5,6-dihydro-phenanthridin-6-yl]-acetic acid and 2-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethylamine dihydrochloride (Reference Example 2) according to the method described in Example 1e.
Reaction SMILES: C(=O)([O-])[O-].[SH:5][C:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][N:7]=1.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:20][CH2:19]1>C(O)C>[CH3:33][C:30]1[CH:31]=[CH:32][C:27]([S:24]([N:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][S:5][C:6]3[N:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]4=[N:8][N:7]=3)[CH2:23][CH2:22]2)(=[O:26])=[O:25])=[CH:28][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(CCCl)CC2)cc1
Reactant: Sc1nnc2ccccn12
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2CCN(CCSc3nnc4ccccn34)CC2)cc1
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
30 g of postassium carbonate are added to a solution of 32.7 g of 3-mercapto-1,2,4-triazolo(4,3-a)pyridine in 300 ml of ethanol and the mixture is heated to the reflux temperature. After 15 minutes, a solution of 65.5 g of 1-chloro-2-[4-(4-methylphenylsulfonyl)piperazin-1-yl]ethane in 100 ml of ethanol is added and refluxing is continued for 3 hours. The reaction mixture is then cooled, the mineral substances are filtered off and the filtrate is concentrated in vacuo. The residue is taken up with chloroform, which is washed with water, and the chloroform phase is then extracted with a 0.5N solution of hydrochloric acid. The acidic aqueous phase is then rendered basic in the cold with a 0.5N aqueous solution of sodium hydroxide and then extracted with chloroform. The chloroform phase is washed with water, dried over sodium sulfate and then concentrated in vacuo to give 73 g of 3-[2-(4-(4-methylphenylsulfonyl)piperazin-1-yl)ethylmercapto]1,2,4-triazolo(4,3-a)pyridine in the form of a thick oil, which is used in the crude state for the next step.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Br:24])[CH:22]=3)[N:17]=[CH:16][C:15]=2[C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[CH2:9][CH2:8]1)(=O)=O.[CH3:30][NH2:31]>>[Br:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([C:25]([CH:27]1[CH2:28][CH2:29]1)=[O:26])=[C:14]2[NH:13][C@H:10]1[CH2:11][CH2:12][C@H:7]([CH2:6][NH:31][CH3:30])[CH2:8][CH2:9]1
Reactant: CN
Reactant: CS(=O)(=O)OC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: CNC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Temperature: 120 °C

Procedure:
A suspension of (trans-4-((6-bromo-3-(cyclopropanecarbonyl)quinolin-4-yl)amino)cyclohexyl)methyl methanesulfonate (175 mg, 0.36 mmol) in methylamine (2.0 M solution in THF, 4.0 mL, 8.0 mmol) in a sealed vessel was heated under microwave irradiation conditions to 120° C. for 2 h. The solution was cooled to room temperature and concentrated. The resultant residue was purified by preparative HPLC (C18 silica, 10-90% methanol/water with 0.05% TFA). The residue was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to obtain the desired product (42 mg, 28%) a white solid. ESI MS m/z 416 [C21H26BrN3O+H]+
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1.N12CCCN=C1CCCCC2>CC#N>[CH2:8]([O:7][C:1](=[O:6])[CH:2]([CH2:16][C:15]1[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)[C:3](=[O:4])[CH3:5])[CH3:9]
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(Cc1ccc(OC)cc1)C(C)=O

Procedure:
A solution of ethyl acetoacetate and 4-methoxybenzyl chloride is stirred under an argon atmosphere with 1,8-diazabicyclo[5.4.0]undec-7-ene at room temperature in CH3CN. The mixture is partitioned between 3 N HCl and EtOAc. The organic extract is washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (Na2SO4). The solvent is removed in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([CH2:8]O)[O:5][N:4]=1.S(Cl)([Cl:12])=O>ClCCl>[Cl:12][CH2:8][C:6]1[O:5][N:4]=[C:3]([O:2][CH3:1])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)on1
Solvent: ClCCl
Product: COc1cc(CCl)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.55 g of (3-methoxyisoxazol-5-yl)methanol was dissolved in 30 ml of dichloromethane, and 2 ml of thionyl chloride was then added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 1.30 g of 5-(chloromethyl)-3-methoxyisoxazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:12][C:13]=2Cl)=[CH:4][CH:3]=1.[F-:21].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:12][C:13]=2[F:21])=[CH:4][CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(Cl)c(-c2ccc(Cl)cc2)c1=O
Reactant: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1c(C(F)(F)F)cc(F)c(-c2ccc(Cl)cc2)c1=O
Temperature: 120 °C
Reaction time: 2 h
Yield: 45.7 %

Procedure:
To 10 ml of dimethylsulfoxide, 0.33 g (1.09 mmol) of 3-(4-chlorophenyl)-4-chloro-1-methyl-6-trifluoromethyl-2(1H)-pyridone and 0.05 g (0.86 mmol) of potassium fluoride were dissolved, followed by heating and stirring at 120° C. for 2 hours. After completion of the at reaction, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.12 g (yield: 38%) of the desired product. Melting point: 120-122° C. 1H-NMR (300 MHz, CDCl3) δ value: 3.42(3H,d), 6.20(1H,d), 7.16(2H,d), 7.40(2H,d)ppm.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH:17][CH2:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.[CH3:32][S-:33].[Na+]>CN(C)C=O.O>[C:20]1([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:18][NH:17][C:4]2[N:3]=[C:2]([S:33][CH3:32])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Clc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Temperature: 100 °C
Reaction time: 72 h
Yield: 99.8 %

Procedure:
A solution of 2-chloro-N-(2,2-diphenylethyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (Preparation 2) (49.7 g, 0.11 mol) in dry N,N-dimethylformamide (200 ml) was treated with sodium thiomethoxide (10 g, 0.14 mol) and the resulting mixture heated under an atmosphere of nitrogen at 100° C. for 90 minutes. The mixture was stirred at room temperature for 72 hours and then reheated at 100° C. for a further 2 hours. The reaction mixture was cooled and diluted with water (1000 ml). A suspension was formed which was extracted with diethyl ether (×2). The combined organic layers were washed sequentially with water and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was azeotroped with diethyl ether followed by pentane to afford the title compound as a foam (48.9 g).