Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)[C:6]([CH3:21])=[C:5]2[CH2:22][C:23]([OH:25])=[O:24].[OH:26]OS([O-])=O.[K+]>C1COCC1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])(=[O:26])=[O:19])=[CH:14][CH:13]=1)[C:6]([CH3:21])=[C:5]2[CH2:22][C:23]([OH:25])=[O:24]
Reactant: O=S([O-])OO
Reactant: CC1=C(CC(=O)O)c2cc(F)ccc2C1=Cc1ccc(S(C)=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC1=C(CC(=O)O)c2cc(F)ccc2C1=Cc1ccc(S(C)(=O)=O)cc1
Reaction time: 24 h

Procedure:
To 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetic acid (12.0 g, 33.66 mmol) in 140 ml THF is added gradually at 0° C. a solution of OXONE (12.47 g, 36.72 mmol) and tetrabutylammoniumhydrogensulfate (1.0 g, 1.62 mmol) in 35 ml H2O. The temperature of the reaction mixture is maintained in the range of 13°-23° C. After 24 h at room temperature, the THF phase is separated from the water phase and is dripped into water (280 ml, 40° C.). The suspension is stirred until it reaches room temperature. The yellow crystals of 5-fluoro-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylacetic acid are filtered off and are washed with water (30 ml). 11.3 g, 30.29 mmol, 90% mp. 204°-206° C.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH3:25][NH2:26]>>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][NH:26][CH3:25])=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CN
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1
Product: CNCc1cc(-c2ccc(C)cc2)nn(CC(C)C)c1=O

Procedure:
Following the procedure of Example 9 (4), 2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-one and methylamine were reacted to yield the title compound as a slightly yellow oil (yield: 94.5%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[Cl:14][C:15]1[C:20]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])=[C:19](Cl)[N:18]=[C:17]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:16]=1>>[Cl:14][C:15]1[N:16]=[C:17]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[N:18]=[C:19]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][N:8]=2)(=[O:12])=[O:11])[C:20]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29]
Reactant: COc1ccccc1Oc1c(Cl)nc(N2CCOCC2)nc1Cl
Reactant: CC(C)c1ccc(S(N)(=O)=O)nc1
Product: COc1ccccc1Oc1c(Cl)nc(N2CCOCC2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
reacting the product of step c) with 4,6-dichloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidine to form 5-isopropyl-pyridine-2-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl-amide,
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[C:16]3[C:12]([C:13]4([CH2:22][CH2:21][CH2:20][CH2:19]4)[C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)O1.[CH:24]1([NH:27][C:28]2[C:32]3[CH:33]=[CH:34][C:35]([CH3:38])=[C:36](I)[C:31]=3[O:30][N:29]=2)[CH2:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH:24]1([NH:27][C:28]2[C:32]3[CH:33]=[CH:34][C:35]([CH3:38])=[C:36]([C:9]4[CH:17]=[C:16]5[C:12]([C:13]6([CH2:19][CH2:20][CH2:21][CH2:22]6)[C:14](=[O:18])[NH:15]5)=[CH:11][CH:10]=4)[C:31]=3[O:30][N:29]=2)[CH2:26][CH2:25]1
Reactant: Cc1ccc2c(NC3CC3)noc2c1I
Reactant: CC1(C)OB(c2ccc3c(c2)NC(=O)C32CCCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ccc2c(NC3CC3)noc2c1-c1ccc2c(c1)NC(=O)C21CCCC1
Temperature: 105 °C
Reaction time: 20 h
Yield: 24 %

Procedure:
An oven-dried resealable Schlenk tube was charged with 6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopentane-1,3′-indolin]-2′-one (preparation 4, 0.060 g, 0.19 mmol), N-cyclopropyl-7-iodo-6-methylbenzo[d]isoxazol-3-amine (WO2006094187, 0.090 g, 0.29 mmol), 1,4-dioxane (1.2 mL) and a 2M aqueous caesium carbonate solution (0.29 mL, 0.58 mmol). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.015 g, 0.02 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated in an oil bath to 100-110° C. After 20 hours, the mixture was cooled and partitioned between water and ethyl acetate. The organic extract was dried (MgSO4) and evaporated in vacuo. Purification of the residue by flash chromatography (98:2 dichloromethane/methanol) gave the title compound (0.017 g, 28%) as a yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[N+:21]([O-])([OH:23])=[O:22].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cc(C(=O)O)ccc1Oc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CS(=O)(=O)c1cc(C(=O)O)ccc1Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
3-Methylsulfonyl-4-(4-nitrophenoxy)benzoic acid was prepared by reacting 0.02 mol of 3-methylsulfonyl-4-phenoxybenzoic acid with 0.96 ml of 100% nitric acid at -10° C. in a mixture composed of 8 ml of acetic anhydride and 4 ml of glacial acetic acid. After the mixture had been stirred at this temperature for 1.5 hours, it was then stirred at room temperature for 24 hours and at 40° C. for a further 6 hours. It was then poured into ice water and the amorphous, oily product was crystallized with water by stirring. Yellow crystalline substance,
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:38]([O:42][C:43](=[O:51])[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43](=[O:51])[NH:44][CH:45]1[CH2:50][CH2:49][N:48]([C:32]([N:12]2[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][C:7]=2[O:35][CH2:36][CH3:37])=[O:33])[CH2:47][CH2:46]1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NC(=O)OC(C)(C)C)CC1

Procedure:
In a manner analogous to the method described in example 3, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was reacted with piperidin-4-yl-carbamic acid tert-butyl ester (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C39H50Cl2N5O4 [(M+H)+] 722.3235, observed 722.3233.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].C1C(=O)N([Br:20])C(=O)C1.O>CN(C=O)C>[Br:20][C:9]1[CH:10]=[CH:11][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C)c1cccc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc(Br)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104.3 %

Procedure:
A solution of 3-(dimethylamino)benzoic acid (5.13 g, 31.0 mmol) in DMF (20 mL) was cooled to 5° C. To this cold solution was added NBS (6.23 g, 35.0 mmol) in several portions in order to keep the internal reaction temperature at 5° C. The reaction mixture was allowed to stir at this temperature for 15 min and then to warm to rt. The mixture was poured into water and extracted with EtOAc. The organic solutions were combined, washed with water and brine, dried over Na2SO4, filtered, and concentrated to give 2-bromo-5-(dimethylamino)benzoic acid (7.89 g, 93%) which was used without purification in the next step.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([O:19][CH3:20])=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)(=O)=O.[CH2:21]([S-:23])[CH3:22].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH2:21]([S:23][CH2:6][CH2:7][CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([O:19][CH3:20])=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)[CH3:22]
Reactant: CC[S-]
Reactant: COC(=O)C12CCC(CCCOS(C)(=O)=O)(CC1)CC2
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCSCCCC12CCC(C(=O)OC)(CC1)CC2
Temperature: 45 °C
Reaction time: 3 h

Procedure:
Mesylate 11-5 (3.30 g, 10.9 mmol) was dissolved in DMF (20 mL) and treated with sodium ethanethiolate (1.82 g, 21.7 mmol). The solution was stirred at 45° C. for 3 h, then the mixture was diluted with 100 mL of ethyl acetate and washed twice with 1N aqueous HCl, then with saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated to afford methyl 4-[3-(ethylthio)propyl]bicyclo[2.2.2]octane-1-carboxylate (11-6) as a crude oil which was used without purification in the next step.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH:25]=[CH:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH2:25][CH:26]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: CCCC=CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Reactant: C1CCNCC1
Product: CCCC(CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)N1CCCCC1

Procedure:
By following the procedure described above, N-cyclopropyl-N-(1-hex-2-enoyl-piperidin-4-yl)-3-trifluoromethylbenzenesulfonamide (30) was reacted with piperidine and N-cyclopropyl-N-{1-[3-(piperidin-1-yl)hexanoyl]piperidin-4-yl}-3-trifluoromethylbenzenesulfonamide (32) was obtained as a white solid. 1H NMR (CDCl3): δ 8.15 (S, 1H), 8.06 (d, 1H), 7.87 (d, 1H), 7.71 (t, 1H), 4.71 (d, 1H), 4.09 (m, 1H), 3.95 (d, 1H), 3.02 (m, 2H), 2.39 (m, 6H), 2.15 (m, 1H), 1.96 (m, 1H), 1.80 (m, 3H), 1.40 (m, 11H), 0.96 (m, 1H), 0.80 (m, 6H). LC: 100%. MS (M+H+): 530.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.[Cl:11]Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:11])=[N:7][OH:8])=[CH:4][CH:3]=1
Reactant: ClCl
Reactant: ON=Cc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: ON=C(Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 16.75 g of 4-chlorobenzaldoxime in 155 ml of chloroform was cooled to 5°. Chlorine gas was passed slowly through the solution until no more was absorbed; a blue-green color developed and the temperature slowly increased to 20°. The mixture was stirred for 1 hour at 5°, then heated under reflux for half an hour. The mixture was cooled to room temperature, then the solvent was evaporated under reduced pressure to give a white solid. The solid was collected and dried in a vacuum desiccator in a refrigerator at 5° to give 20.4 g of 4-chlorobenzohydroximoyl chloride, m.p. 81°-85°.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[N:28]1([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][N:35]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38](=[O:39])[C:37]5[CH:41]=[CH:42][C:34]([N:28]6[CH2:29][CH2:30][O:31][CH2:32][CH2:33]6)=[N:35][CH:36]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc(N2CCOCC2)nc1

Procedure:
The title compound, white solid (122 mg, 94%), MS (ISP) m/z=521.5 [(M+H)+], mp 231° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 6-morpholin-4-yl-nicotinic acid.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1([CH3:34])[CH2:33][O:32][CH2:31]1>C(#N)C>[CH3:21][O:20][C:3]1[C:2]([O:1][CH2:29][C:30]2([CH3:34])[CH2:33][O:32][CH2:31]2)=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[O:14][CH2:13]2
Reactant: CC1(CBr)COC1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1OCC1(C)COC1
Temperature: 80 °C
Yield: 48.4 %

Procedure:
To a stirring solution of 5-(3-Hydroxy-2,4-dimethoxy-phenyl)-3H-isobenzofuran-1-one (80 mg, 0.279 mmol) in acetonitrile (10 mL) was added potassium carbonate (115 mg, 0.837 mmol) and 3-bromomethyl-3-methyl-oxetane (138 mg, 0.837 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (50 mg, 48.4%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)=[N:13]2)=[N:6][CH:7]=1.C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:53][CH2:54][N:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[CH3:24][N:22]1[CH:23]=[C:19]([C:14]2[CH:15]=[CH:16][C:17](=[O:18])[N:12]([CH2:11][C:10]3[CH:25]=[CH:26][CH:27]=[C:8]([C:5]4[N:6]=[CH:7][C:2]([O:1][CH2:53][CH2:54][N:55]5[CH2:60][CH2:59][O:58][CH2:57][CH2:56]5)=[CH:3][N:4]=4)[CH:9]=3)[N:13]=2)[CH:20]=[N:21]1
Reactant: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(O)cn4)c3)n2)cn1
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(OCCN5CCOCC5)cn4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 360 mg (1.00 mmol) of 2-[3-(5-hydroxy-pyrimidin-2-yl)-benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one in 2 ml THF 394 mg (1.50 mmol) of triphenylphosphine and 242 μl (2.00 mmol) of 4-(2-hydroxyethyl)morpholine are added one after the other. Under ice cooling 294 μl (1.50 mmol) of diisopropylazodicarboxylate are slowly added dropwise. The resulting solution is stirred for 18 hours at room temperature. The reaction mixture is then concentrated in vacuo and the oily residue is dissolved in 2-propanol. The resulting solid of 6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4-yl-ethoxy)-pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one resulted after some time is sucked off, washed with 2-propanol and tert-butylmethylether and dried in vacuo.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:20]=[N:21][NH:22][CH:23]=4)[CH:18]=[C:13]3[C:12]([C:24]3[N:29]=[C:28]([O:30][CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]4)[CH:27]=[N:26][CH:25]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH2:45][CH3:46].[H-].[Na+]>CN(C=O)C>[CH2:45]([N:22]1[CH:23]=[C:19]([C:17]2[CH:18]=[C:13]3[C:12]([C:24]4[N:29]=[C:28]([O:30][CH:31]5[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:36]5)[CH:27]=[N:26][CH:25]=4)=[CH:11][N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:8])=[O:9])[C:14]3=[N:15][CH:16]=2)[CH:20]=[N:21]1)[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cncc(-c3cn(S(=O)(=O)c4ccccc4)c4ncc(-c5cn[nH]c5)cc34)n2)CC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(-c2cnc3c(c2)c(-c2cncc(OC4CCN(C(=O)OC(C)(C)C)CC4)n2)cn3S(=O)(=O)c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 4-({6-[1-(phenylsulfonyl)-5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]pyrazin-2-yl}oxy)piperidine-1-carboxylate (0.075 g, 0.13 mmol) and iodoethane (11 pt, 0.14 mmol) in DMF (1.3 mL) at 0° C. was added sodium hydride (60% mineral oil dispersion; 6.0 mg, 0.15 mmol). The reaction mixture was stirred at 0° C. for 1 h then quenched with aqueous saturated sodium bicarbonate (5 mL). The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford tert-butyl 4-({6-[5-(1-ethyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]pyrazin-2-yl}oxy)piperidine-1-carboxylate as a yellow oil. LRMS (ESI) calculated for C32H35N7O5S [M+H]+, 630.2; found 630.2.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]1([C:25]2[N:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([C:25]2[N:26]=[CH:27][C:28]([NH:31][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:29][N:30]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: Nc1cnc(N2CCOCC2)nc1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: O=C(Nc1cnc(N2CCOCC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a procedure similar to example 1 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2-morpholin-4-yl-pyrimidin-5-yl)-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 2-morpholin-4-yl-pyrimidin-5-ylamine. LCMS calcd for C19H16F3N5O3 (m/e) 419, obsd 420 (M+H).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[OH:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][C:19]#[N:20])=[CH:16][CH:15]=1.[CH2:23](O)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:25]1([CH2:24][CH2:23][O:13][C:14]2[CH:22]=[CH:21][C:17]([CH2:18][C:19]#[N:20])=[CH:16][CH:15]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N#CCc1ccc(O)cc1
Reactant: OCCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#CCc1ccc(OCCc2ccccc2)cc1
Reaction time: 24 h
Yield: 65.8 %

Procedure:
Diethylazodicarboxylate (DEAD, 7.85 g, 45.1 mmol), was added to a solution of 4-hydroxybenzyl cyanide (5.0 g, 37.6 mmol), phenethylalcohol (5.04 g, 41.3 mmol), and triphenylphosphine (11.82 g, 45.1 mmol) in anhydrous THF (100 mL) at room temperature. A water bath was used to maintain the temperature of the exothermic reaction near ambient. The water bath was removed after 40 minutes and the yellow solution stirred 24 hours. Water was added and the mixture extracted with ether (3×100 mL). The combined organic layers were washed with water (2×75 mL), brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give an oily yellow solid. The residue was washed with ether, and the resulting white solid removed by filtration. The filtrate was concentrated in vacuo to give a yellow oil, which was purified by chromatography on silica gel with elution by EtOAc/hexanes (2:8) to give the desired product (5.87 g, 66%) as a light yellow oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[C:16]([CH2:20][CH2:21][C:22](Cl)=[O:23])([O:18][CH3:19])=[O:17]>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:22](=[O:23])[CH2:21][CH2:20][C:16]([O:18][CH3:19])=[O:17])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: COC(=O)CCC(=O)Cl
Product: COC(=O)CCC(=O)Nc1nc2cccc(-c3ccoc3)n2n1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 660 mg; 0.30 mmol; 1.0 eq.) and 3-carbomethoxypropionyl chloride (65 mg, 0.60 mmol; 2.0 eq.) as a white powder (83.5 mg, 88%). HPLC, Rt: 2.40 min. (purity 95.4%). LC/MS, M−(ESI): 313.2.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=1[NH:14][C:15](=[O:31])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:36]2[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]2)=[O:13])=[CH:7][C:6]=1[NH:14][C:15](=[O:31])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccccc1OC
Reactant: CN1CCNCC1
Product: CCCCCC(CC(=O)Nc1cc(C(=O)N2CCN(C)CC2)ccc1C(C)(C)C)c1ccccc1OC

Procedure:
Following a similar procedure to that described in Example 8, but using N-(2-t-butyl-5-carboxyphenyl)-3-(2-methoxyphenyl)octanamide (prepared as described in Preparation 74F) and 4-methylpiperazine, the title compound was obtained as a colorless foam-like substance.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:3]=1.O.[NH2:20][NH2:21]>>[NH:20]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:3]=1)[NH2:21]
Reactant: Cn1cnc2c(Nc3ccncc3)nc(Cl)nc21
Reactant: NN
Solvent: O
Product: Cn1cnc2c(Nc3ccncc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (2-chloro-9-methyl-9H-purin-6-yl)pyridin-4-yl-amine and hydrazine monohydrate.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:14][NH2:15])[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)[CH:2]=1.[F:22][C:23]([F:39])([F:38])[C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:30]=[N:31][CH:32]=[C:33]([CH:37]=2)[C:34](O)=[O:35])[N:25]=1>>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:14][NH:15][C:34](=[O:35])[C:33]3[CH:37]=[C:29]([C:26]4[N:25]=[C:24]([C:23]([F:39])([F:38])[F:22])[O:28][N:27]=4)[CH:30]=[N:31][CH:32]=3)[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)[CH:2]=1
Reactant: CN1CCC(CN)(c2cccc(-c3ccccc3)c2)CC1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: CN1CCC(CNC(=O)c2cncc(-c3noc(C(F)(F)F)n3)c2)(c2cccc(-c3ccccc3)c2)CC1
Yield: 30 %

Procedure:
This compound was synthesized from (4-([1,1′-biphenyl]-3-yl)-1-methylpiperidin-4-yl)methanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (60 mg, yield 30%) as an off white solid. 1H NMR (400 MHz, MeOD) δ 9.32 (d, J=2.0 Hz, 1H), 9.01 (d, J=2.0 Hz, 1H), 8.68-8.67 (t, J=2.0 Hz, 1H), 7.65 (m, 1H), 7.57-7.55 (m, 2H), 7.50-7.47 (m, 3H), 7.40-7.36 (t, J=7.4 Hz, 2H), 7.31-7.28 (m, 1H), 3.62 (m, 2H), 2.79-2.76 (m, 2H), 2.44-2.31 (m, 4H), 2.24 (m, 3H), 2.11-2.05 (m, 2H). MS (ESI) m/z: Calculated for C23H26F3N5O2: 521.20. found: 522.2 (M+H)+.