Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=O)=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.Cl.[NH2:17][C:18]([CH2:26][CH3:27])([CH2:24][CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19](=[O:20])[C:18]([NH:17][C:13]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([O:8][CH2:9][CH:10]2[CH2:11][CH2:12]2)[N:6]=1)=[O:15])([CH2:26][CH3:27])[CH2:24][CH3:25])[CH3:23]
Reactant: CCOC(=O)C(N)(CC)CC
Reactant: O=C(O)c1ccc(Br)c(OCC2CC2)n1
Agent: Cl
Product: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(Br)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid (Example 9 d) and ethyl 2-amino-2-ethylbutanoate hydrochloride (CAN 1135219-29-2) as starting materials. MS (EI): m/e=415.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[OH:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)c1cc(N)ccc1O
Product: CCOC(=O)c1cc(N=Cc2ccccc2)ccc1O
Temperature: 100 °C
Yield: 66.7 %

Procedure:
Ethyl 2-hydroxy-5-aminobenzoate (31.8 g, 0.176 mole) was mixed with benzaldehyde (17.8 ml, 0.176 mole), and the mixture was heated to 100° C. for 10 minutes and subsequently cooled with ice-water. The resulting oil was recrystallized from 96% ethanol, with activated carbon, to give the title compound (31.6 g, 67%), m.p. 63°-65° C. Found (Calc. for C16H15NO3) C 71.18 (71.38), H 5.63 (5.58), N 5.22 (5.20).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:31])[CH3:30])[C:25]([NH:27][OH:28])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.CC(C)[C@@H](CS(N1CCN(C2N=CC(C3C=CC([C:60]([F:63])([F:62])[F:61])=CC=3)=CN=2)CC1)(=O)=O)C(O)=O>>[F:61][C:60]([F:63])([F:62])[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[N:12][C:11]([N:14]3[CH2:15][CH2:16][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:31])[CH3:30])[C:25]([NH:27][OH:28])=[O:26])(=[O:21])=[O:22])[CH2:18][CH2:19]3)=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C(F)(F)F)cc3)cn2)CC1)C(=O)O
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C(F)(F)F)cc3)cn2)CC1)C(=O)NO
Yield: 35 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide, from 3-methyl-2-(R)-{4-[5-(4-trifluoromethylphenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}butyric acid (0.086 g), to provide the title compound as a white solid (0.031 g, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:15][C:14]=3[F:25])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[Br:35][CH2:36][C:37](Br)=[O:38]>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:35][CH2:36][C:37]([O:24][CH2:23][CH2:22][CH2:21][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([F:25])[CH:15]=1)[N:12]=[CH:11][C:10]([C:8]([NH:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:27][CH:26]=1)=[O:9])=[C:19]2[OH:20])=[O:38]
Reactant: O=C(Br)CBr
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(CCCO)cc2c1O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CBr)OCCCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
A solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide from Example 110 (0.23 g), Et3N (0.090 mL), and catalytic DMAP (5-10 mol %) in 20 mL DMF is cooled to 0° C. Bromoacetyl bromide (0.050 mL) is added in one portion. The reaction is stirred at 0° C. for 20 minutes, then at room temperature for 1.5 h. Once the reaction was complete, it is partitioned between CH2Cl2 and H2O. The aqueous layer is extracted 3× with CH2Cl2. The organics are combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a liquid which subsequently crystallizes to an off-white solid when it is dried on the vacuum pump overnight. The solid is triturated in CH2Cl2 /hexanes, filtered, and dried to give the desired product (0.27 g, 0.53 mmol, 91%).
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.[NH:33]1[C:37]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[C:36](=[O:43])[NH:35][CH2:34]1>>[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[CH2:39][CH2:38][C:37]6([NH:33][CH2:34][NH:35][C:36]6=[O:43])[CH2:42][CH2:41]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:30])[F:31])[CH:3]=1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: O=C1NCNC12CCNCC2
Product: O=C1N=C(N2CCC3(CC2)NCNC3=O)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
8-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-1,3,8-triaza-spiro[4.5]decan-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and 1,3,8-Triaza-spiro[4.5]decan-4-one following General Procedure B.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=O)[NH:18][C:19](=[O:33])[N:20]([CH2:22][C:23]4[S:24][CH:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=4)[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>O1CCOCC1.C(OCC)(=O)C>[CH:3]1[C:4]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[S:44])[NH:18][C:19](=[O:33])[N:20]([CH2:22][C:23]4[S:24][CH:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=4)[CH:21]=3)[C:5]=2[CH:11]=[CH:1][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1csc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)n1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1csc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=S)[nH]c2=O)n1

Procedure:
A mixture of the product of step (iv) (2.1 g) and Lawesson's reagent (1.78 g) in dry 1,4-dioxane (36 ml) was heated at reflux for 16 hours. After cooling, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 50% ethyl acetate in isohexane. Yield 1.5 g.
Reaction SMILES: [C:1]([N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH2:11]([Li])[CH2:12][CH2:13]C.C(Br)C#C>C1COCC1>[C:1]([N:5]1[CH2:9][CH2:8][N:7]([CH2:13][C:12]#[CH:11])[C:6]1=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1CCNC1=O
Reactant: [Li]CCCC
Agent: C#CCBr
Solvent: C1CCOC1
Product: C#CCN1CCN(C(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Dissolve 1-tert-butyl-imidazolidin-2-one (2 g, 14 mmol) in anhydrous THF (60 mL) and cool at −78° C. Slowly add n-butyllithium (6.8 mL, 17 mmol, 2.5 M solution in hexanes). Stir the solution for 30 min. Rapidly add propargyl bromide (3.2 mL, 28.2 mmol, 80% solution in toluene). Warm the solution to room temperature while stirring overnight Concentrate the reaction mixture in vacuo and filter the residue on a short pad of silica gel eluting with dichloromethane/diethyl ether (1:1) to give the title compound as a yellow oil that solidifies on standing (1.77 g, 70%). GC-MS m/z (%) 180 (M+, 7), 165 (100), 123 (12), 84 (17).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][O:8][C:9]([C:11]1[CH:15]=[C:14]([CH3:16])[S:13][C:12]=1[NH2:17])=[O:10].O>CN(C)P(N(C)C)(N(C)C)=O>[C:9]([C:11]1[CH:15]=[C:14]([CH3:16])[S:13][C:12]=1[NH:17][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])([O:8][CH3:7])=[O:10]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1cc(C)sc1N
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: COC(=O)c1cc(C)sc1NC(=O)C(C)C
Reaction time: 16 h
Yield: 82.1 %

Procedure:
isoButyryl chloride (22.4 g) was added dropwise during 40 minutes to a stirred solution of methyl-2-amino-5-methyl-3-thiophenecarboxylate (34.2 g, 0.2 mol) in dry hexamethylphosphoramide (100 ml) kept at 5°-10° C. This temperature was maintained for a further 1 hour and then the reaction was kept at room temperature for 16 hours. The reaction mixture was poured into water (1600 ml) and the yellow precipitate was filtered off, washed with water and dried at 50° C. Recrystallization of the solid from petroleum ether (b.p. 60°-80° C. yielded cream crystals (39.6 g, 88%), m.p. 63°-65° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]([CH2:24][CH3:25])([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[CH:17]=3)[CH2:14][CH3:15])[S:10][C:9]=2[CH:26]=1)=[O:4].Br[CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[C:18]([CH3:23])[CH:17]=3)([CH2:24][CH3:25])[CH2:14][CH3:15])[S:10][C:9]=2[CH:26]=1)=[O:4]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1cc2ccc(C(=O)OC)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)OC)cc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
A solution of 2-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-benzo[b]thiophene-6-carboxylic acid methyl ester (4.05 g, 11.0 mmol) and 1-bromopinacolone (2.36 g, 13.2 mmol) in acetone (100 mL) is treated with K2CO3 (3.04 g, 22.0 mmol) and stirred at RT for 16 h. The mixture is filtered, and the filtrate is concentrated. The residue is purified by silica gel column chromatography (10-15% EtOAc/Hex) to provide the title compound (4.50 g, 88%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[O:8][C@@H:7]1[C:9]([OH:11])=O)=[O:5])[CH3:2].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:35][CH:36]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(OCC)(=O)C.CCCCCC>[C:37]1([CH:36]([NH:35][C:9]([C@H:7]2[O:8][C@@H:6]2[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:11])[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)O
Reactant: NC(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)NC(c1ccccc1)c1ccccc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,3S)-3-ethoxycarbonyloxirane-2-carboxylic acid (8.01 g, 50.0 mmol.) in ethyl acetate (120 mL) was added N-hydroxysuccinimide (5.76 g, 50.0 mmol.) and then added N,N'-dicyclohexylcarbodiimide (5.75 g, 50.0 mmol) under chilling with ice. The resulting mixture was stirred at 5° C. for one hour, and to the mixture was a solution of aminodiphenylmethane (9.17 g, 50.0 mmol.) in ethyl acetate (30 mL). The mixture was stirred at 5° C. for one hour and then at room temperature for one hour. The resulting N,N'-dicyclohexylurea (DC-Urea) was removed by filtration, and the filtrate was washed successively with 1N hydrochloric acid, an aqueous sodium hydrogen carbonate saturated solution, and an aqueous sodium chloride saturated solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystalized from ethyl acetate--n-hexane, to give the desired compound as a white crystalline product (1.25 g, yield: 77%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.N1C=CN=C1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCc1ccc(Br)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To a solution of 2-(4-bromophenyl)ethanol (3.0 g) and imidazole (2.03 g) in N,N-dimethylformamide (30 mL) was added tert-butylchlorodiphenylsilane (4.66 mL), and the mixture was stirred at room temperature for 7 days. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1) to give 1-bromo-4-[2-(tert-butyldiphenylsilyloxy)ethyl]benzene (6.27 g). The title compound was prepared in a similar manner to that described in Step 2 of Reference Example 46 using this material instead of 1-bromo-2-fluoro-4-methoxybenzene.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[CH:21]=[C:20]([CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.ClCCl>[CH2:5]([O:12][C:13]1[CH:21]=[C:20]([CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:19]=[CH:18][C:14]=1[C:15]([Cl:3])=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(NCc1ccc(C(=O)O)c(OCc2ccccc2)c1)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCc1ccc(C(=O)Cl)c(OCc2ccccc2)c1)OCc1ccccc1

Procedure:
Thionyl chloride (1.55 ml) and dimethylformamide (2 drops) were added to a solution of 2-benzyloxy-4-benzyloxycarbonylaminomethylbenzoic acid (7.1 mg) in dichloromethane (50 ml), and the mixture was refluxed under heating for 1.5 hours. After the reaction, the solvent was evaporated under reduced pressure to give 2-benzyloxy-4-benzyloxycarbonylaminomethylbenzoyl chloride as crystals. Then, the crystals were dissolved in acetonitrile (50 ml), and the solution was dropwise added to a solution of 4-aminopyridine (1.42 g) and diisopropylethylamine (5.27 ml) in acetonitrile (50 ml) under ice-cooling. The mixture was stirred at room temperature for 4 hours. After the reaction, water was added, and the mixture was extracted with chloroform. The extract was washed with water and dried. The solvent was evaporated under reduced pressure, and the obtained crystals were recrystallized from ethyl acetate-hexane to give N-(4-pyridyl)-2-benzyloxy-4-benzyloxycarbonylaminomethylbenzamide as crystals.
Reaction SMILES: [F:1][C:2]([F:23])([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6](=[O:16])[N:7]([CH2:12][C:13]([OH:15])=O)[C:8]([CH3:11])=[CH:9][N:10]=1.[F:24][C:25]([F:34])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH2:26][NH2:27]>>[F:34][C:25]([F:24])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH2:26][NH:27][C:13](=[O:15])[CH2:12][N:7]1[C:8]([CH3:11])=[CH:9][N:10]=[C:5]([NH:4][CH2:3][C:2]([F:1])([F:23])[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[C:6]1=[O:16]
Reactant: NCC(F)(F)c1ccccn1
Reactant: Cc1cnc(NCC(F)(F)c2ccncc2)c(=O)n1CC(=O)O
Product: Cc1cnc(NCC(F)(F)c2ccncc2)c(=O)n1CC(=O)NCC(F)(F)c1ccccn1

Procedure:
N-(2,2-Difluoro-2-pyridin-2-yl-ethyl)-2-[3-(2,2-difluoro-2-pyridin-4-yl-ethylamino)-6-methyl-2-oxo-2H-pyrazin-1-yl]-acetamide (6-3) 6-3 was prepared from [3-(2,2-difluoro-2-pyridin-4-ylethylamino)-6-methyl-2-oxo-2H-pyrazin-1-yl]-acetic acid and 2,2-difluoro-2-(2-pyridyl)ethyl amine essentially according to the procedure of Example 1, Step K. Mass Spectrum: Found: (M+1) 465.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[N:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 60 °C

Procedure:
A mixture of 5-nitroindazole (3.00 g, 18.4 mmol) and potassium carbonate (7.50 g, 54.4 mmol) in DMF (60 mL) was stirred for 30 minutes after which 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (4.80 g, 28.4 mmol) was added. The mixture was heated to 60° C. for 6 hours, cooled to room temperature and filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure and the residue purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.60 (m, 4H), 2.44 (m, 4H), 2.90 (t, 2H, J=6.45), 4.59 (t, 2H, J=6.45), 7.90 (m, 1H), 8.20 (m, 1H), 8.39 (s, 1H), 8.80 (s, 1H); MS (DCI/NH3) m/z 261 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH:24]4[CH2:26][CH2:25]4)=[CH:22][C:21]([CH:27]4[CH2:29][CH2:28]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[S:30]1(=[O:37])(=[O:36])[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]1>>[CH:24]1([C:23]2[C:18]([N:15]3[CH2:16][CH2:17][N:12]([C:10]([C:5]4[CH:4]=[CH:3][C:2]([N:31]5[CH2:32][CH2:33][CH2:34][CH2:35][S:30]5(=[O:37])=[O:36])=[CH:9][C:6]=4[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]3)=[N:19][CH:20]=[C:21]([CH:27]3[CH2:29][CH2:28]3)[CH:22]=2)[CH2:26][CH2:25]1
Reactant: N#Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: O=S1(=O)CCCCN1
Product: N#Cc1cc(N2CCCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 86.7 %

Procedure:
Using 5-bromo-2-[4-(3,5-dicyclopropylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (451 mg) described in Preparation Example 245 and [1,2]thiazinane 1,1-dioxide (176 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (438 mg) was obtained.
Reaction SMILES: C(N(N=O)[C:9](=[O:38])[CH:10]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[N:11]1[C:15]2[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C:22]1[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)C1C=CC=CC=1.O.[OH-].[Li+].OO.C(O)(=[O:48])C>O1CCCC1.O>[CH:32]1([CH:10]([N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C:22]2[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:9]([OH:38])=[O:48])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CC(=O)O
Reactant: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)N(Cc2ccccc2)N=O)C2CCCCC2)c(OC)n1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)O)C2CCCCC2)c(OC)n1
Reaction time: 1 h

Procedure:
To a suspension of 12.1 g (22.02 mmol) N-benzyl-N-nitroso-2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetamide in 65 ml tetrahydrofuran and 15 ml water were added dropwise over 20 min. a solution of 9.24 g (220 mmol) lithium hydroxide monohydrate in 45 ml (440 mmol) hydrogen peroxide and 30 ml water. The reaction mixture turned into a turbid solution and a slight temperature raise was observed (cooled temporarily using an ice-bath). After 1 h the pH of the mixture was adjusted to pH 4 using acetic acid. The resulting light yellow solution was extracted three times with ethyl acetate. The combined organic layers were washed twice with saturated aqueous sodium bicarbonate solution, once with water and once with brine. The solution was dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in 200 ml tert-butyl methyl ether and partially evaporated until a precipitation formed. The suspension was cooled in the refrigerator for 30 min, then the solid was filtered off, washed with 50 ml ice-cold tert-butyl methyl ether and dried in high vacuum. White solid (99%). MS (Turbo Spray): m/z=432.2 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][N:6]=1)=[O:4].[H-].[Na+].[CH3:18][Si:19]([CH2:22][CH2:23][O:24][CH2:25]Cl)([CH3:21])[CH3:20]>C1COCC1.CCOC(C)=O>[C:10]1([C:8]2[N:7]([CH2:25][O:24][CH2:23][CH2:22][Si:19]([CH3:21])([CH3:20])[CH3:18])[N:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:9]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2ccccc2)n(COCC[Si](C)(C)C)n1
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of 5-phenyl-1H-pyrazole-3-carboxylic acid methyl ester (250 mg, 1.236 mmole) in THF (5 mL) was added NaH (60% dispersion in mineral oil, 60 mg, 1.500 mmole) portionwise at RT. After gas evolution had ceased SEMCl (0.263 mL, 1.484 mmol) was added. After stirring overnight the mixture was diluted with EtOAc, filtered through a pad of Celite washing with EtOAc, and concentrated. Flash column (Biotage-SNAP-25 g SiO2, 0-20% EtOAc/hexanes) gave methyl 5-phenyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-carboxylate (380 mg, 92%) as a clear oil. 1H NMR (399 MHz, CDCl3): δ 7.64 (dd, J=7.3, 1.9 Hz, 3 H); 7.46 (d, J=7.4 Hz, 3 H); 6.94 (s, 1 H); 5.49 (s, 2 H); 3.96 (s, 3 H); 3.80-3.71 (m, 3 H); 0.97-0.88 (m, 2 H); 0.02 (s, 9H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:28]([CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH3:29]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:29][CH2:28][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:19]1
Reactant: CC(I)C1CCCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCNC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCN(CCC4CCCCC4)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(3-piperidinyl)propyl]-9H-purin-6-amine and (1-iodoethyl)cyclohexane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[CH3:21][C:20]1[C:14]2[C:15](=[N:16][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:13]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Brc1ccccn1
Reactant: C#CCCn1nc2cccc(C)c2n1
Product: Cc1cccc2nn(CCC#Cc3ccccn3)nc12
Yield: 50 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (66 mg, 0.42 mmol) and 2-but-3-ynyl-4-methyl-2H-benzo[d][1,2,3]triazole (70 mg, 0.38 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 50 mg (0.19 mmol, 50%) of 4-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow semi-solid.