Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][NH:22][N:21]=1)=[CH:16][CH:15]=3.[CH2:30]([O:32][CH2:33]Cl)[CH3:31]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:33][O:32][CH2:30][CH3:31])[N:21]=1)=[CH:16][CH:15]=3
Reactant: CCOCCl
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4cc[nH]n4)ccc3n(C)c21
Product: CCOCn1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as in Example 36 above with the compound from Example 39, 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(1H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one and chloromethyl ethyl ether.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([I:10])=[C:8]([F:11])[CH:7]=[CH:6][C:5]=1[CH2:12]Br.[OH-].[NH4+:16]>C1COCC1>[F:11][C:8]1[C:9]([I:10])=[C:4]2[C:5]([CH2:12][NH:16][C:3]2=[O:2])=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: COC(=O)c1c(CBr)ccc(F)c1I
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1NCc2ccc(F)c(I)c21
Temperature: 100 °C
Reaction time: 2 h
Yield: 25.3 %

Procedure:
A solution of 2-bromomethyl-5-fluoro-6-iodo-benzoic acid methyl ester (0.373 g, 1.0 mmol), in THF (4 mL) was treated with 30% aq. Ammonium hydroxide (0.256 mL, 2.2 mmol) and heated with stirring at 100° C. for 2 h. After this time, the resulting mixture was concentrated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 6-fluoro-7-iodo-2,3-dihydro-isoindol-1-one (0.070 g, 25%). GC-MS: m/z 277 (M)+, 249 (M−28)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](Cl)=[O:13])[CH:10]=2)[N:5]=[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][N:3]12.O1CCOCC1.[NH3:25]>C(O)(=O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH2:25])=[O:13])[CH:10]=2)[N:5]=[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][N:3]12
Reactant: N
Reactant: O=C(Cl)c1ccc2nc3ccccn3c(=O)c2c1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: NC(=O)c1ccc2nc3ccccn3c(=O)c2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
10 gm of 11-oxo-11-H-pyrido[2,1-b]quinazoline-2-carboxylic acid chloride, prepared as in Example 12, were introduced into a mixture consisting of 200 ml of dioxane and 50 ml of concentrated ammonia, and the resulting mixture was stirred for 5 hours at room temperature. Thereafter, the reaction mixture was acidified with dilute acetic acid, and the crystals precipitated thereby were collected by suction filtration, yielding the compound of the formula ##STR22##
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5]1)[CH2:2][CH3:3].CN(C1C=CC=CN=1)C.[O:25]1[C:29]([C:30]2[S:34][C:33]([S:35](Cl)(=[O:37])=[O:36])=[CH:32][CH:31]=2)=[CH:28][CH:27]=[N:26]1>O1CCCC1>[CH2:1]([N:4]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][S:35]([C:33]3[S:34][C:30]([C:29]4[O:25][N:26]=[CH:27][CH:28]=4)=[CH:31][CH:32]=3)(=[O:36])=[O:37])=[CH:13][CH:14]=2)[CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCN1CC[C@@H](c2ccc(N)cc2)C1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccno2)s1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CCCN1CC[C@@H](c2ccc(NS(=O)(=O)c3ccc(-c4ccno4)s3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
4-((S)-1-Propyl-pyrrolidin-3-yl)-phenylamine (100 mg, 0.49 mmol) was dissolved in tetrahydrofuran (5 ml). Subsequently, dimethylaminopyridine (24 mg, 0.20 mmol) and 5-(5-isoxazyl)thiophene-2-sulfonyl chloride (159 mg, 0.64 mmol) were added and the reaction mixture stirred overnight at room temperature. The solvent was evaporated under reduced pressure, the residue treated with water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to give the crude product. The crude product was purified with silica gel chromatography with dichloromethane/methanol (100:0 to 96:4) as eluent, yielding the purified product (67 mg, 33%).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:33].[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[CH:37][CH:36]=1>C1COCC1>[N:41]1([C:38]2[CH:37]=[CH:36][C:35]([NH:34][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]6[N:24]([C:29]([CH3:31])([CH3:30])[CH3:32])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:33])=[CH:40][CH:39]=2)[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1
Reactant: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)n(C(C)(C)C)n1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCOCC4)cc3)cc2)n(C(C)(C)C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 4.9 %

Procedure:
A small screw cap test tube was charged with 2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 2.25 mmol) and THF (2 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (44 mg, 2.48 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 49% (67 mg, 0.111 mmol) of the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[CH3:34][N:35]1[CH:39]=[CH:38][N:37]=[C:36]1[Sn](CCCC)(CCCC)CCCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:33][S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH2:23][NH:22][C:20]([C:4]2[C:5](=[O:19])[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[C:7]([CH3:8])=[C:2]([C:36]3[N:35]([CH3:34])[CH:39]=[CH:38][N:37]=3)[CH:3]=2)=[O:21])=[CH:25][CH:26]=1)(=[O:32])=[O:31]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: Cc1c(-c2nccn2C)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 9.2 %

Procedure:
5-Iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoro-methyl)phenyl]1,2-dihydropyridine-3-carboxamide (0.06 g, 0.1 mmol), 1-methyl-2-tributylstannyl-1H-imidazole (0.11 g, 0.5 mmol, prepared according to literature procedures), Pd(PPh3)4 (0.015 g, 0.012 mmol), DME (2 ml) and a magnetic stirrer bar were placed in a vial. The suspension was degassed and the vial was sealed, and subsequently heated (100° C.) with stirring overnight. LC-MS confirmed the conversion of the iodide to the desired product, and the solvents were removed in vacuo. Purification on preparative HPLC afforded the title compound (0.005 g, 10%) as a white solid after freeze-drying the pure fractions.
Reaction SMILES: [F:1][C:2]1[C:3]([O:29][CH3:30])=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][N:21]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[CH:22]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[F:1][C:2]1[C:3]([O:29][CH3:30])=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][N:21]([CH:23]5[CH2:24][CH2:25][N:26]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:27][CH2:28]5)[CH:22]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COc1c(F)cc(F)cc1-c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(F)cc(F)cc1-c1c[nH]c2ncc(-c3cnn(C4CCN(S(C)(=O)=O)CC4)c3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 282 (100 mg, 0.244 mmol) in DCM was added triethylamine (49 mg, 0.4887 mmol). Methanesulfonyl chloride 335 (41 mg, 0.3665 mmol) was added to the reaction and stirred for 2 h at rt. The reaction mixture was diluted with dichloromethane and washed with water twice. The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified by flash column using 100-200 mesh silica gel. The compound was eluted at 2% methanol in chloroform as off white coloured solid 3-(3,5-difluoro-2-methoxyphenyl)-5-(1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H pyrrolo[2,3-b]pyridine 336. 1H NMR (400 MHz, DMSO) δ: 12.05 (s, 1H), 8.55 (d, 1H), 8.30 (s, 1H), 8.19 (d, 1H), 7.97 (s, 1H), 7.82 (d, 1H), 7.24 (m, 2H), 4.33 (m, 1H), 3.65 (d, 2H), 3.60 (s, 3H), 2.94, (m, 2H), 2.92 (s, 3H), 2.03 (m, 2H), 1.98 (m, 2H) and MS ES+488.0.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][C:9](=[O:11])[CH2:8][C:7](=[O:12])[CH2:6]1)[CH:2]([CH3:4])[CH3:3].[C:13]1([CH3:25])[CH:18]=[CH:17][C:16]([S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1>C1C=CC=CC=1>[CH2:1]([CH:5]1[CH2:6][C:7](=[O:12])[CH:8]([C:23](=[O:24])[NH:22][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:25])=[CH:14][CH:15]=2)(=[O:20])=[O:21])[C:9](=[O:11])[CH2:10]1)[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CC(C)CC1CC(=O)CC(=O)C1
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)C2C(=O)CC(CC(C)C)CC2=O)cc1

Procedure:
Reaction of equimolar amounts of 5-isobutyl-1,3-cyclohexanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-ISOBUTYL-2-(N-p-TOLUENESULFONYLCARBAMOYL)-1,3-CYCLOHEXANEDIONE, m.p. 128°-130° C. (corr.).
Reaction SMILES: [C:1]([NH:4][C:5](=[NH:7])[SH:6])(=[O:3])[CH3:2].[Cl:8][CH2:9][C:10](=O)[CH2:11]Cl.N1C=CC=CC=1>CC(C)=O>[Cl:8][CH2:9][C:10]1[N:7]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][CH:11]=1
Reactant: O=C(CCl)CCl
Reactant: CC(=O)NC(=N)S
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(=O)Nc1nc(CCl)cs1
Temperature: 25 °C
Yield: 50.5 %

Procedure:
N-(4-(chloromethyl)thiazol-2-yl)acetamide was prepared following a literature procedure (Silberg, A.; Frenkel, Z.; Bull. Soc. Chim. Fr.; 1967; 2235-2238). A suspension of 1-acetylisothiourea (3.55 g, 0.03 mol), 1,3-dichloropropan-2-one (3.8 g, 0.03 mol) and pyridine (1.96 g, 2 ml, 0.025 mol) in acetone (10 ml) was heated at 100 C in an oil bath for 20 minutes. A flocculent white solid formed. After cooling to room temperature, the reaction mixture was filtered to collect the white solid. The filtrate was evaporated, and the resulting residue was taken into water resulted in a white suspension which was stirred for a couple of minutes. The suspension was filtered. The collected solid was washed with water, dried under vacuum and combined with the above-mentioned white solid to give 2.89 g (51% yield) of N-(4-(chloromethyl)thiazol-2-yl)acetamide. LC/MS m/z 191.05, 193.05 (M+H)+); HPLC Rt: 1.71 min.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]3[CH:26]=[CH:25][C:20]4[NH:21][C:22](=[O:24])[O:23][C:19]=4[CH:18]=3)[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[BH-](OC(C)=O)(OC(C)=O)O[C:30](C)=O.[Na+].[OH-].[Na+]>CO>[CH3:30][N:10]([CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C@H:11]1[CH2:12][CH2:13][C@H:14]([C:17]2[CH:26]=[CH:25][C:20]3[NH:21][C:22](=[O:24])[O:23][C:19]=3[CH:18]=2)[CH2:15][CH2:16]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccccc4)CC3)cc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(CCCc1ccccc1)[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Reaction time: 3 h

Procedure:
To a stirred solution of 6-[trans-4-(3-phenylpropylamino)cyclohexyl]-3H-benzoxazol-2-one (263 mg, 0.750 mmol) in MeOH (10 mL) was added H2O (0.5 mL) and p-formaldehyde (113 mg, 3.75 mmol). After stirring the reaction mixture for 3 hours, NaBH(OAc)3 was added, and stirring was continued for 12 hours. Solid NaOH was added to give a clear solution, which was then concentrated under reduced pressure. Purification by flash chromatography (silica, 95:4:1 CH2Cl2:MeOH:NH4OH) gave 6-{trans-4-[methyl(3-phenylpropyl)-amino]cyclohexyl}-3H-benzoxazol-2-one (160 mg, 59%), as a white solid: mp 58-62° C.; IR (KBr): 2929, 1774 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 8.97 (br s, 1H), 7.26-7.12 (m, 6H), 6.99-6.98 (m, 2H), 2.63 (m, 2H), 2.57 (t, J=7 Hz, 2H), 2.56 (m, 1H), 2.38 (m, 2H), 2.18 (s, 3H), 1.78 (m, 2H), 1.68 (m, 2H), 1.37 (m, 2H), 1.27 (m, 2H); CI-MS (methane) (m/z): 365 [M+H]+; HRMS-API (m/z): [M+H]+ calcd for C23H28N2O2, 365.2229; found, 365.2231; HPLC: method A, 5.95 minutes (95.3%); method B, 10.12 minutes (97.6%); Anal. Calcd for C23H28N2O2.0.25H2O: C, 74.87; H, 7.79; N, 7.59. Found: C, 74.77; H, 7.71; N, 7.81.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9](Cl)=[O:10])=[CH:3][CH:2]=1.[CH3:12][NH:13][CH:14]1[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(Cl)Cl>[CH3:12][N:13]([CH:14]1[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]1)[C:9](=[O:10])[O:8][CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: CNC1CCNC(=O)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)C1CCNC(=O)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 27 %

Procedure:
Cbz-Cl (7.2 ml, 21.259 mol, 1.5 eq., 50% solution in toluene) was added at 0° C. to a mixture of 4-(methylamino)piperidin-2-one (1.814 g, 14.173 mmol, 1.0 eq.) and K2CO3 (3.91 g, 28.346 mmol, 2.0 eq.) in THF (50 ml) and the mixture was stirred for 14 hours at RT. After monitoring by TLC, the reaction mixture was diluted with DCM (300 ml), washed with water and saturated NaCl solution (in each case 150 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Alox, 1% MeOH in DCM). Yield: 27% (1.0 g, 3.82 mmol)
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:13]([CH3:25])[C:12]=2[CH3:26])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].O.Cl>CO>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:9][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[C:12]([CH3:26])[C:13]=1[CH3:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C1(COc2ccc(OCc3ccccc3)c(C)c2C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(OCc2ccccc2)ccc(OCC2(C(=O)O)CC2)c1C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of the ester prepared as above (0.78 g) in MeOH (20 mL), was added NaOH solution (10% wt, 3 mL) and water (2 mL). After stirring the solution at 50° C. for 4 h it was poured into water, and diluted HCl solution was added to adjust pH to 3. The mixture was partitioned between EtOAc and water, and the organic layer was washed with water, dried over MgSO4 and evaporated. The residue was purified by silica gel column eluting with 40% EtOAc in hexane to give 0.6 g of 1-(4-benzyloxy-2,3-dimethyl-phenoxymethyl)-cyclopropanecarboxylic acid as a pale solid.
Reaction SMILES: CN(C=O)C.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[C:15](=O)[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>O>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]2[O:6][C:25]([C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[C:15]([CH3:16])[C:8]=2[CH:9]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: COc1ccc(O)c(C(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2oc(C(=O)C(C)(C)C)c(C)c2c1
Temperature: 85 °C

Procedure:
DMF (4 mL) was added to a mixture of 166 mg 1-(2-hydroxy-5-methoxyphenyl)ethanone and 370 mg cesium carbonate followed by 188 mg 1-bromopinacolone. After heating this mixture in an 85° C. oil bath for 3 hours, it was poured into cold water and extracted with ether. The combined ether extract was washed with water, 1.5 N NaOH, water, and saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product. It was purified on silica gel (9:1 hexanes and EtOAc) to give the title compound as a colorless solid. 1H NMR (CDCl3, 500 MHz) δ 7.41 (d, J=9.0 Hz, 1H), 7.11 (dd, J=2.5 & 9.0 Hz, 1H), 7.04 (d, J=2.5 Hz, 1H), 3.90 (s, 3H), 2.59 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH:18][CH2:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)=[CH:16][CH:15]=[N:14]1.[F:26][C:27]([F:31])([F:30])[S:28]Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[C:17]([NH:18][CH2:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)=[C:16]([S:28][C:27]([F:31])([F:30])[F:26])[CH:15]=[N:14]1
Reactant: FC(F)(F)c1cc(Cl)c(-n2nccc2NCc2cnccn2)c(Cl)c1
Reactant: FC(F)(F)SCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)Sc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1NCc1cnccn1
Reaction time: 8 h

Procedure:
To a solution of 3.0 g of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(pyrazin-2-ylmethylamino)pyrazole dissolved in 30 ml of dried methylene chloride under a nitrogen atmosphere was added 14 ml of dried methylene chloride solution of trifluoromethylsulfenyl chloride at room temperature over about 1 hour, followed by stirring overnight. Saturated aqueous sodium hydrogen carbonate solution was added thereto, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and water several times. Thereafter, the layer was purified by a silica gel column chromatography. After removal of solvent, drying in vacuo afforded 3.59 g of 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfenyl-5-(pyrazin-2-ylmethylamino)pyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=O)[CH2:9]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:9]1
Reactant: Cc1ccnc2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Yield: 156.7 %

Procedure:
A mixture of 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.20 g), aminoguanidine hydrochloride (0.085 g), concentrated hydrochloric acid (0.11 ml), water (0.11 ml) and ethanol (20 ml) was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The mixture was washed with ethyl acetate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-ethanol to give 7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 61) (0.21 g) as colorless crystals.
Reaction SMILES: [C:1]1([C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=3)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1(=[O:26])[NH:24][C:23](=[O:25])[CH:22]=[CH:21]1>>[CH3:19][O:18][C:14]1[CH:13]=[CH:12][C:11]2[NH:10][C:9]3[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:8][C:22]4[C:23](=[O:25])[NH:24][C:20](=[O:26])[C:21]=4[C:17]=3[C:16]=2[CH:15]=1
Reactant: O=C1C=CC(=O)N1
Reactant: C=C(c1ccccc1)c1cc2cc(OC)ccc2[nH]1
Product: COc1ccc2[nH]c3c(-c4ccccc4)cc4c(c3c2c1)C(=O)NC4=O
Yield: 73 %

Procedure:
Reaction of (818) prepared as described in example 418 with maleimide at 180° C. using the procedure described in example 69 gave the adduct (XCVIII; R=phenyl, R′═H) (819), which was used without further purification. The crude Diels-Alder adduct was aromatised with MnO2 using the procedure described in example 79 to give (820) (73%), mp 281–285° C. 1H NMR δ [(CD3)2SO] 11.63 (br s, 1H), 11.15 (br s, 1H), 8.45 (d, J=2.5 Hz, 1H), 7.78–7.76 (m, 2H), 7.68 (s, 1H), 7.65–7.62 (m, 2H), 7.57–7.53 (m, 2H), 7.22 (dd, J=8.8, 2.5 Hz, 1H), 3.89 (s, 3H). Found: C, 72.06; H, 4.57; N, 7.69. C21H14N2O3.1/3H2O requires: C, 72.41; H, 4.24; N, 8.04.
Reaction SMILES: [OH:1][C:2]1[N:14]2[C:5]([C:6]3[CH:7]=[C:8]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:9]([C:15]4[CH:20]=[CH:19][C:18]([C:21]5([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)=[N:10][C:11]=3[CH:12]=[CH:13]2)=[N:4][N:3]=1.Br[CH2:40][CH3:41]>[Ag]=O.CN1C(=O)CCC1>[CH2:40]([O:1][C:2]1[N:14]2[C:5]([C:6]3[CH:7]=[C:8]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:9]([C:15]4[CH:16]=[CH:17][C:18]([C:21]5([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:24][CH2:23][CH2:22]5)=[CH:19][CH:20]=4)=[N:10][C:11]=3[CH:12]=[CH:13]2)=[N:4][N:3]=1)[CH3:41]
Reactant: CCBr
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccn5c(O)nnc5c4cc3-c3ccccc3)cc2)CCC1
Agent: O=[Ag]
Solvent: CN1CCCC1=O
Product: CCOc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)nc3ccn12
Temperature: 80 °C

Procedure:
To a microwave vial was added tert-butyl {1-[4-(3-hydroxy-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (1-5e) (113 mg, 0.223 mmol), silver oxide (310 mg, 1.336 mmol), bromoethane (0.062 mL, 0.826 mmol), and finally NMP (1 mL). The reaction mixture was then heated to 80° C. under microwave irradiation for 10 minutes. Upon completion the reaction mixture was filtered and then purified by reverse phase column chromatography (Sunfire C18) eluting with 20 to 100% acetonitrile/(0.1% TFA/water) gradient. The appropriate fractions were then combined, suspended in ethyl acetate, washed with a saturated solution of sodium bicarbonate, water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give tert-butyl {1-[4-(3-ethoxy-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (9-1) as a tan solid. MS (M+H)+: observed=536.4, calculated=536.64.
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: COC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: C[Si](C)(C)CCOCCl
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).