Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:6]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: Cc1ncc(C(CN)N2CCOCC2)cn1
Product: Cc1ncc(C(CNC(=O)c2c(Cl)cccc2Cl)N2CCOCC2)cn1

Procedure:
From 2,6-dichlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-morpholinoethanamine.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[S:10][C:11]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([S:26]([CH3:28])=[O:27])[N:21]=2)=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1>O1CCCC1.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9]2[S:10][C:11]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([S:26]([CH3:28])=[O:27])[N:21]=3)=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)[CH2:4][CH2:3]1
Reactant: CS(=O)c1nccc(-c2sc(Cl)nc2-c2ccccc2)n1
Reactant: CN1CCNCC1
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2nc(-c3ccccc3)c(-c3ccnc(S(C)=O)n3)s2)CC1
Temperature: 25 °C

Procedure:
A solution of N-methylpiperazine (0.6 g, 6.0 mmol) in tetrahydrofuran (5 ml) is added to a well stirred solution of 4-(2-chloro-4-phenyl-thiazol-5-yl)-2-methylsulfinyl-pyrimidine (1.0 g, 3.0 mmol) in tetrahydrofuran (20 ml) at +5° C. The reaction mixture is allowed to warm to room temperature over night. Evaporation of the solvent leaves a crystalline residue that is suspended in water, filtered with suction, washed with diethyl ether and dried under vacuum. The product 4-[2-(4-methylpiperazin-1-yl)-4-phenyl-thiazol-5-yl]-2-methylsulfinyl-pyrimidine shows a m.p. of 166–169° C.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([S:15]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:17])=[O:16])[CH:9]=[CH:8]2)(=O)C.C(O)CC.[ClH:30]>O>[ClH:30].[NH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([S:15]([NH:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:17])=[O:16])[CH:9]=[CH:8]2
Reactant: CC(=O)Nc1ccc2cc(S(=O)(=O)NCc3ccccc3)ccc2c1
Agent: Cl
Solvent: CCCO
Solvent: O
Product: Nc1ccc2cc(S(=O)(=O)NCc3ccccc3)ccc2c1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
6-Acetylamino-N-benzylnaphthalene-2-sulfonamide (compound No. 9-1; 185 mg, 0.522 mmol) was suspended to a mixed solvent of 1-propanol (3.0 ml) and water (1.5 ml). Concentrated hydrochloric acid (1.5 ml) was added to the suspension and the mixture was refluxed for 1 hour. After cooling to room temperature, the separated crystal was collected and washed with 1-propanol and isopropyl ether to give the title compound as a light yellow crystal (135 mg, 74.2%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46](=[O:53])[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.Cl[C:56]([O:58][CH3:59])=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46]([N:47]1[CH2:52][CH2:51][N:50]([C:56]([O:58][CH3:59])=[O:57])[CH2:49][CH2:48]1)=[O:53]
Reactant: COC(=O)Cl
Reactant: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1CCN(C(=O)COc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and methyl chloroformate as the starting materials in 60% yield. LCMS for C25H27ClN7O4 (M+H)+: m/z=524.1.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([NH:13][C:14]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[S:16][C:15]=1[C:23]([O:25]C)=O)([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[C-]#N.[Na+].O>CO>[CH3:1][NH:2][C:23]([C:15]1[S:16][C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:18][C:14]=1[NH:13][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])=[O:25]
Reactant: COC(=O)c1sc(C(C)(C)C)cc1NC(=O)OCc1ccccc1
Reactant: CN
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNC(=O)c1sc(C(C)(C)C)cc1NC(=O)OCc1ccccc1
Temperature: 50 °C
Yield: 20 %

Procedure:
To a saturated solution of methylamine in MeOH (200 mL) in a screw top vessel was added methyl 3-(N-carbobenzyloxyamino)-5-tert-butylthiophene-2-carboxylate (13.6 g, 39.2 mmol) and NaCN (0.98 g, 20 mmol). The vessel was sealed and the reaction mixture was heated to 50° C. for 8 h. The resulting solution was poured into water (500 mL) and extracted with EtOAc. The organic layer was washed with water and a concentrated NaCl solution, dried (Na2SO4), and concentrated under reduced pressure. The crude material was purified by flash chromatography (EtOAc/hexane) affording N-methyl-3-(N-carbobenzyloxyamino)-5-tert-butylthiophene-2-carboxamide (2.76 g, 20%).
Reaction SMILES: [C:1]12([S:11](Cl)(=[O:13])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17]1>>[C:23]1([CH2:22][CH2:21][N:18]2[CH2:19][CH2:20][C@H:16]([NH:15][S:11]([C:1]34[CH2:10][CH:5]5[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]5)[CH2:2]3)[CH2:8]4)(=[O:13])=[O:12])[CH2:17]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Reactant: O=S(=O)(Cl)C12CC3CC(CC(C3)C1)C2
Product: O=S(=O)(N[C@H]1CCN(CCc2ccccc2)C1)C12CC3CC(CC(C3)C1)C2

Procedure:
1-Adamantanesulfonyl chloride and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-1-adamantanesulfonamide.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:24])[NH:9][C@@H:10]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:13]=2[O:12][C@@H:11]1[CH3:23])([CH3:6])([CH3:5])[CH3:4].[CH2:25](Br)[CH:26]=[CH2:27]>CN(C)C=O>[C:3]([O:7][C:8](=[O:24])[NH:9][C@@H:10]1[C:16](=[O:17])[N:15]([CH2:27][CH:26]=[CH2:25])[C:14]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:13]=2[O:12][C@@H:11]1[CH3:23])([CH3:6])([CH3:4])[CH3:5]
Reactant: C[C@H]1Oc2ccc(F)cc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)Oc2ccc(F)cc21
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a suspension of 0.28 g (6.44 mmol) sodium hydride in 40 ml dimethylformamide were added at 0° C. 2.0 g (6.44 mmol) ((6R,7S)-2-fluoro-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester in 20 ml dimethylformamide. After 30 minutes 0.55 ml (6.44 mmol) allyl bromide was added. Stirring was continued for 3 hours. Extraction with ethylacetate/water and chromatography on silicagel with heptane to ethylacetate/heptane 1:1 yielded 2.24 g (99%) ((6R,7S)-9-allyl-2-fluoro-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester, MS m/e (%): 351.2 (M+H+, 80), 295.3 (100), 251.1 (82).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2.[OH:14]O.O>C(O)(=O)C.OS(O)(=O)=O>[Cl:11][C:10]1[C:2]([Cl:1])=[C:3]2[C:4]([O:12][C:5](=[O:14])[NH:6][C:7]2=[CH:8][CH:9]=1)=[O:13]
Reactant: OO
Reactant: O=C1Nc2ccc(Cl)c(Cl)c2C1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(Cl)c(Cl)c2c(=O)o1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 89.6 %

Procedure:
To a suspension of 4,5-dichloroisatin (13f, 216 mg, 1.0 mmol) in glacial acetic acid (5 mL) and 2 drops (about 0.02 mL) of conc H2SO4 was added 0.34 mL (about 3 mmol) of 30% H2O2. The mixture was stirred at 70° C. (bath) for 2.5 h (the mixture turned into a solution, then formed a precipitate), allowed to cool to 22° C. and cold water (10 mL) was added. The precipitate was filtered, washed with water (6×10 mL), dried to give 208 mg (90%) of 14e as an orange-yellow powder, mp 267°-9° C. (dec). IR, 1810, 1779, 1762, 1711, 1600, 1335, 1254, 1041, 1024 cm-1 ; 1H NMR δ 11.952 (bs, 1H), 7.928 (d, J=8.7 Hz, 1H), 7.110 (d, J=8.7Hz, 1H); HRMS Calcd for C8H3Cl2NO3 : 230.9490; Found: 230.9489.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C@@H:10]2[CH2:15][CH:14]=[CH:13][CH2:12][C@H:11]2[N+:16]([O-:18])=[O:17])[CH:7]=[CH:6][C:5]=1[O:19][CH3:20])[CH3:2].[OH-].[K+].S(=O)(=O)(O)O>C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C@@H:10]2[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]2[N+:16]([O-:18])=[O:17])[CH:7]=[CH:6][C:5]=1[O:19][CH3:20])[CH3:2]
Reactant: CCOc1cc([C@@H]2CC=CC[C@H]2[N+](=O)[O-])ccc1OC
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cc([C@@H]2CC=CC[C@@H]2[N+](=O)[O-])ccc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
89.25 g of (+/-)-trans-2-ethoxy-1-methoxy-4-(2-nitrocyclohex-4-enyl)benzene (compound D1) and 37 g of potassium hydroxide are dissolved in 500 ml of absolute ethanol. A solution of 23.5 ml of conc. sulfuric acid in 120 ml of absolute ethanol is then added dropwise such that the internal temperature does not exceed -2° C. After stirring for 1 h, the mixture is added to 4 l of ice water, and the precipitate is filtered off with suction, washed with water and dried. M.p.: 66-67° C.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][N:28]([CH3:33])[S:29](Cl)(=[O:31])=[O:30]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][S:29]([N:28]([CH3:33])[CH3:27])(=[O:31])=[O:30])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CN(C)S(=O)(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, light yellow solid (19 mg, 17%), MS (ISP) m/z=436.3 [(M+H)+], mp 122° C., was prepared in accordance with the general method of example 47 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and dimethylsulfamoylchloride.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[CH:20]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)=[CH2:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:18][CH:17]([CH3:19])[CH2:16][N:15]1[C:5]2[C:4]3[CH:3]=[C:2]([CH:21]=[CH:20][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=[CH:14]1
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)Cn1cnc2c(N)nc3ccc(C=Cc4ccncc4)cc3c21
Temperature: 100 °C
Yield: 65.1 %

Procedure:
Nitrogen was bubbled through a solution of 8-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-amine (3.0 g, 9.4 mmol), 4-vinylpyridine (2.0 mL, 19 mmol), triphenylphosphine (246 mg, 0.94 mmol), and triethylamine (2.7 mL, 19 mmol) in acetonitrile (50 mL) for 15 minutes. Palladium (II) acetate (105 mg, 0.47 mmol) was added, and the reaction was heated at 100° C. for three days. The solvent was removed under reduced pressure, and the residue was adjusted to pH 2 with the addition of concentrated hydrochloric acid. Water was added, and the mixture was filtered through a layer of CELITE filter aid. Aqueous sodium carbonate (2 N) was added to the filtrate to adjust the solution to pH 10. The solution was then extracted with dichloromethane, and the combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 95:5 to 80:20) to provide 2.1 g of 1-(2-methylpropyl)-8-(2-pyridin-4-ylvinyl)-1H-imidazo[4,5-c]-quinolin-4-amine as a yellow solid.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17](B(O)O)=[CH:18]4)=[CH:13][C:12]=3[O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:31][C:32]1[CH:41]=[C:40](I)[CH:39]=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35]>>[OH:31][C:32]1[CH:41]=[C:40]([C:17]2[CH:16]=[CH:15][C:14]3[C:19](=[CH:20][C:11]([C:1]45[CH2:10][CH:5]6[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]6)[CH2:8]4)[CH2:2]5)=[C:12]([O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:13]=3)[CH:18]=2)[CH:39]=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35]
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: COCCOCOc1cc2ccc(B(O)O)cc2cc1C12CC3CC(CC(C3)C1)C2
Product: COCCOCOc1cc2ccc(-c3ccc(C(=O)OC)c(O)c3)cc2cc1C12CC3CC(CC(C3)C1)C2
Yield: 81.3 %

Procedure:
Following the procedure of Example 1(c), but reacting 2.25 g (5.5 mmol) of 7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthylboronic acid with 1.39 g (5 mmol) of methyl 2-hydroxy-4-iodobenzoate, 2.1 g (81%) of the expected ester were obtained, which ester had a melting point of 101°-2° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:37]=[CH:36][CH:35]=[CH:34][C:26]=1[C:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[O:28]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([C:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[O:28])=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CCN(CC)C(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CCN(CC)C(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 2-bromo-N,N-diethylbenzamide. MS (ESI): mass calcd. for C21H21FN4O, 364.17; m/z found, 365.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.59-8.54 (m, 1H), 8.11 (d, J=1.5, 1H), 8.00-7.90 (m, 1H), 7.50-7.36 (m, 5H), 7.36-7.29 (m, 1H), 4.69 (s, 2H), 3.87-3.69 (m, 1H), 3.17-2.92 (m, 2H), 2.85-2.66 (m, 1H), 0.99 (t, J=7.1, 3H), 0.81 (t, J=7.1, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][CH:14]=2)=[N:3]1.S(Cl)([Cl:24])=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1([CH3:21])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][Cl:24])=[CH:15][CH:14]=2)=[N:3]1
Reactant: CC1(C)COC(c2ccccc2-c2ccc(CO)cc2)=N1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)COC(c2ccccc2-c2ccc(CCl)cc2)=N1
Reaction time: 1 h
Yield: 98.7 %

Procedure:
1.0 g (3.55 mmol) of 4,4-dimethyl-2-(4'-hydroxymethylbiphenyl-2-yl)oxazoline was dissolved in methylene chloride (15 ml). Under cooling with ice, 0.51 g (4.29 mmol) of thionyl chloride was dropwise added thereto, followed by stirring for one hour. The reaction liquid was poured into an aqueous solution of sodium hydrogencarbonate, followed by the extraction with methylene chloride. After washing with water and drying, vacuum concentration was conducted. 1.05 g of the title compound was obtained as a crystal (yield 99%). m.p.; 72°-75° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Li])CCC.[CH3:14][C:15](N(C)C)=[O:16].[Cl-].[NH4+]>CCOCC.O>[C:15]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1)(=[O:16])[CH3:14]
Reactant: Brc1cccc(Br)n1
Reactant: CC(=O)N(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CC(=O)c1cccc(Br)n1
Temperature: -60 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A 5 L 3-neck flask was charged with 2,6-dibromopyridine (181 g; 0.75 mole) and 2.0 L ether. The suspension was stirred under nitrogen at -60° C. and then n-butyllithium (300 mL; 2.5M) was added from a pressure equalizing dropping funnel over 20 minutes. The bath was lowered and the near solution was allowed to warm to -50° C. After 15 minutes, the dark yellow solution was re-cooled to -78° C. in a dry ice/ether bath and dimethylacetamide (70 g; 0.86 mole) in 70 mL ether was added at such a rate that the temperature did not exceed -75° C. The addition took about one hour for completion, after which the bath was removed to allow the reaction to warm to -60° C. A solution of ammonium chloride (50 g; 0.93 mole) in 150 mL of H2O was added dropwise over 10 minutes under nitrogen and the temperature rose to -40° C. The mixture was stirred for 45 minutes and the layers were separated. The aqueous layer was back-extracted with 500 mL ether and the pooled organic layers were washed twice with H20 and once with saturated salt solution. The organic layer was dried over MgSO4 and, after evaporating to dryness, gave 150 g of yellow oil. This material, after pooling with another run of the same scale, was kugelrohred at 80° C./0.1 mm Hg to give 257 g (86%) of a near colorless oil that crystallized readily on cooling; silica gel TLC system: 90 hexane: 10 ether.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][C:10]#[N:11].[H-].[Na+].[CH3:15][C:16]1[N:21]=[C:20](Cl)[C:19]([CH3:23])=[C:18]([Cl:24])[N:17]=1>C1COCC1>[Cl:24][C:18]1[N:17]=[C:16]([CH3:15])[N:21]=[C:20]([CH:9]([C:2]2[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=2[CH3:12])[C:10]#[N:11])[C:19]=1[CH3:23]
Reactant: Cc1nc(Cl)c(C)c(Cl)n1
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(C(C#N)c2nc(C)nc(Cl)c2C)c(C)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 106.3 %

Procedure:
To a solution of mesitylacetonitrile (0.900 g, 5.65 mmol) in 8 ml dry THF was added sodium hydride (60% in oil, 0.250 g, 6.21 mmol) and the mixture was stirred at room temperature for 40 minutes. 2,5-Dimethyl-4,6-dichloropyrimidine (1.000 g, 5.65 mmol) was added and the resulting mixture was heated at reflux for 5 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 1.800 g of a yellow oil. The oil residue was purified through silica gel column chromatography using 10% ethyl acetate in hexane as eluent to give 0.986 g (58.3%) of the title compound as a white solid, mp 100–102° C. 1H NMR (CDCl3) δ 6.86 (s, 2H), 5.60 (s, 1H), 2.69 (s, 3H), 2.25 (s, 3H), 2.18 (s, 6H), 1.92 (s, 3H) ppm.
Reaction SMILES: C(O[C:6]([N:8]1[C:13](=[O:14])[CH:12]2[CH:10]([CH:11]2[C:15]([O-:17])=[O:16])[CH:9]1[C:18]([O-:20])=[O:19])=O)(C)(C)C.C[NH2:22]>C1COCC1.[C-]#N.[K+]>[C:15]([CH:11]1[CH:12]([C:13]([NH:8][CH3:6])=[O:14])[CH:10]1[CH:9]([C:18]([OH:20])=[O:19])[NH2:22])([OH:17])=[O:16]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C(C(=O)[O-])C2C1C(=O)[O-]
Reactant: CN
Agent: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)C1C(C(=O)O)C1C(N)C(=O)O
Reaction time: 8 h
Yield: 139.8 %

Procedure:
To a solution of ethyl (1SR, 2 SR, 5RS, 6RS) 3-tert-butoxycarbonyl-4-oxo-3-azabicyclo[3.1.0]hexane-2,6-dicarboxylate (312 mg, 0.9 mmol) in dry THF (6 mL) under argon was added methylamine (2.74 mL, 5.4 mmol) and potassium cyanide (3 mg, 0.05 mmol). After stirring overnight in an ultrasonic bath, the solvent was removed under reduced pressure. The residue was directly purified by flash chromatography (hexane/ethyl acetate 1/1) to give 272 mg of the desired compound (80% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:23][C:22]2[C:21]3[CH:24]=[C:25]([C:28]#[N:29])[CH:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=1.C([O-])([O-])=[O:31].[K+].[K+].OO>CS(C)=O.CO>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:23][C:22]2[C:21]3[CH:24]=[C:25]([C:28]([NH2:29])=[O:31])[CH:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=1
Reactant: N#Cc1ccc2c(c1)-c1sc(-c3nncn3-c3ccc(F)cc3Cl)cc1CCO2
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Product: NC(=O)c1ccc2c(c1)-c1sc(-c3nncn3-c3ccc(F)cc3Cl)cc1CCO2
Yield: 88.6 %

Procedure:
To a stirred solution of 2-[4-(2-chloro-4-fluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carbonitrile (90 mg; 0.21 mmol) in DMSO (3 ml) and MeOH (5 ml) was added K2CO3 (36 mg; 0.26 mmol) then H2O2 (30 μl of a 30% aqueous soln.). The reaction mixture was stirred at room temperature overnight (16 h) upon which time the methanol was removed on a rotary evaporator and the residue was diluted with water (40 ml). The resulting solid was collected by filtration, washed with water and dried to give 281 as a white solid (82 mg; 89%). δH (400 MHz, CDCl3) 3.15 (t, J=5.2, 2H), 4.34 (t, J=5.2, 2H), 5.50-6.30 (br s, 2H), 6.88 (s, 1H), 7.07 (d, J=8.4, 1H), 7.22-7.27 (m, 1H), 7.42-7.63 (m, 3H), 8.06 (d, J=2.0, 1H), 8.22 (s, 1H). [M+H]+: 441
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[O:11]=[CH:12][C:13]1[CH:21]=[CH:20][C:18]([OH:19])=[C:15]([O:16][CH3:17])[CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:19][C:18]2[CH:20]=[CH:21][C:13]([CH:12]=[O:11])=[CH:14][C:15]=2[O:16][CH3:17])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1Oc1cc(Cl)ccc1C#N
Yield: 87.3 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.60 g, 3.9 mmol), vanillin (0.59 g, 3.9 mmol) and cesium carbonate (1.26 g, 3.9 mmol) were heated with stirring in dry DMF (4 ml) at 50° C. for 22 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water, 10% aqueous sodium carbonate (2×), water (2×), brine, and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(4-formyl-2-methoxy-phenoxy)-benzonitrile (0.98 g, 88%) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH:24]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:29][CH2:30][C:31]([NH:1][C:2]2[C:3]([C:7]3[NH:23][C:10]4=[CH:11][C:12]5[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=5[CH:17]=[C:9]4[N:8]=3)=[N:4][NH:5][CH:6]=2)=[O:32])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)CCC1CCCC1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)CCC4CCCC4)nc3cc21

Procedure:
3-Cyclopentyl-N-[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-propionamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and cyclopentylpropionyl chloride (136 ml, 0.89 mmol. The title compound was obtained as brown powder (177 mg, 50%).