Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([NH:15][NH2:16])=[O:14].[CH:21](OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]1[O:14][CH:21]=[N:16][N:15]=1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(=O)NN)c1Cl
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1ccc(Cl)c(Nc2ccccc2-c2nnco2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a room temperature suspension of 2-[(2,6-dichloro-3-methylphenyl)amino]-benzoic acid hydrazide (355.1 mg, 1.15 mmoles) in 6 ml of ethanol is added 2 ml of triethyl orthoformate followed by p-toluenesulfonic acid (20 mg, 0.11 mmoles). After stirring at room temperature overnight, the clear yellow solution is concentrated in vacuo. The residue is subjected to flash chromatography eluting with hexane:ethyl acetate (3:1). Subsequent recrystallization from ethanol yields 244.1 mg (67%) of 2,6-dichloro-3-methyl-N-[2-(1,3,4-oxadiazol-2-yl)phenyl]benzenamine, mp 180°-181° C.
Reaction SMILES: C[O:2][CH2:3][C:4](=[O:13])[CH2:5][C:6](=[O:12])[C:7]([O:9][CH2:10]C)=O.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]2[N:30]([CH2:29][C:28]3[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[C:3](=[O:2])[C:4]([OH:13])=[C:5]2[C:6](=[O:12])[CH2:7][O:9][CH3:10])=[CH:17][CH:16]=1
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(=O)C(=O)CC(=O)COC
Reactant: O=Cc1ccc(Cl)cc1
Product: COCC(=O)C1=C(O)C(=O)N(Cc2ccc(OC)cc2)C1c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
The title compound was prepared using an analogous procedure to that described in Step 57.1 but using equimolar amounts of ethyl 5-methoxy-2,4-dioxopentanoate (Step 130.1), 4-chlorobenzaldehyde, and 4-methoxybenzylamine. The reaction mixture was stirred for 2 h at 120° C. and allowed to cool to rt. The precipitate was collected by filtration to provide the title compound (5.21 g) as a colorless solid. tR: 0.94 min (LC-MS 2); ESI-MS: 402.1 [M+H]+ (LC-MS 2).
Reaction SMILES: [CH:1]([O:14][C:15]1[C:16](=[O:43])[N:17]=[C:18]([S:22][CH:23]2[C:28]([CH3:29])=[C:27]([C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])=[O:31])[N:26]3[C:36](=[O:40])[C@H:37]([O:38][CH3:39])[C@H:25]3[S:24]2(=[O:42])=[O:41])[N:19]([CH3:21])[N:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:51](Br)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>C(#N)C.ClCCl>[CH:1]([O:14][C:15]1[C:16](=[O:43])[N:17]=[C:18]([S:22][C:23]2([CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:28]([CH3:29])=[C:27]([C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])=[O:31])[N:26]3[C:36](=[O:40])[C@H:37]([O:38][CH3:39])[C@H:25]3[S:24]2(=[O:41])=[O:42])[N:19]([CH3:21])[N:20]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1C(=O)N2C(C(=O)C(C)(C)C)=C(C)C(Sc3nc(=O)c(OC(c4ccccc4)c4ccccc4)nn3C)S(=O)(=O)[C@H]12
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: CO[C@H]1C(=O)N2C(C(=O)C(C)(C)C)=C(C)C(Cc3ccccc3)(Sc3nc(=O)c(OC(c4ccccc4)c4ccccc4)nn3C)S(=O)(=O)[C@H]12
Reaction time: 4 h

Procedure:
A solution of 2-(6-benzhydryloxy-2-methyl-5-oxo-2,5-dihydro-1,2,4-triazin-3-yl)thio-4-tert-butylcarbonyl-7α-methoxy-3-methyl-3-cephem 1,1-dioxide (300 mg) in acetonitrile (5 ml) was treated at room temperature with triethylamine (0.067 ml) and benzyl bromide (0.172 ml). After 4 hr, the reaction mixture was diluted with dichloromethane, washed with brine and dried over Na2SO4. The solvent was then removed and the residue purified by flash chromatography, thereby obtaining the title compound as a white solid (180 mg).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH2:20][O:21][C:22]4[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=4[CH:24]=3)(=[O:18])=[O:17])[CH2:12][C:11]2=[O:30])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(N(CC)CC)C.[C:40](Cl)(=[O:43])[O:41][CH3:42]>ClCCl>[Cl:29][C:27]1[CH:26]=[CH:25][C:23]2[CH:24]=[C:19]([S:16]([N:13]3[CH2:14][CH2:15][N:10]([CH2:9][C:8]4[CH:7]=[CH:6][C:5]([C:2](=[NH:3])[NH:4][C:40]([O:41][CH3:42])=[O:43])=[CH:32][CH:31]=4)[C:11](=[O:30])[CH2:12]3)(=[O:18])=[O:17])[CH2:20][O:21][C:22]=2[CH:28]=1
Reactant: COC(=O)Cl
Reactant: N=C(N)c1ccc(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NC(=N)c1ccc(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 1-(4-amidinobenzyl)-4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-piperazinone hydrochloride (99 mg) and triethylamine (0.084 ml) in dichloromethane (10 ml) was added dropwise a solution of methyl chlorocarbonate (0.023 g) in dichloromethane (2 ml) at 0° C., and the mixture was stirred at 0° C. for 1 hour. The reaction solution was diluted with dichloromethane, washed with sodium bicarbonate solution and saturated brine, dried (MgSO4) and concentrated. Precipitated crystals were washed with ether to give colorless crystals of the title compound (95 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[CH:16]=[C:17]([F:25])[C:18]([C:20](OCC)=[O:21])=[CH:19][C:12]=2[N:11]=1.C[Al](C)C.[CH3:30][C:31]1[C:36]([CH3:37])=[CH:35][N:34]=[C:33]([NH2:38])[CH:32]=1>CCCCCC.C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[CH:16]=[C:17]([F:25])[C:18]([C:20]([NH:38][C:33]3[CH:32]=[C:31]([CH3:30])[C:36]([CH3:37])=[CH:35][N:34]=3)=[O:21])=[CH:19][C:12]=2[N:11]=1
Reactant: Cc1cnc(N)cc1C
Reactant: CCOC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)n(C)c2cc1F
Agent: C[Al](C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cnc(NC(=O)c2cc3nc(Nc4c(Cl)cccc4Cl)n(C)c3cc2F)cc1C

Procedure:
Prepared analogously to example 131f from ethyl 2-(2,6-dichlorophenylamino)-6-fluoro-1-methyl-1H-benzimidazole-5-carboxylate, 2 M trimethyl aluminium solution in hexane and 4,5-dimethylpyridin-2-amine in THF.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C:7]1[N:8]([CH3:21])[C:9]2[C:14]([C:15]=1[C:16](O)=[O:17])=[CH:13][CH:12]=[C:11]([O:19][CH3:20])[CH:10]=2)[CH3:6].[CH3:22][NH2:23]>>[CH3:22][NH:23][C:16]([C:15]1[C:14]2[C:9](=[CH:10][C:11]([O:19][CH3:20])=[CH:12][CH:13]=2)[N:8]([CH3:21])[C:7]=1[CH2:5][CH3:6])=[O:17]
Reactant: CCc1c(C(=O)O)c2ccc(OC)cc2n1C
Reactant: CN
Solvent: O=S(Cl)Cl
Product: CCc1c(C(=O)NC)c2ccc(OC)cc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
Thionyl chloride (0.383 ml, 4.45 mmole) was added to a solution of 2-ethyl-6-methoxy-1-methyl-1H-indole-3-carboxylic acid 73e (0.347 g, 1.48 mmole). The reaction mixture was heated to reflux for 30 min and concentrated. The residue was dissolved in 5 ml CH2Cl2 and added methylamine (2.0 M in THF, 2.22 ml, 4.44 mmole). The reaction mixture was stirred at room temperature for 1 hr, then concentrated. The residue was purified by flash column chromatography (2–5% CH3OH in CH2Cl2) to give yellow color solid (0.267 g, 73%). 1H NMR (CDCl3) δ 7.47 (1H, d, J=8.7 Hz), 6.80 (1H, s), 6.69 (1H, d, J=8.7 Hz), 3.47 (3H, s), 3.58 (3H, s), 3.00 (2H, q, J=7.4 Hz), 2.83 (3H, s), 1.14 (3H, t, J=7.4 Hz). ESIMS (MH+): 247.10.
Reaction SMILES: [C:1]([O:9]C)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:11]1[CH2:16]OC(=O)[CH2:12]1.C[O-].[Na+].[ClH:20].C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:20][CH:12]([CH2:11][CH3:16])[C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: COC(=O)c1cccnc1
Reactant: O=C1CCCO1
Reactant: Cl
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCC(Cl)C(=O)c1cccnc1

Procedure:
A solution of methyl nicotinate (59 g, 0.43 mol), 4 hydroxybutyric acid lactone (51.8 g, 0.602 mol), and sodium methoxide (70 g, 1.29 mol) in dioxane (500 mL) is refluxed for 1 hour and then cooled. Concentrated hydrochloric acid (650 mL) is added, and the reaction mixture is refluxed for 12 hours. The resulting solution is neutralized with solid sodium bicarbonate and extracted with chloroform. The organic phase is dried (sodium sulfate), and the solvent evaporated in vacuo. The residue is taken up in 2-propanol (50 mL) and treated with a saturated solution of hydrogen chloride in 2-propanol. The hydrochloride salt of 4 chloro-1-(3-pyridinyl)-1-butanone is obtained as a white solid (30 g); mp 73°-76° C.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:28][C:29]([F:41])([F:40])[C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:39][S:36]([C:33]3[CH:32]=[CH:31][C:30]([C:29]([F:28])([F:40])[F:41])=[CH:35][CH:34]=3)(=[O:37])=[O:38])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 4-(trifluoromethyl)-benzenesulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method B described hereinabove. Yield (18%); 1H NMR (d6-DMSO) δ 12.46 (br s, 1H), 8.11 (d, J=8.5 Hz, 2H), 7.99 (d, J=8.5 Hz, 2H), 7.40–7.07 (m, 13H), 6.84 (d, J=8.1 Hz, 2H), 6.40 (d, J=15.7 Hz, 1H), 2.35 (q, J=7.3 Hz, 2H), 0.81 (t, J=7.3 Hz, 3H); APcI m/z: 562 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]([O:20][C:21](=O)[CH:22]=2)=[O:19])=[CH:13][CH:12]=1>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:21]([CH2:22][CH:17]([C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=3)[C:18]([OH:20])=[O:19])[NH:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Cl)cc1N
Reactant: O=C1C=C(c2ccc(Cl)cc2)C(=O)O1
Solvent: ClCCl
Product: Cl
Product: O=C(O)C(Cc1nc2ccc(Cl)cc2[nH]1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
4-Chloro-1,2-phenylenediamine (285 mg) and 2-(4-chlorophenyl)maleic anhydride (420 mg) were dissolved in dichloromethane (4 ml) with heating. The dark solution was stirred at rt for 1 h. The solvent was removed in vacuo and the residue was dissolved in 1M HCl in acetic acid (4 ml). The solution was heated to reflux for 1 h, treated with charcoal, and filtered. From the filtrate the solvent was removed and the residue crystallised from acetone/ethyl acetate to give 3-(5-chloro-2-benzimidazolyl)-2-(4-chlorophenyl)propanoic acid HCl (130 mg) as light orange solid.
Reaction SMILES: BrC[C:3]1[CH:12]=[C:11]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=2)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].Cl.[CH3:31]NC.C([N:36]([CH2:39][CH3:40])CC)C.O>CN(C)C=O>[Cl:29][C:24]1[CH:23]=[C:22]([C:16]2([C:18]([F:20])([F:19])[F:21])[O:15][N:14]=[C:13]([C:11]3[CH:12]=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:9]([C:39]([CH3:40])([CH3:31])[NH2:36])[CH:10]=3)[CH2:17]2)[CH:27]=[C:26]([Cl:28])[CH:25]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1CBr
Reactant: CCN(CC)CC
Reactant: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(C)(C)N
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
In a solution of 1.50 g of methyl 2-bromomethyl-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]benzoate in 20 mL of N,N-dimethylformamide, 0.48 g of dimethylamine hydrochloride and 1.48 g of triethylamine were added, and stirred at room temperature for 2 hours. After the completion of the reaction, 20 mL of water was added in the reaction mixture, and extracted with ethyl acetate (20 mL×2). The combined organic phases were dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that were eluated with ethyl acetate-hexane (1:3) to obtain 1.35 g of the aimed product as colorless resinous substance.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.CCCCCC.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1>O1CCCC1.CCOCC>[O:4]=[C:3]([CH2:5][CH2:24][C:25]1[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=1)[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)CCc1cccc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
Ethyl acetoacetate (16.0 g; 0.123 mole) was added dropwise with stirring under nitrogen to 50% sodium hydride (6.5 g; 0.135 mole) in dry tetrahydrofuran (300 ml) at 0°. The resulting solution was stirred for 10 minutes at 0° before adding a solution of n-butyl lithium in hexane (95 ml, 1.6 M; 0.152 mole) dropwise. The resulting yellowish orange dianion solution was stirred for 10 minutes at 0° before adding α-bromo-m-xylene (34 g, 0.189 mole) in ether (20 ml) and allowed to warm to room temperature 30 minutes after completing the addition. The reaction mixture was quenched by addition of conc. HCl (25 ml) in H2O (60 ml) followed by ether (180 ml). The layers were separated and the aqueous further extracted with ether (3×125 ml). The combined organic layers were washed with water until the wash was neutral, then dried (anhydrous MgSO4) and evaporated to dryness. The resulting yellow oil was distilled under vacuum to give a pale yellow oil (22.0 g, 76%), b.p. 132°-139° at 0.19 mmHg, n.m.r. δ(CDCl3) 7.07 (4H, m), 4.25 (2H, q, J=7 Hz), 3.47 (2H, s), 2.95 (4H, s), 2.40 (3H, s) and 1.35 (3H, t, J=7 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][CH:10]2[CH:22]=O.Cl.[NH2:25][OH:26].N1C=CC=CC=1.Cl>C(O)C>[CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][CH:10]2[CH:22]=[N:25][OH:26]
Reactant: NO
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)C(C=O)CC[C@H]4[C@@H]3CC[C@@H]12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)C(C=NO)CC[C@H]4[C@@H]3CC[C@@H]12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 85.8 %

Procedure:
A stirred mixture of 4-methyl-3-oxo-5α-4-azaandrostan-17-carboxaldehyde (0.952 g, 3.0 mM), hydroxylamine hydrochloride (1.10 g, 15.8 mM), anhydrous pyridine (6 mL) and anhydrous ethanol (12 mL) was refluxed gently under a nitrogen atmosphere for 6.3 hours. After cooling, the ice-cooled mixture was diluted, with stirring, with a slight excess of chilled dilute hydrochloric acid (ca. 0.3N), the suspension aged for ca. 20 minutes, filtered, washed with water and dried to give (38) 0.855 g. MS M+ calcd for C20H32N2O2 332.48, observed m/e 332.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:10]=[C:11]([S:16][C:17]2[N:18]=[C:19]3[C:25]([NH:26][C:27](=[O:54])[C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]5)=[CH:30][C:29]=4[N:41]([CH:48]4[CH2:53][CH2:52][O:51][CH2:50][CH2:49]4)C(=O)C(F)(F)F)=[N:24][N:23](C(=O)C4C=CC(N5CCN(C)CC5)=CC=4N(C4CCOCC4)C(=O)C(F)(F)F)[C:20]3=[N:21][CH:22]=2)[CH:12]=[C:13]([F:15])[CH:14]=1>CO>[F:8][C:9]1[CH:10]=[C:11]([S:16][C:17]2[N:18]=[C:19]3[C:25]([NH:26][C:27](=[O:54])[C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]5)=[CH:30][C:29]=4[NH:41][CH:48]4[CH2:49][CH2:50][O:51][CH2:52][CH2:53]4)=[N:24][NH:23][C:20]3=[N:21][CH:22]=2)[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: CN1CCN(c2ccc(C(=O)Nc3nn(C(=O)c4ccc(N5CCN(C)CC5)cc4N(C(=O)C(F)(F)F)C4CCOCC4)c4ncc(Sc5cc(F)cc(F)c5)nc34)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ncc(Sc5cc(F)cc(F)c5)nc34)c(NC3CCOCC3)c2)CC1
Temperature: 65 °C
Yield: 57 %

Procedure:
0.27 ml (1.95 mmol) of triethylamine is added to 0.21 g (0.19 mmol) of a solution of N-(5-(3,5-difluorophenylthio)-1-(4-(4-methylpiperazine-1-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)benzoyl)-1H-pyrazolo[3,4-b]pyrazine-3-yl)-4-(4-methylpiperazine-1-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)benzamide in 5 ml of methanol. The reaction medium is heated at 65° C. for 4 hours, and then overnight at room temperature. After evaporation of the solvent, the product is extracted several times with ethyl acetate. The organic phases are combined, washed with saturated sodium bicarbonate solution, dried on magnesium sulfate and concentrated. The residue is purified by silica gel chromatography (95:4:1 dichloromethane/methanol/ammonium as eluent) to yield 0.065 g (57%) of N-(5-(3,5-difluorophenylthio)-1-H-pyrazolo[3,4-b]pyrazine-3-yl)-4-(4-methylpiperazine-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide in the form of a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.C([Li])CCC.CN(C)[C:18](=[O:20])[CH3:19].O>C1COCC1>[C:18]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9][C:5]=2[N:6]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)N(C)C
Reactant: Cc1ccc2ncsc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1nc2ccc(C)cc2s1
Temperature: 25 °C
Yield: 47.2 %

Procedure:
A solution of 6-methylbenzothiazole (6.1 g, 41 mmol) in anhydrous THF (150 ml) was cooled to -78° C. To the cooled solution was added, with stirring, n-butyl lithium (28.1 ml of 1.6 M n-BuLi-containing hexane solution, 45 mmol) dropwise under nitrogen atmosphere. Further, a solution of N,N-dimethyl acetamide (3.9 g, 45 mmol) in anhydrous THF (70 ml) was added dropwise to the mixture at the same temperature. After completion of the addition, the mixture was stirred for an hour, and then warmed to room temperature. The reaction mixture was poured into water, and then extracted with benzene. The extract was washed with water, dried over magnesium sulfate, and then evaporated. The resulting residual powders were subjected to purification using column chromatography on silica gel (eluant, n-hexane/ethyl acetate=95/5) to afford 2-acetyl-6-methylbenzothiazole (3.7 g, 47%) as a pale yellow powder, together with the starting material (2.5 g).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH2:15])=[CH:12][CH:11]=1.ClCCC1C=CC=CC=1.P(=O)(O)(O)O>>[CH3:15][CH:14]1[C:13]2[C:12](=[CH:11][CH:10]=[CH:17][CH:16]=2)[CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:1]1
Reactant: C=Cc1ccc(Cl)cc1
Reactant: C=Cc1ccccc1
Agent: ClCCc1ccccc1
Agent: O=P(O)(O)O
Product: CC1CC(c2ccccc2)c2ccccc21

Procedure:
A mixture of 90 parts of styrene, 234 parts of p-chlorostyrene and 66 parts of p-chloroethylbenzene is added to 722 parts of 93 per cent strength by weight phosphoric acid at 35° to 40° C over 5 hours. After a further 2 hours at 35° to 40° C the organic phase is separated off and washed with 200 parts of 3 per cent strength by weight sodium hydroxide solution. Fractional distillation gives 16 parts of 1-methyl-3-phenylindan, 78 parts of 1-methyl-3-(p-chloro)-phenylindan (b.p. 166° to 170° C (10 mm), nD25 : 1.5869) and 13 parts of 1-methyl-3-(p-chloro)-phenyl-5-chloroindan (b.p. 197° to 204° C (10 mm)).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O>CS(O)(=O)=O>[CH2:11]1[C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]=2[C:14](=[O:16])[CH2:13][CH2:12]1
Reactant: O=C(O)CCCc1ccc2ccccc2c1
Agent: CS(=O)(=O)O
Product: O=C1CCCc2ccc3ccccc3c21
Yield: 73.8 %

Procedure:
To 300 ml of methane-sulfonic acid contained in a 1 liter, 3-neck flask equipped with thermometer, drying tube and magnetic stirring bar was added 82.0 g (0.38 mole) of γ-(2-naphthyl)butyric acid as prepared above and the reaction mixture was heated at 90°-95° C. for one hour with vigorous stirring. The yellow reaction mixture was cooled, poured on crushed ice and extracted with two 350 ml portions of ethyl acetate. The combined organic portions were washed with 5% aqueous sodium hydroxide, water, dried over anhydrous sodium sulfate and then treated with some silica gel powder and Norit A charcoal before filtering. Upon removing the solvent an off-white solid was obtained. Recrystallization from 375 ml of hexane containing 7-10 ml of chloroform gave an oil that solidified to yield 55.0 g (73.3% by weight) of 1,2,3,4-tetrahydro-4-phenanthrone as an off-white solid. M.P. 64°-66° C.; λmax 312 nm (7,510) ethanol; T.L.C. CH2Cl2. Rf =.7.
Reaction SMILES: [Cl-].O[NH3+].[C:4](=[O:7])([O-])[OH:5].[Na+].[CH2:9]([C:11]1[S:45][C:14]2[N:15]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)[C:16](=[O:29])[CH2:17][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:19](=[O:20])[C:13]=2[CH:12]=1)[CH3:10].[N:46]12CCCN=C1CCCCC2>C(Cl)(Cl)Cl.C(Cl)Cl.CS(C)=O>[CH2:9]([C:11]1[S:45][C:14]2[N:15]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:46][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)[C:16](=[O:29])[CH2:17][N:18]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[C:19](=[O:20])[C:13]=2[CH:12]=1)[CH3:10]
Reactant: O=C([O-])O
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCc1cc2c(s1)N(Cc1ccc(-c3ccccc3C#N)cc1)C(=O)CN(Cc1ccc(F)cc1)C2=O
Agent: [Cl-]
Agent: [NH3+]O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCc1cc2c(s1)N(Cc1ccc(-c3ccccc3-c3noc(=O)[nH]3)cc1)C(=O)CN(Cc1ccc(F)cc1)C2=O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
A mixture of hydroxylammonium chloride (0.43 g), sodium hydrogencarbonate (0.63 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[7-ethyl-4-(4-fluorobenzyl)-2,5-dioxo-2,3,4,5-tetrahydro-1H-thieno[2,3-e][1,4]diazepin-1-yl]methyl}biphenyl-2-carbonitrile (0.38 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methylene chloride (20 mL), N,N′-carbonyldiimidazole (0.13 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction Mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.19 g, 49%).