Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]1([CH3:20])[O:19][C:17](=[O:18])[CH2:16][C:14](=[O:15])[O:13]1.N1CCCC1C(O)=O.[F:29][C:30]1[CH:31]=[C:32]2[C:36](=[C:37]([CH2:39][S:40][CH3:41])[CH:38]=1)[NH:35][CH:34]=[CH:33]2>C(#N)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]([C:33]1[C:32]2[C:36](=[C:37]([CH2:39][S:40][CH3:41])[CH:38]=[C:30]([F:29])[CH:31]=2)[NH:35][CH:34]=1)[CH:16]1[C:17](=[O:18])[O:19][C:12]([CH3:20])([CH3:11])[O:13][C:14]1=[O:15]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CSCc1cc(F)cc2cc[nH]c12
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: O=C(O)C1CCCN1
Solvent: CC#N
Product: CSCc1cc(F)cc2c(C(c3ccc(Cl)cc3Cl)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.81 g (4.60 mmol) of 2,4-dichlorobenzaldehyde, 0.66 g (4.60 mmol) of Meldrum's acid and 25 mg (0.22 mmol) of D,L-proline were added to a solution of 0.95 g (4.38 mmol) of the compound from Example 11A in 36 ml of acetonitrile. The reaction mixture was stirred at RT overnight. It was concentrated to result in 3.10 g (97% of theory) of the title compound with a purity of 68% which were reacted without further purification.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:34])[NH:6]2.FC(F)(F)S(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O.[CH3:48]O>>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][N:31]([CH2:41][C:42]([F:45])([F:44])[F:43])[CH2:30][CH2:29]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:34][CH3:48])[NH:6]2
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CO
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCNCC1
Product: CCc1cc2c(F)c(Oc3ncnc4cc(OCCCN5CCN(CC(F)(F)F)CC5)c(OC)cc34)ccc2[nH]1
Yield: 44 %

Procedure:
Using an analogous procedure to that described for the preparation of Example 14, 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-piperazin-1-ylpropoxy)quinazoline (250 mg, 0.54 mmol) was reacted with 2,2,2-trifluoroethyl trifluoromethanesulphonate (128 mg, 0.59 mmol) and purified by column chromatography, eluting with 5% methanol/methylene chloride to give a sticky solid. The sticky solid was dissolved in methanol and absorbed onto an Isolute SCX column. The column was washed with methanol and eluted with 7N ammonia in methanol. The product was triturated in ether/isohexane and filtered to give 4-[(4-fluoro-2-ethyl-1H-indol-5-yl)oxy]-6-methoxy-7-{3-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]propoxy}quinazoline (130 mg, 44%).
Reaction SMILES: [CH3:1][CH:2]([C:4](=[CH:7][CH:8]=[C:9]([CH3:21])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[C:5]#N)[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.O.C(O)(=O)C(O)=[O:35]>CCCCCC.C1(C)C=CC=CC=1>[CH3:1][CH:2]([C:4](=[CH:7][CH:8]=[C:9]([CH3:21])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH:5]=[O:35])[CH3:3]
Reactant: O=C(O)C(=O)O
Reactant: CC(C)=CCCC(C)=CCCC(C)=CC=C(C#N)C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: O
Product: CC(C)=CCCC(C)=CCCC(C)=CC=C(C=O)C(C)C
Temperature: -70 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of 2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenenitrile (856 mg, 3.0 mmol) in n-hexane.(30 ml) was added a 0.5M solution of diisobutylaluminium hydride in toluene (6 ml) with stirring at -70° C. under argon atmosphere. After one hour, water (3 ml) was added, the cooling bath was removed, and the reaction mixture was stirred well. Resultant white precipitates were filtered and washed. The filtrate was concentrated to give a residue, which was dissolved in n-hexane (10 ml). The n-hexane solution was combined with a aqueous solution of oxalic acid (5 ml) and stirred for 3 hours. The organic layer was extracted and separated, washed with water, dried over MgSO4, and concentrated. The resultant residue was subjected to silica gel column chromatography (solvent: n-hexane/ethyl acetate=10:1) to obtain 2 -(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenal (865 mg, 84%).
Reaction SMILES: [CH:1]([N:4]([CH3:34])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16]C(=O)OCC3C=CC=CC=3)[C:12]2=[O:27])[C@H:7]([CH2:28][S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[CH2:6]1)([CH3:3])[CH3:2].Br.CC(O)=O>CCOCC>[NH2:16][C@H:13]1[CH2:14][CH2:15][N:11]([C@H:8]2[CH2:9][CH2:10][C@@H:5]([N:4]([CH:1]([CH3:3])[CH3:2])[CH3:34])[CH2:6][C@H:7]2[CH2:28][S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[C:12]1=[O:27]
Reactant: CCS(=O)(=O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCS(=O)(=O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 82.4 %

Procedure:
The entirety of benzyl (S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(ethylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate prepared in Step 2 (250 mg) was charged with 30% HBr/AcOH (5 mL). The reaction vessel warms and a vigorous gas evolution occurs. The mixture was stirred for 25 min at RT and then the flask was placed in a cool water bath before the addition of 20 mL of Et2O. The resulting solid was collected, washed with Et2O twice, and concentrated in vacuo to give (S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(ethylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one (150 mg). MS found: (M+H)+=360.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)N)([O-:3])=[O:2].[ClH:11].[Cl-].[N+](C1C=C([N+]#N)C=CC=1)([O-])=O.[Cl:24][C:25](=[CH2:28])[C:26]#[N:27]>O.CC(C)=O.C(O)(=O)C>[Cl:24][C:25]([Cl:11])([CH2:28][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:26]#[N:27]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: C=C(Cl)C#N
Reactant: Cl
Agent: N#[N+]c1cccc([N+](=O)[O-])c1
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: O
Product: N#CC(Cl)(Cl)Cc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
138 g (1 mole) of m-nitro-aniline are slowly added in a 2-liter reactor to a mixture of 300 ml of concentrated HCl, 150 ml of water and 150 ml of acetic acid. The mixture is heated until the amine hydrochloride dissolves, whereafter the mixture is cooled to 0° C. with vigorous agitation. With the temperature remaining between 0° and 3° C., 70 g of NaHO2 dissolved in 150 ml of H2O are added.. The m-nitro-benzene-diazonium chloride solution is added simultaneously with an aqueous solution of 25 g of CuCl2.2H2O to a solution of 87 g of α-chloro-acrylonitrile in 150 ml of acetone. The temperature is kept at 30° C. Evolution of nitrogen ceases after about 6 hours. The α,α-dichloro-β-(3-nitrophenyl)propionitrile is extracted with benzene, washed in sodium hydroxide, then washed with water. After drying and removal of the solvent the product is distilled at low pressure. 215 g of α,α-dichloro-β-(3-nitrophenyl)propionitrile, corresponding to an 88% yield, are obtained, in the form of a slightly pinkish oil distilling at 140° C. at a pressure of 0.1 mm.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:7]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>CC(C)=O>[CH2:16]([O:15][C:7]([CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C@H:3]1[CH2:4][CH2:5][C:1](=[O:6])[CH2:2]1)=[O:14])[CH3:17]
Reactant: O=C1C=CCC1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CC(C)=O
Product: CCOC(=O)C(C(=O)OCC)[C@H]1CCC(=O)C1
Temperature: 40 °C
Reaction time: 24 h
Yield: 95.3 %

Procedure:
Under an atmosphere of argon, 24.0 mg (0.04 mmol, S/C=50) of RuH[(R,R)-Tsdpen] (1,3,5-trimethylbenzene), 168 μL (2.0 mmol) of 2-cyclopentenone, 304 μL (2.0 mmol) of diethyl malonate, and 2 mL of acetone were placed in a 20 mL Schlenk tube and stirred at 40° C. for 24 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 462 mg (95% yield) of the title compound. After this was converted into an ethylene ketal derivative by the same procedure as in Example 3, the optical purity was measured by HPLC (CHIRALCEL OD manufactured by Daicel Chemical Industries, Ltd., hexane:2-propanol=97: 3, flow rate 0.5 mL/min, detection at 210 nm) and it was found to be 91% ee.
Reaction SMILES: [C:1]1([N:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][C:28]([CH3:31])([O-])[CH3:29].[Na+]>[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]1([N:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:8]2[CH:13]=[CH:12][C:11]([N:14]([C:20]3[CH:15]=[CH:16][C:27]4[N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[C:8]5[C:29]([C:28]=4[CH:31]=3)=[CH:12][CH:11]=[CH:10][CH:9]=5)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)[O-]
Reactant: c1ccc(Nc2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(N(c2ccccc2)c2ccc(N(c3ccccc3)c3ccc4c(c3)c3ccccc3n4-c3ccccc3)cc2)cc1
Temperature: 80 °C
Yield: 65 %

Procedure:
Specifically, 627.64 mg (1.7 mmol) of 3-iodine-9-phenylcarbazole, 672.86 mg (2.0 mmol) of N-(4-diphenylaminophenyl)-N-phenylamine, 57.5 mg (0.1 mmol) of bis(dibenzylidene acetone) palladium and 335 mg (3.5 mmol) of sodium tert-butoxide were mixed in a three-neck flask. Nitrogen was substituted for air inside of the three-neck flask. Then, 3.5 ml of dehydrated toluene was added in the mixture in the three-neck flask, and degassed for about 3 minutes. Subsequently, 0.4 ml of tri-tert-butyl phosphine (a 10 wt % hexane solution) was added to the mixture and the content was mixed by lightly shaking the container up and down. The content was stirred further for 10 minutes while being irradiated and heated at 80° C. with 200 W of microwave. After the reaction, saturated saline was added and a product was extracted with 100 ml of ethyl acetate. Further, magnesium sulfate was added to the product to remove moisture, and then the magnesium sulfate was filtered to be removed. The filtrate was concentrated, and a target matter was taken out by a silica gel column using a solvent containing ethyl acetate and hexane with a ratio of 1:1. Hexane was added to the thus-obtained solution and the resultant was heated to be recrystallized. Consequently, 650 mg (the yield: 65%) of a cream-colored powder was obtained. The NMR data is shown below. The 1H-NMR (300 MHz, DMSO-d); δ=6.89-7.05 (m, 13H), 7.21-7.28 (m, 9H), 7.32-7.43 (m, 3H), 7.50-7.69 (m, 5H), 8.02 (s, 1H), 8.14 (d, j=7.2, 1H). Also, a chart of 1H-NMR is shown in FIG. 13. Also, a chart of an enlarged portion of FIG. 13 in the range of 6.0 ppm and 9.0 ppm is shown in FIG. 14.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.C(N(CC)C(C)C)(C)C.[F:50][C:51]1[CH:62]=[CH:61][C:54]([O:55][C:56]([CH3:60])([CH3:59])[CH2:57][NH2:58])=[CH:53][CH:52]=1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:58][CH2:57][C:56]([O:55][C:54]2[CH:53]=[CH:52][C:51]([F:50])=[CH:62][CH:61]=2)([CH3:60])[CH3:59])=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: CC(C)(CN)Oc1ccc(F)cc1
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(CNC(=O)c1ccc(N)c(F)c1)Oc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a mixture of 4-amino-3-fluorobenzoic acid (200.0 mg, 1.289 mmol) and HBTU (490 mg, 1.3 mmol) in DMF (2 mL, 20 mmol) at 0° C. were added N,N-diisopropylethylamine (0.67 mL, 3.9 mmol) and 2-(4-fluorophenoxy)-2-methylpropan-1-amine (Preparation 91, 280 mg, 1.5 mmol). The reaction mixture was slowly warmed to ambient temperature. The reaction mixture was quenched with an equal volume of saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic layers were washed successively with water, aqueous lithium chloride, and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on the Isco (120 g cartridge, chloroform to 12% MeOH in chloroform).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:7]([N:10]1[S:15](=[O:17])(=[O:16])[NH:14][C:13]([O:18][CH3:19])=[N:12][C:11]1=O)[CH2:8][CH3:9].P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:11]1[N:10]([CH2:7][CH2:8][CH3:9])[S:15](=[O:17])(=[O:16])[N:14]=[C:13]([O:18][CH3:19])[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCN1C(=O)N=C(OC)NS1(=O)=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCCN1C(Cl)=NC(OC)=NS1(=O)=O
Temperature: 110 °C
Reaction time: 7 h

Procedure:
50 parts of phosphorus pentachloride were added to a stirred mixture of 44 parts of 6-n-propyl-3-methoxy-6H-1,2,4,6-thiatriazin-5-one-1,1-dioxide and 268 parts of phosphorus oxychloride at 22° C., and the batch was heated to 110° C. in the course of 20 minutes. After 7 hours' stirring under reflux, the reaction mixture was evaporated down under reduced pressure, giving 45 parts of oily 5-chloro-6-n-propyl-3-methoxy-6H-1,2,4,6-thiatriazine-1,1-dioxide; NMR: (CDCl3) N-CH2 4.0-4.28δ.
Reaction SMILES: C=O.[CH3:3][C:4]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]2[C:5]=1[CH:6]=[CH:7][CH2:8]2.[CH3:14][CH2:15][O-].[Na+].Cl>CS(C)=O>[CH3:3][C:4]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]2[C:5]=1[C:6]([CH2:10][C:9]1[C:5]3[C:6](=[C:15]([CH3:14])[CH:11]=[CH:12][C:4]=3[CH3:3])[CH2:7][CH:8]=1)=[CH:7][CH2:8]2
Reactant: Cc1ccc(C)c2c1C=CC2
Reactant: CC[O-]
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(C)c2c1CC=C2CC1=CCc2c(C)ccc(C)c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
Formalin (37% aq. solution, 0.28 g, 3.47 mmol) was added to a mixture of 4,7-dimethylindene (1.0 g, 6.94 mmol) and EtONa (0.15 g, 2.20 mmol) in dimethylsulphoxide (10 mL) at 25° C. After stirring at room temperature for 12 hours, the reaction mixture was heated at 80° C. for further 4 hours and then cooled to room temperature. A solution of HCl (1 M, 10 mL) was added. The mixture was extracted with CH2Cl2 (2×50 mL); the organic phases were combined, washed with a saturated solution of NaCl and then with water, dried over anhydrous MgSO4, filtered and finally concentrated to yield a brown solid (GC analysis shows 75% conversion). After washing with MeOH, bis(4,7-dimethyl-3-indenyl)methane was isolated as a yellow solid (0.52 g; yield 50%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.[C:17]([OH:25])(=[O:24])[C:18]([CH2:20][C:21](O)=[O:22])=[CH2:19]>C1(C)C=CC=CC=1.C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:21](=[O:22])[CH2:20][CH:18]([C:17]([OH:25])=[O:24])[CH2:19]2)=[CH:9][CH:8]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C(O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 101 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
4-(3-Fluoro-benzyloxy)-phenylamine (31.2 g, 144 mmol) was dissolved in toluene (208 mL) and acetic acid (52 mL). Itaconic acid (18.96 g, 144 mmol) was added to the stirred mixture. The mixture was heated to reflux (101° C.) and kept at this temperature for 3 h. On cooling, the product started to crystallize. At 10° C., heptane (125 mL) was added to the suspension which was stirred 1 h at 0° C. and filtered. The crystals were washed with toluene/heptane 1:1 and with heptane and dried in vacuo to afford the crude product (43.2 g). The crude product was purified by treatment with hot isopropyl acetate to give rac-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid (40.5 g, 86%; HPLC: 99.2% area), m.p. 148-149° C. (uncorr.).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[S:5][CH:6]=1.C(O)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:3]=[C:4]([N:7]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]3=[O:13])[S:5][CH:6]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C1CCCCN1c1nc(Br)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1CCCCN1c1nc(-c2ccc(Cl)cc2)cs1
Temperature: 100 °C
Yield: 71.3 %

Procedure:
To a solution of 1-(4-bromothiazol-2-yl)piperidin-2-one (Step-1 of compound 10, 1.0 g, 3.83 mmol) in a mixture of toluene:ethanol (10 ml: 30 ml) were added (4-chlorophenyl) boronic acid (0.72 g, 4.60 mmol) and potassium carbonate (1.06 g, 7.66 mmol) at 25° C. in a tube, the nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (0.44 g, 0.38 mmol) under nitrogen the tube was sealed. The reaction mixture was heated at 100° C. for 10 hr with stirring. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and filtered through celite. The residue was washed with ethyl acetate (2×30 ml). The filtrate was concentrated under reduced pressure to obtain a crude product; which was purified by flash column chromatography using 10% ethyl acetate in hexanes as an eluent to obtain the title compound (0.80 g, 71.4%). MS: m/z 293 (M+1).
Reaction SMILES: C1C2C(=CC=CC=2)C=C1.CCC(C[O:16][C:17](C(N(CC[NH+](C)C)C)=O)([C:24]1[CH:29]=CC=CC=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)CC.[Cl-].[BrH:40].OO>ClCCl.O>[Br:40][C@@H:24]1[CH2:29][C:19]2[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:17]1[OH:16]
Reactant: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Reactant: Br
Agent: C1=Cc2ccccc2C1
Agent: OO
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O[C@@H]1c2ccccc2C[C@H]1Br
Reaction time: 8 h
Yield: 83.9 %

Procedure:
237 ml of water, 173.9 g of indene (92 wt %; 1.38 mol), 2.8 g of Triton X-100 and 262.0 g of hydrogen bromide (47 wt %; 1.52 mol, 1.1 mol/mol indene) were put into a 1000-ml 3-mouthed flask, and emulsified by stirring together with a magnetic stirrer. The emulsion was stirred at 60° C. as 147.2 g of hydrogen peroxide (35 wt %; 1.52 mol, 1.1 mol/mol indene) was added dropwise over 4 hours and 20 minutes. After stirring for 2 hours at the same temperature, stirring was continued at room temperature overnight. 200 ml of dichloromethane was added to the reaction mixture, and after stirring at room temperature for 1 hour it was filtered at decreased pressure. The wet crystals were dried, to obtain 246.1 g of pale yellow crystals of trans-2-bromoindan-1-ol (yield 83.9%; GC purity 97.0%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]>>[Cl:11][C:8]1[CH:9]=[N:10][C:2]([O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:15]([C:16]#[N:17])[CH:14]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Reactant: N#Cc1cccc(O)c1
Product: N#Cc1cccc(Oc2ncc(Cl)cc2C(=O)O)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 46 from 2,5-dichloronicotinic acid (Syn. Commun. 1989, 19, 553–9) and 3-hydroxybenzonitrile: 1H-NMR (CDCl3) δ 8.40–8.33 (2H, m), 7.74–7.52 (4H, m), a peak of COOH was not observed; MS (ESI) m/z 229 (M−COOH)−.
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH:12]=[C:11]([CH:13]=O)[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-].[CH2:28]([O:35][CH2:36][CH2:37][CH2:38][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC(C)([O-])C.[K+]>O1CCCC1>[C:29]1([CH2:28][O:35][CH2:36][CH2:37]/[CH:38]=[CH:13]\[C:11]2[N:10]=[CH:9][N:8]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: c1ccc(COCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C(=C\c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)\CCOCc1ccccc1
Temperature: 15 °C
Reaction time: 2 h

Procedure:
To a mechanically stirred solution of the aldehyde (16) (19.65 g, 58.1 mmol) in dry tetrahydrofuran (1 L), was added (3-benzyloxypropyl)triphenyl phosphonium bromide (30.02 g, 61.1 mmol). The resulting suspension was cooled to 15° C., and then a 1.0M solution (61.4 mL; 61.4 mmol) of potassium t-butoxide in tetrahydrofuran was added over five minutes. The reaction mixture was allowed to warm to room temperature and was stirred for 2 h. The reaction mixture was filtered through Celite; the filter cake was washed with tetrahydrofuran (2×150 mL); the filtrate and washings were combined, diluted with ether (800 mL) and refiltered through fresh Celite. The filtrate was concentrated under vacuum, and the residue was chromatographed on silica gel, eluting with a gradient of hexanes-ethyl acetate (3:1 to 2:1), to obtain the title compound (17) as a pale yellow powder, mp 101-104° C. MS(FAB) 471 (MH+).
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH:5][C:6]([O:8][CH2:9][CH:10]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7].C(=O)=O.CC(C)=O.[H-].C([Al+]CC(C)C)C(C)C.CO>C1(C)C=CC=CC=1>[NH:5]([C:6]([O:8][CH2:9][CH:10]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[C@H:4]([CH:3]=[O:2])[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C=O
Agent: [H-]
Solvent: CO
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H](C=O)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C

Procedure:
Fmoc-Leucine methyl ester (35 g, 134 mmoles) in dry toluene (250 ml) under N2 is cooled with dry ice/acetone, and 150 ml of 25 % di-isobutyl-aluminum hydride in toluene are added over 30 mins. The mixture is stirred for 20 min in a bath of dry ice/acetone after the addition of the di-isobutyl aluminum hydride, then methanol (15 ml) is added cautiously. The mixture is poured into 1000 ml ice-cold water, shaken and filtered. The toluene is separated and the aqueous phase re-extracted with ether (3×300 ml). Toluene and ether extracts are combined and dried over Na2SO4. The resulting oil is passed rapidly though a silica gel column (3×50 cm) in 1500 ml 15% EtOAc/petrol. The Fmoc-Leu-CHO is obtained as a solid (27.6 g).
Reaction SMILES: C[OH:2].Cl.Cl.Cl.[CH2:6]([NH:13][C:14]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[NH:18])=[NH:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:28][C:29]([CH3:31])=[O:30]>>[C:29]([OH:2])(=[O:30])[CH3:31].[CH3:28][C:29]1([CH3:31])[N:15]=[C:14]([NH:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N:18]1
Reactant: CC(C)=O
Reactant: CCCCCCCCNC(=N)NC(=N)NCc1ccccc1
Reactant: CO
Agent: Cl
Product: CC(=O)O
Product: CCCCCCCCNC1=NC(C)(C)N=C(NCc2ccccc2)N1

Procedure:
100 ml of methanol, 100 ml of acetone and 0.4 ml of concentrated hydrochloric acid were added to 5.0 g (13.3 mmol) of N1-benzyl-N5-octyl-biguanide dihydrochloride. The mixture was refluxed for 22 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in 100 ml of ethanol, and to the solution were added 80 ml of water and 5.8 ml of 5N aqueous sodium hydroxide. The mixture was refluxed for 1.5 hours, concentrated under reduced pressure, and extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled off under reduced pressure, and a portion (2.8 g) of 5.8 g of the resulting crystals were recrystallized from ether to obtain 1.1 g of colorless crystals having a melting point of 88 to 91° C.