Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:26])([F:25])[CH2:6][N:7]([C:15]1[C:20]([N+:21]([O-])=O)=[CH:19][N:18]=[C:17]([Cl:24])[N:16]=1)[CH2:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)C>C(O)(=O)C.[Fe]>[Cl:24][C:17]1[N:18]=[CH:19][C:20]2[NH:21][C:4](=[O:3])[C:5]([F:26])([F:25])[CH2:6][N:7]([CH2:8][CH2:9][C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)[C:15]=2[N:16]=1
Reactant: CCOC(=O)C(F)(F)CN(CCc1cccs1)c1nc(Cl)ncc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Nc2cnc(Cl)nc2N(CCc2cccs2)CC1(F)F
Reaction time: 0.17 h
Yield: 43.1 %

Procedure:
To a solution of 1.48 g (0.0035 mole) of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(2-thiophen-2-yl-ethyl)-amino]-2,2-difluoro-propionic acid ethyl ester (IV-269) in 20 mL of acetic acid was added 1.5 g (0.027 g-atom) of iron powder. The mixture was heated to 80 degrees for 2 hours and then filtered while hot. Water and ethyl acetate were added to the filtrate and the mixture was stirred for 10 minutes and then filtered. The layers were separated. The organic layer was washed successively with ammonium hydroxide and water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Recrystallization of the residue from ethyl acetate and hexane gave 0.52 g of 2-chloro-7,7-difluoro-9-(2-thiophen-2-yl-ethyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-269).
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[CH:19]1[C:27]2[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[CH:32]=O>>[CH:19]1[C:27]2[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[CH2:32][N:1]1[CH:2]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])[CH2:3][CH2:4][C:5]1=[O:7]
Reactant: O=Cc1ccc2oc3ccccc3c2c1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1ccc2oc3ccccc3c2c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available dibenzo[b,d]furan-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.92 min.; [M+H]+: δ 401.83 g/mol.
Reaction SMILES: [C:1]([OH:7])#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.[S:15](Cl)([CH3:18])(=[O:17])=[O:16]>C(OCC)C.O>[CH3:18][S:15]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6])(=[O:17])=[O:16]
Reactant: CCCCC#CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: C#CCCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2.3 ml of hexynol 17a, in 15 ml of diethyl ether was added 3 ml of triethyl amine, followed by 1.6 ml of mesyl chloride at 0° C. The mixture was stirred for 1 hr at 0° C., then diluted with 20 ml of water and extracted with diethyl ether. The extract was washed with 1N NaOH, water, dried and concentrated, to give 3.5 g of mesylate 17b as a colorless oil. Rf 0.65 (heptane/acetone 1/1).
Reaction SMILES: [N:1]#[N:2].C([O:5][C:6](=[O:41])[CH2:7][N:8]([C:13](=[O:40])[C@H:14]([CH2:33][CH2:34][CH2:35][NH:36][C:37](=[NH:39])[NH2:38])[NH:15][S:16]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][C:23]([O:31][CH3:32])=[C:24]([O:29][CH3:30])[CH:25]=2)[CH:20]=1)(=[O:18])=[O:17])[CH2:9][CH2:10][O:11][CH3:12])C>C(O)C.[OH-].[Na+]>[N:1]#[N:2].[CH3:30][O:29][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:31][CH3:32])[CH:20]=[C:19]([S:16]([NH:15][C@H:14]([C:13]([N:8]([CH2:9][CH2:10][O:11][CH3:12])[CH2:7][C:6]([OH:41])=[O:5])=[O:40])[CH2:33][CH2:34][CH2:35][NH:36][C:37](=[NH:38])[NH2:39])(=[O:18])=[O:17])[CH:28]=[CH:27]2
Reactant: CCOC(=O)CN(CCOC)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCN(CC(=O)O)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Yield: 55.4 %

Procedure:
A solution of 2.5 g of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester in 5 ml of ethanol and 7 ml of 1N sodium hydroxide solution was stirred for 30 hours at room temperature. At the end of this period, the solution was concentrated to 5 ml, chromatographed on 80 ml of Daiaion ® SK 102 ion exchange resin (200 - 300 mesh, H+ form manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water, and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness, and the residue was purified by reprecipitation with ethanol-ethyl ether to give 1.32 g (72 percent) of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine as an amorphous solid. I.R. (KBr): 3,380, 3,180, 1,630 cm-1.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[C:6](Cl)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[N:3]=1>CO.[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[N:3][CH:2]=1
Reactant: O=[N+]([O-])c1c(Cl)cc(-c2ccccc2F)nc1Cl
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2ccccc2F)nc1
Reaction time: 8 h

Procedure:
To a suspension of 2,4-dichloro-3 -nitro-6-(2-fluorophenyl)pyridine (1.6 g, 5.6 mmol) in methanol (100 ml) was added a catalytic amount of 10% palladium on carbon (100 mg). The mixture was hydrogenated at 50 psi for 8 hours then filtered through celite. The methanol was removed under reduced pressure and the residue was extracted with ethyl acetate from an aqueous solution saturated with potasssium carbonate. The extract was washed with brine, dried over sodium sulfate, filtered and concentrated to give 5-amino-2-(2-fluorophenyl)pyridine, which was used without further purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([CH3:19])=[N:17][C:16]([CH3:20])=[C:15]([C:21](=[O:23])[NH2:22])[N:14]=2)=[CH:9][CH:8]=1)(=O)=O.[Cl:26][C:27]1[CH:28]=[C:29]([C:42]2([C:45]([O:47][CH3:48])=[O:46])[CH2:44][CH2:43]2)[CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[C:21]([C:15]1[N:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:32]3[CH:31]=[CH:30][C:29]([C:42]4([C:45]([O:47][CH3:48])=[O:46])[CH2:44][CH2:43]4)=[CH:28][C:27]=3[Cl:26])=[CH:8][CH:9]=2)[C:18]([CH3:19])=[N:17][C:16]=1[CH3:20])(=[O:23])[NH2:22]
Reactant: COC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)c(Cl)c2)CC1
Reactant: Cc1nc(C)c(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)nc1C(N)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CO
Solvent: COCCOC
Product: COC(=O)C1(c2ccc(-c3ccc(-c4nc(C(N)=O)c(C)nc4C)cc3)c(Cl)c2)CC1
Temperature: 90 °C
Yield: 49.8 %

Procedure:
A solution of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl trifluoromethanesulfonate (Intermediate 7-4; 245 mg, 0.65 mmol) and methyl 1-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxylate (Intermediate 10-2; 220 mg, 0.65 mmol) and potassium phosphate, tri-basic (166 mg, 0.78 mmol) in DME (4 mL), methanol (2 mL) and water (1 mL) was thoughroughly degassed. The mixture was treated with PdCl2(dppf)-DCM adduct (26.7 mg, 0.03 mmol), degassed again and the atmosphere replaced with nitrogen before being heated to 90° C. for 4 hours in the microwave. The reaction mixture was allowed to cool to room temperature and then evaporated. The crude product was partitioned between EtOAc (75 mL), and saturated brine (75 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 70% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 1-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)cyclopropanecarboxylate (141 mg, 49.5%) as a colourless gum.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:46])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:47])[C:3]=1[C:48]([O:50][CH3:51])=[O:49])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:44])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C:35](=[N:39][OH:40])[C@@H:34]([O:41][CH3:42])[C@H:33]([CH3:43])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:45].Cl.O(N)[CH3:54].N1C=CC=CC=1>CO>[CH3:38][O:37][C@H:36]1[C@@H:31]([NH:30][C:14]2[C:13](=[O:44])[C:12]3[CH:11]=[C:10]4[C:19]([C:20](=[O:27])[C@@:21]5([O:25][CH3:26])[C@@:8]([OH:46])([C:9]4=[O:45])[C:7]4[C:2]([OH:1])=[C:3]([C:48]([O:50][CH3:51])=[O:49])[C:4]([CH3:47])=[CH:5][C:6]=4[CH2:23][C@H:22]5[OH:24])=[C:18]([OH:28])[C:17]=3[C:16](=[O:29])[CH:15]=2)[O:32][C@@H:33]([CH3:43])[C@H:34]([O:41][CH3:42])/[C:35]/1=[N:39]/[O:40][CH3:54]
Reactant: CON
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)C(=NO)[C@H]1OC)C4=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CO/N=C1/[C@@H](OC)[C@H](C)O[C@H](NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)OC)c(O)c5[C@]3(O)C4=O)C2=O)[C@@H]1OC
Reaction time: 2 h
Yield: 54 %

Procedure:
To a solution of the ketone from Step A of the preparation of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,5R,6S)-4-(hydroxyimino)-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate [Isomer A] (Example 48) (53 mg, 0.076 mmol) in methanol (1 mL) was added methoxylamine hydrochloride (6.4 mg, 0.076 mmol) and pyridine (0.1 mL) at room temperature. The mixture was stirred under nitrogen for 2 h. The reaction mixture was quenched with 1N HCl and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by preparative TLC (silica gel, 95:5 chloroform/methanol) to afford (6R,6aS,14aR)-methyl 11-((2S,3R,5R,6S,Z)-3,5-dimethoxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-ylamino)-1,6,8,14a-tetrahydroxy-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (30 mg, 54%) as a red solid: 1H NMR (500 MHz, CDCl3) δ 14.15 (s, 1H), 12.09 (s, 1H), 8.20 (s, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.54 (s, 1H), 5.86 (s, 1H), 5.21 (s, 1H), 4.98-4.94 (m, 2H), 4.67-4.64 (m, 2H), 3.97 (s, 3H), 3.84 (s, 3H), 3.71 (d, J=9.5 Hz, 1H), 3.59 (s, 3H), 3.57-3.52 (m, 2H), 3.47 (s, 3H), 3.40 (s, 3H), 3.34 (d, J=19.5 Hz, 1H), 2.40 (s, 3H), 1.38 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 725 (M+H); HPLC 95.9% (AUC), tR 17.05 min.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].C[N:12]1[CH2:17][CH2:16][C:15]2([C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:24][C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:14][CH2:13]1>C(Cl)Cl>[O:4]([C:2]([N:12]1[CH2:13][CH2:14][C:15]2([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[O:24][C:25]3[C:30]2=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:16][CH2:17]1)=[O:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CN1CCC2(CC1)c1ccccc1Oc1ccccc12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCC2(CC1)c1ccccc1Oc1ccccc12
Reaction time: 8 h

Procedure:
A solution of phenyl chloroformate (8 ml.) in methylene chloride (75 ml.) is added dropwise with stirring to a solution of 1'-methylxanthene-9-spiro-4'-piperidine (17.0 g.) in methylene chloride (200 ml.) at 5° C. The mixture is allowed to reach room temperature and stirred overnight. The mixture is washed successively with 3N sodium hydroxide solution, 3N hydrochloric acid and water, dried (MgS04) and the methylene chloride evaporated to dryness. The gummy residue is crystallised from methanol to give 1'-phenoxycarbonylxanthene-9-spiro-4'-piperidine, m.p. 105°-107° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][OH:21])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH2:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1O)[CH:36]=[CH2:37].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOCC>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:21][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[CH2:35][CH:36]=[CH2:37])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CO)nn23)CC1
Reactant: C=CCc1ccccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COc4ccccc4CC=C)nn23)CC1
Temperature: 25 °C
Yield: 19.7 %

Procedure:
To a stirred solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.190 g, 0.320 mmol), 2-allylphenol (0.084 ml, 0.641 mmol) and Ph3P (0.126 g, 0.480 mmol) in THF (5 mL) was added DEAD (0.101 ml, 0.641 mmol) at 0° C. The reaction was slowly warming to rt over 3 h and after 1 h at rt, diluted with Et2O (50 mL), washed with water (2×10 mL), brine (10 mL), dried (MgSO4), filtered, concentrated and the resulting yellow residue purified by flash chromatography using 10 and 20% EtOAc/Hex to afford (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((2-allylphenoxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.0374 g, 0.063 mmol, 19.77% yield) as colorless paste. 1H NMR (500 MHz, CDCl3) δ 7.17-7.23 (m, 2H), 7.08 (d, J=7.9 Hz, 1H), 6.94 (t, J=7.4 Hz, 1H), 6.63 (s, 1H), 6.00-6.10 (m, 2H), 5.88-5.98 (m, 1H), 5.44-5.55 (m, 1H), 5.31 (s, 2H), 5.22 (dd, J=1.3, 10.4 Hz, 1H), 4.15-4.27 (m, 2H), 4.00-4.06 (m, 2H), 3.47 (d, J=6.5 Hz, 2H), 2.62 (s, 3H), 1.88-2.06 (m, 3H), 1.68-1.77 (m, 2H), 1.37 (br. s., 3H), 1.21-1.28 (m, 12H). LCMS (M+H)=591.6.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)=O.[CH2:23]([NH2:25])[CH3:24].C([BH3-])#N.[Na+]>CO.O.[Cl-].[Zn+2].[Cl-]>[CH2:23]([NH:25][CH2:1][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:24]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2CCC(C=O)CC2)cc1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCNCC1CCN(c2ccc(NC(=O)OC(C)(C)C)cc2)CC1
Reaction time: 0.33 h
Yield: 122.7 %

Procedure:
To a suspension of tert-butyl [4-(4-formyl-piperidin-1-yl)-phenyl]carbamate (0.20 g, 0.66 mmol) in methanol (5 mL) is added ethylamine (2.0 M solution in tetrahydrofuran, 0.66 mL, 1.3 mmol). The reaction mixture is stirred for 20 minutes and then a mixture of zinc chloride (53 mg) and sodium cyanoborohydride (50 mg) in methanol (2 mL) is added in a dropwise fashion. After stirring overnight at room temperature, the reaction mixture is diluted with water and extracted 3× with ethyl acetate. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give tert-butyl [4-(4-ethylaminomethyl-piperidin-1-yl)-phenyl]-carbamate as a foam (0.27 g, >100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[O:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:26]2[CH:27]=[CH:28][O:24][CH:25]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: OB(O)c1ccoc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2ccoc2)cc1
Yield: 27.5 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(furan-3-ylmethyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.080 g; 0.230 mmol), furan-3-ylboronic acid (0.027 g; 0.242 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, complex with dichloromethane (0.019 g; 0.023 mmol), sodium carbonate (0.050 g; 0.460 mmol), sodium iodide (0.069 g; 0.460 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 20 to 80% ethyl acetate in heptane) furnished 0.024 g (26%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12](C#C)=[CH:11][CH:10]=1)([CH3:8])[CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6].O=C(C1C=CC([Br:30])=CC=1)CCC(C)C.C[Al](C)C>CCCCCC>[CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([Br:30])=[CH:11][CH:10]=1)([CH3:8])[CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: C#Cc1ccc(C(C)(C)CCC(C)C)cc1
Reactant: CC(C)CCC(=O)c1ccc(Br)cc1
Agent: C[Al](C)C
Solvent: CCCCCC
Product: CC(C)CCC(C)(C)c1ccc(Br)cc1

Procedure:
Reaction Scheme 6 discloses specific synthetic steps leading to 4-(1,1,4-trimethylpentyl)phenylethyne (Compound 32). In this synthetic route 4-(1-oxo-4-methyl-pentyl)bromobenzene (Compound 29, obtained as shown in Reaction Scheme 5) is reacted under a nitrogen atmosphere with trimethylaluminum in hexane to yield 4-(1,1,4-trimethylpentyl)bromobenzene (Compound 33). The bromobenzene derivative 33 is converted through the corresponding trimethylsilylethyne derivative 34 into the target intermediate 32 by treatment with trimethylsilyl ethyne and subsequently with KOH in isopropanol, as described above. ##STR10##
Reaction SMILES: C(NCC)C.[CH2:6]([O:8][C:9](=[O:37])[CH:10]([CH2:14][C:15]1[CH:16]=[N:17][C:18]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:19]([CH3:21])[CH:20]=1)[C:11](O)=O)[CH3:7].C=O.C(OCC)(=O)C>C(Cl)Cl>[CH2:6]([O:8][C:9](=[O:37])[C:10]([CH2:14][C:15]1[CH:16]=[N:17][C:18]([N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:30]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])=[C:19]([CH3:21])[CH:20]=1)=[CH2:11])[CH3:7]
Reactant: CCOC(=O)C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1)C(=O)O
Agent: C=O
Solvent: CCOC(C)=O
Solvent: CCNCC
Solvent: ClCCl
Product: C=C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.5 %

Procedure:
Diethylamine (0.26 g, 2.67 mmol) was added a mixture of 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]-5-methyl-pyridin-3-ylmethyl)-malonic acid monoethyl ester (1.0 g, 2.2 mmol) and 37% aq. solution of formaldehyde (0.24 g, 3.00 mmol) in methylene chloride (2 mL) at 0° C. The mixture was stirred for 16 h at room temperature and ethyl acetate was added. The organic layer was washed with water and 5% NaHCO3 and dried. Concentration under reduced pressure followed by flash chromatography (toluene/ethyl acetate, 3:1→1:2) gave 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]-5-methyl-pyridin-3-ylmethyl)-acrylic acid ethyl ester (0.68 g, 73%).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:27]([C:3]1[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]=1[C:33]1[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=1)[CH3:28]
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCc1nc(CC)c(-c2ccc(F)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 90.8 %

Procedure:
To a solution of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (1.0 g) and 4-fluorophenylboronic acid (0.48 g) in 1,4-dioxane (20 mL) were added 2 M aqueous cesium carbonate solution (4 mL) and [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium (0.1 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.94 g, 91%) as a colorless solid.
Reaction SMILES: II.Br[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:12][CH:13]([CH3:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[O:26].Cl>O1CCCC1.[Zn]>[OH:26][CH:25]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([CH3:27])[CH3:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)CCCCCCCCCCCC=O
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Product: CC(C)CCCCCCCCCCCC(O)CC(=O)OC(C)(C)C
Yield: 52.6 %

Procedure:
A suspended solution of activated zinc (118 mg), a small crystal of iodine, and tetrahydrofuran (3 ml) was stirred under refluxing. To the mixture was added a solution of tert-butyl bromoacetate (312 mg) and 13-methyltetradecanal (226 mg) in tetrahydrofuran (3 ml), and the reactants were stirred under refluxing for 1 hour. Anhydrous conditions were maintained throughout this experiment. The cooled solution was poured into 0.1N hydrochloric acid (5.6 ml) and the resultant solution was adjusted to pH 2.0 with 2N hydrochloric acid. The excess of zinc was filtered off and the crude products were extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate solution and brine, and then dried over magnesium sulfate. The ethyl acetate was evaporated off under reduced pressure to give the crude ester, which was purified by column chromatography on silica gel (Merck) and eluted with a mixture of cyclohexane and ethyl acetate (19:1). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was dried by high vacuum pump to afford an oil of tert-butyl 3-hydroxy-15-methylhexadecanoate (180 mg).
Reaction SMILES: [Br:1][C:2]([Br:12])=[CH:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C>ClCCl>[Br:1][C:2]([Br:12])=[CH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: OCc1ccc(C=C(Br)Br)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=Cc1ccc(C=C(Br)Br)cc1
Yield: 64.6 %

Procedure:
The above alcohol (3.18 g) was oxidised using the conditions of Swern oxalyl chloride, 0.96 ml, dimethyl sulphoxide, 1.56 ml; triethylamine, 6.9 ml) in dichloromethane to give 4-(2,2-dibromoethenyl)benzaldehyde (2.04 g). NMR 1H 10.94 (1H,s), 7.86(2H,d), 7.61(2H,d), 7.45(1H,s).