Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH3:10].[Li]CCCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH3:10])=[C:2]([B:16]([OH:21])[OH:17])[CH:7]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CSc1ccc(F)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(F)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
The (2-bromo-4-fluorophenyl)(methyl)sulfane (700 mg, 3.17 mmol) was dissolved in THF (5 mL) and cooled to −78° C. To the cooled solution was added n-BuLi (2.18 mL, 3.48 mmol) dropwise. The reaction was stirred for 2 min at −78° C. then the triisopropyl borate (0.804 mL, 3.48 mmol) was added dropwise and the reaction mixture was allowed to warm to 0° C. over a period of approximately 90 min. The reaction was quenched by addition of 1N HCl solution and was stirred for 5 min. The mixture was then extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (1×30 mL), brine (1×30 mL) and dried over magnesium sulfate. The crude product was then triturated with hexanes. The resulting solid was purified by medium pressure chromatography (silica gel, 0 to 50% EtOAc:hexanes) to give 5-fluoro-2-(methylthio)phenylboronic acid. Mass Spectrum (ESI) m/e=187.0 (M+1).
Reaction SMILES: Cl[C:2]1[CH:42]=[CH:41][C:5]([CH2:6][O:7][CH:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[CH:16][CH:15]=3)[CH2:12][CH2:11][N:10]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:9]2)=[CH:4][C:3]=1[O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48].[C-:49]#[N:50].[Na+].C1OCCOCCOCCOCCOC1.O>C1(C)C=CC=CC=1.[Ni]>[C:49]([C:2]1[CH:42]=[CH:41][C:5]([CH2:6][O:7][CH:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[CH:16][CH:15]=3)[CH2:12][CH2:11][N:10]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:9]2)=[CH:4][C:3]=1[O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48])#[N:50]
Reactant: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1Cl
Reactant: [C-]#N
Agent: [Ni]
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C#N

Procedure:
The mixture, prepared under argon, of 0.280 g of tert-butyl 3-[4-chloro-3-(3-methoxypropoxy)benzyloxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 31a), 0.080 g of sodium cyanide and 0.005 ml of 15-crown-5 in 2 ml of toluene is initially charged at room temperature with stirring and admixed with 0.75 ml of Ni-catalyst solution (preparation described below). The reaction mixture is stirred at 80° C. for 24 hours and then admixed with a further 0.75 ml of Ni catalyst solution. The reaction mixture is stirred at 80° C. over a further 24 hours and then admixed once more with 0.75 ml of Ni catalyst solution. After stirring for a further 24 hours, the mixture is cooled, admixed with water (30 ml) and extracted with ethyl acetate (2×30 ml). The organic phases are washed with brine (1×30 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.38 (2:1 EtOAc-heptane); Rt=6.10.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[OH:28][C@H:24]1[CH2:25][CH2:26][CH2:27][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC[C@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC[C@H](O)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 118 using (S)-5-bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 124.1) and pyrimidin-5-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=2.22 min, m/z=460.0 [M+H]+, m/z=458.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.21-1.39 (m, 2H) 1.56-1.65 (m, 1H) 1.77-1.86 (m, 1H) 2.63 (dd, J=11.86, 8.19 Hz, 1H) 2.75-2.84 (m, 1H) 3.35-3.39 (m, 1H) 3.43-3.49 (m, 1H) 3.49-3.55 (m, 1H) 4.74 (s, 1H) 7.37 (d, J=8.31 Hz, 2H) 7.83-7.89 (m, 2H) 8.19 (d, J=2.20 Hz, 1H) 8.80 (d, J=2.20 Hz, 1H) 9.08 (s, 2H) 9.21 (s, 1H) 10.30 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([CH3:19])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:20]([O-:23])(O)=O.[Na+]>C1(C)C=CC=CC=1.CCO>[CH3:19][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[CH:3]=[C:2]([C:2]3[C:7]([CH:20]=[O:23])=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:7]=[CH:6][CH:5]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(Nc2cccc(Br)c2)c2ccccc2n1
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(Nc2cccc(-c3ccccc3C=O)c2)c2ccccc2n1
Temperature: 80 °C
Yield: 37.4 %

Procedure:
To a stirred suspension of 71 (411 mg, 1.31 mmol) in toluene (12.8 mL) under N2 were sequentially added saturated NaHCO3 (aq. 0.5 mL), a solution of 99 (303 mg, 2.02 mmol) in EtOH (8.9 mL), and PdCl2(Ph3P)3 (52 mg, 0.07 mmol). The reaction was heated at 80° C. for 41 hours before it was allowed to cool to room temperature and extracted with ethyl acetate (50 mL). The ethyl acetate extracts were washed with water (30 mL), brine (30 mL), dried (MgSO4), and concentrated. The residue was chromatographed on silica gel (dichloromethane to 20:1 dichloromethane/methanol) to give 100 as a yellow solid (166 mg, 37.4%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:25]4[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=4)=[CH:15][N:16]3[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.Cl[CH2:34][CH2:35][N:36]([CH3:38])[CH3:37].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:37][N:36]([CH3:38])[CH2:35][CH2:34][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:14]2[C:13]3[C:17](=[CH:18][C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)=[CH:11][CH:12]=3)[N:16]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)[CH:15]=2)=[CH:26][CH:27]=1
Reactant: O=[N+]([O-])c1cccc(-c2ccc3c(-c4ccc(O)cc4)cn(-c4ccncc4)c3c2)c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CN(C)CCOc1ccc(-c2cn(-c3ccncc3)c3cc(-c4cccc([N+](=O)[O-])c4)ccc23)cc1

Procedure:
The target compound was prepared as in Example 18 using 4-(6-(3-nitrophenyl)-1-(pyridin-4-yl)-1H-indol-3-yl)phenol (32 mg, 0.079 mmol), 2-chloro-N,N-dimethylethylamine hydrochloride (34 mg, 0.237 mmol) and cesium carbonate (154 mg, 0.237 mmol).
Reaction SMILES: C(OC([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:28])(=[O:27])[NH2:26])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:36]([CH2:38][CH2:39][CH3:40])[CH3:37]>CN(C=O)C>[CH3:37][CH:36]([NH:26][S:25]([N:20]1[C:21]2([CH2:22][CH2:23]2)[CH2:24][N:17]([C:16]2[C:11]3[CH:10]=[CH:9][NH:8][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:18][CH2:19]1)(=[O:27])=[O:28])[CH2:38][CH2:39][CH3:40]
Reactant: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(N)(=O)=O)C4(CC4)C3)ncnc21
Reactant: CCCC(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCC(C)NS(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 60 °C
Reaction time: 16 h

Procedure:
4-(4-Sulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 2) (0.049 mmol) was dissolved in dry DMF (1 mL) and added Cs2CO3 (0.147 mmol) and 2-bromopentane (0.074 mmol). Stirred at 60° C. for 16 h and then filtered through a syringe filter. The obtained filtrate was added 2,2,2-trifluoroethanol (1 mL) and heated to 100° C. for 1 h. The pure compound was obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:29]=[CH:28][C:17]2[C@:18]3([CH3:27])[C@@H:23]([CH2:24][CH2:25][C:16]=2[CH:15]=1)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3)([O-:3])=[O:2].[C:30](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:30][N:22]1[C@H:23]2[C@@:18]([CH3:27])([C:17]3[CH:28]=[CH:29][C:14]([C:5]4[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:4]=4[N+:1]([O-:3])=[O:2])=[CH:15][C:16]=3[CH2:25][CH2:24]2)[CH2:19][CH2:20][C:21]1=[O:26]
Reactant: CC(C)(C)O
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccc(C(F)(F)F)cc3[N+](=O)[O-])ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(C(F)(F)F)cc4[N+](=O)[O-])cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(2-nitro-4-trifluoromethylphenyl )-10b-methyl -1,2,3,4, 4a, 5,6,10b-octahydrobenzo[f]quinolin-3-one (48 mg, 0.12 mmol), 0.3 mL of t-butanol, and potassium t-butoxide (40 mg, 0.36 mmol). Methyl iodide (0.022 mL, 0.36 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 38 mg (76%) of the title compound as an off- white solid. mp 55°-57°. FDMS: m/e =418. α[D]589 =+60.50 (c=0.16, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13].C(OC(=O)C)(=O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:13][CH2:12][C:11]([OH:15])=[O:14]
Reactant: C=CC(=O)O
Reactant: Clc1ccc2[nH]ccc2c1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)CCc1c[nH]c2ccc(Cl)cc12
Temperature: 100 °C
Reaction time: 48 h
Yield: 24.4 %

Procedure:
A mixture of 5-chloro-1H-indole (2.5 g; 16.49 mmol), acrylic acid (2.49 mL; 36.28 mmol) and acetic anhydride (3.09 mL; 32.98 mmol) in acetic acid was stirred at 100° C. for 48 hours, concentrated under reduced pressure and diluted in NaOH 3N (water), the precipitate was filtered off and the solution acidified to pH 2 and extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure and the crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) and (eluent: 15 to 60% of ethyl acetate in heptane) to give 0.900 g (24%) of 3-(5-chloro-1H-indol-3-yl)propanoic acid as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([NH:13][C:14]1[CH:38]=[CH:37][C:17]([C:18]([NH:20][CH2:21][C:22]3[CH:36]=[CH:35][C:25]([CH2:26][NH:27]C(=O)OC(C)(C)C)=[CH:24][CH:23]=3)=[O:19])=[CH:16][CH:15]=1)=[O:12])[CH2:5]2.FC(F)(F)C(O)=O>ClCCl>[NH2:27][CH2:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][NH:20][C:18]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:11]([N:6]3[CH2:5][C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[CH2:7]3)=[O:12])=[CH:38][CH:37]=2)=[O:19])=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNC(=O)c2ccc(NC(=O)N3Cc4ccc(F)cc4C3)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(CNC(=O)c2ccc(NC(=O)N3Cc4ccc(F)cc4C3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 4-((4-(5-fluoroisoindoline-2-carboxamido)benzamido)methyl)benzylcarbamate (392 mg, 0.756 mmol) was dissolved in dichloromethane, treated with trifluoroacetic acid (582 μl, 7.56 mmol), stirred for 3 hours at ambient temperature and then concentrated to dryness. The resulting solid was triturated with ether, collected and dried under vacuum to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.01 (q, J=5.6 Hz, 2H), 4.46 (d, J=6.0 Hz, 2H), 4.76 (d, J=7.9 Hz, 4H), 7.08-7.29 (m, 2H), 7.32-7.44 (m, 5H), 7.67 (d, J=8.7 Hz, 2H), 7.76-7.86 (m, 2H), 8.12 (s, 2H), 8.63 (s, 1H), 8.91 (t, J=6.2 Hz, 1H); MS (ESI(+)) m/e 419 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:16](C1C=C(C=CC=1)C(Cl)Cl)C1C=CC=CC=1.C1N2CN3CN(C2)CN1C3.Cl>C(O)C.C(O)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)c1cccc(Oc2ccccc2)c1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: O=Cc1cccc(Oc2ccccc2)c1

Procedure:
A process according to claim 1, wherein the mixture of m-phenoxybenzyl chloride (II) and m-phenoxybenzal chloride (III) (X = chlorine) is reacted with 1 to 2 molar equivalent of hexamethylenetetramine in hot aqueous ethanol or hot aqueous acetic acid and hydrolyzing the mixture with dilute hydrochloric acid to yield m-phenoxybenzaldehyde (I).
Reaction SMILES: [NH3:1].[CH3:2][S:3][C:4]1[S:8][C:7]([C:9](OC)=[O:10])=[CH:6][C:5]=1[C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1>>[CH3:2][S:3][C:4]1[S:8][C:7]([C:9]([NH2:1])=[O:10])=[CH:6][C:5]=1[C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1
Reactant: N
Reactant: COC(=O)c1cc(-c2nc(-c3ccccc3)cs2)c(SC)s1
Product: CSc1sc(C(N)=O)cc1-c1nc(-c2ccccc2)cs1
Temperature: 80 °C
Yield: 88 %

Procedure:
Liquid ammonia (5 mL) was condensed into a cold (−78° C.) Teflon-lined steel bomb. Methyl 5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate (0.6 g, 1.7 mmol) as prepared in Example 10 step (a) was introduced in one portion and the bomb was sealed and heated in an oil bath at 80° C. for 48 h. The bomb was cooled to −78° C., opened and the ammonia was allowed to evaporate at room temperature. The residual solid was collected and dried under vacuum to give 0.5 g (88%) of 5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamide. 1H-NMR (DMSO-d6; 300 MHz) δ2.75 (s, 3H), 7.35-7.40 (m, 1H), 7.40-7.51 (m, 2H), 8.04-8.18 (m, 2H), 8.19 (s, 1H), 8.20 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([NH:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25]C(=O)C)=O)=[C:3]([C:5](=[O:15])[NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].[OH-].[K+].Cl>C(O)C.O>[OH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[C:3]([CH3:4])=[C:2]([CH3:1])[N:16]=1
Reactant: CC(=O)Oc1ccccc1C(=O)NC(C)=C(C)C(=O)NCCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccccc2O)n(CCc2ccccc2)c(=O)c1C
Yield: 37 %

Procedure:
Acetic acid 2-(1-methyl-2-phenethylcarbamoyl-propenylcarbamoyl)-phenyl ester of Example 1f (220 mg, 0.59 mmol) was dissolved in the mixture of ethanol (8 mL) and water (8 mL) which contained 85% potassium hydroxide (0.80 g, 1.2 mmol). The mixture was refluxed overnight. After cooling, the reaction mixture was acidified with hydrochloric acid to pH=1 and extracted with dichloromethane (3×30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL) and dried over anhydrous sodium sulfate. After concentration, the product was purified by flash chromatography on silica gel (39 g) eluting with hexanes-ethyl acetate (1:1) to give 2-(2-hydroxy-phenyl)-5,6-dimethyl-3-phenethyl-3H-pyrimidin-4-one (70 mg, 37%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=O.C(Cl)(=O)C([Cl:14])=O.CN(C)C=O>ClCCl>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][Cl:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccnc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: ClCc1cccnc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-chloronicotinic acid (500 mg, 3.17 mmol) in anhydrous dichloromethane (10 ml) was added dropwise oxalyl chloride (0.407 ml, 4.76 mmol) at a room temperature. A drop of anhydrous N,N-dimethylformamide was added and the reaction mixture stirred for 2 hours at a room temperature. Once the reaction was completed, intermediate product, i.e., 2-chloronicotinyl chloride was obtained with vacuum-concentration. Anhydrous dichloromethane (10 ml) was added, and then 3-anisidine (0.390 ml, 3.49 mmol) in anhydrous dichloromethane (5 ml) was added dropwise at 0° C. to a solution of the above mixture. Triethylamine (0.885 ml, 6.347 mmol) was added and the mixture was stirred for one hour at 0° C. Once the reaction was completed, water was added and the resultant mixture was extracted with dichloromethane. The separated organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain the title compound (970 mg, ivory oil).
Reaction SMILES: [CH2:1]([C:13]1[C:21]2[S:22][CH:23]=[CH:24][C:20]=2[C:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[C:15]2[S:16][CH:17]=[CH:18][C:14]=12)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([Li])CCC.[CH3:42][Sn:43](Cl)([CH3:45])[CH3:44].O>O1CCCC1>[CH2:1]([C:13]1[C:21]2[S:22][C:23]([Sn:43]([CH3:45])([CH3:44])[CH3:42])=[CH:24][C:20]=2[C:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[C:15]2[S:16][C:17]([Sn:43]([CH3:45])([CH3:44])[CH3:42])=[CH:18][C:14]=12)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1c2ccsc2c(CCCCCCCCCCCC)c2ccsc12
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCc1c2cc([Sn](C)(C)C)sc2c(CCCCCCCCCCCC)c2cc([Sn](C)(C)C)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
Preparation of 4,8-didodecyl-2,6-Bis-trimethylstannylbenzo[1, 2-1):4,5-b′]dithiophene. To a solution of 4,8-didodecylbenzo[1,2-b:4,5-b′]dithiophene (553 mg, 1.05 mmol) in dry tetrahydrofuran (16 mL) was added n-butyllithium (2.5 M in hexane, 0.92 mL, 2.31 mmol) at −78° C. After 1 hour, trimethyltin chloride (488 mg, 2.45 mmol) was added in one portion. The mixture was stirred at room temperature for 2 hours, poured into water and extracted with ether three times. The organic layer was washed with brine and dried over anhydrous MgSO4. Upon evaporating the solvent, a pale yellow oil was obtained which is recrystallized from EtOH to give a white solid (524 mg, yield 58%). 1H NMR (CDCl3, 500 MHz) δ=7.51 (s, 2H), 3.22 (t, J=8.0 Hz, 4H), 1.76-1.91 (m, 4H), 1.36-1.42 (m, 4H), 1.22-1.42 (bs, 32H), 0.91 (t, J=7.0 Hz, 6H), 0.47 (s, 18 H). See also, Chem. Mater. 2006, 18, 3237.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:34]=[CH:33][C:13]([C:14]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:17]=3)=[O:15])=[CH:12][C:11]=2[O:35][CH2:36][CH2:37][CH2:38]Cl)=[CH:4][CH:3]=1.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:34]=[CH:33][C:13]([C:14]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:17]=3)=[O:15])=[CH:12][C:11]=2[O:35][CH2:36][CH2:37][CH2:38][N:51]2[CH2:50][CH2:49][N:48]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[O:41][CH3:40])[CH2:53][CH2:52]2)=[CH:4][CH:3]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(OCc3ccc(C)cc3)c(OCCCCl)c2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(OCc3ccc(C)cc3)c(OCCCN3CCN(c4ccccc4OC)CC3)c2)c2ccccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
Ethyl 4-{3-[4-(4-methylphenylmethoxy)-3-(3-chloropropoxy)benzoyl]indol-1-yl}butanoate (2.59 g) obtained in Step 2 was dissolved in N,N-dimethylformamide (30 ml). 1-(2-Methoxyphenyl)piperazine (1.36 g), potassium carbonate (0.85 g), and potassium iodide (1.02 g) were added to the resultant solution and stirred overnight at 60° C. The reaction mixture was poured into water and extracted with ethyl acetate. The resultant extract was washed with brine and then dried. The solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2), obtaining 2.47 g of ethyl 4-{3-{4-(4-methylphenylmethoxy)-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzoyl}indol-1-yl}butanoate as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][C:8](C(O)=O)=[CH:7][C:6]=2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1.Cl.C(OCC)(=O)C>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[F:1][C:2]1[C:10]2[S:9][CH:8]=[CH:7][C:6]=2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2sc(C(=O)O)cc12
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: COc1ccc(F)c2sccc12
Temperature: 190 °C

Procedure:
A mixture of 7-fluoro-4-methoxy-1-benzothiophene-2-carboxylic acid (61.4 g, 271 mmol) and copper powder (22.4 g, 352 mmol) in quinoline (500 mL) was heated at 190° C. for 1 h. Cooled to ambient and poured onto aqueous hydrochloric acid (2 N, 750 mL). Stirred with ethyl acetate (500 mL) for 15 minutes. Filtered through Celite, washing with ethyl acetate. The aqueous layer was extracted into ethyl acetate and the combined organic layers were washed with aqueous hydrochloric acid (2 N, 500 mL), water (500 mL), brine (500 mL), dried over MgSO4 and evaporated in vacuo. Purified by column chromatography, eluting silica gel with iso-hexane/diethyl ether 0–5% to give the product as a brown oil which crystallised to give the title compound (41.3 g, 84%); δH (300 MHz, CDCl3) 7.51 (1H, m, ArH), 7.38 (1H, d, ArH), 6.98 (1H, t, ArH), 6.65 (1H, dd, ArH) and 3.92 (3H, s, OCH3).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](Br)=[CH:4][C:3]=1[CH3:10].C([O-])([O-])=O.[Na+].[Na+].[O:17]1[CH2:22][CH2:21]O[CH2:19][CH2:18]1>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:19]2[CH:21]=[CH:22][O:17][CH:18]=2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(Br)cc(C)c1Br
Reactant: C1COCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(-c2ccoc2)cc(C)c1Br
Temperature: 100 °C

Procedure:
A mixture of 2,5-dibromo-1,3-dimethylbenzene (2.00 g), 1-furan-3-ylboronic acid (856 mg), and 2 M aqueous Na2CO3 solution (11 mL) in 1,4-dioxane (40 mL) is purged with argon for 5 min. Tetrakis-triphenylphosphine-palladium-(0) (270 mg) is added and the mixture is stirred at 100° C. over night. More tetrakis-triphenylphosphine-palladium-(0) (50 mg) is added and the mixture is stirred for another 5 h at 100° C. After cooling to room temperature the mixture is diluted with ethyl acetate and aqueous NH4Cl solution. The aqueous phase is extracted with ethyl acetate and the combined extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 100:0→90:10) to give the title compound. LC (method 7): tR=1.22 min; Mass spectrum (EI+): m/z=250 [M]+.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25](NC3CCCC3)=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19].[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH:39][CH2:38][C:37]3[CH:40]=[CH:41][C:34]([Cl:33])=[CH:35][CH:36]=3)=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19]
Reactant: Nc1nc(-n2cc(C(=O)NC3CCCC3)cn2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NCc1ccc(Cl)cc1
Product: Nc1nc(-n2cc(C(=O)NCc3ccc(Cl)cc3)cn2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Compound 22 was prepared in a manner similar to that of compound 21 using 4-chlorobenzylamine instead of cyclopentylamine, MS 501.19 (M+1).