Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=O)[NH:19][CH:20]([C:37]2[C:42]([Cl:43])=[N:41][CH:40]=[CH:39][N:38]=2)[C:21]2[CH:30]=[C:29]3[C:24]([CH:25]=[CH:26][C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:28]3)=[CH:23][CH:22]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.CN(C=O)C>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][C:18]2[N:38]3[CH:39]=[CH:40][N:41]=[C:42]([Cl:43])[C:37]3=[C:20]([C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[N:28]4)=[CH:23][CH:22]=3)[N:19]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CC1CCN(C(=O)OCc2ccccc2)CC1)NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1CCC(Cc2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)CC1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A solution of 4-({[(3-chloro-pyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]-carbamoyl}-methyl)-piperidine-1-carboxylic acid benzyl ester in anhydrous acetonitrile (165 mL) was charged with POCl3 (2.03 mL, 21.84 mmol) and DMF (2.15 mL) and heated to 55° C. under N2 condition. After 2 h, LC/MS and TLC analysis showed the reaction to be completed. The reaction mixture was concentrated in vacuo, diluted with CH2Cl2, and quenched with 2N (7N NH3) in 2-propanol to pH 9. 2-Propanol was removed in vacuo. The crude product was purified by silica gel flash chromatography (loaded with 40% EtOAc/Hexanes, and run 50% EtOAc/Hexanes→80% EtOAc/Hexanes), which afforded the desired product; 1H NMR (400 MHz, DMSO-d) 5 ppm 8.53 (1H, d, J=8.52), 8.45 (1H, d, J=5.00), 8.31 (3H, m), 8.21 (1H, d, J=8.66), 8.08 (1H, d, J=8.47), 7.56 (3H, m), 7.49 (1H, d, J=5.00), 7.34 (5H, m), 5.07 (2H, s), 4.02 (2H, d, J=12.8), 3.32 (2H, s), 3.11 (2H, d, J=6.92), 2.82 (1H, m), 2.13 (1H, m), 1.73 (2H, d, J=12.26), 1.21 (2H, m); MS (ES+): m/z 589.97 (5) [MH+]; HPLC: tR=3.72 min (OpenLynx, polar—5 min).
Reaction SMILES: CN(C(ON1N=[N:16][C:11]2[CH:12]=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:25]([C:32]1[CH:33]=[C:34]([CH:49]=[CH:50][CH:51]=1)[CH2:35][NH:36][C:37]1[CH:42]=[CH:41][C:40]([C@@H:43]2[CH2:45][C@H:44]2[C:46](O)=[O:47])=[CH:39][CH:38]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N)(C)C.CCCCCC>CN(C)C=O.O.C(OCC)(=O)C>[CH3:10][CH:11]([NH:16][C:46]([C@@H:44]1[CH2:45][C@H:43]1[C:40]1[CH:39]=[CH:38][C:37]([NH:36][CH2:35][C:34]2[CH:49]=[CH:50][CH:51]=[C:32]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:33]=2)=[CH:42][CH:41]=1)=[O:47])[CH3:12]
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.6 %

Procedure:
HATU (0.159 g, 0.42 mmol) was added to a solution of (+)-(trans)-2-{4-[(3-phenoxybenzyl)amino]phenyl}cyclopropanecarboxylic acid (III-3b) (0.100 g, 0.28 mmol) in 3 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 10 minutes and 0.059 mL (0.69 mmol) of isopropylamine was added. After stirring at room temperature for 15 minutes, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate and concentrated. Chromatography on silica gel with hexane:ethyl acetate gave 0.068 g (61% yield) of the title compound as a white powder. NMR (400 MHz, CDCl3) δ 7.32 (d, J=8.61 Hz, 2H), 7.28 (d, J=8.6 Hz, 2H), 7.10 (t, J=8.42 Hz, 1H), 7.00 (m, 1H), 6.97 (d, J=6.59 Hz, 2H), 6.89 (d, J=8.61 Hz, 2H), 6.87 (m, 1H), 6.52 (d, J=8.61 Hz, 2H), 5.37 (d, J=7.51 Hz, 1H), 4.27 (s, 2H), 4.10 (septet, J=6.59 Hz, 1H), 4.00 (br s, 1H), 2.36 (m, 1H), 1.52 (m, 1H), 1.40 (m, 1H), 1.15 (d, J=4.21 Hz, 3H), 1.14 (d, J=4.40 Hz, 3H), 1.10 (m, 1H). ES-MS m/z 401 (M-H)+. [α]25,D=+183° (chloroform, c=1.5).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1)=[O:31]
Reactant: COc1ccc(-c2ccccc2)c2sc(N)nc12
Reactant: COc1ccccc1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)Nc1nc2c(OC)ccc(-c3ccccc3)c2s1

Procedure:
To a solution of 2-amino-4-methoxy-7-phenyl-benzothiazole (200 mg, 0.67 mmol) in THF (10 m) was added DMAP (10 mg, 0.08 mmol), triethylamine (163 □l, 1.17 mmol) and 2-methoxybenzoyl chloride (136 □l, 1 mmol) in THF (2 ml). The mixture was then heated to reflux for 2 h, after cooling, it was partitioned between 1:1 AcOEt/THF (70 ml) and 5% NaHCO3 solution (40 ml). The organic phase was washed with saturated NaCl solution (50 ml), dried with Na2SO4, filtered and the solvent removed under reduced presure. The residue was suspended in ether (10 ml), filtered, washed with ether then dried under vacuum (0.05 mmHg, 60° C.), to afford the title compound was a white solid (260 mg, 85% yield), MS: m/e=390.0 (M+).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([CH:18]=1)[CH:16]=[O:17].C(=O)([O-])[O-].[Na+].[Na+].C(O)(C)C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O>[CH3:20][O:19][C:14]1[C:13]([O:21][CH3:22])=[CH:12][C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(Br)cc(C=O)c1OC
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1cc(-c2ccccc2)cc(C=O)c1OC

Procedure:
A stirred mixture of benzeneboronic acid (0.610 g; 5 mmol), 5-bromo-2,3-dimethoxybenzaldehyde (1.00 g; 4.1 mmol), bis(triphenylphosphine)palladium (II) chloride (0.050 g; 0.071 mmol), sodium carbonate (0.848 g; 8 mmol), isopropanol (40 mL) and water (4.0 mL) was bubbled with nitrogen for fifteen minutes then heated under reflux overnight. The mixture was evaporated, the residue stirred with water and dichloromethane and the organic layer dried and evaporated. The residue was taken up in boiling cyclohexane (40 mL twice) and filtered hot. The solution was chromatographed on silica using cyclohexane to elute triphenylphosphine and 10% ethyl acetate—90% cyclohexane to elute product 21 (0.87 g) as a white crystalline solid:
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=2[O:2]1.[C:13]([NH:16][CH2:17]CO)(=[O:15])[CH3:14]>>[OH:2][C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1[O:9][CH2:1][CH2:17][NH:16][C:13](=[O:15])[CH3:14]
Reactant: O=[N+]([O-])c1ccc2c(c1)OCO2
Reactant: CC(=O)NCCO
Product: CC(=O)NCCOc1ccc([N+](=O)[O-])cc1O
Temperature: 100 °C

Procedure:
0.05 mol (8.35 g) of 3,4-methylenedioxynitrobenzene is introduced into 42 ml of N-acetylethanolamine. The mixture is heated to the region of 100° C., with stirring, and 0.055 mol (3.7 ml) of 15N potassium hydroxide solution is then added. After heating for one hour, 0.050 mol (3.3 ml) of 15N potassium hydroxide solution is added and the reaction medium is stirred at 100° C. for a further 3 hours and then poured onto 120 g of crushed ice. The unreacted starting material, which is insoluble in an alkaline medium, is filtered off. The filtrate is then acidified to pH=5.6 with hydrochloric acid in order to precipitate the expected product. It is filtered off, washed with water and dried in vacuo. It melts at 165° C.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH2:13]1[CH2:23]CN2C(=NCCC2)C[CH2:14]1.C(Br)C=C>CN(C=O)C>[CH2:23]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[CH:13]=[CH2:14]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C1CCC2=NCCCN2CC1
Solvent: C=CCBr
Solvent: CN(C)C=O
Product: C=CCON1C(=O)c2ccccc2C1=O
Reaction time: 0.17 h
Yield: 93.4 %

Procedure:
To a cooled solution (5 to 10° C.) of N-hydroxyphthalimide (53.80 g, 0.33 mol) in DMF (120 mL), was added DBU (46.36 mL, 0.31 mol) was added in one portion, with stirring. After 10 minutes, allyl bromide (25.96 mL, 0.30 mol) was added in portions. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 hour, until the color turned from dark burgundy to yellow. Ethyl acetate (300 mL) and water (150 mL) were added, the aqueous phase was separated, and the organic phase was washed with water (4×50 mL). The combined aqueous extracts were back-extracted with EtOAc (3×50 mL) and the total EtOAc solution was washed with saturated NaHCO3 (10×50 mL) until the aqueous phase was pale yellow, then with brine (2×75 mL) and dried over anhydrous MgSO4. Removal of the solvent afforded 58.83 g (96% yield) of the product as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]1[CH:22]=[CH:21][C:7]([CH:8]=[N:9][NH:10][C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:23]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[N:9][N:10]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:21][CH:22]=1)[CH3:24]
Reactant: CCN(CC)c1ccc(C=NNC(=O)c2ccc(OC)cc2)cc1
Reactant: Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)c1ccc(C=NN(Cc2ccc(C)cc2)C(=O)c2ccc(OC)cc2)cc1
Temperature: 45 °C
Yield: 89.3 %

Procedure:
To a solution of 4-methoxy-benzoic acid (4-diethylamino-benzylidene)-hydrazide (1) (0.28 g, 0.00086 mol) in DMF (10 ml), was added α-bromo-p-xylene (0.48 g, 0.0026 mol) and powdered K2CO3 (0.83 g, 0.006 mol) and the resulting mixture heated at 45° C. overnight. After cooling to ambient temperature, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were concentrated to an oil, which was purified by flash chromatography (gradient elution, 9:1 to 7:3 Hexanes/EtOAc to give the desired product as oil 0.33 g in 88% yield. 1H NMR (CDCl3) δ 7.91 (d, 2H), 7.63 (s, 1H), 7.30 (d, 2H), 7.20 (d, 2H), 7.14 (d, 2H), 6.97 (d, 2H), 6.57 (d, 2H), 5.38 (s, 2H), 3.90 (s, 3H), 3.37 (q, 4H), 2.32 (s, 3H), 1.16 (t, 6H). 13C NMR (CDCl3) δ 167.3, 158.3, 145.8, 137.9, 133.8, 129.9, 126.7, 125.8, 124.2, 118.9, 111.2, 109.8, 108.3, 52.5, 42.5, 41.5, 18.2, 9.6.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[C:5]([CH2:21][OH:22])[N:4]=1.I[CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33].C(N(C(C)C)CC)(C)C>C(#N)C>[OH:22][CH2:21][C:5]1[CH:6]=[C:7]([O:9][CH2:10][CH2:11][N:12]([CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]=[C:3]([CH2:2][OH:1])[N:4]=1
Reactant: COCCOCCOCCI
Reactant: CCOC(=O)CCCNCCOc1cc(CO)nc(CO)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN(CCOCCOCCOC)CCOc1cc(CO)nc(CO)c1
Temperature: 80 °C
Yield: 19.3 %

Procedure:
To a solution of 180 mg of ethyl 4-[2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethylamino]-butanoate in 18 ml of acetonitrile was added 207 mg of 1-iodo-2-[2-(2-methoxy-ethoxy)-ethoxy]-ethane and 192 μl of diisopropylethylamine. The mixture was heated for 3 days at 80° C. and then concentrated under reduced pressure and purified by flash chromatography on silica (Merck SuperVarioFlash 15 g column, Si60 15-40 μm), using a DCM/MeOH/water mixture (40/5/0.5). The fractions containing the desired product were combined and concentrated under reduced pressure. 51 mg of ethyl 4-([2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethyl]-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl}-amino)-butanoate were obtained. LC/MS (B): tr=0.70 min; [M+H]+: m/z 459.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.C(C)(C)C([O-])=O.[K+].O>CS(C)=O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:11])=[CH:16][CH:15]=1
Reactant: Cc1cccc([N+](=O)[O-])c1F
Reactant: COc1ccc(N)cc1
Agent: CC(C)C(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Nc2c(C)cccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42 %

Procedure:
To a solution of 50 g of 2-fluoro-3-nitrotoluene in 1.1 L of DMSO are added at room temperature 59.5 g of para-anisidine (1.5 equivalents). After 5 minutes of stirring at room temperature, 57.9 g of potassium tert-butanoate (1.6 equivalents) are added to the reaction medium and the whole is heated to 110° C. for 1 hour. The reaction medium is directly hydrolyzed by adding 1 L of ice and water and then the aqueous phase is extracted several times with ethyl acetate. The organic phases are collected, dried on sodium sulphate, filtered and then dry concentrated. The raw product is chromatographed on silica gel (ether/cyclohexane:0/100, 5/95 and then 20/80) in order to provide 34.95 g of the expected compound as a dark red solid.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:10]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[N:12]=[CH:11]1>>[NH:10]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:7](=[O:9])[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[N:12]=[CH:11]1
Reactant: O=C(O)CC1CCCC1
Reactant: NCCCCc1c[nH]cn1
Product: O=C(CC1CCCC1)NCCCCc1c[nH]cn1

Procedure:
The preparation is carried out as in Example 1 with 2-cyclopentylacetic acid and 4-(1H-imidazol-4-yl)butanamine. The title compound is extracted from water with diethyl ether and recrystallized in the hydrogenmaleate form from ethanol/diethyl ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH2:7][NH:8][CH2:9][CH2:10][O:11][CH3:12])([CH3:4])(C)C.C(O)[C:15]1[CH:20]=[CH:19]C=[CH:17][CH:16]=1.O.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1.O>C1C=CC=CC=1>[C:23]1([CH3:33])[CH:24]=[CH:25][C:26]([S:29]([OH:32])(=[O:30])=[O:31])=[CH:27][CH:28]=1.[CH2:1]([O:5][C:6](=[O:13])[CH2:7][NH:8][CH2:9][CH2:10][O:11][CH3:12])[C:4]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1
Reactant: OCc1ccccc1
Reactant: COCCNCC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COCCNCC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a solution of 55.8 g of N-(2-methoxyethyl)glycine tert-butyl ester in 200 ml of benzene was added 63.8 g of benzyl alcohol and 72.9 g of p-toluenesulfonic acid monohydrate. The mixture was heated at reflux for 10 hours with the continuous removal of water through a Dean-Stark water trap. At the end of this period, the solution was concentrated in vacuo, and to the residue was added 300 ml of dry ethyl ether. After 2 hours at room temperature, the formed precipitate was filtered, washed with dry ethyl ether and then recrystallized from ethyl acetate to yield 99.2 g (85 percent) of N-(2-methoxyethyl)glycine benzyl ester p-toluenesulfonate, M.P. 95°-96° C.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH:18]1(B(O)O)[CH2:20][CH2:19]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1.O>[CH:18]1([C:2]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:3]=2[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH2:20][CH2:19]1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1Br
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1C1CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a solution of tert-butyl 2-bromo-4-nitrobenzoate (1.5 g) obtained in Step A of Example 301 in a mixed solvent of toluene-water (v/v=5/1, 18 mL) were successively added cyclopropylboronic acid (1.3 g), tripotassium phosphate (4.7 g), tricyclohexyl phosphine (280 mg) and palladium acetate (110 mg), and the mixture was stirred overnight at 100° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([F:29])=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26](O)=[O:27])=[CH:21][CH:20]=[CH:19]2.S(Cl)([Cl:32])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([F:29])=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([Cl:32])=[O:27])=[CH:21][CH:20]=[CH:19]2
Reactant: COc1cc2nccc(Oc3ccc4c(C(=O)O)cccc4c3F)c2cc1OC
Reactant: O=S(Cl)Cl
Product: COc1cc2nccc(Oc3ccc4c(C(=O)Cl)cccc4c3F)c2cc1OC

Procedure:
A suspension of 6-(6,7-dimethoxyquinolin-4-yloxy)-5-fluoro-1-naphthoic acid (1.23 g, 3.12 mmol) in thionyl chloride (3 mL, excess) was refluxed for 1.5 h. The reaction mixture was concentrated in-vacuo and azeotroped with toluene (×2) to give the title compound as a brown solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH3:9])[C:3]=1[CH3:10].[CH3:11][O-:12].[Na+].CS(C)=O>O>[CH3:11][O:12][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH3:9])[C:3]=1[CH3:10]
Reactant: Cc1cnc(C)c(C)c1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1c(C)cnc(C)c1C
Reaction time: 8 h

Procedure:
60 g (0.39 mol) 4-chloro-2,3,5-trimethylpyridine and 21.7 g (0.40 mol) sodium methoxide and 180 ml dry dimethylsulfoxide was heated with stirring to 55°-60° C. for 8 hrs. The reaction mixture was diluted with 600 ml water and extracted with 3x100 ml toluene and the organic layer washed with 2x50 ml water. The organic phase was added to 200 ml water and pH adjusted to 4.1 with stirring. This process was repeated twice with 200 ml and 100 ml of water. The organic layer contained almost pure starting material. The combined water phase was made alkaline and extracted with 2×150 ml methylene chloride. Evaporation of solvent gave 40.7 g of almost pure 4-methoxy-2,3,5-trimethylpyridine. NMR: 2×3H, 2,2: 3H, 2,45(s); 3H, 3,75(s); 1H, 8,2(s). (CDCl3)
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([Si](C)(C)C)[S:4][C:3]=1[C:11]1[S:12][C:13]([Si](C)(C)C)=[CH:14][C:15]=1Br.C([Li])CCC.Cl[Si:27](Cl)([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].O>O1CCCC1.CCCCCC>[CH2:38]([Si:27]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:11]2[S:12][CH:13]=[CH:14][C:15]1=2)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: C[Si](C)(C)c1cc(Br)c(-c2sc([Si](C)(C)C)cc2Br)s1
Reactant: CCCCCCCCCC[Si](Cl)(Cl)CCCCCCCCCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCC[Si]1(CCCCCCCCCC)c2ccsc2-c2sccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
3,3′-dibromo-5,5′-bis(trimethylsilyl)-2,2′-bithiophene (Compound E4, synthesized in accordance with WO 2010/136353, 5.0 g) was placed in a 200 mL four-necked flask in a nitrogen atmosphere, and dissolved in tetrahydrofuran (75 mL). This was cooled to −78° C., and a solution of n-butyl lithium in hexane (KANTO CHEMICAL CO., INC., 1.64 M, 13.7 mL) was added dropwise. After about 30 minutes of agitation, the dichlorodi-n-decylsilane (Compound E21) (4.89 g) synthesized in Synthesis Example A19 was added dropwise. The temperature was gradually raised to room temperature over the course of about 2 hours, after which water was added, and the product was extracted with hexane. The organic layer was washed with water, dried with anhydrous sodium sulfate, and concentrated by filtration. The resulting yellow-orange oily substance was dissolved in hexane (50 mL) and chloroform (25 mL), trifluoroacetic acid (2.2 mL) was added with the internal temperature at 2° C., and after 10 minutes of agitation water was added, and the organic layer was washed, dried with anhydrous sodium sulfate and then and concentrated by filtration. Heptane (32 mL) was added to the reaction solution, which was then concentrated under reduced pressure. The resulting yellow-green oily substance was dissolved in hexane, and subjected to silica gel column chromatography (solvent: hexane) to obtain the target 4,4-di-n-decyl-dithieno[3,2-b:2′,3′-d]silole (Compound E22, 4.46 g, yield 88%).
Reaction SMILES: Cl[C:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12].[N-:16]=[N+]=[N-].[Na+].O>CS(C)=O>[CH:7]12[CH2:8][CH:4]([CH2:5][CH2:6]1)[C:3]1[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:16][C:2]2=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)/C=C/C1=C(Cl)C2CCC1C2
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2c([nH]1)C1CCC2C1
Temperature: 105 °C
Yield: 59.8 %

Procedure:
To a solution of 334b (5.0 g, 22 mmol) in DMSO (30 mL) was added NaN3 (2.2 g, 33 mmol) and the mixture was heated at 105° C. for 6 hours. Water (13 mL) was added to reaction the mixture after cooling down to room temperature, and resulting mixture was extracted with methylene chloride (50 mL×3). The organic phase was dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography eluting with 20:1 methylene chloride/methanol to give 334c as a brown solid (2.7 g, 60%). MS: [M+H]+ 206. 1H NMR (500 MHz, CDCl3) δ 11.51 (s, 1H), 6.45 (dd, 1H), 4.14-4.19 (m, 2H,), 3.25 (d, 2H,), 1.79-1.82 (m, 2H), 1.73 (d, 1H), 1.22-1.25 (t, J=6.5, 3H), 0.89-0.91 (m, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]2[C:17]3[CH:18]=[C:19]([CH2:22][C:23](OCC)=[O:24])[CH:20]=[CH:21][C:16]=3[O:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCC1C=C(O)C=CC=1OC(C)=O.BrCC(C1C=CC=CC=1)=O>CCOCC>[OH:24][CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]2[O:15][CH:14]=[C:13]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:17]=2[CH:18]=1
Reactant: CCOC(=O)Cc1ccc2occ(-c3ccccc3)c2c1
Agent: CCc1cc(O)ccc1OC(C)=O
Agent: O=C(CBr)c1ccccc1
Agent: [Al+3]
Solvent: CCOCC
Product: OCCc1ccc2occ(-c3ccccc3)c2c1

Procedure:
To a mixture of 200 ml. of diethyl ether and 3.8 g. (0.1 mole) of lithium aluminum hydride under nitrogen is added dropwise a solution of 16 g. (0.057 mole) of ethyl 3-phenylbenzofuran-5-acetate (prepared from ethyl 4-hydroxyphenyl acetate and α-bromoacetophenone by the method described in Belgian Pat. No. 846,502) in 70 ml. of ether at a rate sufficient to maintain reflux for a total of one hour. The reaction is terminated by cautiously adding water (a total of 100 ml.). A 65 ml. portion of 10 percent sulfuric acid is added, the layers are separated and the organic layer is washed twice with water, twice with saturated sodium chloride solution and dried. Evaporation to dryness provides an orange residue of 5-(2-hydroxyethyl)-3-phenylbenzofuran. The structural assignment is confirmed by infrared and nuclear magnetic resonance spectral analysis.