Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ICCO.O1CCC[CH2:7][CH:6]1[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[F:18][C:19]1[CH:37]=[C:36]([I:38])[CH:35]=[CH:34][C:20]=1[NH:21][C:22]1[C:23]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][NH:25][C:26](=[O:28])[CH:27]=1.[H-].[Na+].[I-]>CN(C=O)C.O>[F:18][C:19]1[CH:37]=[C:36]([I:38])[CH:35]=[CH:34][C:20]=1[NH:21][C:22]1[C:23]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][N:25]([CH2:7][CH2:6][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:26](=[O:28])[CH:27]=1
Reactant: C1CCC(OC2CCCCO2)OC1
Reactant: CCOC(=O)c1c[nH]c(=O)cc1Nc1ccc(I)cc1F
Agent: OCCI
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(CCOC2CCCCO2)c(=O)cc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Iodoethanol was protected as the tetrahydropyranyl ether according to a literature method [J. Org. Chem., 54(10), 2407 (1989)]. Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate (383 mg, 0.95 mmol) was dissolved/suspended in dry DMF (15 mL) and the solution cooled (ice/water). NaH (42 mg, 1.05 mmol) was added, the flask placed under nitrogen, and the resulting mixture allowed to warm and stirred at R.T. for 2 h. A solution of the protected iodide (1.22 g, 4.77 mmol) in dry DMF (5 mL) was added as a single portion and the entire mixture stirred at R.T. for 15 h. Water (100 mL) was added and the resulting aqueous suspension extracted with EtOAc (3×50 mL). The combined EtOAc fractions were then washed with water (2×50 mL) and brine (50 mL), then dried (Na2SO4). The solvent was removed under reduced pressure to afford an oil which was purified by chromatography on silica gel (50% EtOAc/hexanes as eluant). Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,6-dihydro-3-pyridinecarboxylate was isolated as a transparent oil which gave a waxy solid over time (249 mg, 49%), this material was used directly in the next step. 1H NMR [(CD3)2SO, 400 MHz] δ 9.31 (s, 1H), 8.49 (s, 1H), 7.78 (dd, J=10.2, 1.9 Hz, 1H), 7.61 (br d, J=8.6 Hz, 1H), 7.31 (t, J=7.5 Hz, 1H), 5.45 (s, 1H), 4.59 (br s, 1H), 4.30 (q, J=7.0 Hz, 2H), 4.11 (t, J=5.0 Hz, 2H), 3.75 (pentet, J=5.5 Hz, 1H), 3.61-3.49 (m, 2H), 3.40-3.32 (m, 1H), 1.74-1.33 (m, 6H), 1.30 (t, J=7.1 Hz, 3H). HRMS (EI+) calcd C21H24FIN2O5 (M+) 530.0714, found 530.0704.
Reaction SMILES: [CH:1](=[C:8]([C:12](=[O:14])[CH3:13])[C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(OCC)(=O)C>[CH2:1]([CH:8]([C:9](=[O:11])[CH3:10])[C:12](=[O:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(=Cc1ccccc1)C(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)C(Cc1ccccc1)C(C)=O
Yield: 99.3 %

Procedure:
3-Benzylidene-2,4-pentanedione (7, 6.50 g, 34.5 mmol) and palladium on activated carbon (0.25 g, 10%) were combined in ethyl acetate (50 ml). The mixture was placed under a hydrogen atmosphere (60 psi) on a Parr apparatus for 4 hr at room temperature. The resulting mixture was filtered through celite and the solvent evaporated to afford an oil. The crude oil was distilled bulb to bulb to give 6.52 g (99%) of a clear oil; 1H NMR: δ enol form: 2.02 (s, 6H), 3.62 (s, 2H), 7.24 (m, 5H); keto form: 2.07 (s, 6H), 3.11 (d, 2H, J=7.4 Hz), 4.01 (t, 1H, J=7.7 Hz), 7.24 (m, 5H); 13C NMR: δ 22.9, 29.4, 32.5, 33.8, 69.2, 107.9, 125.9, 126.3, 127.0, 128.1, 128.2, 137.7, 139.3, 191.4, 202.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: C1CCNCC1
Product: O=C(Nc1ccc(Oc2ccnc(N3CCCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and piperidine according to conditions described in general procedure C. 1H NMR (400 MHz, DMSO-d6) δ 1.34-1.58 (m, 12 H), 3.21-3.35 (m, 8 H), 6.18 (d, J=5.5 Hz, 1 H), 6.95 (d, J=12.4 Hz, 1 H), 7.15 (d, J=10.6 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.46 (s, 1 H), 7.55-7.60 (m, 3 H), 7.81-7.83 (m, 1 H), 7.97 (d, J=7.3 Hz, 1 H), 8.24 (d, J=5.5 Hz, 1 H), 10.43 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[C:13]([F:19])[CH:12]=1.ClC1C=CC(C(C2C=CC(OC)=CC=2)O)=CC=1>>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[CH3:9])[OH:16])=[C:13]([F:19])[CH:12]=1
Reactant: O=Cc1ccc(Cl)cc1F
Reactant: Cc1cc(F)ccc1Br
Agent: COc1ccc(C(O)c2ccc(Cl)cc2)cc1
Product: Cc1cc(F)ccc1C(O)c1ccc(Cl)cc1F

Procedure:
The title compound was prepared starting from 5.00 g (26.45 mmol) of 2-bromo-5-fluorotoluene and 5.03 g (31.74 mmol) of 4-chloro-2-fluorobenzaldehyde in analogy to the synthesis of the compound from Example 175A. A difference was that the crude product was purified twice by preparative HPLC. 4.84 g (65% of theory) of the title compound were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][C:7]([C:14]([F:17])([F:16])[F:15])=[C:6]([C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)[C:5]2=[O:28].[C:29]([Cu])#[N:30]>CN1C(=O)CCC1>[C:29]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][C:7]([C:14]([F:17])([F:16])[F:15])=[C:6]([C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)[C:5]2=[O:28])#[N:30]
Reactant: COC(=O)c1ccc(-c2c(C(F)(F)F)oc3cc(OC)c(Br)cc3c2=O)cc1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(-c2c(C(F)(F)F)oc3cc(OC)c(C#N)cc3c2=O)cc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
To a solution of methyl 4-(6-bromo-7-methoxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzoate (350 mg, 0.76 mmol) in NMP (3 mL) was added CuCN (340 mg, 3.8 mmol). The mixture was stirred at 150° C. for 8 h under the protection of nitrogen. The mixture was cooled to room temperature and quenched with water (10 mL) and filtered. The cake was washed with acetone (15 mL×2). The filtrate was concentrated in vacuo to give brown oil, which was purified by prep-TLC (PE/EA=5/1) to give product (125 mg, 40%) as a yellow solid. MS (ESI): 404.0 [M+1]+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C[Si]([C:15]#[C:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=1)[C:22]#[N:23])(C)C>>[C:8]([C:4]1[CH:3]=[C:2]([C:15]#[C:16][C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=2)[C:22]#[N:23])[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(I)c1
Reactant: C[Si](C)(C)C#Cc1cncc(C#N)c1
Product: CC(=O)c1cccc(C#Cc2cncc(C#N)c2)c1
Yield: 48.7 %

Procedure:
Prepare according to the general procedure outlined in EXAMPLE 72 using 3′-iodoacetophenone (1.29 g, 5.24 mmol) and 5-trimethylsilanylethynyl-nicotinonitrile (1.0 g, 5.0 mmol), (prepared as described in PREPARATION 3), to give the title compound (600 mg, 49%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:13]([OH:18])[C:14]([O:16][CH3:17])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(NC(C(O)C1C=CC=CC=1)C(OC)=O)=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C@H:13]([OH:18])[C:14]([O:16][CH3:17])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(O)C(NC(=O)OCc1ccccc1)c1ccccc1
Agent: COC(=O)C(NC(=O)OCc1ccccc1)C(O)c1ccccc1
Product: COC(=O)[C@@H](O)[C@H](NC(=O)OCc1ccccc1)c1ccccc1

Procedure:
(±)-(2RS,3SR)-Methyl 3-(benzyloxycarbonylamino)-2-hydroxy-3-phenylpropanoate ((±)-22a) and (±)-(2RS,3SR)-Methyl 2-(benzyloxycarbonylamino)-3-hydroxy-3-phenylpropanoate ((±)-22b).
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])[CH:9]([CH2:15]Br)[O:8][CH2:7][C:6]2([CH3:18])[CH3:17].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:31][CH2:30][N:29]([CH2:15][CH:9]3[C:10]4[CH:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[CH:4][C:5]=4[C:6]([CH3:18])([CH3:17])[CH2:7][O:8]3)[CH2:28][CH:27]=2)=[CH:22][CH:21]=1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: COc1cc2c(cc1OC)C(C)(C)COC2CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)C(C)(C)COC2CN1CC=C(c2ccc(Cl)cc2)CC1
Yield: 21 %

Procedure:
A mixture of 1.52 g of 6,7-dimethoxy-4,4-dimethyl-1-bromomethylisochroman, 1.35 g of 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine, and 2 ml. of triethylamine in 5 ml of DMF are heated at 50° C. for 23 hr. The mixture is partitioned between methylene chloride and aqueous potassium carbonate. The organic phase is dried over sodium sulfate and concentrated. The residue is chromatographed over silica gel utilizing 5% methanol/1/2% ammonium hydroxide/methylene chloride to give a 21% yield 4-(4-chloro phenyl)-1-[(3,4-dihydro-4,4-dimethyl-6,7-dimethoxy-1H-2-benzopyran-1-yl)methyl]-1,2,3,6-tetrahydropyridine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.[C:26](Cl)(=[O:28])[CH3:27].N1C=CC=CC=1>C(OCC)C>[C:26]([O:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])[C:4]([F:25])=[CH:3][C:2]=1[Cl:1])(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCCO)c(Cl)cc2F)c1=O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)OCCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
using 3-[4-chloro-2-fluoro-5-(2-hydroxyethoxy)-phenyl]-1-methyl-6 -trifluoromethyl-2,4(1H,3H)-pyrimidinedione and acetyl chloride with pyridine in diethyl ether there is obtained 2-{2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H) -pyrimidinyl]-4-fluorophenoxy}-ethyl acetate, m.p. 88°-90° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[NH:25]1[CH2:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:25]1[CH2:28][CH2:27][CH2:26]1)=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: C1CNC1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CCC2)c(Cl)c1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, azetidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.25 minutes; C19H16Cl2N4O3 (403.27); mass spectrum: (M+H)+=403.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].CC#N.[Br:19][CH:20](Br)[CH3:21]>CCOCC>[Br:19][CH2:20][CH2:21][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: O=Cc1cccc(OCCBr)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-hydroxybenzaldehyde (5.17 g, 42.33 mmol), K2CO3 (58.5 g) and CH3CN (100 ml) was stirred at room temperature for 15 minutes, then dibromoethane (18.3 ml) was added. The reaction mixture was stirred at room temperature for 30 minutes, then at reflux for 3-4 hours. Additional dibromoethane was added and then the reaction mixture was refluxed overnight. The reaction mixture was cooled, filtered, and the filtrate was stripped to afford an oil. The oil was dissolved in ether (300 ml), washed with 5N NaOH (2×75 ml) and the ether layer was dried over MgSO4 and stripped. The residue was purified by column chromatography on silica gel eluting with 10% ethyl acetate/hexane to afford 5.23 g of 3-(2-bromoethoxy)benzaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:17])=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][N:9]2[CH3:18])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2cc(Br)ccc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2cc(Br)ccc2c1=O
Reaction time: 3 h
Yield: 86.7 %

Procedure:
A suspension of 4.04 g of ethyl 7-bromo-4-hydroxy-quinoline-3-carboxylate (J. Am. Chem. Soc. 71,3226, (1949)) and 4.71 g of potassium carbonate in 30 ml of dimethylformamide is treated with 9.68 g of methyl iodide at room temperature. The reaction mixture is heated to 90° and stirred at this temperature for 3 hrs. The reaction mixture is concentrated in a high vacuum. The residue is suspended in 50 ml of water, filtered off under suction and washed with 50 ml of water. Recrystallization of the crude product from ethanol/diethyl ether yields 3.67 g (86%) of ethyl 7-bromo-1-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylate as a colourless solid. M.p. 189°-191°.
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.[CH3:26][CH:27]([CH2:43][CH2:44][CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:28][CH2:29][Si:30]([CH2:33][CH2:34][CH:35]([CH3:42])[CH2:36][CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])(Cl)Cl.O>O1CCCC1.CCCCCC>[CH3:26][CH:27]([CH2:43][CH2:44][CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:28][CH2:29][Si:30]1([CH2:33][CH2:34][CH:35]([CH3:42])[CH2:36][CH2:37][CH2:38][CH:39]([CH3:40])[CH3:41])[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
Reactant: C[Si](C)(C)c1cc(Br)c(-c2sc([Si](C)(C)C)cc2Br)s1
Reactant: CC(C)CCCC(C)CC[Si](Cl)(Cl)CCC(C)CCCC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCCC(C)CC[Si]1(CCC(C)CCCC(C)C)c2ccsc2-c2sccc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
3,3′-dibromo-5,5′-bis(trimethylsilyl)-2,2′-bithiophene (Compound G4, synthesized in accordance with WO 2010/136353, 11.6 g, 24.7 mmol) was placed in a 500 mL four-necked flask in a nitrogen atmosphere, and dissolved in tetrahydrofuran (200 mL). This was cooled to −78° C., and a solution of n-butyl lithium in hexane (KANTO CHEMICAL CO., INC., 1.59 M, 32.7 mL) was added dropwise. After about 20 minutes of agitation, the bis(3,7-dimethyloctyl)dichlorosilane (Compound G21, 11.3 g) synthesized in Synthesis Example B18 was added dropwise. The temperature was raised gradually to room temperature over the course of about 2 hours, water was added, and the product was extracted with hexane. The organic layer was washed with water, dried over sodium sulfate, and concentrated by filtration. The resulting oily substance was dissolved in chloroform (40 mL) and hexane (80 mL), trifluoroacetic acid (3.7 mL) was added, and the mixture was agitated for about 10 minutes at room temperature. Saturated sodium bicarbonate solution was added to the reaction solution, which was extracted with hexane and then concentrated under reduced pressure. The resulting yellow oily substance was dissolved in hexane, and subjected to silica gel column chromatography (solvent: hexane) to obtain the target 4,4-bis(3,7-dimethyloctyl)-dithieno[3,2-b:2′,3′-d]silole (Compound G22, 6.5 g, yield 56%.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18](I)[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH2:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.[Si:21]([C:25]#[CH:26])([CH3:24])([CH3:23])[CH3:22]>C1COCC1.CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:19]=[C:18]([C:26]#[C:25][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH2:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cn1cc(C(N)=O)c(Nc2ccc(I)cc2F)cc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1cc(C(N)=O)c(Nc2ccc(C#C[Si](C)(C)C)cc2F)cc1=O
Yield: 100 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide was reacted with TMS-acetylene in the presence of CuI, (Ph3P)2PdCl2 and TEA in THF/DMF (1:1) as for example 2. The residue resulting from removal of the reaction solvents under reduced pressure was purified by column chromatography on silica gel (10% MeOH/CH2Cl2 as eluant) to give 4-{2-fluoro-4-[(trimethylsilyl)ethynyl]anilino}-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a pale yellow solid (100%), used directly in the next step. 1H NMR [(CD3)2SO, 400 MHz] δ 10.66 (s, 1H), 8.38 (s, 1H), 7.92 (br s, 1H), 7.50 (t, J=8.5 Hz, 1H), 7.48 (br s, 1H), 7.42 (dd, J=11.5, 1.8 Hz, 1H), 7.30 (dd, J=8.3, 1.4 Hz, 1H), 5.73 (s, 1H), 3.38 (s, 3H), 0.23 (s, 9H). HRMS (EI+) calcd C18H20FN3O2Si (M+) 357.1309, found 357.1308.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O)#[N:15].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCCC1.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].O>[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1)#[N:15]
Reactant: N#Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(Br)cc1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2C#N)cc1OC
Temperature: 70 °C
Reaction time: 3 h
Yield: 35.6 %

Procedure:
A suspension of methyl 4-bromo-2-methoxybenzoate (4.9 g), (2-cyanophenyl)boronic acid (5.9 g), Pd(dppf)2Cl2 (0.49 g) and 2M aqueous cesium carbonate solution (20 mL) in tetrahydrofuran (60 mL) was stirred under an argon atmosphere at 70° C. for 3 hr. The mixture was allowed to cool, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (1.9 g, 35%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N+:6]([O-])=[CH:5][CH:4]=1.F[B-](F)(F)F.[CH3:15][O+:16](C)C>ClCCl>[OH:16][CH2:15][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][N:6]=1
Reactant: COc1cc[n+]([O-])cc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COc1ccnc(CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
The 4-methoxypyridine--N-oxide (6.3 g, 0.05 mol) was suspended in 150 ml of dichloromethane (CH2Cl2). Trimethyloxoniumtetrafluoroborate (7.5 g, 0.05 mol) was added all at once and the reaction was stirred at room temperature for 2 hrs. After evaporation of the solvent, the residue was dissolved in methanol (150 ml) and heated to reflux. To this solution was added of ammonium persulfate (2.3 g) in 20 ml of water. After 30 min. a further portion of 1.2 g of persulfate in 5 ml of water was added. After refluxing for one hour the solution was cooled and concentrated under vacuum. The residue was chromatographed over silica with 9:1 chloroform/methanol to give 3.52 g (51% yield) of the subtitle compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:4]=1[I:11].[C:12]([O-:15])(=[O:14])[CH3:13].[Na+]>CC(O)=O.C(Cl)Cl>[C:12]([O:15][CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:4]=1[I:11])(=[O:14])[CH3:13]
Reactant: Clc1cc(Cl)c(I)c(CBr)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)OCc1cc(Cl)cc(Cl)c1I
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 1-(bromomethyl)-3,5-dichloro-2-iodobenzene (1.29 mmol) [WO2011/027156] and sodium acetate (9.91 mmol) in 4 mL AcOH was heated to 100° C. for 1 h and then to 80° C. for 20 h. The mixture was diluted with DCM and extracted with water and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by CC (KP-SIL™ from Biotage) using Hept to Hept/EtOAc (9/1) gives the desired compound as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:29][CH2:28][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=3)[CH2:32][CH2:31]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Reactant: Clc1cccc(N2CCNCC2)c1
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 86 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 86%). 1H NMR (300 MHz, CDCl3): δ 3.30 (s, 4H), 3.76 (s, 4H), 4.15 (s, 3H), 6.79-6.90 (m, 3H), 7.15-7.45 (m, 3H), 7.62-7.75 (m, 2H).
Reaction SMILES: C1COCC1.[CH2:6]([Mg]Br)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(Br)CCCCCCCCC.Br[C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([O:40][CH3:41])[CH:34]=[CH:33]2>O.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:6]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([O:40][CH3:41])[CH:34]=[CH:33]2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CCCCCCCCCC[Mg]Br
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: CCCCCCCCCCBr
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCc1ccc2cc(OC)ccc2c1

Procedure:
A THF solution of n-decyl magnesium bromide (prepared as a THF (2 ml) solution of n-decyl bromide (2.2 ml, 11 mmol) and Mg (292 mg, 12 mmol)) was added to 6-bromo-2-methoxynaphthalene (2.37 g, 10 mmol) easily available from a reagent manufacturer and a THF (10 ml) solution of Ni(dppp)Cl2 (271 mg, 0.5 mmol), and the mixture was heated under reflux for 19 hours. After cooling, the mixed solution was diluted with water (10 ml), and non-reacted Mg was filtered out. The filtered solution was extracted with ether (5 ml×3). The extracted organic phases were collected (10 ml×3), and dried with MgSO4, and condensed with an evaporator. The condensed organic phase was recrystallized with hexane to obtain 6-n-decyl-2-methoxynaphthalene (compound (3)-64) as a light yellow solid.