Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](Cl)=[O:10].[CH3:15][N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:21][C:22]#[N:23]>ClCCCl>[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([C:20]1[N:16]([CH3:15])[C:17]([CH2:21][C:22]#[N:23])=[CH:18][CH:19]=1)=[O:10]
Reactant: Cn1cccc1CC#N
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cn1c(CC#N)ccc1C(=O)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To a cooled suspension of 16.6 g. (0.12 mole) aluminum chloride in 60 ml. 1,2-dichloroethane is added dropwise 23 g. (0.12 mole) m-chlorobenzoylchloride. The resulting suspension is added dropwise to a cooled solution of 15 g. (0.12 mole) 1-methylpyrrole-2-acetonitrile in 60 ml. 1,2-dichloroethane. The reaction mixture is stirred for about twenty minutes at room temperature and then heated and refluxed for three minutes. The reaction is terminated by pouring the mixture into ice acidified with 3N hyrochloric acid. The resulting two fractions are separated. The aqueous fraction is washed with chloroform. The organic fractions are combined and washed consecutively with N,N-dimethyl-1,3-propanediamine, 3N hydrochloric acid and saturated sodium chloride solution. The organic fraction is then dried over anhydrous magnesium sulfate. The solvent is evaporated, and the resulting residue is triturated with cold methanol to yield a precipitate of the desired product which is filtered off and set aside. The methanol filtrate is concentrated in vacuo, and the remaining oily residue is chromatographed on a column packed with neutral alumina using hexane, benzene and ether as the successive solvents. The desired product is isolated by evaporation of the first few compound-bearing (ether) fractions. The solids are combined and recrystallized from methanol to yield 5-(m-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile, m.p. 122-127° C. Analysis: Calcd. for C14H11ClN2O: N, 10.83%. Found: N, 10.52
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([CH3:27])=[CH:25][N:24]=[CH:23][C:22]=1[CH3:28].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:28][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([CH3:27])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: C1CCNC1
Reactant: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCCl
Product: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCN1CCCC1

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 6) and pyrrolidine following the procedure outlined in Example 15 (modifications: 40° C., 18 h). 1H NMR (400 MHz, DMSO-d6; HCl salt): δ 10.51 (br, 1H), 9.73 (s, 1H), 8.58 (s, 1H), 8.44 (s, 2H), 7.92 (d, 1H), 7.03 (d, 1H), 4.63 (s, 1H), 3.97 (t, 2H), 3.90 (s, 3H), 3.46 (m, 2H), 3.06 (m, 2H), 2.93 (m, 2H), 2.15 (s, 6H), 1.95 (m, 2H), 1.84 (m, 2H), 1.76 (m, 2H), 1.67 (m, 2H), 1.43 (m, 2H), 1.35 (m, 2H); MS (ESI): 465.4.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[CH3:44][C:45]1([CH3:55])[CH2:49][C:48]2[CH:50]=[CH:51][CH:52]=[C:53]([NH2:54])[C:47]=2[O:46]1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:33])([CH3:34])[C@:27]([C:36]2[CH:41]=[C:40]([NH:54][C:53]3[C:47]4[O:46][C:45]([CH3:55])([CH3:44])[CH2:49][C:48]=4[CH:50]=[CH:51][CH:52]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC1(C)Cc2cccc(N)c2O1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3cccc4c3OC(C)(C)C4)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 2,2-dimethyl-2,3-dihydro-benzofuran-7-ylamine according to procedure B followed by deprotection yielded the title compound as an off-white solid. MS (ESI): m/z=425.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:29])[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]=[C:13]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=O)[CH:14]=1)#[N:2].[BH4-].[Na+].C[OH:33]>C(=O)([O-])O.[Na+]>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:29])[N:11]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:12]=[C:13]([CH2:15][C:17]2([OH:33])[CH:22]=[CH:21][CH:20]=[CH:19][NH:18]2)[CH:14]=1)#[N:2]
Reactant: CO
Reactant: N#Cc1ccccc1-c1cc(C(=O)c2ccccn2)cn(-c2ccccc2)c1=O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Product: N#Cc1ccccc1-c1cc(CC2(O)C=CC=CN2)cn(-c2ccccc2)c1=O
Reaction time: 0.5 h

Procedure:
To a solution of 25 mg of 3-(2-cyanophenyl)-5-(2-pyridinecarbonyl)-1-phenyl-1,2-dihydropyridin-2-one in 5 ml of methanol was added 2 mg of sodium borohydride under ice-cooling. After 30 minutes, the mixture was diluted with a saturated aqueous solution of sodium hydrogen carbonate, followed by extracting with ethyl acetate. The ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl acetate), to give 15 mg of the title compound as a pale yellow powder.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]#[C:12][CH2:13][OH:14].C[N+]1([O-])CCOCC1.C(=O)(O)[O-].[Na+]>C([N+](CCC)(CCC)CCC)CC.ClCCl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]#[C:12][CH:13]=[O:14]
Reactant: OCC#Cc1ccc2ccccc2c1
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Agent: O=C([O-])O
Solvent: ClCCl
Product: O=CC#Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
3-(Naphthalen-2-yl)prop-2-yn-1-ol (2.48 g, 13.6 mmol), tetrapropylammonium perruthanate (0.09 g, 0.27 mmol, 2 mol %), and dichloromethane (150 mL) were stirred under nitrogen at 0° C. A portion of N-methylmorpholine-N-oxide (2.87 g, 245 mmol) was added and the reaction was stirred at room temperature for 1 h. The remaining N-methylmorpholine-N-oxide was then added over 3 h at room temperature and the reaction stirred for a further 1 hour. Saturated sodium bicarbonate (75 mL) was added and the mixture was extracted with dichloromethane (3×75 mL), dried over sodium sulphate filtered and concentrated in vacuo to afford the desired compound (2.45 g, 81%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.47-7.54 (4H, m, ArH), 7.77-7.87 (3H, m, ArH), 8.19 (1H, s, ArH), 9.48 (1H, s, CHO).
Reaction SMILES: [F:1][C:2]1[CH:33]=[C:32]([NH:34][C:35]([NH:37][C:38](=[O:48])[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[O:46][CH3:47])=[S:36])[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21](C)[C:22](=O)OC(C)(C)C)[CH:18]=3)[S:13][C:6]=12.Cl.Cl.FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1C=CN=C2C=C(C3C=CC(N4CCNCC4)=CC=3)SC=12>>[F:1][C:2]1[CH:33]=[C:32]([NH:34][C:35]([NH:37][C:38](=[O:48])[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[O:46][CH3:47])=[S:36])[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][NH:21][CH3:22])[CH:18]=3)[S:13][C:6]=12
Reactant: COc1ccccc1CC(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4cnn(CCN(C)C(=O)OC(C)(C)C)c4)sc23)c(F)c1
Agent: Cl
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(N5CCNCC5)cc4)sc23)c(F)c1
Product: CNCCn1cc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5OC)cc4F)c3s2)cn1
Yield: 66 %

Procedure:
Starting from the compound 183 and following the procedure described above for the synthesis of compound 159 (scheme 30, step 4, example 121), title compound 184 was obtained in 66% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.45(d, J=5.6 Hz, 1H), 8.33(s, 1H), 8.00 (s, 1H), 7.85-7.75 (m, 1H), 7.69 (s, 1H), 7.39(t, J=8.4 Hz, 1H), 7.35-7.28 (m, 1H), 7.28-7.22 (m, 1H), 7.22(d, J=7.6 Hz, 1H), 6.97(d, J=8.4 Hz, 1H), 6.89(t, J=7.6 Hz, 1H), 6.57(d, J=5.6 Hz, 1H), 4.19(t, J=6.4 Hz, 2H), 3.82 (s, 2H), 3.77 (s, 3H), 2.88(t, J=6.4 Hz, 2H), 2.28 (s, 3H).
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=1)[C:10](O)=[O:11]>C(OCC)(=O)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH2:10][OH:11])[CH:13]=[CH:14][N:15]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 908.5 %

Procedure:
Borane-dimethyl sulfide complex (14.30 mL, 14.30 mmols) was added to tetrahydrofuran solution of 2-chloroisonicotinic acid (17.56 g, 11.5 mmols) under cooling with ice, and stirred at room temperature for 2.5 days, followed by further an hour's stirring at 50° C. Cooling the reaction liquid to room temperature, ethyl acetate was added, followed by washing with saturated aqueous ammonium chloride solution and saturated brine and drying over anhydrous sodium sulfate. Concentrating the solvent under reduced pressure, the tide compound (15.0 g, 93%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][NH2:13].C[O-].[Na+].C(O[CH:20]=[C:21]([C:24]#[N:25])[C:22]#[N:23])C>CO>[NH2:25][C:24]1[N:12]([C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=2[F:1])[N:13]=[CH:20][C:21]=1[C:22]#[N:23]
Reactant: CS(=O)(=O)c1ccc(NN)c(F)c1
Reactant: CCOC=C(C#N)C#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)c1ccc(-n2ncc(C#N)c2N)c(F)c1
Reaction time: 0.17 h
Yield: 87.6 %

Procedure:
(2-Fluoro-4-methanesulfonyl-phenyl)-hydrazine (1 g, 4.89 mmol) and sodium methoxide (30 mg, 0.489 mmol) were dissolved in methanol under N2 at room temperature. The mixture was stirred for 10 min and 2-ethoxymethylene-malononitrile (0.6 g, 4.91 mmol) was added. The reaction mixture was stirred for 30 min and then brought to reflux for 2 hours. The solvent was removed under reduced pressure; the residue was suspended in water and extracted with ethyl acetate. The organic layer was washed with water, brine and was dried over sodium sulfate. The solvent was concentrated, affording 5-amino-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazole-4-carbonitrile as a yellow solid (1.2 g, 87.5%). 1H NMR (400 MHz DMSO-d6) δ (ppm): 7.96 (d, 1H); 7.93 (m, 1H); 7.80 (s, 1H); 7.74 (m, 1H); 6.89 (s, 2H); 3.24(s, 3H). Exact mass calculated for C11H9FN4O2S 280.04, found 281.30 (MH+, 100%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][C@H:18]([CH:27]([CH3:29])[CH3:28])[C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:5]2=[N:6][CH:7]=1.ClC1C=C2C(C3C=C(N[C@H](C(NCC(F)(F)F)=O)C(C)C)C=NC=3)=CN(COCC[Si](C)(C)C)C2=NC=1.[N:75]1([CH2:80][CH2:81][O:82][CH2:83][B-](F)(F)F)[CH2:79][CH2:78][CH2:77][CH2:76]1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[CH3:28][CH:27]([CH3:29])[C@@H:18]([NH:17][C:13]1[CH:14]=[N:15][CH:16]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([CH2:83][O:82][CH2:81][CH2:80][N:75]4[CH2:79][CH2:78][CH2:77][CH2:76]4)[CH:3]=3)[N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=2)[CH:12]=1)[C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20]
Reactant: CC(C)[C@@H](Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(Cl)cc23)c1)C(=O)NCC(F)(F)F
Reactant: F[B-](F)(F)COCCN1CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)[C@@H](Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(COCCN4CCCC4)cc23)c1)C(=O)NCC(F)(F)F
Temperature: 150 °C

Procedure:
In a microwave vial purged with nitrogen containing (R)-2-(5-(5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-ylamino)-3-methyl-N-(2,2,2-trifluoroethyl)butanamide, 2-1a (52 mg, 0.094 mmol), Potassium 2-(pyrrolidin-1-yl)ethoxymethyltrifluoroborate (CA) (44.4 mg, 0.189 mmol), cesium carbonate (105.3 mg, 0.323 mmol), palladium acetate (4.2 mg, 0.019 mmole) and RuPhos catalyst (17.45 mg, 0.037 mmol) was added a degassed mixture of 10:1 dioxane (500 μl)/water (50 μl). The reaction vessel was sealed and heated at 150° C. for 15 minutes in the microwave. LC/MS indicated product as a major peak. The reaction was cooled, passed through a celite cartridge, to remove water, the cartridge was washed with dichloromethane, ethyl acetate and the filtrate concentrated. The crude product 9-1a (60.7 mg) was used directly in the next step. LRMS (ESI) m/z 649.2 [(M+H)+; calcd for C32H47F3N6O3Si: 649.35].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(=O)(O)[O-].[Na+].CO.ClCCl.[I:19](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[I:19])[NH2:5]
Reactant: Nc1cccc(F)c1
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc(I)c(F)c1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a suspension of 3-fluoroaniline (1.0 mL, 1.16 g, 10.39 mmol) and solid sodium bicarbonate (1.75 g, 20.79 mmol) in 1:1 methanol-dichloromethane (20 mL) at 0° C. was added a solution of benzyl trimethylammonium dichloroiodate (3.62 g, 10.39 mmol) in dichloromethane (15 mL) over 30 minutes. The mixture was then allowed to warm to room temperature for 1 hour. The mixture was quenched by addition of water and the organic layer was extracted with water (2×). Drying (Na2SO4) and concentration in vacuo afforded an oil, which was chromatographed over a 100 g silica gel cartridge, eluting with 10-100% ethyl acetate in hexanes. These procedures afforded the title compound (2.20 g, 89%) as a pink solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.41 (dd, J=8.3, 7.3 Hz, 1H), 6.42 (dd, J=9.9, 2.5 Hz, 1H), 6.27 (dd, J=8.5, 2.5 Hz, 1H), 3.81 (s, 2H); MS+ESI m/z (rel abundance) 238 (100, M+H).
Reaction SMILES: N(C(C)C)(C(C)C)CC.[Cl:10][C:11]1[C:12]([CH:17]([NH2:34])[C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[CH:23][C:24](C4C=CC=CC=4)=[N:25]3)=[CH:20][CH:19]=2)=[N:13][CH:14]=[CH:15][N:16]=1.[CH:35]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:10][C:11]1[C:12]([CH:17]([NH:34][C:39]([CH:35]2[CH2:38][CH2:37][CH2:36]2)=[O:40])[C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[CH:23][CH:24]=[N:25]3)=[CH:20][CH:19]=2)=[N:13][CH:14]=[CH:15][N:16]=1
Reactant: O=C(Cl)C1CCC1
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC(c1ccc2cccnc2c1)c1nccnc1Cl)C1CCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of NEt(iPr)2 (520 μL, 386 mg, 2.99 mmol), DMAP (12 mg, 0.098 mmol), and C-(3-chloropyrazin-2-yl)-C-quinolin-7-ylmethylamine (compound of Formula IV where Q1=quinolin-7-yl) (608 mg, 1.97 mmol) in dry CH2Cl2 (10 mL), cooled by ice/water, was added cyclobutanecarbonyl chloride (250 μL, 260 mg, 2.19 mmol), then the cooling bath was removed, and the reaction mixture was stirred at ambient temperature for 2.5 h. Water was added, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined CH2Cl2 layers were washed with dilute HCl (pH ≈2), water, saturated NaHCO3 solution, and brine and dried over MgSO4. The crude material is chromatographed on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with hexanes:EtOAc 1:1 (1-21)→1:3 (22-44)→EtOAc (45-56)], yielding the title compound as an orange foam; 1H NMR (CDCl3, 400 MHz) δ 1.81-1.91 (m, 1H), 1.91-2.03 (m, 1H), 2.11-2.23 (m, 2H), 2.23-2.35 (m, 2H), 3.12 (quint, J=8.6 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.39 (dd, J=4.0, 8.0 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.83 (s, 1H), 8.13 (d, J=8.4 Hz, 1H), 8.37 (d, J=2.2 Hz, 1H), 8.56 (d, J=2.2 Hz, 1H), 8.87 (dd, J=1.6, 4.0 Hz, 1H); MS (ES+): m/z 353.1/355.0 (100/39) [MH+].
Reaction SMILES: [OH-].[Na+].[SH:3][C:4]1[NH:5][C:6]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:7]=2[N:8]=1.[CH3:15][C:16]1[CH:17]=[N:18][C:19]2[CH:20](Br)[CH2:21][CH2:22][CH2:23][C:24]=2[CH:25]=1>O.CO>[CH3:15][C:16]1[CH:17]=[N:18][C:19]2[CH:20]([S:3][C:4]3[NH:5][C:6]4[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:7]=4[N:8]=3)[CH2:21][CH2:22][CH2:23][C:24]=2[CH:25]=1
Reactant: Cc1cnc2c(c1)CCCC2Br
Reactant: COc1ccc2nc(S)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2nc(SC3CCCc4cc(C)cnc43)[nH]c2c1
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
2.80 Grams of sodium hydroxide was dissolved in 15 ml of water and 200 ml of methanol, then to this solution was added 10.63 g of 2-mercapto-5-methoxybenzimidazole and the reaction mixture was heated with stirring at 55° C. for 30 minutes. Next, 13.33 g of 3-methyl-8-bromo-5,6,7,8-tetrahydroquinoline was added to the reaction mixture, then the whole reaction mixture was stirred under heating for 2.5 hours. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, then to the residued thus obtained was added a small amount of 30% sodium hydroxide aqueous solution, and extracted with chloroform. The chloroform layer was washed wih an aqueous solution saturated with sodium chloride, then the extract was dried with anhydrous magnesium sulfate, and the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane/methanol=100/1) to obtain 18.80 g of 3-methyl-8-(5-methoxy-2-benzimidazolyl)thio-5,6,7,8-tetrahydroquinoline as in the form of colorless caramel-like substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:20][C@H:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH3:22])=[O:9])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)cnc1Cc1cccc(F)c1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cc2cccc(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(3-fluorobenzyl)nicotinic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 9.18 (1H, d, J=7.7 Hz), 8.65 (1H, d, J=2.6 Hz), 7.96 (1H, d, J=2.6 Hz), 7.93 (2H, d, J=8.3 Hz), 7.50 (2H, d, J=8.4 Hz), 7.27–7.20 (1H, m), 7.02–6.89 (3H, m), 5.20–5.10 (1H, m), 4.20 (1H, d, J=14.1 Hz), 4.13 (1H, d, J=14.1 Hz), 3.85 (3H, s), 1.42 (3H, d, J=7.2 Hz); MS (ESI) m/z 427 (M+H)+, 425 (M−H)−.
Reaction SMILES: [Li+].[Cl-].I[C:4]1[CH:9]=[C:8]([Si:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=[C:6]([O:14][CH3:15])[C:5]=1[CH2:16][O:17][CH2:18][O:19][CH3:20].C([Sn](CCCC)(CCCC)/[C:26](/[CH2:33][CH3:34])=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Cu].CS(C)=O>[CH2:31]([O:30][C:28](=[O:29])[CH:27]=[C:26]([C:4]1[CH:9]=[C:8]([Si:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=[C:6]([O:14][CH3:15])[C:5]=1[CH2:16][O:17][CH2:18][O:19][CH3:20])[CH2:33][CH3:34])[CH3:32]
Reactant: COCOCc1c(I)cc([Si](C)(C)C)nc1OC
Reactant: CCCC[Sn](CCCC)(CCCC)/C(=C/C(=O)OCC)CC
Agent: Cl[Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CS(C)=O
Product: CCOC(=O)C=C(CC)c1cc([Si](C)(C)C)nc(OC)c1COCOC
Temperature: 60 °C
Yield: 80 %

Procedure:
A round bottom flask was charged with LiCl (66.6 mg, 1.57 mmol) and flamed dried under vacuum. Pd(PPh3)4 (32.6 mg, 0.026 mmol), CuCl (129.6 mg, 1.31 mmol) and DMSO (2.0 mL) were added and the mixture was degassed. 3a (100 mg, 0.262 mmol) was added, followed by ethyl (E)-3-(tri-n-butylstannyl)-2-pentenoate (131.4 mg, 0.314 mmol) and the resulting mixture was degassed. See Piers, E., et al., Can. J. Chem., 2058 (1992). The reaction mixture was then heated at 60° C. for 17 h. After cooling, the reaction was diluted with Et2O (30 mL) and washed with a mixture of brine (40 mL) and 5% aq. NH4OH (8 mL). The aqueous layer was extracted 3 times with Et2O. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (gradient hexane to hexane-EtOAc 95:5) to yield 4a (80 mg, 80%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ0.28 (s, 3H), 0.99 (t, J=7.5 Hz, 3H), 1.3 (t, J=7.1 Hz, 3H), 2.98 (q, J=7.5 Hz, 2H), 3.42 (s, 3H), 4.02 (s, 3H), 4.2 (q, J=7.1 Hz, 2H), 4.47 (s, 2H), 4.72 (s, 2H), 5.79 (s, 1H), 6.84 (s, 1H); 13C NMR (75 MHz, CDCl3) δ−1.96, 12.3, 14.25, 26.57, 53.58, 55.35, 60.01, 61.95, 9672, 115.49, 119.49, 121.17, 151.15, 159.9, 162.21, 164.81, 165.83; IR (film, NaCl, cm−1) 2; LRMS (70 eV, EI) m/z (rel int %) 381 (M+), 366, 336, 320, 308 (100), 290, 262, 246, 89, 73. HRMS m/z calcd for C19H31NO5Si (M+) 381.1976, found 381.19667.
Reaction SMILES: C(NC(C)C)(C)C.C([Mg]Cl)CCC.O1CCCC1.[Cl:19][CH2:20][C:21]([OH:23])=O.C(OC)(=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>O1CCCC1>[CH2:20]([Cl:19])[C:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]
Reactant: COC(=O)c1ccccc1
Reactant: O=C(O)CCl
Agent: CCCC[Mg]Cl
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.7 %

Procedure:
Under the atomosphere of nitrogen gas, diisopropylamine (0.6605 g) was added to 6.67 mL of 0.9 M n-butylmagnesium chloride/tetrahydrofuran (6 mmol). The mixture was stirred a room temperature for 4 hours, after which it was cooled to 0° C. Then, a solution of 284 mg (3.0 mmol) of monochloroacetic acid and 136 mg (1 mmol) of methyl benzoate in 5 mL of tetrahydrofuran was added portionwise for 1 minutes. This mixture was stirred at 0° C. for 30 minutes and, while the temperature was allowed to rise to room temperature, further stirred for 30 minutes. This reaction mixture was poured in 1N-HCl (30 mL) and extracted with ethyl acetate (30 mL×2). The extract was washed with saturated aqueous NaHCO3 solution (30 mL×1) and water (30 mL×1) in that order and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to provide a light-yellow oil. Comparative HPLC analysis of this oil with an authentic sample revealed that the oil was predominantly composed of the objective phenacyl chloride (reaction yield 73.7%). Diisopropylbenzamide (reaction yield 0.4%) was obtained as a byproduct.
Reaction SMILES: CON(C)[C:4](=O)[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[CH2:12][CH3:13].[CH:16]1[CH:17]=[CH:18][C:19]2[S:24][CH:23]=[CH:22][C:20]=2[CH:21]=1>>[S:24]1[C:23]([CH2:4][C:5]2[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=2[CH2:12][CH3:13])=[CH:22][C:20]2[CH:21]=[CH:16][CH:17]=[CH:18][C:19]1=2
Reactant: c1ccc2sccc2c1
Reactant: CCc1ccc(Br)cc1C(=O)N(C)OC
Product: CCc1ccc(Br)cc1Cc1cc2ccccc2s1

Procedure:
The above N-methoxy-N-methyl-5-bromo-2-ethylbenzamide and thianaphthene were treated in a manner similar to Reference Example 45 to give 1-(Benzo[b]thiophen-2-ylmethyl)-5-bromo-2-ethylbenzene as oil.