Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:11][CH2:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC/C=C\CCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC/C=C\CCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a cooled solution (0° C.) of (Z)-dec-4-en-1-ol 9 (20 g, 128.0 mmol) and triethylamine (26.7 mL, 191.9 mmol) in anhydrous dichloromethane (200 mL) was slowly added methane sulfonyl chloride (14.9 mL, 191.9 mmol). The solution was stirred for 30 min at room temperature then diluted with dichloromethane (100 mL). The solution was washed with saturated sodium bicarbonate (3×150 mL) and then the combined aqueous washes were extracted with dichloromethane (150 mL). The combined dichloromethane extracts were dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was filtered through a pad of silica (100% dichloromethane) to afford (Z)-dec-4-enyl methanesulfonate 2 as a yellow oil (28.5 g, 95%). Rf 0.5 (100% CH2Cl2).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.N#N.C1C[O:28]CC1>>[CH:10]1([NH:9][C:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:28])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C1CCOC1
Agent: N#N
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 12 h

Procedure:
By mixing 0.1 g of polymer coupling agent from step 2, 0.15 g of 1,3-dicyclohexylcarbodiimide (DCC) in 2 g of THF, a 5 wt % polymer coupling agent solution is prepared. 20 μL of triethylamine is added into the mixture. The solution is then pumped into the capillary by N2 pressure. After 3 drops of the initiator solution come out of the other end of the capillary, both ends of the capillary are sealed with a silicon rubber septum. The reaction is allowed to proceed for 12.0 hour at room temperature. The capillary is then rinsed with acetone for 1.0 hour.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:10](=[CH:11][CH2:12][C@@H:13]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[C@H:18]([CH3:23])[CH2:19][CH2:20][CH2:21][OH:22])[CH2:9]1.[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].N1C=CN=C1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Si:33]([O:22][CH2:21][CH2:20][CH2:19][C@H:18]([C@@H:17]1[C@:24]2([CH3:32])[C@H:14]([C@H:13]3[C@H:27]([CH2:26][CH2:25]2)[C@:28]2([CH3:31])[C:10]([CH2:9][C@@H:8]([O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[CH2:30][CH2:29]2)=[CH:11][CH2:12]3)[CH2:15][CH2:16]1)[CH3:23])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](CCCO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Compound 2002 (7.6 g, 17 mmol) in dry CH2Cl2 (300 ml) was treated with a solution of t-butyldimethylsilylchloride (TBDMSCl, 1.0M) and imidazole (0.5M) in dry CH2Cl2 (38.0 ml, 38.0 mmol TBDMSCl). The solution was stirred at room temperature under argon overnight. The resultant solution was poured into an aqueous saturated NaHCO3 solution and the mixture extracted with CH2Cl2 (3×). The combined organic layers were washed with saturated sodium chloride, dried over anhydrous MGSO4, filtered, and the solvent removed in vacuo. The resultant solid was purified by flash chromatography (SiO2, hexanes:EtOAc gradient from 20:1 to 5:1) giving compound 2003 (9.4 g, 17 mmol, 98%). 1H NMR (500 MHz, CDCl3) δ: 5.38-5.32 (m, 1H, C-6 H), 4.72 (brs, 1H, THP methine H), 3.95-3.88 (m, 1H, THP CH2O), 3.60-3.46 (m, 4H THP CH2O & C-3 H & C-24 H), 1.01 (s, 3H, C-19 H), 0.93 (d, J=6.6 Hz, C-21 H), 0.89 (s, 9H, t-Bu), 0.67 (s, 3H, C-18 H), 0.05 (s, 6H, TBDMS CH3); IR (CHCl3) 2900 cm-1 ; MS (CI/isobutane) m/z 559 (M+1, 1%), 474 (M+1-THP, 12%), 457 (M+1-THPOH, 18%), 343 (M+1-THP-TBDMSOH, 6%), 325 (M+1-THPOH-TBDMSOH, 100%); m.p. 116-118° C.; Anal. calcd. for C35H62O3Si: C=75.21, H=11.18; Found: C=75.37, H=11.24.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([OH:15])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])[CH2:2][CH2:3][CH3:4].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl>C(O)C.O>[CH2:16]([O:15][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCCOc1ccc(O)c(C(=O)O)c1
Reactant: ClCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCOc1ccc(OCc2ccccc2)c(C(=O)O)c1
Temperature: 25 °C

Procedure:
A suspension containing 1.9 g (9 mmol) of 5-butoxy-2-hydroxybenzoic acid, 3.85 g (30 mmol) of benzyl chloride and 5 g (36 mmol) of anhydrous potassium carbonate in 18 ml of anhydrous ethanol was boiled under reflux for 20 hours while stirring. The reaction mixture was cooled to room temperature and after adding 20 ml of water and thoroughly shaking, the three phases formed were separated. The medium phase was boiled under reflux with 1.1 g (27.5 mmol) of sodium hydroxide dissolved in 7 ml of ethanol and 5 ml of water for 2.5 hours under stirring. After cooling down the solution was mixed with 15 ml of water under cooling by ice, the pH value of the mixture was adjusted to 4 by adding 5M hydrochloric acid and stirred for 1 hour. After extracting the product with ethyl acetate and drying, the solution was evaporated to dryness under reduced pressure to give 1.5 g (55%) ot the aimed product, m.p.: 79°-82° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:44])[CH2:10][CH2:11][CH2:12][O:13][C:14]1[C:15]([F:43])=[CH:16][C:17]2[N:21]=[C:20]([C:22]3[C:26]([NH:27][C:28]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:29])=[CH:25][N:24](C4CCCCO4)[N:23]=3)[NH:19][C:18]=2[CH:42]=1>ClCCl>[CH3:44][N:9]([CH3:8])[CH2:10][CH2:11][CH2:12][O:13][C:14]1[C:15]([F:43])=[CH:16][C:17]2[N:21]=[C:20]([C:22]3[C:26]([NH:27][C:28]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:29])=[CH:25][NH:24][N:23]=3)[NH:19][C:18]=2[CH:42]=1
Reactant: CN(C)CCCOc1cc2[nH]c(-c3nn(C4CCCCO4)cc3NC(=O)N3CCCCC3)nc2cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCCOc1cc2[nH]c(-c3n[nH]cc3NC(=O)N3CCCCC3)nc2cc1F
Temperature: 22 °C
Reaction time: 16 h
Yield: 170.8 %

Procedure:
0.5 mL of trifluoroacetic acid is added to a solution of 28 mg of piperidine-1-carboxylic acid [3-[6-(3-dimethylaminopropoxy)-5-fluoro-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide in solution in 1.5 mL of dichloromethane. The reaction medium is stirred at 22° C. for 16 hours. The reaction medium is concentrated under reduced pressure in a rotary evaporator, taken up several times with isopropyl ether and concentrated under reduced pressure in a rotary evaporator each time. 40 mg of N-{3-[6-(3-dimethylaminopropoxy)-5-fluoro-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}piperidine-1-carboxamide are obtained in the form of trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.47 to 1.72 (m, 6H); 2.19 (m, 2H); 2.84 (s, 6H); 3.27 (m, 2H); 3.42 (m, 4H); 4.22 (t, J=6.0 Hz, 2H); 7.40 (d, J=7.5 Hz, 1H); 7.65 (d, J=10.0 Hz, 1H); 8.00 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[N:7][O:8][C:9]=1[NH2:10])=[O:4].[OH-].[Na+]>CO>[NH2:10][C:9]1[O:8][N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1c(-c2ccccc2Cl)noc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1onc(-c2ccccc2Cl)c1C(=O)O
Yield: 64.5 %

Procedure:
In a similar manner as described in Preparation Example 25, by using methanol (60 mL), methyl-5-amino-3-(2-chlorophenyl)isoxazol-4-carboxylate (6.0 g, 23.75 mmol) and 3% sodium hydroxide aqueous solution (60 mL), a white solid required compound (3.66 g, 15.33 mmol, 65%) was obtained.
Reaction SMILES: C([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])=[C:27]([C:37]([F:40])([F:39])[F:38])[CH:26]=3)=[O:23])=[C:17]([F:41])[CH:16]=2)=[C:11]([O:42][CH2:43][CH3:44])[CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[CH2:43]([O:42][C:11]1[C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C:32]([CH3:35])([CH3:36])[CH2:33][OH:34])=[C:27]([C:37]([F:39])([F:40])[F:38])[CH:26]=3)=[O:23])=[C:17]([F:41])[CH:16]=2)=[CH:13][NH:14][C:9](=[O:8])[CH:10]=1)[CH3:44]
Reactant: CCOc1cc(OCc2ccccc2)ncc1-c1ccc(CC(=O)Nc2ccc(CC(C)(C)CO)c(C(F)(F)F)c2)c(F)c1
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(=O)[nH]cc1-c1ccc(CC(=O)Nc2ccc(CC(C)(C)CO)c(C(F)(F)F)c2)c(F)c1
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 66.7 %

Procedure:
The reaction mixture of 2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-2-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (20 mg, 0.033 mmol) and Pd/C (3.49 mg, 0.033 mmol) in MeOH (3 mL) was stirred at 20° C. for 20 min under a H2 atmosphere. Then the solution was concentrated and purified by preparative HPLC (MeCN/H2O as eluants, acidic condition) to yield a white solid of 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (11.88 mg, 0.022 mmol, 67.7% yield): 1H NMR (400 MHz, CD3OD) δ 7.95 (d, J=1.98 Hz, 1H), 7.79 (s, 1H), 7.71 (dd, J=8.49, 1.87 Hz, 1H), 7.40-7.46 (m, 2H), 7.25-7.32 (m, 2H), 6.37 (s, 1H), 4.24 (q, J=6.84 Hz, 2H), 3.82 (s, 2H), 3.35 (br. s., 2H), 2.77 (s, 2H), 1.41 (t, J=6.95 Hz, 3H), 0.83 (s, 6H); ES-LCMS m/z 521 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](C2C=CC(C(O)=O)=CC=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[CH3:33][CH:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:8]4[CH:7]=[CH:6][C:5]([C:3](=[O:2])[NH:41][CH:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH3:33])=[CH:10][CH:9]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: CC(N)c1ccccc1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Product: CC(NC(=O)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1)c1ccccc1
Yield: 114.6 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with DL-alpha-methylbenzylamine (available from Aldrich Chemical Company, Inc.; 75 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(1-phenyl-ethylcarbamoyl)-biphenyl-2-carboxylic acid (69 mg, 59%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.22 (br s, 1H), 8.90 (d, J=8.0 Hz, 1H), 8.48 (s, 1H), 8.38 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.0, 1.8 Hz, 1H), 8.10 (dd, J=8.5, 2.0 Hz, 1H), 7.96 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.3 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.49 (d, J=8.3 Hz, 2H), 7.39-7.45 (m, 2H), 7.34 (t, J=7.7 Hz, 2H), 7.18-7.28 (m, 1H), 5.20 (quin, J=7.3 Hz, 1H), 1.50 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[N:4]=1.C([Li])CCC.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27]>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2([OH:27])[C:8]1[C:3]([O:2][CH3:1])=[N:4][C:5]([O:9][CH3:10])=[CH:6][CH:7]=1
Reactant: COc1cccc(OC)n1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2(O)C(=O)Nc3ccc(Cl)cc32)c(OC)n1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a stirred solution of 2,6-dimethoxypyridine (50 mmol, 6.61 mL) in THF (100 mL) was added slowly a 1.6 M solution of n-butyllithium in hexanes (55 mmol, 34.4 mL) at −78° C. The mixture was allowed to warm slowly to 10° C. and kept at this temperature for 30 min. The reaction mixture was re-cooled to −78° C. and a slurry of 5-chloroisatin (20 mmol, 3.63 g) in THF (150 mL) was added portionwise, keeping the temperature below −60° C. The reaction was allowed to come to room temperature. The mixture was quenched with 10% aqueous ammonium chloride solution and extracted several times with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate and evaporated in vacuo. Recrystallization from ethyl acetate yielded 4.56 g (71%) of the desired intermediate as a white crystalline solid (71%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[CH:5]=1)([O-])=O.[Cl-].[NH4+].O.C(O)C>O1CCCC1.[Fe]>[Br:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][CH2:10][C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(COc2cccc(Br)c2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1cccc(COc2cccc(Br)c2)c1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
To a solution of the product from Example 74A (1.64 g, 5.32 mmol), iron powder (1.49 g, 26.62 mmol) and ammonium chloride (430 mg, 7.98 mmol) in a mixture of tetrahydrofuran (20 mL), water (6 mL) and ethanol (20 mL) was heated to reflux for 3 hours. The mixture was cooled to room temperature, filtered through a pad of celite, which was washed with ethanol and the resultant filtrate concentrated under vacuum. The material was then dissolved in water (50 mL) and extracted with ethyl acetate (50 mL), the organic layer dried and concentrated under vacuum to provide the title compound as a yellow oil (1.43 g, 97%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[S:8].[H-].[Na+].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:1][CH2:2][CH2:3][CH2:4][C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[S:8])=[CH:21][CH:20]=1
Reactant: COC(=S)c1ccccc1CCCO
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=S)c1ccccc1CCCOCc1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
To an ice bath cooled solution of methyl 2-(3-hydroxyprop-1-yl)thiobenzoate (3.7 g) in N,N-dimethylformamide (30 ml) was added sodium hydride (60% in oil, 719 mg) and the solution was stirred at the same temperature for 30 minutes. 4-Methoxybenzyl chloride (2.56 g) was added to the solution and the mixture was stirred at ambient temperature for 5 hours. The mixture was diluted with ethyl acetate (100 ml) and the solution was washed with water and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give a crude oil. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate=10:1) to give methyl 2-[3-(4-methoxyphenyl)methoxyprop-1-yl]thiobenzoate (2.13 g).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.[C:31]1([S:37](F)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[C:31]1([S:37]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=2)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=S(=O)(F)c1ccccc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(Br)cc21
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(S(=O)(=O)c3ccccc3)cc21
Temperature: -78 °C
Reaction time: 0.1 h
Yield: 45.3 %

Procedure:
To as stirred solution of 6-bromo-1-triisopropylsilanyl-1H-indole (0.687 g, 1.95 mmol) in THF (12 mL) at −78° C. under nitrogen was added, dropwise over 0.3 h, a solution of tert-butyllithium in pentane (1.7 M, 2.52 mL, 4.29 mmol) (internal temperature was kept below −70° C.). The mixture was stirred at −78° C. for 0.1 h then phenylsulfonyl fluoride (0.26 mL, 0.343 g, 2.15 mmol) was added dropwise. The mixture was stirred at −78° C. then warmed to 20° C. and stirred thus for 1 h. Excess tert-butyllithium was quenched by addition of ice and the resulting mixture was partitioned between water (100 mL) and EtOAc (3×50 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give semi-solid. Chromatography (SiO2; gradient elution with 0-40% Et2O in petrol) gave the title compound (0.365 g, 45%). 1H NMR (CDCl3): 8.21 (1H, s), 8.00-7.89 (2H, m), 7.70 (1H, d), 7.63 (1H, dd), 7.57-7.41 (4H, m), 6.69 (1H, d), 1.82-1.65 (3H, m), 1.16 (18H, d).
Reaction SMILES: C(O)C.C([O:11][C:12]1[CH:37]=[CH:36][C:15]([CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][O:31]4)=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[CH:14][CH:13]=1)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[O:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH:30]1[O:29][C:26]1[CH:27]=[CH:28][C:23]([N:20]2[CH2:21][CH2:22][CH:17]([CH2:16][C:15]3[CH:36]=[CH:37][C:12]([OH:11])=[CH:13][CH:14]=3)[CH2:18][CH2:19]2)=[CH:24][CH:25]=1
Reactant: C(=C1CCN(c2ccc(OC3CCCCO3)cc2)CC1)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Oc1ccc(CC2CCN(c3ccc(OC4CCCCO4)cc3)CC2)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Ethanol (20 ml) and ethyl acetate (10 ml) were added to 4-[4-(benzyloxy)benzylidene]-1-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]piperidine prepared in Reference Example 366. A palladium on carbon (0.378 g) was added to the mixture, and stirred at 50° C. for 4 hours under a hydrogen atmosphere. The insoluble matter was removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1→4:1) to afford the title compound as a colorless amorphous compound (1.10 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH2:9][CH:8]=[CH:7]2.[Br:11]N1C(=O)CCC1=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CS(C)=O.C(OCC)C.O>[Br:11][C:8]1[CH2:9][C:10]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[Br:1]
Reactant: Brc1cccc2c1CC=C2
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: BrC1=Cc2cccc(Br)c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
Using a 200 ml Erlenmeyer flask, 7.00 g (35.89 millimoles) of 7-bromoindene produced by the method described in J. Org. Chem. 49, 4226–4237(1984) was dissolved in a mixed solvent of 1.42 g (79.00 millimoles) of distilled water and 70 ml of dimethyl sulfoxide. To this reaction solution there was added 7.67 g (43.07 millimoles) of N-bromosuccinimide while cooling on ice, and the mixture was then stirred for one hour at room temperature. After hydrolysis with distilled water while cooling on ice, extraction was performed several times with diethyl ether, and the extract was washed with saturated saline and then dried over anhydrous magnesium sulfate. After filtration of the magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained product was transferred to a 200 ml Erlenmeyer flask and dissolved in 100 ml of toluene. To this solution there was added 0.68 g (3.59 millimoles) of p-toluenesulfonic acid hydrate, and the mixture was heated to reflux for 4 hours. After reflux, hydrolysis was performed with distilled water while cooling on ice, and extraction was performed several times with diethyl ether. The extract was washed once with a saturated sodium bicarbonate aqueous solution, washed once with saturated saline, and then dried over anhydrous magnesium sulfate. After drying, the magnesium sulfate was filtered off, the solvent was distilled off under reduced pressure, and purification was performed with a silica gel column to obtain 6.6 g of 2,7-dibromoindene as white crystals (67% yield).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:31]=[CH:32][CH:33]=1)[O:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([NH:22][C:23](=[O:30])OCC(Cl)(Cl)Cl)[N:21]=2)[N:18]=1)=[O:7].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.C(N(C(C)C)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CS(C)=O>[F:37][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:31]=[CH:32][CH:33]=1)[O:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([NH:22][C:23]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:30])[N:21]=2)[N:18]=1)=[O:7]
Reactant: C1COCCN1
Reactant: O=C(Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1)OCC(Cl)(Cl)Cl
Agent: CC(C)N(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)N4CCOCC4)cn3n2)c1)c1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 73.7 %

Procedure:
A mixture of 2,2,2-trichloroethyl [6-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]carbamate (140 mg, 0.237 mmol), morpholine (31 mL, 0.356 mmol), N,N-diisopropylpropan-2-amine (123 μL, 0.713 mmol) and dimethyl sulfoxide (10 mL) was heated to 80° C. and the mixture was stirred for 24 hr. After the reaction mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0) and precipitated from diisopropyl ether to give the title compound (92 mg, 73%) as a pale-green powder.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[N:13]([CH3:14])[CH3:12])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C1CCc2ccc(Br)cc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)C1CCc2ccc(Br)cc21
Yield: 80 %

Procedure:
(Method 2): 6-Bromo-indan-1-one (0.58 mmol) was dissolved in MeOH. Dimethyl-amine (3.7 mmol), acetic acid (0.059 mmol) and sodium cyanoborohydride (1.74 mmol) were added under argon atmosphere. The suspension was refluxed overnight and then cooled. The crude was evaporated to dryness and then suspended in water. The product was extracted with CH2Cl2 and washed with water. The CH2Cl2 extract was dried with anhydrous Na2SO4, filtered and evaporated to dryness to give the crude product (6-bromo-indan-1-yl)-dimethyl-amine (80% conversion LC-MS). The crude product was used in the next synthetic step (Suzuki coupling), without further purification.