Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH2:9][F:10])[C:5]([F:12])=[C:4]([Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:3]=1.C1COCC1.[CH3:25][C:26]([S@:29]([NH2:31])=[O:30])([CH3:28])[CH3:27].CCOC(C)=O>[Cl-].[Na+].O.CCOC(C)=O.CCCCCC.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[N:7]=[C:6](/[C:8](=[N:31]\[S@@:29]([C:26]([CH3:28])([CH3:27])[CH3:25])=[O:30])/[CH2:9][F:10])[C:5]([F:12])=[C:4]([Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC[Si](CC)(CC)c1cc(Br)nc(C(=O)CF)c1F
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC[Si](CC)(CC)c1cc(Br)nc(/C(CF)=N\[S@](=O)C(C)(C)C)c1F
Temperature: 30 °C
Reaction time: 15 h
Yield: 83 %

Procedure:
To a 1000 mL, 3-neck, round-bottomed flask equipped with an internal temperature probe was added 1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2-fluoroethanone (35 g, 100 mmol), THF (350 mL), (R)-2-methylpropane-2-sulfinamide (AK Scientific; 25.4 g, 210 mmol) and titanium (iv) ethoxide (Aldrich; 51.7 mL, 250 mmol). The solution was heated and stirred at 30° C. for 15 h and then at 40° C. for 2 h. The solution was allowed to cool to rt and then brine (200 mL) was added followed by EtOAc (200 mL). A white precipitate formed. The solution was filtered through Celite (600 mL medium fritted funnel) and the filtercake was washed with EtOAc. The filtrate was washed with brine, dried (Na2SO4) and concentrated to afford the crude product as a yellow semi-solid. The material was dissolved in 20% EtOAc/hexane (300 mL) and washed with water (2×100 mL) and brine (100 mL) and then dried and concentrated to afford (R,E)-N-(1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (37.8 g, 83 mmol, 84% yield) as a yellow oil which was carried on directly. MS m/z=453.0 [M+H]+. Calculated for C17H27BrF2N2OSSi: 452.1.
Reaction SMILES: C(O[CH2:5][C:6]1[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:8]2[C:13]([C:14]=1[C:15](=[O:19])[C:16]([OH:18])=[O:17])=[CH:12][C:11]([O:20][CH3:21])=[CH:10][CH:9]=2)(=O)C.[OH-].[K+].Cl>>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:7]2[C:8]3[C:13](=[CH:12][C:11]([O:20][CH3:21])=[CH:10][CH:9]=3)[C:14]3[C:15](=[O:19])[C:16](=[O:17])[O:18][CH2:5][C:6]2=3)=[CH:24][CH:25]=1)([CH3:31])([CH3:32])[CH3:30]
Reactant: COc1ccc2c(c1)c(C(=O)C(=O)O)c(COC(C)=O)n2Cc1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COc1ccc2c(c1)c1c(n2Cc2ccc(C(C)(C)C)cc2)COC(=O)C1=O

Procedure:
The title compound was prepared from [2-[(acetyloxy)methyl]-1-(4-tert-butylbenzyl)-5-methoxy-1H-indol-3-yl](oxo)acetic acid and aqueous potassium hydroxide in substantially the same manner as described in step 6 of Example 1, followed by the treatment with aq HCl in substantially the same manner as described in step 7 of Example 1. The product was obtained as an off-white solid; mp: 238–239° C. Mass spectrum (ESI, [M−H]−) m/z 376. 1H NMR (400 MHz, DMSO-d6) δ 7.56 (d, 1H, J=9.01 Hz), 7.48 (d, 1H, J=2.45 Hz), 7.35 (d, 2H, J=8.40 Hz), 7.14 (d, 2H, J=8.25 Hz), 6.98 (dd, 1H, J=8.86 and 2.44 Hz), 5.87 (s, 2H), 5.42 (s, 2H), 3.81 (s, 3H), 1.22 ppm (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:7]=1.[CH3:22][O:23][C:24]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[NH2:36])[N:27]=1)=[O:25].C(O)(=O)C.O>C1(C)C=CC=CC=1.[Ti]>[CH3:22][O:23][C:24]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[N:36]=[CH:11][C:10]([OH:17])([C:13]([F:14])([F:16])[F:15])[CH2:9][C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:20][CH3:21])([CH3:18])[CH3:19])[N:27]=1)=[O:25]
Reactant: COc1ccc(Cl)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: COC(=O)c1ccc2c(N)cccc2n1
Agent: [Ti]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc2c(N=CC(O)(CC(C)(C)c3cc(Cl)ccc3OC)C(F)(F)F)cccc2n1

Procedure:
224 mg (0.69 mmol) of 4-(5-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 195 mg (0.96 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester are dissolved in 20 ml of toluene. After 5.0 ml of concentrated acetic acid is added, it is refluxed for 16 hours in a water separator. After the solvent is removed, the residue is taken up in 10 ml of tetrahydrofuran, 0.3 ml (1.4 mmol) of titanium tetraethylate is added, and the reaction is allowed to reflux again. After the solvent is removed as well as after purification on silica gel with hexane/ethyl acetate (0-100%), 120 mg (33% of theory) of the product is obtained.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH2:16][CH2:17][CH3:18])[N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[O:19]1[C:23]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=2)=[CH:22][N:21]=[CH:20]1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH2:16][CH2:17][CH3:18])[N:12]=3)[CH2:7][CH2:6]2)[C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([C:23]3[O:19][CH:20]=[N:21][CH:22]=3)=[N:25][CH:26]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(-c2cnco2)nc1
Reactant: CCCc1noc(N2CCC(NC3CC3)CC2)n1
Product: CCCc1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)nc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from cyclopropyl-[1-(3-propyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine and 6-oxazol-5-yl-nicotinic acid following a procedure analogous to that described in Example 1. LC (method 7): tR=1.09 min; Mass spectrum (ESI+): m/z=423 [M+H]+.
Reaction SMILES: N.[Na].[C:3]1([P:9](C2C=CC=CC=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:23]1[N:28]=[C:27]([NH2:29])[CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[C:10]1([P:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:23]2[N:28]=[C:27]([NH2:29])[CH:26]=[CH:25][CH:24]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cccc(Br)n1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: N
Agent: [Na]
Solvent: Cc1ccccc1
Product: Nc1cccc(P(c2ccccc2)c2ccccc2)n1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 59.1 %

Procedure:
At −78° C., 200 ml of ammonia were condensed in and 5.00 g of sodium (216.8 mmol) were dissolved therein within 5 min. The resulting dark blue solution was admixed with 11.70 g of triphenylphosphine (108.4 mmol) in portions, stirred at −78° C. for approx. 2 h and then admixed with 15.00 g (86.7 mmol) of 6-bromo-2-aminopyridine from example 14.1. After 250 ml of toluene had been added, the cold bath was removed and the ammonia evaporated off overnight. The residue was hydrolyzed with 150 ml of dist. H2O and admixed with 150 ml of saturated NaCl solution, the resulting phases were separated and the aqueous phase was extracted once with 200 ml of toluene. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The product was purified by column chromatography (first with dichloromethane to remove diphenylphosphine, then with 9:1 dichloromethane/ethyl acetate). Resulting mixed fractions were purified by sublimation at 180° C. and 10−2 mbar. 14.26 g (51.2 mmol, 59%) of 6-(diphenylphosphino)-2-aminopyridine were obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]([NH2:14])=O)=[C:9]([CH3:11])[N:10]=2)[N:7]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]#[N:14])=[C:9]([CH3:11])[N:10]=2)[N:7]=1
Reactant: Cc1nc2ccc(Cl)nn2c1C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1nc2ccc(Cl)nn2c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a mixture of 6-chloro-2-methylimidazo[1,2-b]pyridazine-3-carboxamide (1.5 g, 7.0 mmol) produced in the above, pyridine (1.7 mL, 21 mmol) and tetrahydrofuran (20 mL) was added dropwise under ice-cooling a solution of trifluoroacetic anhydride (1.5 mL, 11 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 2 hr. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound (887 mg, 66%) as a colorless solid.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]2[O:17][CH2:18][O:19][C:13]=2[CH:12]=1.C(N(CC)CC)C.CS([Cl:31])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:31][C@@H:6]1[CH2:7][CH2:8][CH2:2][CH2:3][N:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)[CH2:5]1
Reactant: OC[C@H]1CCCCN1CCc1ccc2c(c1)OCO2
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cl[C@@H]1CCCCN(CCc2ccc3c(c2)OCO3)C1
Reaction time: 14 h

Procedure:
(R)-2-Hydroxymethyl-1-(3,4-methylenedioxyphenethyl)piperidine (370 mg) was dissolved in 10 ml of dichloromethane. Triethylamine (184 mg, 1.82 mmol) and methanesulfonyl chloride (208 mg, 1.82 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred under cooling on ice for 1 hour and then at room temperature for 14 hours. The reaction liquid was distributed in dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain (R)-3-chloro-1-(3,4-methylenedioxyphenethyl) homopiperidine in the form of a light yellow oil (375 mg, 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N+:9]=[N-:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CCCC[Sn](OC(C)=O)(CCCC)CCCC.[Cl:31][C:32]1[N:40]=[C:39]2[C:35]([N:36]=[CH:37][N:38]2[C@@H:41]2[C@@H:46]3[C@@H:44]([CH2:45]3)[C@@H:43]([OH:47])[C@H:42]2[OH:48])=[C:34]([NH:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([C:57]#[C:58][CH2:59][CH2:60][CH2:61][C:62]#[CH:63])[CH:52]=2)[N:33]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>C(Cl)Cl.C(O)(C)(C)C.S([O-])([O-])(=O)=O.[Cu+2].O>[Cl:31][C:32]1[N:40]=[C:39]2[C:35]([N:36]=[CH:37][N:38]2[C@@H:41]2[C@@H:46]3[C@@H:44]([CH2:45]3)[C@@H:43]([OH:47])[C@H:42]2[OH:48])=[C:34]([NH:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([C:57]#[C:58][CH2:59][CH2:60][CH2:61][C:62]3[N:10]=[N:9][N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=4)[CH:63]=3)[CH:52]=2)[N:33]=1
Reactant: C#CCCCC#Cc1cccc(CNc2nc(Cl)nc3c2ncn3[C@H]2[C@H](O)[C@H](O)[C@@H]3C[C@@H]32)c1
Reactant: [N-]=[N+]=Nc1ccc(F)c([N+](=O)[O-])c1
Agent: [Cu+2]
Agent: CCCC[Sn](CCCC)(CCCC)OC(C)=O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: ClCCl
Solvent: O
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1cc(-n2cc(CCCC#Cc3cccc(CNc4nc(Cl)nc5c4ncn5[C@H]4[C@H](O)[C@H](O)[C@@H]5C[C@@H]54)c3)nn2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
4-Fluoro-3-nitro-phenylazide (7.5 mg, 0.041 mmol) and TBTA (1 mg, 0.001 mmol) were added to a solution of compound 211 (13.5 mg, 0.029 mmol) in CH2Cl2-t-butanol (0.6 mL)-water (0.6 mL) at room temperature. Freshly prepared 1M solution of sodium ascorbate (29.2 μL) followed by 7.5% solution of copper sulfate (48 μL, 0.015 mmol) was also added into the reaction mixture stirred at room temperature overnight. Solvent was evaporated, and the residue was purified on flash silica gel column chromatography (CH2Cl2:MeOH=45:1) to give compound 214 (17 mg, 91%) as a syrup. 1H NMR (CD3OD, 400 MHz) δ 861-8.59 (m, 1H), 8.49 (s, 1H), 8.23-8.19 (m, 1H), 8.14 (s, 1H), 7.65 (t, J=9.2 Hz, 1H), 7.39 (s, 1H), 7.33-7.24 (m, 3H), 4.79 (s, 1H), 4.72-4.70 (m, 3H), 3.90 (d, J=6.4 Hz, 1H), 2.99 (t, J=7.6 Hz, 2H), 2.53 (t, J=6.8 Hz, 2H), 2.08-1.96 (m, 3H), 1.69-1.65 (m, 1H), 1.33-1.30 (m, 1H), 0.79-0.75 (m, 1H). HRMS calculated for C31H28ClFN9O4 (M+H)+: 644.1937. Found 644.1962.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.Cl.O>C(O)C.[Pt](=O)=O>[NH:12]1[CH2:13][CH2:14][CH:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:16][CH:15]=2)[CH2:10][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(Cc2ccncc2)cc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(CC2CCNCC2)cc1
Reaction time: 12 h
Yield: 86.3 %

Procedure:
A mixture of 4-(4-nitrobenzyl)pyridine (12.85 g, 60 mmol), platinum(IV) oxide (1.0 g), 12N hydrochloric acid (5 ml, 60 mmol), water (5 ml) in ethanol (200 ml) was hydrogenated at 40 psi in a Parr apparatus for 12 hours. The reaction mixture was concentrated in vacuo, and the residue was diluted with cold water and basified with 10% sodium hydroxide solution. The resulting mixture was extracted into ethyl acetate. The combined organic extracts were washed with water and brine, dried (Na2SO4), and concentrated in vacuo. The residue on crystallization from ethyl acetate/hexanes gave 4-(piperidin-4-ylmethyl)-phenylamine (9.85 g, 86%) as a white crystalline solid, m.p. 110-113° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:38]=[CH:37][C:9]2[N:10]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23](=[O:30])[NH:24][CH:25]([C:27](=[O:29])[NH2:28])[CH3:26])[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])C.N[C@H](C(N)=O)C[OH:42].C(C(NC(C1C=CC2C(=CC=C(C3N(C4CCCCC4)C4C=CC(C(O)=O)=CC=4N=3)C=2)N=1)=O)C)(=O)N>>[C:27]([CH:25]([NH:24][C:23]([C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:11]3[N:10]([CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[C:9]4[CH:37]=[CH:38][C:6]([C:4]([OH:3])=[O:5])=[CH:7][C:8]=4[N:12]=3)[CH:14]=2)[N:19]=1)=[O:30])[CH2:26][OH:42])(=[O:29])[NH2:28]
Reactant: NC(=O)[C@@H](N)CO
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(C(=O)NC(C)C(N)=O)ccc3c1)n2C1CCCCC1
Agent: CC(NC(=O)c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1)C(N)=O
Product: NC(=O)C(CO)NC(=O)c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1

Procedure:
The title compound (5 mg yield) was prepared as described for Compound 497a using L-serinamide in place of L-alaninamide and hydrolyzed as described for Compound 497.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][CH2:26][C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)=[CH:20][CH:19]=1)[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:1]([O:8][C:9](=[O:32])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]([CH2:26][C:27]2[NH:31][CH:30]=[CH:29][N:28]=2)[CH2:39][C:35]2[N:34]([CH3:33])[CH:38]=[CH:37][N:36]=2)=[CH:22][CH:23]=1)[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ccnc1C=O
Reactant: CN(CCCCNC(=O)OCc1ccccc1)Cc1ccc(CNCc2ncc[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CCCCNC(=O)OCc1ccccc1)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.9 %

Procedure:
The compound (608.7 mg) obtained in Example 103-5 was dissolved in anhydrous methanol (24 ml) and added with 1-methyl-2-imidazole carboxaldehyde (231.3 mg) and sodium cyanoborohydride (176.0 mg). The solution was adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 3 days. After the reaction, the solvent was distilled off. The residue was added with a 1 mol/l sodium hydroxide aqueous solution and subjected to extraction with chloroform. The extract was dried with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (502.6 mg) as a colorless oily substance.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[C:20]3[N:19]=[C:18]([CH2:21][O:22][C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[N:17]([CH2:30][CH2:31][CH2:32][CH:33]4[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]4)[C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[C:20]3[N:19]=[C:18]([CH2:21][O:22][C:23]4[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=4)[N:17]([CH2:30][CH2:31][CH2:32][CH:33]4[CH2:34][CH2:35][NH:36][CH2:37][CH2:38]4)[C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CC1CCN(CCCOc2cccc3c2nc(COc2ccc(Cl)cc2)n3CCCC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC1CCN(CCCOc2cccc3c2nc(COc2ccc(Cl)cc2)n3CCCC2CCNCC2)CC1

Procedure:
The title compound was prepared from 4-[3-[4-(methyl)piperidin-1-yl]propoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole by standard trifluoroacetic acid deprotection as described supra.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.[CH2:10]([NH2:12])[CH3:11]>O>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([NH:12][CH2:10][CH3:11])=[O:9])[CH:3]=1
Reactant: CCN
Reactant: O=C(O)c1csc(Br)c1
Solvent: O
Product: CCNC(=O)c1csc(Br)c1
Yield: 70 %

Procedure:
5-Bromo-N-ethyl-3-thiophenecarboxamide was prepared from 5-bromo-3-thiophenecarboxylic acid (2.1 g, 10 mmol) and 70% ethylamine in water according to the methods of steps a and b of Example 248 in 70% yield.
Reaction SMILES: C([O:9][C@H:10]1[C@@H:15]([O:16]C(=O)C2C=CC=CC=2)[C@H:14]([O:25]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:34][O:35]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[CH2:44][CH:45]([NH:93][C:94](=[O:103])[O:95][CH2:96][C:97]1[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=1)[CH2:46][C:47]([OH:92])([OH:91])[C@H:48]1[O:80][C@H:79]([CH2:81][O:82]C(=O)C2C=CC=CC=2)[C@@H:69]([O:70]C(=O)C2C=CC=CC=2)[C@H:59]([O:60]C(=O)C2C=CC=CC=2)[C@@H:49]1[O:50]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[C@H:11]1([CH2:44][CH:45]([NH:93][C:94](=[O:103])[O:95][CH2:96][C:97]2[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=2)[CH2:46][C:47]([OH:91])([OH:92])[C@H:48]2[O:80][C@H:79]([CH2:81][OH:82])[C@@H:69]([OH:70])[C@H:59]([OH:60])[C@@H:49]2[OH:50])[O:12][C@H:13]([CH2:34][OH:35])[C@@H:14]([OH:25])[C@H:15]([OH:16])[C@@H:10]1[OH:9]
Reactant: O=C(NC(C[C@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)CC(O)(O)[C@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(NC(C[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O)CC(O)(O)[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of Benzyl (1[2,3,4,6-tetra-O-benzoyl-α-D-mannopyranosyl],4[2,3,4,6-tetra-O-benzoyl-α-D-mannopyranosyl]-dihydroxybutan-2-yl)carbamate (9.72 g, 6.96 mmol) in Methanol (30 mL) was added 0.5M sodium methoxide (1.5 mL, 0.750 mmol) in methanol. After stirring at room temperature for 48 hour, amberlite IR 120 (H) ion exchange resin (pre-washed with methanol 3×30 ml) was added to reaction mixture, and allowed stirring for additional 15 minutes. The ion exchange resin was filtered off and washed with methanol (2×5 mL). The filtrate was concentrated down and the residue was purified on 86 g C18 column reverse phase, eluting with 5% CH3CN in water (3 cv) then 5% to 50% CH3CN in water (20 cv) to give the title compound as a white solid. UPLC-MS: calculated for C24H37NO14 563.22 observed m/e: 564.24 (M+H)+(Rt: 2.31/5.00 min).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=O)[CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1>C1(C)C(C)=CC=CC=1>[N:13]1[CH:14]=[CH:15][C:10]([N:9]2[C:1](=[O:8])[CH2:2][CH2:3][CH2:4][C:5]2=[O:7])=[CH:11][CH:12]=1
Reactant: Nc1ccncc1
Reactant: O=C1CCCC(=O)O1
Solvent: Cc1ccccc1C
Product: O=C1CCCC(=O)N1c1ccncc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The starting material is prepared as follows: The mixture of 34.2 g of glutaric anhydride, 28.2 g of 4-aminopyridine and 650 ml of xylene is refluxed with stirring for 6 hours. It is allowed to cool to room temperature, the solids are filtered off and extracted twice with 200 ml chloroform at reflux. The combined extracts are evaporated and the residue recrystallized twice from ethyl acetate to yield the 1-(4-pyridyl)-piperidine-2,6-dione melting at 153°-155°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH2:5][O:6][CH2:7][CH2:8][OH:9].N1C=CN=C1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH2:5][O:6][CH2:7][CH2:8][O:9][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCOCc1cccc(Br)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCOCc1cccc(Br)c1

Procedure:
A solution of 2-(3-bromobenzyloxy)ethanol [Aromatic Intermediate 25, step a] (3 g), imidazole (2.2 g) and tert-butyldimethylchlorosilane (2.2 g) in DCM (50 mL) was stirred at RT for 17 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (×2). The combined organic phases were dried and evaporated in vacuo. The crude product was purified by silica gel chromatography, gradient elution 10 to 40% ethyl acetate in isohexane. Fractions containing the product were evaporated to dryness to afford the subtitled compound as a colourless oil. Yield 3.8 g.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:23][CH2:2][C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)=[O:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reaction time: 48 h
Yield: 29.6 %

Procedure:
293 mg of 5-acetyl-8-benzyloxycarbostyril are dissolved in 15 ml of chloroform, and 200 mg of N-bromosuccinimide are added thereto. The mixture is refluxed for 2 hours under stirring. 300 mg of N-bromosuccinimide are added to the mixture and 4 hours after the commencement of the reaction. 100 mg of N-bromosuccinimide are further added thereto. Six hours after the reaction is started, the mixture is cooled and is allowed to stand at 20° C. for 2 days. Precipitated crystals are collected by filtration. Then, the crystals are washed with methanol and ether and then dried. 110 mg of 5-bromoacetyl-8-benzyloxycarbostyril are thereby obtained as colorless crystals. On the other hand, the filtrate is concentrated to dryness, and the residue is treated in the same manner as above, whereby 60 mg of 5-bromoacetyl-8-benzyloxycarbostyril are further recovered from the filtrate. Total yield: 170 mg (45.8)