Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O-])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[K+].Cl>O>[C:9]([O:8][PH:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)(C)O[PH](=O)OC(C)(C)C

Procedure:
Potassium di-tert-butyl phosphate (45 g) was dissolved in water (160 mL). Hydrochloric acid (1M, aq) was added until the pH was ˜3. The resultant precipitate was collected by filtration, washed with water, and dried under vacuum overnight to give di-tert-butyl phosphonic acid as a white solid. Then, to a suspension of i (18.68 g, 39.28 mmol), triphenylphosphine (17.51 g, 66.78 mmol), and di-tert-butyl hydrogen phosphate (10.73 g, 51.06 mmol) in THF and triphenylphosphine were suspended in anhydrous THF (200 mL). A solution of DIAD (13.5 g, 66.78 mmol) in THF (20 mL) was added dropwise. The mixture was stirred at room temperature and monitored by LCMS to completion then was concentrated under reduced pressure. Et2O (300 mL) was added and the mixture sonicated, resulting in a bright white solid, which was filtered, washed with Et2O (100 mL) and air dried. The filtrate also contained some product. After concentration to 150 mL the filtrate was chilled in ice, yielding more solid material. The solids were collected, redissolved in DCM, and plugged (50-100% EtOAc/DCM to remove Mitsonobu by-products then 10% MeOH/DCM to elute the desired product. After concentrating the relevant fraction to a white solid, this material was recrystallized from DCM/ether/heptane, filtered, washed with heptane, and dried overnight to give ii as a white solid (17.09 g, 64%). 1H NMR (400 MHz) δ 9.41 (s, 2H); 8.83 (d, J=4.4 Hz, 1H); 8.53 (d, J=8 Hz, 1H); 8.43 (d, J=1.2 Hz, 1H); 8.21 (d, J=1.2 Hz, 1H); 8.01 (dt, J=8, 1.6 Hz, 1H); 7.46 (dd, J=7.2, 4.8 Hz); 5.43 (m, 1H); 5.16 (s, 2H); 4.38 (s, 2H); 3.39 (q, J=7.2 Hz, 2H); 3.32 (br s, 2H); 2.55 (s, 3H); 1.64 (d, J=6.8 Hz, 3H); 1.38 (s, 9H); 1.36 (s, 9H); 1.14 (t, J=7.2 Hz). MS: 667.78 (M+H)+. Chiral HPLC: Column. Chirapak IC, 0.46 cm×25 cm; 25 min isocratic gradent 100% MeOH retention time=17.12 min.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([S:11][CH3:12])[C:7]=1[C:13]#[N:14])=[O:4].[OH:15]O>C(O)(=O)C>[CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([S:11]([CH3:12])=[O:15])[C:7]=1[C:13]#[N:14])=[O:4]
Reactant: OO
Reactant: CNC(=O)Nc1snc(SC)c1C#N
Solvent: CC(=O)O
Product: CNC(=O)Nc1snc(S(C)=O)c1C#N

Procedure:
The reaction was repeated using 24.2 of 1-methyl-3-(4-cyano-3-(methylthio)-5-isothiazolyl)urea and 12 ml of 30% hydrogen peroxide in 175 ml of acetic acid to give 7.9 g of 1-methyl-3-(4-cyano-3-(methylsulfinyl)-5-isothiazolyl)urea, m.p. 241° (decomposes).
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([N:15]2[CH2:20][CH2:19][C@:18]([CH2:27][C:28](=O)[CH3:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][C:16]2=[O:31])[CH3:14])=[CH:9][CH:8]=1>C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br-].C1COCC1>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C@@H:13]([N:15]2[CH2:20][CH2:19][C@:18]([CH2:27][C:28]([CH3:2])=[CH2:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][C:16]2=[O:31])[CH3:14])=[CH:11][CH:12]=1
Reactant: [Li]CCCC
Reactant: CC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(C)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a solution of CH3PPh3Br (863.9 mg 2.42 mmol) in THF (8 mL) was added n-BuLi (0.678 ml, 1.69 mmol) at −78° C. under N2. The mixture was stirred at rt for 1 h, a solution of (R)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-oxopropyl)-4-phenylpiperidin-2-one (100 mg 0.24 mmol) in THF (5 mL) was added, and the mixture was stirred at reflux overnight. The reaction was quenched by satd aq NH4Cl and extracted with EtOAc. The combined organic phase was dried and concentrated to give the crude product, which was purified by preparative TLC to give (S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-methylallyl)-4-phenylpiperidin-2-one (60 mg, 60%).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[CH:6][CH:5]=1)([O-])=O.O1CCCC1>[C].[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[CH:18][CH:19]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
A mixture of ethyl 3-[(4-nitrobenzoyl)amino]propanoate (26.6 g) synthesized above, 5% palladium-carbon (8.9 g), tetrahydrofuran (150 mL) and ethanol (150 mL) was stirred at room temperature overnight under a hydrogen atmosphere. 5% Palladium-carbon was filtered off, and the filtrate was concentrated under reduced pressure to give a white solid. Recrystallization from ethyl acetate-diisopropyl ether gave the title object compound (22.6 g, 95%) as white crystals.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15]([O:17][C:18]3[C:23]([CH3:24])=[CH:22][C:21]([C:25](=[O:27])[CH3:26])=[CH:20][C:19]=3[CH3:28])=[N:14][C:13](Cl)=[N:12][C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1.C(O)(C(F)(F)F)=O>O>[C:25]([C:21]1[CH:22]=[C:23]([CH3:24])[C:18]([O:17][C:15]2[C:16]3[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:9]=[CH:10][C:11]=3[N:12]=[C:13]([NH:30][C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=3)[N:14]=2)=[C:19]([CH3:28])[CH:20]=1)(=[O:27])[CH3:26]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(=O)c1cc(C)c(Oc2nc(Cl)nc3ccn(Cc4ccccc4)c23)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)c1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3ccn(Cc4ccccc4)c23)c(C)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 51.7 %

Procedure:
In a sealed tube was added 1-(4-(5-benzyl-2-chloro-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3,5-dimethylphenyl)ethanone (111 mg, 0.27 mmol), 4-aminobenzonitrile (129 mg, 1.1 mmol), TFE (1.7 mL) and TFA (0.2 mL, 2.16 mmol). The reaction mixture was stirred at 90° C. for 16 h. Upon completion of the reaction, the resulting mixture was cooled, diluted with water, and washed with EtOAc. The combined organic layers were washed with NaHCO3 and brine; dried over Na2SO4; filtered; and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with hexanes:ethyl acetate (9:1-100% EtOAc), to give the product as an off-white solid (68 mg, 51%).
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:24]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:30]([OH:32])=[O:31])[CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:24]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:30]([OH:32])=[O:31])[CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1
Reactant: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(NC(=O)OC(C)(C)C)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a solution of 2-(6-(tert-butoxycarbonylamino)pyridin-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid (140.0 mg, 0.32 mmol) in dichloromethane (50 mL) was added CF3COOH (182.6 mg, 1.60 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (10 mL) and adjusted to pH 6 with sodium bicarbonate. The product were collected by filtration to afford 2-(6-aminopyridin-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (88.6 mg, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][N:3]=1.[CH2:14]([Mg]Cl)[CH3:15].CCOCC.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6](=[O:7])[CH2:14][CH3:15])=[CH:12][CH:13]=1
Reactant: CC[Mg]Cl
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 60 %

Procedure:
To a solution of 6-chloro-N-methoxy-N-methyl nicotinamide (6.0 g, 30 mmol) (produced as disclosed in Perner, R. J. J. Med. Chem. 2003, 46, 5249) in THF (100 mL) was added a 3M solution of ethyl magnesium chloride in ether (15 mL, 45 mmol). The reaction mixture was heated under reflux for 4 hours and then stirred at approximately 25° C. for 14 hours. The reaction mixture was treated with a saturated aqueous solution of ammonium chloride (100 mL) and then extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography over silica gel, eluting with 10 percent ethyl acetate in hexane to give product as a white solid. (2.8 g, 60 percent yield).
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[CH:10][C:5]2=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.[H-].[Na+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:5]2[CH:10]=[CH:9][N:8]([CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[F:18])[C:6]=2[N:7]=1
Reactant: Clc1nc(-c2ccco2)c2ccnc-2[nH]1
Reactant: Fc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccccc1Cn1ccc2c(-c3ccco3)nc(Cl)nc21
Reaction time: 0.33 h
Yield: 76.3 %

Procedure:
A solution of 2-chloro4(2-furyl)-1H-pyrrolo[2,3-d]pyrimidine (219 mg, 1 mmol) in DMF (2 mL) at 0° C. was treated with NaH (40 mg, 60%, 1 inmol), stirred for 20 min, treated with 2-fluorobenzyl bromide (120 μL, 1 mmol), stirred at room temperature for 1 h, quenched with water, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by chromatography (EtOAc:Heptane, 1:4) to give the title compound (250 mg, 76%) as a cream solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>CN(C=O)C.C(OCC)C>[CH2:12]([O:11][C:4]1[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=[C:2]([Br:1])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1cc(Br)cn2nccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Brc1cc(OCc2ccccc2)c2ccnn2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-bromopyrazolo[1,5-a]pyridin-4-ol (1.10 g, 5.16 mmol) and benzyl bromide (0.676 ml, 5.68 mmol) were dissolved in DMF (20 ml) at 0° C. NaH (413 mg, 10.3 mmol, 60 wt %) was added in one portion and the mixture was allowed to stir at 0° C. After 30 minutes, additional benzyl bromide 0.068 ml, 0.57 mmol) was added and the mixture was allowed to stir 30 minutes at 0° C. The reaction mixture was diluted in diethyl ether, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/isohexane gradient) to afford 4-(benzyloxy)-6-bromopyrazolo[1,5-a]pyridine.
Reaction SMILES: [CH2:1]([N:3]1[CH2:20][C@H:19]([CH3:21])[N:18]2[C:5](=[C:6]([O:22][CH3:23])[C:7]3[C:12](=[O:13])[NH:11][N:10]=[C:9]([C:14]([NH:16][CH3:17])=[O:15])[C:8]=32)[C:4]1=[O:24])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[F:44])[CH2:39]Br>CN(C=O)C>[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[F:44])[CH2:39][N:11]1[C:12](=[O:13])[C:7]2[C:6]([O:22][CH3:23])=[C:5]3[C:4](=[O:24])[N:3]([CH2:1][CH3:2])[CH2:20][C@H:19]([CH3:21])[N:18]3[C:8]=2[C:9]([C:14]([NH:16][CH3:17])=[O:15])=[N:10]1
Reactant: CCN1C[C@H](C)n2c(c(OC)c3c(=O)[nH]nc(C(=O)NC)c32)C1=O
Reactant: Fc1ccc(CBr)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCN1C[C@H](C)n2c(c(OC)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(C(=O)NC)c32)C1=O
Reaction time: 0.42 h

Procedure:
To a cold (0° C.) solution of (6S)-8-ethyl-10-methoxy-N,6-dimethyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-4-carboxamide (1.58 g, 4.73 mmol) in anhydrous DMF (50 mL), a solution of lithium bis(trimethylsilyl)amide (4.97 mL, 4.97 mmol, 1 M in THF) was added. After stirring at the same temperature for 25 minutes, 3-chloro-4-fluorobenzyl bromide (1.27 g, 5.68 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes and concentrated under vacuum. The residue was partitioned between chloroform and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 1-5% methanol in ethyl acetate gradient. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]2[S:18][CH:19]=[CH:20][C:16]=2[CH:15]=1.[Br:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]([CH:34]=[O:35])[CH:25]=1.[Cl-].[NH4+]>C1COCC1>[Br:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]([CH:34]([C:19]2[S:18][C:17]3[CH:21]=[CH:22][C:14]([O:13][CH3:12])=[CH:15][C:16]=3[CH:20]=2)[OH:35])[CH:25]=1
Reactant: O=Cc1cc(Br)c2ccccc2c1
Reactant: COc1ccc2sccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc2sc(C(O)c3cc(Br)c4ccccc4c3)cc2c1
Reaction time: 0.17 h
Yield: 80.7 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.6 M, 1.48 ml, 2.36 mmol) was added dropwise to a solution of 5-methoxybenzo[b]thiophene (388 mg, 2.36 mmol) in THF (6 ml) at −78° C. and the reaction solution was stirred at the same temperature for 10 minutes. To this solution, a solution of 4-bromonaphthalene-2-carbaldehyde (530 mg, 2.25 mmol) in THF (4 ml) was added dropwise. The reaction mixture was stirred at the same temperature for two hours, and then a saturated ammonium chloride aqueous solution added and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (725 mg, 77%).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]2=[N:4][CH:3]=1.C(O)(=O)C(O)=O.C([Sn](CCCC)(CCCC)[C:23]1[CH:24]=[C:25]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=[CH:27][CH:28]=1)CCC>CCO>[Cl:11][C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:27]3[CH:28]=[CH:23][CH:24]=[C:25]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[CH:26]=3)=[CH:3][N:4]=[C:5]2[CH:10]=1
Reactant: Clc1ccn2c(Br)cnc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2cccnc2)c1
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: Clc1ccn2c(-c3cccc(-c4cccnc4)c3)cnc2c1

Procedure:
The title compound was prepared in a similar manner to that described in Example 11 from 3-bromo-7-chloroimidazo[1,2-α]pyridine and 3-[3-(tri-n-butylstannanyl)phenyl]pyridine. Oxalate salt, white crystalline solid, m.p. 178-180° C. (EtOH). 1H NMR (360 MHz, d6-DMSO) δH 7.05 (1H, dd, J 7 and 2), 7.50-7.56 (1H, m), 7.67-7.89 (4H, m), 7.96 (1H, s), 8.01 (1H, s), 8.21 (1H, d, J 7), 8.61 (1H, d, J 4), 8.70 (1H, d, J 7), 9.02 (1H, d, J 2); m/z (ES+) 306 (M++H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:31])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([NH:25]C(=O)C)=[CH:18][C:17]=2[O:29][CH3:30])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:32].CO>O>[ClH:32].[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:31])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([NH2:25])=[CH:18][C:17]=2[O:29][CH3:30])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(NC(C)=O)c([N+](=O)[O-])cc1C(=O)NC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1cc(N)c([N+](=O)[O-])cc1C(=O)NC1CCN(Cc2ccccc2)CC1

Procedure:
A mixture of N-(1-benzylpiperid-4-yl)-2-methoxy-4-acetamido-5-nitrobenzamide (4.26 g; 0.01 mol) [prepared by the procedure described in Example 1], concentrated hydrochloric acid (5 ml), methanol (40 ml) and water (40 ml) was boiled under reflux for 2 hours. The solvent was removed in vacuo and the solid recrystallized from ethanol to give 3.4 g of N-(1-benzylpiperid-4-yl)-2-methoxy-4-amino-5-nitrobenzamide hydrochloride, m.p. 218°-220° C. (dec).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:7]1([S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CS(=O)(=O)c1ccccc1
Temperature: 42.5 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
(β-chloroethylsulfonyl)benzene (40.9 g, 200 mmol) was dissolved in 100 g of toluene, to this solution were added 30.7 g of 49% aqueous potassium carbonate solution (potassium carbonate 109 mmol) and 1.01 g (10 mmol) of triethylamine, and the mixture was stirred for 3 hours at from 40 to 45° C. Then, the mixture was washed with 70 g of water once, with 35 g of 5% aqueous sulfuric acid solution once and further with 35 g of water once, and the solvents were distilled off to obtain 33.1 g (yield 98.4%) of phenylvinylsulfone.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C>[Si:23]([O:22][CH2:21][CH2:20][CH2:19][O:10][C:8]1[CH:9]=[C:2]([F:1])[C:3]([CH:4]=[O:5])=[C:6]([F:11])[CH:7]=1)([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: O=Cc1c(F)cc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCOc1cc(F)c(C=O)c(F)c1
Yield: 95.9 %

Procedure:
As described in the previous experiment, a mixture of 2,6-difluoro-4-hydroxybenzaldehyde (515 mg, 3.25 mmol), K2CO3 (675 mg, 4.88 mmol) and (3-bromopropoxy)-tert-butyldimethylsilane (1.00 mL, 4.23 mmol) in DMF (8 mL) were reacted, processed and purified by flash chromatography (15% EtOAc/Hex) to afford 4-(3-(tert-butyldimethylsilyloxy)propoxy)-2,6-difluorobenzaldehyde as a white solid (1.03 g, 96%). MS (EI) m/z 331.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:25]=[C:26]([C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:31])[CH:27]=[CH:28][CH:29]=1>>[C:30]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][O:21][CH:9]1[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10]1)(=[O:31])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(O)C1
Reactant: O=C(c1ccccc1)c1cccc(CBr)c1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(OCc2cccc(C(=O)c3ccccc3)c2)C1

Procedure:
(jj) In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-(4-fluoro-phenyl)-3-hydroxy-piperidine-1-carboxylate [Example 3(b)] with (3-bromomethyl-phenyl)-phenyl-methanone [J.Med.Chem. 1984, 27 (12), 1682-1690] there was obtained tert-butyl (3RS,4RS)-3-(3-benzoyl-benzyloxy)-4-(4-fluoro-phenyl)-piperidine-1-carboxylate as a yellowish liquid; MS: 490 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([S:16][CH:17]([CH3:19])[CH3:18])=[C:12]([CH:14]=O)[S:13][C:7]=2[N:6]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:5]1=[O:24].[CH2:25](O)[CH3:26]>O>[N:4]1([CH2:14][C:12]2[S:13][C:7]3[N:6]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:5](=[O:24])[N:4]([CH3:3])[C:9](=[O:10])[C:8]=3[C:11]=2[S:16][CH:17]([CH3:19])[CH3:18])[C:9]2[CH:8]=[CH:11][CH:12]=[CH:25][C:26]=2[N:6]=[CH:5]1
Reactant: CCO
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SC(C)C)c(C=O)sc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SC(C)C)c(Cn3cnc4ccccc43)sc21
Reaction time: 24 h

Procedure:
Sodium borohydride (0.11 g) was added to 1,2,3,4-tetrahydro-3-methyl-5-[(1-methylethyl)thio]-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-6-carboxaldehyde (0.50 g) in ethanol (20 ml) and the mixture was stirred for 24 hours. The reaction was diluted with water (50 ml) and was then extracted with ethyl acetate (3×50 ml). The organic phases were washed with brine and then dried, filtered and evaporated to give the subtitle compound as a yellow solid (0.45 g).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([CH3:21])[N:16]([CH:18]([F:20])[F:19])[CH:17]=2)=[CH:9][CH:8]=1.C(=O)([O-])O.[Na+]>ClC(Cl)(Cl)Cl>[Cl:4][C:17]1[N:16]([CH:18]([F:20])[F:19])[C:15]([CH3:21])=[N:14][C:13]=1[C:10]1[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)cn1C(F)F
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc(-c2ccc(Cl)cc2)c(Cl)n1C(F)F
Reaction time: 2 h

Procedure:
26.7 g (0.19 mol) of sulfuryl chloride were added dropwise with ice-cooling to a suspension of 24 g (98 mmol) of 4-(4-chlorophenyl)-1-difluoromethyl-2-methyl-1H-imidazole in 200 ml of tetrachloromethane. After the reaction mixture had been stirred for 2 hours, an excess of saturated aqueous sodium hydrogen carbonate solution was added dropwise (still with ice-cooling). The solids were subsequently filtered off. The organic phase was washed with water until neutral, dried over magnesium sulfate and concentrated. The crude product was purified by means of silica gel column chromatography (eluent: hexane/ethyl acetate=8:1). Yield: 7.4 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20]>O1CCCC1>[CH3:17][N:18]([CH3:22])[C:19](=[O:20])[O:14][CH:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1
Reactant: OC1CCN(c2ccc(Br)cc2)CC1
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)OC1CCN(c2ccc(Br)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(4-Bromophenyl)piperidin-4-ol (200 mg) is dissolved under argon in tetrahydrofurane (4 mL), cooled to 0° C. and treated with NaH (60% in mineral oil, 36 mg). The mixture is stirred for 30 minutes, treated with dropwise with dimethylcarbamoylchloride (110 μL) and stirred for 4 hours at room temperature. Then the mixture is partitioned between water and ethylacetate. The organic phase is washed with water and brine and is dried (MgSO4). The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→50:50) to give the title compound. LC (method 3): tR=1.05 min; Mass spectrum (ESI+): m/z=327 [M+H]+.