Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](OC2C=CC=CC=2)=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][C:3]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1.[CH2:27]([NH2:30])[CH:28]=[CH2:29]>O1CCOCC1>[Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[CH:23][CH:24]=2)=[CH:4][CH:5]=[C:6]([N+:15]([O-:17])=[O:16])[C:7]=1[NH:30][CH2:27][CH:28]=[CH2:29]
Reactant: N#Cc1ccc(Oc2ccc([N+](=O)[O-])c(Oc3ccccc3)c2Cl)cc1
Reactant: C=CCN
Solvent: C1COCCO1
Product: C=CCNc1c([N+](=O)[O-])ccc(Oc2ccc(C#N)cc2)c1Cl
Reaction time: 30 h

Procedure:
A mixture of 4 gm of 2-chloro-4-nitro-3-phenoxy-1-(4-cyano-phenoxy)-benzene, 10 ml of dioxane and 2 gm of allylamine was allowed to stand at room temperature for 30 hours. Thereafter, the dioxane was distilled off, the residue was taken up in chloroform, the resulting solution was extracted with dilute sodium hydroxide, the organic phase was dried with sodium sulfate, the chloroform was distilled off, and the residue was recrystallized from ethanol. 3.5 gm (97.2% of theory) of the yellow crystalline title compound, m.p. 85°-87° C., were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][N:12]2C(OCC1C=CC=CC=1)=O)=[O:5])[CH3:2].[H][H]>C(O)C.[Pd]>[NH:12]1[C:13]2[C:9](=[C:8]([O:7][CH:6]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:11]1
Reactant: CCOC(=O)C(Oc1cccc2c1ccn2C(=O)OCc1ccccc1)C(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(Oc1cccc2[nH]ccc12)C(=O)OCC
Yield: 82 %

Procedure:
A solution of 12 (8.51 g, 20 mmol) in ethanol (250 mL) was mixed with 10% palladium on carbon (1.5 g) and hydrogenated at atmospheric pressure for 1 h until hydrogen uptake ceased. The catalyst was filtered off through a Celite bed and washed with ethanol, and the filtrate was evaporated to give a brown oil. Filtration through flash silica with ethyl acetate-hexanes (3:2) as eluent, followed by trituration with diethyl ether-hexanes at −20° C. gave 8 as white crystals (4.78 g, 82%), mp 52-53° C. (from diethyl ether-hexanes), identical to the material described above.
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([NH2:13])=[CH:12][C:7]=2[N:6]=[CH:5]1)[CH2:2][CH3:3].[Br:14]Br.N.CO.C(Cl)Cl>CC(O)=O>[CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([NH2:13])=[C:12]([Br:14])[C:7]=2[N:6]=[CH:5]1)[CH2:2][CH3:3]
Reactant: CCCn1cnc2cc(N)ccc21
Reactant: BrBr
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CCCn1cnc2c(Br)c(N)ccc21
Yield: 48 %

Procedure:
To a solution of 1-propyl-5-aminobenzimidazole (1.2 g, 7.1 mmol) in 10 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5%) NH3 sat'd MeOH/CH2Cl2) to provide 0.83 g (3.4 mmol, 48%) of the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH2:44]([N:46]([C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[CH:51]=1)[CH2:47][CH2:48][NH2:49])[CH3:45]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:49][CH2:48][CH2:47][N:46]([CH2:44][CH3:45])[C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[CH:51]=2)=[O:42])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: CCN(CCN)c1cccc(C)c1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCN(CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1C)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (139 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1-ethyl-N1-(3-methylphenyl)-1,2-ethanediamine (84 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (112 mg, yield 68%).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:27])=[C:5]([C@@H:10]2[CH2:15][N:14]3[CH2:16][CH2:17][NH:18][CH2:19][C@H:13]3[CH2:12][N:11]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].FC1C(C#N)=C(C)C(C2CO2)=CC=1.OC[C@@H]1NCCN(C(OC(C)(C)C)=O)C1>>[C:1]([C:3]1[C:4]([CH3:27])=[C:5]([C@H:10]2[CH2:15][N:14]3[CH2:16][CH2:17][NH:18][CH2:19][C@@H:13]3[CH2:12][N:11]2[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: Cc1c([C@@H]2CN3CCNC[C@H]3CN2C(=O)OC(C)(C)C)ccc(F)c1C#N
Agent: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Agent: Cc1c(C2CO2)ccc(F)c1C#N
Product: Cc1c([C@H]2CN3CCNC[C@@H]3CN2C(=O)OC(C)(C)C)ccc(F)c1C#N

Procedure:
The title compound was prepared in an analogous fashion to that described for the synthesis of (3R,9aS)-tert-butyl 3-(3-cyano-4-fluoro-2-methylphenyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate starting from 6-fluoro-2-methyl-3-(oxiran-2-yl)benzonitrile and (R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate. LC/MS: 375.16 (M+1)+.
Reaction SMILES: [CH2:1]([CH2:4][NH:5][C:6]([CH3:10])([CH3:9])[C:7]#[N:8])[CH:2]=[CH2:3].O>C1C=CC=CC=1>[CH2:1]([CH2:4][NH:5][C:6]([CH3:10])([CH3:9])[CH2:7][NH2:8])[CH:2]=[CH2:3]
Reactant: C=CCCNC(C)(C)C#N
Solvent: c1ccccc1
Solvent: O
Product: C=CCCNC(C)(C)CN
Reaction time: 8 h

Procedure:
2-Allylmethylamino-2-methylpropionitrile (1.3 g.,) in benzene (20 ml., dry) was added dropwise to a stirred solution of sodium dihydro-bis [2-methoxy-ethoxy]aluminate (6.7 g.,) in benzene (30 ml., dry) under an atmosphere of nitrogen and stirred overnight. The excess reducing agent was decomposed by the dropwise addition of water. The phases were separated, the organic phase was washed with water, the aqueous phase was washed with benzene and the combined organic extract was dried (MgSO4) and the solvent was removed in vacuo to give a pale yellow liquid (1.8 g.). Distillation at 80°-90°/15 mm. gave 2-allylmethylamino-2-methylpropylamine as a colourless liquid (0.8 g., 60%).
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3](O)[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6].Cl.O>[Cl-].C[N+](C)(C)CCCCCCCCCCCCCCCC.C1(C)C=CC=CC=1.COCCOC>[O:8]=[C:7]1[O:9][C@H:3]([C@H:2]([CH2:1][OH:13])[OH:12])[C:4]([OH:10])=[C:5]1[OH:6]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: COCCOC
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 2-keto-L-gulonic acid (250 g, 1.15 mol, content: 89.6%, water: 8.6%) and trimethylcetylammonium chloride (0.275 g) was stirred in toluene (960 ml), and 36% conc. hydrochloric acid (30.0 g) was added. At this time, the amount of water in the reaction system was calculated as 2.0 mol per mol of 2-keto-L-gulonic acid. This mixture was stirred at 60° C. for 1 hour, a solution of hydrogen chloride gas (30.0 g) in ethylene glycol dimethyl ether (130 g) was added, and the mixture was stirred at the same temperature for 5 hours. Then, about 1200 g of the solvent was distilled away under reduced pressure while continuously introducing toluene (850 ml). The residue was filtered to give crude crystals of L-ascorbic acid. The crude crystals were dissolved in water. Quantitative analysis of the solution by high performance liquid chromatography (HPLC) showed that the solution contained L-ascorbic acid (191.1 g, yield: 94.1%) and 2-keto-L-gulonic acid (2.7 g, residual ratio: 1.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH:6]=[CH:7][CH2:8][N:9]([CH2:11][CH2:12][NH:13][S:14]([C:17]2[C:18]3[CH:19]=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH3:10])=[CH:4][CH:3]=1.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]([CH2:11][CH2:12][N:13]([CH2:32][CH2:31][N:30]([CH3:34])[CH3:29])[S:14]([C:17]2[C:18]3[CH:19]=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:15])=[O:16])[CH3:10])=[CH:27][CH:28]=1
Reactant: CN(CC=Cc1ccc(Cl)cc1)CCNS(=O)(=O)c1cccc2cnccc12
Reactant: CN(C)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)CCN(CCN(C)CC=Cc1ccc(Cl)cc1)S(=O)(=O)c1cccc2cnccc12
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a solution of 1.0 g of the amorphous compound obtained in Example 190, 0.267 g of 2-dimethylamino ethanol and 0.982 g of triphenylphosphine in 5 ml of tetrahydrofuran, was added dropwise a solution of 0.652 g of diethyl azodicarboxylate in 2 ml of tetrahydrofuran with stirring under ice cooling. After 2 hours, the reaction mixture was concentrated under a reduced pressure to remove tetrahydrofuran, and resulting residue was dissolved in 10 ml of ethyl acetate and extracted three times with 10 ml of 1N hydrochloric acid. The aqueous layer was alkalized with sodium bicarbonate and extracted three times with 10 ml of ethyl acetate, and the organic layer was dried over magnesium sulfate and evaporated to removed the solvent under a reduced pressure. The resulting residue was then applied to a silica gel column and eluted with 3% methanol in chloroform, to obtain 0.77 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH:6]=[CH2:7])[CH2:3][CH:4]=O.[NH3:9].CC1C=CC(S([CH2:20][N+:21]#[C-:22])(=O)=O)=CC=1>CO>[CH3:1][C:2]([CH3:8])([CH:6]=[CH2:7])[CH2:3][C:4]1[N:9]=[CH:20][NH:21][CH:22]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: C=CC(C)(C)CC=O
Reactant: N
Solvent: CO
Product: C=CC(C)(C)Cc1c[nH]cn1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
At 30° C., 3,3-dimethylpent-4-enal (126 g, 0.34 mol) was added over 20 minutes to an ambient temperature, saturated solution of ammonia in methanol (2.7 L). After stirring at 40° C. for 30 minutes, TosMIC (67 g, 0.4 mol) was added. After stirring at reflux overnight, the reaction mixture was concentrated, dissolved in ether and poured into 2N ammonium hydroxide (1500 mL) and stirred. The aqueous phase was extracted with ether. The combined organic extracts were washed with brine, dried (magnesium sulfate), filtered, and concentrated in vacuo to afford 4-(2,2-dimethylbut-3-en-1-yl)-1H-imidazole which was used in the subsequent step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=CC=1.C1(CCN2CCN(C3SC(C(O)=O)=C(C)N=3)C2=O)CC1.[F:43][C:44]1[CH:51]=[CH:50][C:47]([CH2:48][NH2:49])=[CH:46][CH:45]=1>>[CH:7]1([CH2:2][CH2:1][N:8]2[CH2:12][CH2:11][N:10]([C:13]3[S:14][C:15]([C:19]([NH:49][CH2:48][C:47]4[CH:50]=[CH:51][C:44]([F:43])=[CH:45][CH:46]=4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[C:9]2=[O:22])[CH2:6][CH2:5]1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1ccc(F)cc1
Agent: Cc1nc(N2CCN(CCC3CC3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CCC3CC3)C2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 34 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(2-cyclopropylethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 4-fluorobenzylamine in place of benzylamine, the title compound was obtained as a white powder in 34% yield: mp 122-123° C.: 1H NMR (300 MHz, CDCl3) δ 7.27-7.23 (m, 2H), 7.00-6.94 (m, 2H), 5.98 (s, 1H), 4.48 (d, J=5.7 Hz, 2H), 4.05 (t, J=7.8 Hz, 2H), 3.56 (t, J=8.7 Hz, 2H), 3.35 (t, J=7.8 Hz, 2H), 2.57 (s, 3H), 1.47-1.40 (m, 2H), 0.67-0.56 (m, 1H), 0.46-0.37 (m, 2H), 0.06-0.01 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 163.8, 162.5, 157.4, 155.3, 153.2, 133.9, 129.5, 116.8, 115.6, 44.0, 43.2, 42.7, 42.0, 32.4, 17.2, 8.4, 4.3; MS (ES+) m/z 403.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.CON(C)[C:21](=[O:31])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][CH3:30])=[CH:24][CH:23]=1>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([C:21](=[O:31])[C:22]2[CH:23]=[CH:24][C:25]([CH2:28][O:29][CH3:30])=[CH:26][CH:27]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: COCc1ccc(C(=O)N(C)OC)cc1
Agent: [Li]CCCC
Product: COCc1ccc(C(=O)c2ccc(OC)cc2C(=O)O)cc1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with N-methoxy-4-methoxymethyl-N-methylbenzamide. The product is crystallized from diisopropyl ether.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1)#[CH:2].C(N(CC)CC)C.Cl[C:17]([O:19][CH3:20])=[O:18]>ClCCl.O>[C:1]([CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:17]([O:19][CH3:20])=[O:18])[CH2:4]1)#[CH:2]
Reactant: COC(=O)Cl
Reactant: C#CC1CCCNC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C#CC1CCCN(C(=O)OC)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 10A (500 mg, 4.58 mmol) in dichloromethane (10 mL) was added triethylamine (2.55 mL, 18.32 mmol) followed by methyl chloroformate (0.532 mL, 6.87 mmol) and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and dichloromethane and the organic layer was separated and washed with water and brine. After drying over sodium sulfate, filtration, and concentration, the residue was purified by column chromatography (silica gel, 20% ethyl acetate in hexane) to afford the title compound. LCMS: 168.3 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C=O)C.[OH:12][CH2:13][CH2:14][CH:15]1[CH2:17][CH:16]1[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]#[N:28])[CH:25]=2)[N:20]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[O:12]=[CH:13][CH2:14][CH:15]1[CH2:17][CH:16]1[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]#[N:28])[CH:25]=2)[N:20]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C3CC3CCO)c3cc(C#N)ccc32)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(C3CC3CC=O)c3cc(C#N)ccc32)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 67.2 %

Procedure:
Oxalyl chloride (0.5 ml of 2.0 M solution in methylene chloride, 1.0 mmol) was diluted with dry methylene chloride (5.0 ml) and cooled to −78° C. under a nitrogen atmosphere. DMF (0.08 ml, 1.12 mmol) was added via a micro syringe and the solution was stirred at −78° C. for 10 min. A solution of 3-[2-(2-hydroxy-ethyl)cyclopropyl]-1-(toluene-4sulfonyl)-1H-indole-5-carbonitrile (250 mg, 0.657 mmol) in dry methylene chloride (5 ml) was added drop wise, and the solution was stirred at −78° C. for 1 hr, and then triethylamine (1.0 ml) was added. The solution was concentrated in vacuo, and the residue was dissolved in ethyl acetate (10 ml). The ethyl acetate solution was extracted with HCl (5 ml of 1 N solution), and with brine (5 ml). The ethyl acetate solution was dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel using methylene chloride as the eluent to give 3-[2-(2-oxo-ethyl)-cyclopropyl]-1-(toluene-4-sulfonyl)-1H-indole-5-carbonitrile (167 mg, 67%). 1H NMR (500 MHz, CDCl3): δ 9.87 (s, 1H), 8.03 (d,1H), 7.96 (s, 1H), 7.74 (d, 2H), 7.56 (d, 1H), 7.35 (s, 1H), 7.25 (d, 2H), 2.59 (m, 2H), 2.36 (s, 3H), 1.67 (m, 1H), 1.30 (m, 1H), 1.30 (m, 1H), 1.02 (m, 1H), 0.89 (m, 1H). MS m/e 379.16 (MH+).
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH3:15])=[CH:5][CH:4]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[N:28]([CH2:29][CH2:30][CH3:31])[CH2:27][CH2:26][C:25]([C:32]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][N:42]([CH3:49])[CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[CH:37][CH:36]=3)=[O:33])=[CH:24][C:23]=2[CH:50]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.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>[CH3:49][N:42]([CH2:41][C:38]1[CH:37]=[CH:36][C:35]([NH:34][C:32]([C:25]2[CH2:26][CH2:27][N:28]([CH2:29][CH2:30][CH3:31])[C:22]3[CH:21]=[CH:20][C:19]([C:3]4[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH3:15])=[CH:5][CH:4]=4)=[CH:50][C:23]=3[CH:24]=2)=[O:33])=[CH:40][CH:39]=1)[CH:43]1[CH2:44][CH2:45][O:46][CH2:47][CH2:48]1
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: CCCN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3CCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
In a mixture of water:ethanol toluene (1:1:10, v/v, 18.0 ml) were dissolved 4-(2-propoxyethoxy)phenyl borate (260 mg) and 7-bromo-1-propyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (396 mg). To the solution was added potassium carbonate (256 mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (36 mg), and the mixture was heated to reflux under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (25 g, ethyl acetate→ethyl acetate ethanol=10:1) and recrystallized from ethyl acetate-IPE to give N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 26) (252 mg, 53%) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[CH2:5]([OH:16])[C@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14]O)[OH:13])[OH:11])[OH:9])[OH:7].[Sb](F)(F)(F)(F)F>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:4])[O:13][CH:12]([CH:10]2[O:11][C:6]([CH3:8])([CH3:5])[O:9][CH:8]2[CH:6]2[O:7][C:12]([CH3:14])([CH3:10])[O:16][CH2:5]2)[CH2:14][O:3]1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)=O
Agent: F[Sb](F)(F)(F)F
Solvent: c1ccncc1
Product: CC1(C)OCC(C2OC(C)(C)OC2C2COC(C)(C)O2)O1
Temperature: 60 °C
Reaction time: 7 h
Yield: 93.3 %

Procedure:
To 200 ml of acetone were added 10.0 g of D-mannitol and 65 mg of antimony pentafluoride, and the mixture was refluxed with stirring in a water bath of 60° C. for 7 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the condenser. After completion of the reaction, a small amount of pyridine was added to the reaction solution, and the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform, and the solution was washed with aqueous sodium bicarbonate and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 17.43 g (93.3%) of 1,2:3,4:5,6-tri-O-isopropylidene-D-mannitol. Melting point, 68.5°-70.5° C. (recrystallized from 70% ethanol).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][NH:12][CH2:13][C:14]([CH3:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18].C(N(CC)C(C)C)(C)C>C1COCC1.C(OCC)(=O)C>[CH3:11][N:12]([CH2:13][C:14]([CH3:26])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: CNCC(C)(CC=C(C)C)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CCC(C)(CN(C)S(=O)(=O)c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 86.4 %

Procedure:
Benzenesulfonyl chloride (0.280 mL, 388 mg, 2.19 mmol) was added dropwise over 5 min to a solution of N-methyl-(2,5-dimethyl-2-phenylhex-4-en-1-yl)amine (415 mg, 1.91 mmol) and N,N-diisopropylethylamine (0.520 mL, 386 mg, 2.99 mmol) in THF (5.0 mL) at RT. After 16 h, the reaction mixture was diluted with 30 mL of ethyl acetate and washed with 15 mL each of 2 N aqueous HCl, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate and evaporated. The crude product was purified by flash column chromatography on silica gel, eluting with 4% ethyl acetate in hexane, to give 0.59 g of the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): δ7.72 (d, 2H, J=7.5 Hz), 7.55 (t, 1H, J=7.5 Hz), 7.48 (t, 2H, J=7.5 Hz), 7.33-7.23 (m, 4H), 7.17 (t, 1H, J=7 Hz), 4.83 (bt, 1H, J=7 Hz), 3.40 (d, 1H, J=13 Hz), 2.9(d, 1H, J=13 Hz), 2.50 (dd, 1H, J=15, 6 Hz), 2.33 (dd, 1H, J=15, 8 Hz), 2.09 (s, 3H), 1.59 (s, 6H), 1.42 (s, 3H). Mass spectrum (NH3/CI): m/z=358 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O.C([Cl:20])(=O)C>>[Cl-:20].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[N+:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: COc1ccccc1C=O
Reactant: C1CCNCC1
Product: COc1ccccc1C=[N+]1CCCCC1
Product: [Cl-]

Procedure:
The reaction of 18.4 g (0.216 mol) piperidine and 25.9 g (0.090 mol) 2-methoxybenzaldehyde in accordance with general synthesis instructions 2 and subsequent reaction with 5.3 ml (0.11 mol) acetyl chloride in accordance with general synthesis instructions 3 gave 13.4 g (corresponding to 62% of the yield calculated by theory) 1-(2-methoxy-benzylidene)-piperidinium chloride.
Reaction SMILES: [C:1]([C:4]1[S:5][C:6](Br)=[CH:7][CH:8]=1)(=O)C.[Br:10][C:11]1[S:15][C:14]([C:16]([CH2:18][C:19]#[N:20])=[O:17])=[CH:13][CH:12]=1.C1(=O)CCCC1.N1CCOCC1.[S]>>[NH2:20][C:19]1[S:5][C:6]2[CH2:1][CH2:4][CH2:8][C:7]=2[C:18]=1[C:16]([C:14]1[S:15][C:11]([Br:10])=[CH:12][CH:13]=1)=[O:17]
Reactant: CC(=O)c1ccc(Br)s1
Reactant: N#CCC(=O)c1ccc(Br)s1
Agent: [S]
Solvent: O=C1CCCC1
Solvent: C1COCCN1
Product: Nc1sc2c(c1C(=O)c1ccc(Br)s1)CCC2
Yield: 73 %

Procedure:
The procedure of Example 1 was followed except that 2-acetyl-5-bromothiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(5-bromothiophene-2-carbonyl)acetonitrile (Steps A and B). Cyclopentanone (Aldrich), 2-(5-bromothiophene-2-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 73%; IR (KBr) cm−1: 3349, 3236, 3130, 1590, 1549, 1431, 1414, 1269, 975; 1H NMR (CDCl3):δ2.285 (m, 2H), 2.51 (t, 2H, J=7.4 Hz), 2.70 (t, 2H, J=7.4 Hz), 6.64 (bs, 2H), 7.02 (d, 1H, J=4 Hz), 7.13 (d, 1H, J=4 Hz); red solid, mp: 154-156° C. (petroleum ether).