Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([N+:28]([O-])=O)[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C>[NH2:28][C:26]1[CH:25]=[CH:24][C:3]([O:4][CH2:5][CH2:6][N:7]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[C:2]([Cl:1])[CH:27]=1
Reactant: CC(C)(C)OC(=O)N(CCOc1ccc([N+](=O)[O-])cc1Cl)Cc1ccc(F)cc1F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CCOc1ccc(N)cc1Cl)Cc1ccc(F)cc1F
Yield: 95.5 %

Procedure:
To a solution of tert-butyl 2-(2-chloro-4-nitrophenoxy)ethyl-(2,4-difluorobenzyl)-carbamate (1.8 g, 4.06 mmol) in 70% aqueous ethanol (30 mL) was added sodium dithionite (2.87 g, 16.25 mmol), and the reaction mixture was heated to reflux for 3 hours. The hot reaction mixture was filtered and the residue washed with EtOAc (30 mL). The combined organic extracts were washed with brine (2×20 mL), dried (Na2SO4) and concentrated to give the title product (1.6 g, 95%) which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]([CH2:13][CH2:14][OH:15])[C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[CH2:1]([N:8]1[CH2:13][CH2:14][O:15][CH2:10][C:9]1=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)N(CCO)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C1COCCN1Cc1ccccc1
Temperature: 27.5 °C
Reaction time: 1.5 h
Yield: 83.6 %

Procedure:
A solution of N-benzyl-N-(2-hydroxyethyl)chloroacetamide (627.7 g, 2.76 mol) in tert-butanol (0.9 L) is stirred under nitrogen while warming to 25-30° C. Potassium tert-butoxide (2.897 L of a 1M solution in tert-butanol, 2.90 mol, 1.05 eq) is added over 2 hours. The reaction mixture is then stirred at room temperature for 90 minutes. Ice-cold water (6 L) is added and the resultant cloudy solution extracted with ethyl acetate. The combined organic layers are washed with brine, dried over magnesium sulphate and evaporated in vacuo to give a light brown oil (441 g, 84%), which is used in the next stage without further purification; MW 191.23; C11H13NO2; 1H NMR (CDCl3): 7.29-7.40 (5H, m), 4.67 (2H, s), 4.28 (2H, s), 3.87 (2H, t, 5 Hz), 3.31 (2H, t, 5 Hz); LCMS: (12 min method) m/z 192 [M+H]+RT 1.00 min.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[CH2:5]([O:12][C:13](=[O:21])[N:14]([CH2:18][C:19]#[CH:20])[CH2:15][C:16]#[CH:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(Cl)Cl>C1(C)C=CC=CC=1>[CH2:5]([O:12][C:13]([N:14]1[CH2:18][C:19]2[C:16](=[CH:17][CH:3]=[C:2]([CH2:1][OH:4])[CH:20]=2)[CH2:15]1)=[O:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#CCN(CC#C)C(=O)OCc1ccccc1
Reactant: C#CCO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1Cc2ccc(CO)cc2C1
Temperature: 55 °C
Reaction time: 1 h
Yield: 113 %

Procedure:
A solution of propargyl alcohol (2.11 Kg, 37.7 mol) in toluene (32.48 L) was degassed and heated to 55° C. The solution of di-prop-2-ynyl-carbamic acid benzyl ester (4.06 Kg, 17.86 mol, step 6) in toluene and Wilkinsons catalyst (0.162 Kg) were added in 10 equal portions such that temperature <65° C. (the exotherm was allowed to subside before the next addition was made). The solution was then stirred at 55° C. for 1 h and then cooled to 20° C. DCM (8.12 L) was added and the mixture was concentrated to a small volume. Toluene (8 L) was added and the solution evaporated to constant weight giving the title compound 5.72 Kg (113%).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[C:5]3[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]=3[CH:13]=[CH:14][CH:15]=2.[H-].[Na+].BrC[CH2:20][CH2:21][CH2:22][C:23]#[N:24].CCOCC>CN(C)C=O>[CH3:1][S:2][C:3]1[C:4]2[C:5]3[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[C:7](=[O:12])[C:6]=3[CH:13]=[CH:14][CH:15]=2
Reactant: CSc1ccc2c3c(cccc13)C(=O)N2
Reactant: N#CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CSc1ccc2c3c(cccc13)C(=O)N2CCCC#N
Temperature: 50 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
A mixture of 2.15 g of 6-(methylthio)-benz-[cd]indol-2(1H)-one (Example 2), 0.6 g of 60% sodium hydride in 70 ml of N,N-dimethylformamide is heated at 50° C. for 30 minutes then cooled. A solution of 2.22 g of 1-bromo-4-cyano-butane in 25 ml of N,N-dimethylformamide is added dropwise to the reaction mixture and stirring continued for 3 hours. The reaction mixture is quenched in 400 ml of ice water and extracted with (2×300 ml) of ethyl acetate. The organic layer is dried with magnesium sulfate and evaporated to afford a solid which is stirred with ether, filtered and dried to yield 2.5 g of the desired product as a solid, m.p. 120°-122° C.
Reaction SMILES: Cl.[CH3:2][S:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[O:20][C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:13][C:12](=[O:21])[C:11]=2[CH:22]=1)(=[O:5])=[O:4].Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32]Cl)=[CH:27][N:26]=1.ClC1N=CC(CC(O)=O)=CC=1.S(Cl)(Cl)=O>>[CH3:2][S:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[O:20][C:14]3([CH2:15][CH2:16][N:17]([CH2:32][CH2:31][C:28]4[CH:29]=[CH:30][C:25]([Cl:24])=[N:26][CH:27]=4)[CH2:18][CH2:19]3)[CH2:13][C:12](=[O:21])[C:11]=2[CH:22]=1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Reactant: ClCCc1ccc(Cl)nc1
Agent: Cl
Agent: O=C(O)Cc1ccc(Cl)nc1
Solvent: O=S(Cl)Cl
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(Cl)nc3)CC1)O2

Procedure:
The title compound was prepared from 3,4-dihydro-6-methanesulfonamidospiro[(2H)-1-benzopyran-2,4'-piperidine]-4-one hydrochloride and 2-chloro-5-chloroethylpyridine hydrochloride by a procedure analogous to that described in Example 92, Step B. [The 2-chloro-5-chloroethylpyridine hydrochloride used in this reaction was obtained by treating 6-chloropyrid-3-yl acetic acid (L. A. Carlson, Acta Pharm. Suecica, 9, 411 (1972)) with borane-tetrahydrofuran complex followed by reaction with thionyl chloride.] mp 213°-215° C. Anal. Calc'd. for C21H24ClN3O4S: C, 56.05; H, 5.38; N, 9.34. Found: C, 55.93; H, 5.41; N, 9.20.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[C:22]2([CH2:27][OH:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1.CI.[CH3:31]COC(C)=O>CN(C=O)C>[F:3][C:4]1[C:5]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[C:22]2([CH2:27][O:28][CH3:31])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1
Reactant: COC(=O)c1ccc(-c2cc(OC)ncc2F)c(C2(CO)CCCC2)c1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COCC1(c2cc(C(=O)OC)ccc2-c2cc(OC)ncc2F)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (20.0 mg 60% in oil, 522 μmol) in DMF (1.0 mL) was slowly added methyl 4-(5-fluoro-2-methoxypyridin-4-yl)-3-(1-(hydroxymethyl)cyclopentyl)benzoate (75.0 mg, 209.0 μmol) at 0° C. The resulting mixture was stirred at room temperature for 30 minutes and then methyl iodide (296.0 mg, 2087 μmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature overnight. EtOAc (60.0 mL) was added, and the organic layers were washed with brine (20×2 mL) and dried over MgSO4. The product was obtained after filtration and solvent removal. The product was used in the next step. MS ESI (pos.) m/e: 374.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[C:9]([O:11][CH2:12]COC)[C:8](OCCOC)=[CH:7][C:6]=1[NH2:21])C.N1C=CC=CC=1.[Cl:29][CH2:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](O)=[O:35]>C(Cl)Cl>[CH3:1][O:3][C:4](=[O:22])[C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[NH:21][C:34](=[O:35])[C:33]1[CH:37]=[CH:38][CH:39]=[C:31]([CH2:30][Cl:29])[CH:32]=1
Reactant: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1N
Reactant: O=C(O)c1cccc(CCl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(OC)ccc1NC(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
2-Amino-5-methoxy-benzoic acid methyl ester (compound A) (2.2 g) produced by the above process was dissolved in anhydrous methylene chloride (40 ml), pyridine (1.5 ml) and 3-(chloromethyl)benzoyl chloride (compound B) (2.1 ml) was added dropwise to the solution at 0° C., and the mixture was then stirred at room temperature for 15 min. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was then subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure to precipitate crystals. The crude crystals were collected by Kiriyama Rohto and was washed with ether to give 2-(3-chloromethyl-benzoylamino)-5-methoxybenzoic acid methyl ester (3.0 g, yield 75%).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[O:6][C:7]2[C:13]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:4].C(O)(=O)C.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]=[CH2:34])[N:28]=1>C(O)C>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[O:6][C:7]2[C:13]([N:14]3[CH2:19][CH2:18][N:17]([CH2:34][CH2:33][C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:36])([F:25])[F:35])[N:28]=4)[CH2:16][CH2:15]3)=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: C=Cc1cccc(C(F)(F)F)n1
Reactant: CN(C)C(=O)c1cc2cccc(N3CCNCC3)c2o1
Solvent: CCO
Solvent: CC(=O)O
Product: CN(C)C(=O)c1cc2cccc(N3CCN(CCc4cccc(C(F)(F)F)n4)CC3)c2o1
Temperature: 73 °C

Procedure:
N,N-dimethyl-7-(piperazin-1-yl)benzofuran-2-carboxamide (0.09 g, 0.33 mmol) (Example 39d) was dissolved in ethanol (0.95 mL), and acetic acid (0.015 mL, 0.26 mmol) was added, followed by 2-(trifluoromethyl)-6-vinylpyridine (0.10 g, 0.58 mmol) (volatile) dissolved in ethanol (1.40 mL). The mixture was heated at 73° C. for 14 h in the microwave and then heated for another 48 h at 86° C. in an oilbath, and finally it was heated in the microwave for 15 min at 100° C. More 2-(trifluoromethyl)-6-vinylpyridine (0.10 g, 0.58 mmol) and ethanol (0.95 mL) were added and the mixture was heated in a oil bath for 7 days at 86° C. The product was purified by flash chromatography (SiO2; DCM/MeOH; gradient 0-7%) and then by preparative HPLC to give the title compound. Yield: 0.075 g (51%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:33]([O:34][CH3:35])=[CH:32][C:24]2[CH2:25][CH2:26][O:27][C:28](=[O:31])[N:29]([CH3:30])[C:23]=2[CH:22]=1>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[C:33]([O:34][CH3:35])=[CH:32][C:24]3[CH2:25][CH2:26][O:27][C:28](=[O:31])[N:29]([CH3:30])[C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)N(C)C(=O)OCC2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCOC(=O)N3C)ncc1Cl
Yield: 20 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide and 3-Amino-2-methoxy-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one. Product isolated as a white solid (20 mg, 20%). mp: 256-258° C., MS (ESI+): 483 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 11.02 (s, 1H), 8.53 (s, J=8 Hz, 1H), 8.34 (s, 1H), 8.15 (s, 1H), 7.51 (d, J=7 Hz, 1H), 7.42 (t, J=7 Hz, 1H), 7.15 (t, J=7 Hz, 1H), 6.73 (s, 1H), 6.26 (br s, 1H), 4.53 (t, 7 Hz, 2H), 3.94 (s, 1H), 3.06 (d, J=5 Hz, 3H), 3.02 (s, 3H), 2.94 (t, J=7, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>>[CH2:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C=O)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
4-hydroxybenzaldehyde (8.2 mmols), 1-bromooctane (12.3 mmols) and cesium carbonate (16.4 mmols) were dissolved in DMF (13.7 mmols). The mixture was then heated to 80° C. and stirred for 3 hours. After this time, the reaction mixture was filtered through a fine fritted funnel; the eluent was collected and diluted with 200 mLs of EtOAc. The organic layer was extracted with seven 10 mL portions of H2O and two 15 mL portions of brine. The organic layer was dried with MgSO4 and evaporated to dryness. After purification by flash chromatography 7.8 mmols of the title product was recovered. 1H NMR (500 MHz, CDCl3) δ 9.86 (d, J=2.9, 1H), 7.94-7.74 (m, 2H), 7.05-6.92 (m, 2H), 4.02 (td, J=3.1, 6.5, 2H), 1.88-1.73 (m, 2H), 1.44 (dd, J=6.8, 14.2, 2H), 1.39-1.21 (m, 8H), 0.99-0.81 (m, 3H). 13C NMR (126 MHz, CDCl3) δ 190.76, 164.24, 131.95, 129.70, 114.71, 68.40, 31.77, 29.28, 29.03, 25.95, 22.63, 14.08.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[CH:40]=[CH:39][C:38]([CH2:41]Br)=[CH:37][CH:36]=1)(=[O:28])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[CH2:1]([C:5]1[N:6]([CH2:41][C:38]2[CH:39]=[CH:40][C:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:26](=[O:28])(=[O:27])[NH:25][C:21]([CH3:22])([CH3:24])[CH3:23])=[CH:36][CH:37]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)[nH]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Yield: 61 %

Procedure:
By the procedure of Example 13, Step A, 5-n-butyl-2,4-dihydro-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step A) was alkylated with [2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl bromide (from Example 12, Step D). Flash chromatography of the crude product on silica gel (gradient elution with 0.5-5% MeOH in CH2Cl2) gave a 61% yield of the title compound as cream-colored crystals, mp 168°-170° C.; satisfactory purity by TLC in 98:2 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 587 (M+1)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClCCCl.[C:9](Cl)(=[O:11])[CH3:10].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1>O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:9](=[O:11])[CH3:10])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: CC(=O)c1ccc(-c2ccc(Br)cc2)cc1
Yield: 102.1 %

Procedure:
Four point three grams (32 mmol) of aluminum chloride was placed into 30 milliliter of 1,2-dichloroethane and a solution made by dissolving 2.0 g (25 mmol) of acetyl chloride, subsequently 5.0 g (21 mmol) of 4-bromo biphenyl into 20 milliliter of 1,2-dichloroethane was added while cooling with ice. The mixed solution was stirred as it is while cooling with ice for 4 hours. After completion of the reaction, adding water and an extraction was carried out using dichloro-methane. Further, washing with water, dried with the use of sodium sulfate. Removing the solvent by distillation, 5.9 g of crude 1-(4′-bromo-biphenyl-4-yl)-ethanone was obtained.
Reaction SMILES: [C:1]([Cl:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)(=O)CCCCCCC/C=C\C/C=C/CCCCC.C(Cl)(=O)CCCCCCC/C=C\C=C\CCCCCC.C(Cl)(=O)CCCCCCCC/C=C/C/C=C/CCCCC.C(Cl)(=O)CCCCCCCCC/C=C/C/C=C/CCCCC>>[C:1]([Cl:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11]/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)Cl
Agent: CCCCC/C=C/C/C=C/CCCCCCCCC(=O)Cl
Agent: CCCCC/C=C/C/C=C/CCCCCCCCCC(=O)Cl
Agent: CCCCC/C=C/C/C=C\CCCCCCCC(=O)Cl
Product: CCCCC/C=C/C/C=C/CCCCCCCC(=O)Cl

Procedure:
In the above example, (Z,Z)-9,12-octadecadienoyl chloride, (Z,E)-9,12-octadecadienoyl chloride, (Z,E)-9,11-octadecadienoyl chloride, (E,E)-10,13-nonadecadienoyl chloride, and (E,E)-11,14-cosadienoyl chloride are substituted, respectively, for (E,E)-9,12-octadecadienoyl chloride, thereby obtaining each respective N vanillyl-alkadienamide.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([Br:16])=[CH:10][CH:11]=3)[C:6](=[O:17])[C:5](=O)[C:4]=2[CH:3]=1.C[Mg]Cl.[C:22]([OH:25])(=O)[CH3:23]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:13]2[C:12]3[C:7](=[CH:8][C:9]([Br:16])=[CH:10][CH:11]=3)[C:6]([OH:17])([CH3:5])[C:22]([OH:25])([CH3:23])[C:14]=2[CH:15]=1
Reactant: CC(=O)O
Reactant: O=C1C(=O)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: C[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(O)c2cc(Br)ccc2-c2ccc(Br)cc2C1(C)O
Reaction time: 8 h

Procedure:
34.3 g (94 mmol) of 2,7-dibromophenanthrene-9,10-quinone were suspended in 600 ml of dry THF at −10° C. under argon, and 141 ml (282 mmol) of methylmagnesium chloride (2 molar solution in THF) were added dropwise at such a rate that the internal temperature did not exceed 0° C. The mixture was subsequently stirred overnight at room temperature. 50 ml of glacial acetic acid were added to the batch with ice cooling, and the mixture was diluted with ethyl acetate. After washing twice with saturated sodium chloride solution, the mixture was dried over sodium sulfate, and the solvents were removed, giving 43.4 g of the product, which was employed without further purification for the next step.
Reaction SMILES: [CH:1]([C@H:14]1[CH2:19][C@H:18]([NH2:20])[CH2:17][CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>>[CH:1]([C@H:14]1[CH2:19][C@H:18]([NH:20][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:17][CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: N[C@@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Fc1ccc(CN[C@@H]2CCO[C@@H](C(c3ccccc3)c3ccccc3)C2)cc1
Yield: 53.3 %

Procedure:
trans-4-Amino-2-diphenylmethylpyran 6b (0.24 g, 0.90 mmol) was reacted with 4-fluorobenzaldehyde (0.11 g, 0.90 mmol) in presence of acetic acid (0.05 g, 0.9 mmol), and then reduced with NaCNBH3 (0.07 g, 1.08 mmol) to yield compound 7b (0.18 g, 54%) (Procedure D).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:25]([OH:30])(=[O:29])[C:26]([OH:28])=[O:27].C(O[C:34]([C:36]1(C2C=CC=CC=2SC2C=CC=CC=2)CCNC[CH2:37]1)=O)C.C(Br)C=C.C(=O)(O)[O-].[Na+].[I-].[K+]>CN(C)C=O.O.CCOCC>[C:25]([OH:30])(=[O:29])[C:26]([OH:28])=[O:27].[CH2:37]([N:9]1[CH2:8][CH2:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:11][CH2:10]1)[CH:36]=[CH2:34]
Reactant: CCOC(=O)C1(c2ccccc2Sc2ccccc2)CCNCC1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: C=CCBr
Product: C=CCN1CCC(C(=O)OCC)(c2ccccc2Sc2ccccc2)CC1

Procedure:
A mixture of 2.8 g of 4-ethoxycarbonyl-4-(2-phenylthiophenyl)piperidine, free base of Example 17, 1.2 g of allyl bromide, 2.5 g of sodium bicarbonate and a crystal of potassium iodide in 30 ml of dimethylformamide is stirred at 70°-80° C. for 16 hours. Thereafter, the mixture is diluted with water and ether, and the ether layer is separated and then dried. The ether is removed in vacuo and the resulting product is purified by passing through an alumina column, eluted with ether. The purified product is converted in ether to its oxalic acid salt. The salt is recrystallized from a methyl alcohol-acetone-ether mixture to provide 1-allyl-4-ethoxycarbonyl-4-(2-phenylthiophenyl)piperidine oxalate.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[K+].[I:13]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([I:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: II
Reactant: Brc1cnc2[nH]ccc2n1
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1cnc2[nH]cc(I)c2n1
Reaction time: 0.17 h

Procedure:
1.5 g of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (7.57 mmol, 1 eq) was dissolved in 20 ml of N,N-dimethylformamide. 1.27 g of crushed potassium hydroxide pellets (22.7 mmol, 3 eq) were then added and the mixture was stirred for 10 min. The reaction flask was cooled in an ice bath and 1.92 g of iodine (7.57 mmol, 1 eq) was added in several portions over 1 hr. After 30 min. more the reaction was complete and about 10 ml 1M sodium thiosulfate solution, water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted with ethyl acetate two times more. The combined ethyl acetate layers were washed with water and saturated sodium chloride solution, and then dried over sodium sulfate. After filtration and evaporation of solvent 2.4 g of solid (97%) was obtained and used directly in the next reaction.
Reaction SMILES: C(C1C=C2C(C3C=C(C=CC=3)CNC(C3C(=O)N(CC4C=CC(F)=C(F)C=4)C=CC=3)=O)=CNC2=NC=1)#N.[F:38][C:39]1[CH:40]=[C:41]([CH:63]=[CH:64][C:65]=1[F:66])[CH2:42][N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([NH:51][CH2:52][C:53]2[CH:54]=[C:55](B(O)O)[CH:56]=[CH:57][CH:58]=2)=[O:50])[C:44]1=[O:62].[B].[Cl:68][C:69]1[CH:70]=[C:71]2[C:77](I)=[CH:76][NH:75][C:72]2=[N:73][CH:74]=1>>[Cl:68][C:69]1[CH:70]=[C:71]2[C:77]([C:55]3[CH:54]=[C:53]([CH:58]=[CH:57][CH:56]=3)[CH2:52][NH:51][C:49]([C:45]3[C:44](=[O:62])[N:43]([CH2:42][C:41]4[CH:63]=[CH:64][C:65]([F:66])=[C:39]([F:38])[CH:40]=4)[CH:48]=[CH:47][CH:46]=3)=[O:50])=[CH:76][NH:75][C:72]2=[N:73][CH:74]=1
Reactant: O=C(NCc1cccc(B(O)O)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Reactant: Clc1cnc2[nH]cc(I)c2c1
Agent: N#Cc1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Agent: [B]
Product: O=C(NCc1cccc(-c2c[nH]c3ncc(Cl)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
Except where indicated, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide was synthesized as per Example 68, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide using 3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenylboronic acid as activated boron species and 5-Chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine as substituted bicyclic heterocycle, to yield the product. 1H NMR (300 MHz, CDCl3-MeOH-d4) d ppm 8.564 (dd, J=7.3, 2.2 Hz, 1H) 8.332 (d, J=2.0 Hz, 1H) 8.230 (d, J=2.1 Hz, 1H) 7.584 (s, 1H) 7.565 (s (br), 1H) 7.538 (dd, J=6.8, 2.1 Hz, 1H) 7.468-7.370 (m, 2H) 7.303 (d, J=6.9 Hz, 1H) 7.168-7.061 (m, 2H) 7.027-6.955 (m, 1H) 6.461 (t, J=6.9 Hz, 1H) 5.134 (s, 2H), 4.716-4.659 (m, 2); MS m/z=50.05 M+H.