Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[CH:22][C:12]2[CH:13]=[C:14]([C:16](O)([CH2:19][CH3:20])[CH2:17][CH3:18])[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([CH3:31])[C:29]([OH:30])=[CH:28][CH:27]=[CH:26][CH:25]=1.B(F)(F)F.O(CC)CC>>[CH2:1]([O:8][C:9]1[CH:23]=[CH:22][C:12]2[CH:13]=[C:14]([C:16]([C:26]3[CH:27]=[CH:28][C:29]([OH:30])=[C:24]([CH3:31])[CH:25]=3)([CH2:19][CH3:20])[CH2:17][CH3:18])[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1O
Reactant: CCC(O)(CC)c1cc2ccc(OCc3ccccc3)cc2o1
Agent: FB(F)F
Solvent: CCOCC
Product: CCC(CC)(c1ccc(O)c(C)c1)c1cc2ccc(OCc3ccccc3)cc2o1
Yield: 78.9 %

Procedure:
3-(6-Benzyloxy-benzofuran-2-yl)-pentan-3-ol (5.40 g, 17.4 mmol) and o-cresol (3.76 g, 34.8 mmol) and BF3—OEt2 (2.47 g, 17.4 mmol) are reacted analogous to Example 1D to give the title compound as a pale yellow oil (5.50 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:17]O)=[S:10].[OH-].[Na+]>Br>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]1[N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[CH2:17][S:10]1
Reactant: OCC1CCCCN1C(=S)Nc1ccccc1Cl
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccccc1N=C1SCC2CCCCN12

Procedure:
1 g 1-(2-Chlorophenylthiocarbamoyl)-2-hydroxymethylpiperidine in 20 ml 48% hydrobromic acid was heated under reflux for 2 hours. The mixture was then neutralised under cooling with 2N caustic soda, extracted with methylene chloride, the extracts dried over magnesium sulphate and the solvent distilled. The residue was recrystallised from diisopropyl ether.
Reaction SMILES: C(OC(=O)[N:7]([C:23]1[C:32]2[C:27](=[N:28][C:29]([S:33][CH2:34][CH3:35])=[N:30][CH:31]=2)[N:26]=[CH:25][N:24]=1)[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[S:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(C)(C)C.Br[CH2:38][C:39]#[N:40].C(=O)([O-])[O-].[Cs+].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:34]([S:33][C:29]1[N:28]=[C:27]2[N:26]=[CH:25][N:24]=[C:23]([NH:7][C:8]3[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=3[S:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:38][C:39]#[N:40])=[CH:20][CH:21]=3)[C:32]2=[CH:31][N:30]=1)[CH3:35]
Reactant: N#CCBr
Reactant: CCSc1ncc2c(N(C(=O)OC(C)(C)C)c3cc(C)ccc3Sc3ccc(O)cc3)ncnc2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCSc1ncc2c(Nc3cc(C)ccc3Sc3ccc(OCC#N)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
The product from Example 164 (52 mg, 0.1 mmol), bromo-acetonitrile (0.008 ml, 0.12 mmol), cesium carbonate (0.065 g, 0.2 mmol) and tetrabutylammonium iodide (0.001 g) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 2 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate), filtered and evaporated under vacuum. To the residue was added dichloromethane (2.5 ml) and trifluoroacetic acid (2.5 ml) then stirred at room temperature for 1 hour. The solvent was evaporated under vacuum and the residue was purified by HPLC with TFA to provide the title compound (9 mg, 20%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.42 (t, J=7.35 Hz, 3H), 2.24 (s, 3H), 3.29 (q, J=7.35 Hz, 2H), 5.25 (s, 2H), 6.81 (m, 5H), 7.20 (d, J=8.46 Hz, 2H), 8.34 (s, 1H), 9.25 (s, 1H), 9.75 (s, 1H); MS (ESI+) m/z 461 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[C:21]([CH:22]=[O:23])=[CH:20][C:19]([Cl:24])=[CH:18][N:17]=1.[BH4-].[Na+]>CCO>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:13][CH2:14]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[C:21]([CH2:22][OH:23])=[CH:20][C:19]([Cl:24])=[CH:18][N:17]=1
Reactant: O=Cc1cc(Cl)cnc1Oc1ccc2c(nnn2CC2CC2)c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc(Cl)cnc1Oc1ccc2c(nnn2CC2CC2)c1Br
Temperature: 25 °C

Procedure:
To a suspension of 2-{[4-bromo-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]oxy}-5-chloropyridine-3-carbaldehyde (32, 722 mg, 1.77 mmol, 1.0 equiv.) in EtOH (17.7 mL), was added slowly NaBH4 (101 mg, 2.66 mmol, 2.0 equiv.). The reaction mixture was stirred at room temperature until LCMS showed only the desired product. The solvent was evaporated in vacuo. The mixture was partitioned between EtOAc and saturated aqueous NaHCO3. The extracted organic layers were dried over Na2SO4, filtered and concentrated to give the crude product which was purified with normal phase silica gel chromatography (EtOAc/Hexane gradient from 0 to 100%) to obtain product 195 1H NMR (400 MHz, CDCl3): δ 7.89 (s, 2H); 7.57 (d, J=8.8 Hz, 1H); 7.38 (d, J=8.8 Hz, 1H); 4.96 (d, J=5.3 Hz, 2H); 4.52 (d, J=7.1 Hz, 2H); 1.43 (m, 1H); 0.69 (m, 2H); 0.52 (m, 2H). LRMS m/z (M+H) 408.9 and 410.9 found, 408.0 and 410.0 required.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=Cc1cncc(Br)c1
Product: Brc1cncc(CN2CCOCC2)c1
Yield: 61 %

Procedure:
The title compound was prepared in a similar way as described in Example 18, Step C, using 5-bromo-pyridine-3-carbaldehyde and morpholine. The crude compound was purified (SiO2: 0-3% 2 M NH3 in MeOH/DCM) to provide the title compound (61%).
Reaction SMILES: O=[O+][O-].[CH2:4]([N:7]([CH2:15][C:16]([O:18]C)=O)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=C.[NH2:20][CH:21]1[CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([C:31]#[N:32])[CH:25]=[CH:24][C:23]=2[CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:31]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[CH2:22][CH:21]([N:20]1[CH2:5][CH2:4][N:7]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:15][C:16]1=[O:18])[CH2:30][CH2:29]2)#[N:32]
Reactant: C=CCN(CC(=O)OC)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc2c(c1)CCC(N)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=[O+][O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C2CCc3cc(C#N)ccc3C2)C(=O)C1
Temperature: 25 °C

Procedure:
Ozone was bubbled into a solution of methyl [allyl(tert-butoxycarbonyl)amino]acetate (3.6 g, 16 mmol) in DCM at −78° C. until it turned pale blue. Nitrogen was then bubbled into the solution to remove excess ozone. When the blue color was gone, 6-amino-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (2.7 g, 16 mmol) and sodium triacetoxyborohydride (20 g, 95 mmol) was added to the reaction, and the mixture was allowed to warm to RT. The reaction was diluted with DCM, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and purified by preparative TLC to afford the title compound. LC-MS (IE, m/z): 256 [M−Boc+1]+.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Br[CH2:11][CH2:12][CH2:13][Cl:14]>O.C(O)C>[C:1]1([S:7][CH2:11][CH2:12][CH2:13][Cl:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCBr
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ClCCCSc1ccccc1

Procedure:
A mixture of thiophenol (1 mole), sodium hydroxide (1 mole) and 3-bromo-1-chloro-propane (2 moles) in water (1000 ml) and ethanol (250 ml) is refluxed duting 20 hours, with stirring. After cooling, sodium hydroxide (30 g) is added to the reaction medium which is then extracted with methylene chloride. The organic phase is washed with water to neutral pH, after which it is dried over sodium sulfate, concentrated and distilled. B.p. = 165° C./15 mm Hg. N.M.R.: consistent.
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].[Mg].[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.S(=O)(=O)(O)O>O1CCCC1>[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]([OH:12])[CH2:3][CH:2]=[CH2:1])=[CH:9][CH:8]=1
Reactant: C=CCCl
Reactant: O=Cc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCC(O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 108.6 %

Procedure:
Allyl chloride (97.88 g, 1.28 mol) in dry tetrahydrofuran (500 ml) was added to a suspension of magnesium turnings (60.08 g, 2.47 mol) in dry tetrahydrofuran (50 ml) at such a rate as to maintain steady reflux. The mixture was then heated under reflux for a further hour. 4-Chloro-benzaldehyde (120 g, 854 mmol) in dry tetrahydrofuran (600 ml) was then added dropwise and the mixture refluxed for a further 2 hours. After being cooled to room temperature the mixture was poured into ice/water, carefully acidified with 1M sulphuric acid and extracted with ether. The combined extracts were washed with brine, dried and evaporated in vacuo to give crude 4-(4-chlorophenyl)but-1-en-4-ol (169.4 g approximately 92% pure) which was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[I:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.CCN(CC)CC.[H-].[Na+]>C1COCC1.CN(C=O)C.O>[I:8][C:9]1[CH:15]=[CH:14][C:12]([N:13]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])=[CH:11][CH:10]=1
Reactant: O=C(Cl)CCCBr
Reactant: Nc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCCN1c1ccc(I)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
A mixture of 4-bromobutanoyl chloride (15.0 g) in THF (dry) (150 mL) was added to a mixture of 4-iodoaniline (7.50 g) and Et3N (9.55 mL) in THF (dry) (150 mL) at 0° C. The mixture was stirred at 60° C. overnight. A mixture of NaH (60%, 4.11 g) in DMF (dry) (50 mL) was added to the mixture at 0° C. The mixture was stirred at 120° C. overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (3.84 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11]C[N:9]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:8]2=[O:19])=[C:4]([Cl:22])[CH:3]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:22][C:4]1[CH:3]=[C:2]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:21]=[CH:20][C:5]=1[CH2:6][CH:7]1[CH2:12][CH2:11][N:9]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[C:8]1=[O:19]
Reactant: O=C1C(Cc2ccc(Br)cc2Cl)CCCN1C1CCCCC1
Reactant: C1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C1C(Cc2ccc(N3CCCCC3)cc2Cl)CCN1C1CCCCC1
Temperature: 90 °C
Yield: 48.4 %

Procedure:
Dissolve 3-(4-bromo-2-chloro-benzyl)-1-cyclohexyl-piperidin-2-one (Example 55) (0.20 g, 0.54 mmol), piperidine (0.21 mL, 2.16 mmol), palladium (II) acetate (12 mg, 0.05 mmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (67 mg, 0.11 mmol) in toluene (1 mL) with cesium carbonate (264 mg, 0.81 mmol) and heat at 90° C. 16 h. Pass the mixture through an SCX ion exchange column washing with methanol and eluting with 1N ammonia in methanol and evaporate. Purify the residue by preparative reversed phase HPLC chromatography to give the title compound (98 mg, 48%). MS (ES+) nz/z=376 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:26][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29].C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC(CC)CC)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:26][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: CCC(CC)CBr
Agent: CCC(CC)Cn1nc2c(c1-c1ccc(Cl)cc1)CCN(C(=O)OC(C)(C)C)CC2
Product: CCC(CC)Cn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 15.1 %

Procedure:
The title compound (0.010 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 1-bromo-2-ethyl-butane (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(2-ethyl-butyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C19H26ClN3, 331.18; found, m/z 332.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.50-7.48 (br m, 4H), 4.11-4.09 (br m, 2H), 3.71-3.69 (br m, 2H), 3.33-3.31 (br m, 2H), 3.26-3.24 (br m, 2H), 3.06-3.04 (br m, 2H), 1.91-1.89 (m, 1H), 1.36-1.34 (m, 4H), 0.93 (t, J=7.3 Hz, 6H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][CH3:16])=[CH:10][C:6]=1[C:7](O)=[O:8])(=[O:3])[CH3:2].S(Cl)([Cl:19])=O>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][CH3:16])=[CH:10][C:6]=1[C:7]([Cl:19])=[O:8])(=[O:3])[CH3:2]
Reactant: CCc1cc(C(=O)O)c(OC(C)=O)cc1C
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCc1cc(C(=O)Cl)c(OC(C)=O)cc1C

Procedure:
A mixture of 2-acetoxy-5-ethyl-4-methylbenzoic acid (11.10 g) and thionyl chloride (20 ml) in dry benzene (100 ml) was heated under reflux for 6 hours, cooled and solvents removed in vacuo. The crude 2-acetoxy-5-ethyl-4-methylbenzoyl chloride was obtained as a liquid which was used as rapidly as possible in the next stage of the synthesis without further purification.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[CH:8](Br)[C:9]([C:11]([F:14])([F:13])[F:12])=O.[NH2:16][CH:17]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])[C:18]([NH2:20])=[O:19].Cl>O>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:17]1[C:18](=[O:19])[NH:20][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][N:16]=1
Reactant: O=C(C(Br)Br)C(F)(F)F
Reactant: NC(=O)C(N)c1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c(C(F)(F)F)cnc1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of 121 g of sodium carbonate and 400 ml of water was added dropwise 77.1 g of 1,1-dibromo-3,3,3-trifluoroacetone at such a rate that the temperature of the reaction mixture became not higher than 55° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes, followed by adding 500 ml of water and then 40 g of 2-amino-2-(2,4-difluorophenyl)acetamide, and the reaction was allowed to proceed at 60° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to 10° C. or lower, made acidic by adding 80 ml of concentrated hydrochloric acid at the same temperature, and extracted with ethyl acetate. The organic layer was washed with water and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=4:1), which afforded 23.3 g (yield, 39%) of the desired compound, 3-(2,4-difluorophenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (compound 1-1004; m.p., 178.9° C.). The continued elution with the above solvent system gave 13.2 g of the configurational isomer, 3-(2,4-difluorophenyl)-5-trifluoromethyl-2-oxo-1,2-dihydropyrazine (m.p., 164.6° C.).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[CH2:11]Cl.[OH-].[Na+]>C(#N)C>[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[CH2:11][NH:3][CH2:2][CH2:1][NH2:4]
Reactant: NCCN
Reactant: ClCc1cnccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: NCCNCc1cnccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
Ethylenediamine (30 g) was dissolved in acetonitrile (200 ml), and pyrazinylmethyl chloride (12.9 g) was added dropwise to this solution at 5 to 10° C. After addition, the mixture was stirred at room temperature for 1 hour. Then, a 50% aqueous solution of sodium hydroxide (8 g) was added, and thereafter, volatile materials were removed at a bath temperature of 60° C. under 5 mmHg. The inorganic salt was then removed by filtration. Thus, N-(pyrazinylmethyl)ethylenediamine (14.1 g) was obtained as a colorless oil. nD20=1.5359.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[C:32]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:32]([C:36]1[CH:37]=[CH:38][C:39]([CH2:40][O:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2/[CH:22]=[CH:21]/[CH:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:31][CH:30]=2)[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:42][CH:43]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)Cc2ccc(C#N)cc2)cc1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)Cc2ccc(C#N)cc2)cc1

Procedure:
A solution of 1.4 g (3.13 mmol, 92% pure) of methyl E-4-[3-(4-cyanobenzyl)-5-(2-hydroxyphenyl)pent-4-enyl]benzoate in 7 ml of dry acetonitrile is mixed with 1.42 g (6.26 mmol) 4-(tert-butyl)benzyl bromide and 1.30 g (9.39 mmol) of anhydrous potassium carbonate and heated under reflux for 12 hours. The mixture is then filtered and concentrated to dryness. The residue is directly purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1, then 1:5). 1.85 g (3.32 mmol, 93% purity, 98% of theory) of an oil are isolated.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][C@@H:7]1[CH:28]([CH3:30])[CH3:29])=[O:5])[CH3:2].N1C=CC=CC=1.Cl[C:38]([O:40][CH3:41])=[O:39].[OH-].[K+]>ClCCl.O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:38]([O:40][CH3:41])=[O:39])[CH2:8][C@@H:7]1[CH:28]([CH3:29])[CH3:30])=[O:5])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2[C@H](NCc2ccccc2)C[C@@H]1C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2[C@H](N(Cc2ccccc2)C(=O)OC)C[C@@H]1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of cis-4-benzylamino6,7-dimethoxy-2-isopropyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 93) (22 mg, 0.05 mmol) and pyridine (0.50 mL, 6.2 mmol) in anhydrous dichloromethane (1 mL) was added methyl chloroformate (0.10 mL, 1.3 mmol) while cooled in an ice bath. After stirring at room temperature overnight, water (10 mL), and aqueous 2N KOH (10 mL) were added to the reaction mixture. The solution was stirred for 30 min, then the mixture was extracted with ethyl acetate (2×10 mL). The organic phases were combined and washed with 1N HCl (2×10 mL), a saturated sodium bicarbonate solution (10 mL), and brine (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 88 mg crude product. Purification by silica gel chromatography using 0-40% ethyl acetate/hexanes as eluent afforded the title product (12 mg, 50%). MS m/z 471 (M++1), 488 (M++18); 1H NMR (CDCl3) δ 0.6-0.8 (m, 6H), 1.25 (t, 3H), 1.4 (m, 1H), 1.8-2.3 (m, 3H), 3.8 (s, 6H), 3.85 (s, 3H), 4.0-4.3 (m, 5H), 5.1 (m, 1H), 6.96 (C8, bs, 1H), 6.42 (C5, bs, 1H), 7.2-7.4 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([N:6]1[C:7]2[C:3](=[C:2]([Br:1])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Brc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccc2c1ccn2Cc1ccccc1

Procedure:
1-Benzyl-4-bromo-1H-indole was prepared from 4-bromo-1H-indole (1.58 g, 8.06 mmol), sodium hydride (0.680 g of 60% dispersion in oil, 17.0 mmol), and benzyl bromide (2.0 mL, 17 mmol) in DMF (15 mL) according to the procedure described in Step 1 of Example 5. Purification by flash chromatography (Biotage apparatus) using hexane as an eluant yielded a light yellow oil (1.61 g, 70%). 1HNMR (300 MHz, DMSO-d6): δ 7.65 (d, 1H, J=3.8 Hz), 7.5 (d, 1H, J=7.7 Hz), 7.15-7.35 (m, 6H), 7.05 (t, 1H, J=7.7 Hz), 6.45 (d, 1H, J=3.1 Hz), and 5.6 ppm (s, 2H).
Reaction SMILES: C[O-].[Na+].[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][S:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[CH3:27][N:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1>CO>[CH3:27][N:28]1[CH2:29][CH:30]=[C:31]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([NH:13][S:14]([C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH:20]=[CH:19][CH:18]=4)(=[O:15])=[O:16])[CH:8]=3)[NH:4][CH:5]=2)[CH2:32][CH2:33]1
Reactant: CN1CCC(=O)CC1
Reactant: O=S(=O)(Nc1ccc2[nH]ccc2c1)c1cccc2ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(NS(=O)(=O)c4cccc5ccccc45)cc23)CC1
Yield: 52 %

Procedure:
To a solution of 712 mg (13.2 mMol) of sodium methoxide in 100 ml of methanol are added 850 mg (2.64 mMol) of N-[1H-indol-5-yl]naphthalene-1-sulphonamide followed by 596 mg (5.28 mMol) of 1-methyl-4-piperidone and the resulting solution is heated to reflux for 48 hours. The reaction mixture is concentrated at reduced pressure and the residue obtained is purified by chromatography over silica gel, using as eluent mixtures of methylene chloride/methanol/ammonia, to yield 573 mg (52%) of N-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide as a solid with m.p.=244–245° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([CH:8]=[O:9])[N:5]=[CH:4]1.Cl[C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1>CN(C=O)C>[N:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:11]=1[N:3]1[CH:7]=[C:6]([CH:8]=[O:9])[N:5]=[CH:4]1
Reactant: Clc1ncccn1
Reactant: O=Cc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cn(-c2ncccn2)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
Sodium hydride (60% in oil, 1.44 g, 36.00 mmol) was added to a 0° C. solution of 1H-imidazole-4-carboxaldehyde (4.40 g, 36.03 mmol) in DMF (16 mL). After stirring for 20 min at 0° C., the mixture was allowed to warm to RT and a solution of 2-chloropyrimidine (4.12 g, 35.97 mmol) in DMF (8 mL) was added. The resulting mixture was heated to 100° C. for 18 h. The solvent was evaporated, the residue was dissolved in ethyl acetate, washed with water and brine, dried (MgSO4), and concentrated to provide 6.20 g (86%) of the title compound. MS 175 (M+H)+.