Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([Br:8])[C:6]=1[CH3:7].[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][C:2]1[S:3][CH:4]=[C:5]([Br:8])[C:6]=1[CH2:7][Br:9]
Reactant: Cc1c(Br)csc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1c(Br)csc1Br
Temperature: 0 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
To a solution of 2,4-dibromo-3-methylthiophene (0.92 g, 3.6 mmol) in carbon tetrachloride was added N-bromosuccinimide (0.64 g, 3.6 mmol) and AlBN (5 mg). The mixture was heated under reflux for 1 h and then for another 4 h in the presence of light. The solution was then cooled to 0° C. and the succinimide was filtered. The residue was washed with carbon tetrachloride. The solvent was removed and the product recrystalized from EtOH to yield 2,4-dibromo-3-(bromomethyl)thiophene (1.08 g, 91%). mp 89-90° C.; 1H NMR (500 MHz, DMSO-d6) δ: 4.53 (s, 2H), 7.89 (s, 1H). MS (EI) m/z 332/334/336 (M+.). Anal. Calcd for C5H3Br3S: C, 17.93; H, 0.90; N, 0.00. Found: C, 18.02; H, 0.86; N, 0.00.
Reaction SMILES: [NH:1]1[C:11]2[C:12]3[N:3]([CH2:4][CH2:5][NH:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)[C:2]1=O.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:2]1[N:3]2[CH2:4][CH2:5][NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([C:12]=32)[N:1]=1
Reactant: O=c1[nH]c2cccc3c2n1CCN3
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc2cccc3c2n1CCN3

Procedure:
3 g (0.0155 mol) of 5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-2(1H)-one in 60 ml of phosphoryl chloride are heated at the reflux temperature for 3 hours. The solvent is evaporated to dryness and the residue taken up successively in ice-cold water and in a concentrated aqueous ammonia solution. Extraction is then carried out twice with ether and the organic phases are combined, dried and evaporated to dryness. The residue is purified by chromatography on a column of silica gel, the eluent being ether. There are obtained 1.8 g of product in the oil form which is used as is in the following stage.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([Cl:13])[C:6]([CH3:12])=[N:7]2.[CH3:14]I.O>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([Cl:13])[C:6]([CH2:12][CH3:14])=[N:7]2
Reactant: Cc1nc2cccc(Br)c2nc1Cl
Reactant: CI
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2cccc(Br)c2nc1Cl
Temperature: -78 °C
Reaction time: 0.12 h
Yield: 54.3 %

Procedure:
LDA(Aldrich) (1.7M in heptane/THF/ethylbenzene; 0.60 mL, 1.01 mmol) was added (dropwise, over 1 min) to a solution of 5-bromo-3-chloro-2-methylquinoxaline (126e) (238 mg, 0.92 mmol) in THF (8.0 mL) in an oven-dried flask under argon at −78° C., and the resulting solution was stirred at −78° C. for 7 min. Methyl iodide (0.12 mL, 1.85 mmol) was then added, and the resulting solution was stirred at −78° C. for 15 min, then warmed to 23° C. and stir at 23° C. for 16 h. The reaction mixture was subsequently cooled to 0° C., water (0.5 mL) was added, and the reaction mixture was concentrated onto silica gel and chromatographically purified (silica gel, 0-15% EtOAc/hexanes) to provide 5-bromo-3-chloro-2-ethylquinoxaline (136 mg, 0.50 mmol, 54% yield) as a light-orange solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.04 (1H, d, J=3.1 Hz), 8.02 (1H, d, J=2.3 Hz), 7.60 (1H, t, J=8.0 Hz), 3.20 (2H, q, J=7.4 Hz), 1.44 (3H, t, J=7.4 Hz). m/z (ESI, +ve) 271.0/272.9 (M+H)+.
Reaction SMILES: Cl[CH:2]([N:7]=[C:8](Cl)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:3]([F:6])([F:5])[F:4].[C:17](#[N:20])[CH:18]=[CH2:19].N12CCCN=C1CCCCC2>CN(C)C=O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[NH:7][C:2]([C:3]([F:6])([F:5])[F:4])=[CH:19][C:18]=2[C:17]#[N:20])=[CH:10][CH:11]=1
Reactant: C=CC#N
Reactant: FC(F)(F)C(Cl)N=C(Cl)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 38.8 %

Procedure:
A solution of N-[1-chloro-(2,2,2-trifluoroethyl)]-4-chlorobenzimidoyl chloride (5.80 g, 0.02 mol) and acrylonitrile (1.33 g, 0.025 mol) in N,N-dimethylformamide (15 mL) is treated with 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU, 8.53 g, 0.056 mol) over 1 hour while maintaining the temperature at 45°-50° C. The reaction mixture is then stirred at 50° C. for 4 hours, quenched with dilute HCl, and extracted with ethyl acetate. The organic extract is concentrated in vacuo to obtain a residue. Flash chromatography of the residue on silica gel, packed and eluted with 20% ethyl acetate in heptane, and crystallization from heptane and small amount of ethyl acetate gives the title product as a white crystalline solid (2.1 g, 38.9% yield): mp 239-240° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH:26]1[O:30][C:29](=[O:31])[N:28]([CH3:32])[CH2:27]1.[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35]>>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH:26]3[O:30][C:29](=[O:31])[N:28]([CH3:32])[CH2:27]3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)C1CCNCC1
Reactant: CN1CC(CCCl)OC1=O
Agent: O=C(O)C(=O)O
Product: CN1CC(CCN2CCC(C(O)(c3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)OC1=O

Procedure:
Following the procedure of Example 1, α,α-bis(4-chlorophenyl)-4-piperidinemethanol and 5-(2-chloroethyl)-3-methyl-2-oxazolidinone are reacted and the product thereof is reacted with oxalic acid to give the title compound.
Reaction SMILES: CN1C=CN=C1.[Cl:7][C:8]1[CH:9]=[C:10]([C:17]2[CH:21]=[CH:20][N:19]([CH2:22][C@@H:23]([NH:25][C:26]([C:28]3[N:29]=[C:30]([CH3:33])[NH:31][CH:32]=3)=[O:27])[CH3:24])[N:18]=2)[CH:11]=[C:12]([F:16])[C:13]=1[C:14]#[N:15].[CH:34]([C:36]([CH3:38])=[O:37])=[CH2:35].O>CS(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([C:17]2[CH:21]=[CH:20][N:19]([CH2:22][C@@H:23]([NH:25][C:26]([C:28]3[N:29]=[C:30]([CH3:33])[N:31]([CH2:35][CH2:34][C:36](=[O:37])[CH3:38])[CH:32]=3)=[O:27])[CH3:24])[N:18]=2)[CH:11]=[C:12]([F:16])[C:13]=1[C:14]#[N:15]
Reactant: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)c[nH]1
Reactant: C=CC(C)=O
Agent: Cn1ccnc1
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)CCn1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)nc1C
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 42.3 %

Procedure:
1-Methylimidazole (1.030 μl, 0.013 mmol) and DMSO (3 ml) were added into a flask. (S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide (100 mg, 0.259 mmol) dissolved in 3 ml of DMSO was added. Lastly methyl vinyl ketone (0.065 ml, 0.776 mmol) was added and the resulting mixture was stirred in 70° C. for 2.5 h. The mixture was stirred at RT during the night and in the next morning the temperature was again raised to 70° C. for 3.5 h. During the last part of the reaction a total of 0.195 ml of methyl vinyl ketone and 16.48 μl of 1-methylimidazole were added and the mixture was stirred at 70° C. for three days. 10 ml of water was poured into the mixture and the resulting white solution was extracted with ethyl acetate. Combined ethyl acetate phases were dried, filtered and evaporated. The product was purified by flash-chromatography and recrystallization from ACN/water, respectively. Yield 42.3%. 1H-NMR (400 MHz; DMSO-d6): δ 1.05 (d, 3H), 2.09 (s, 3H), 2.35 (s, 3H), 2.97 (t, 2H), 4.04 (t, 2H), 4.23-4.45 (m, 3H), 7.01 (d, 1H), 7.48 (s, 1H), 7.85 (d, 1H), 7.93 (dd, 1H), 8.00 (s, 1H), 8.05 (d, 1H).
Reaction SMILES: O1CCOCC1.[CH:7]1([CH2:10][O:11][C:12]2[C:17]([O:18]COC)=[CH:16][CH:15]=[CH:14][C:13]=2[I:22])[CH2:9][CH2:8]1.Cl>O>[CH:7]1([CH2:10][O:11][C:12]2[C:13]([I:22])=[CH:14][CH:15]=[CH:16][C:17]=2[OH:18])[CH2:8][CH2:9]1
Reactant: COCOc1cccc(I)c1OCC1CC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Oc1cccc(I)c1OCC1CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.9 %

Procedure:
To 100 ml of 1,4-dioxane solution containing 33.9 g (0.10 mol) of 2-cyclopropylmethoxy-1-iodo-3-methoxymethoxybenzene obtained in Reference example 12-(b) was added 150 ml of 1,4-dioxane solution containing 4N hydrogen chloride, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, 100 ml of water was added to the reaction mixture, and the resulting mixture was extracted with diethyl ether. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 22.3 g of the title compound as a colorless oil. (Yield: 77%)
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[S:9][CH:8]=[C:7]([CH:10]([N:14]2[CH:18]=[C:17]([C:19]3[C:20]4[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH:16]=[N:15]2)[CH2:11][C:12]#[N:13])[CH:6]=1)C.C1COCC1.Cl>O>[CH:4]([C:5]1[S:9][CH:8]=[C:7]([CH:10]([N:14]2[CH:18]=[C:17]([C:19]3[C:20]4[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH:16]=[N:15]2)[CH2:11][C:12]#[N:13])[CH:6]=1)=[O:3]
Reactant: CCOC(OCC)c1cc(C(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)cs1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4csc(C=O)c4)c3)ncnc21
Temperature: 25 °C

Procedure:
A solution of 3-[5-(diethoxymethyl)-3-thienyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (70 mg, 0.0001 mol) in THF (1 mL, 0.01 mol) was treated with 1 M HCl in water (400 μL). The reaction was stirred at room temperature. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-(5-formyl-3-thienyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile as a semisolid residue (60 mg, 98%). 1H NMR (400 MHz, CDCl3): 9.96 (s, 1H), 8.89 (s, 1H), 8.44 (m, 2H), 7.46 (1H), 5.73 (s, 2H), 4.15 (m, 1H), 3.73-3.43 (m, 3H), 1.35 (m, 1H), 1.01 (m, 2H), 0.03 (s, 9H); MS(ES): 479 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([NH:30][C@H:31]([C:35]([O:37][CH3:38])=[O:36])[C@@H:32]([CH3:34])[OH:33])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOCC>[CH2:3]([O:33][C@H:32]([CH3:34])[C@@H:31]([C:35]([O:37][CH3:38])=[O:36])[NH:30][C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)O
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
A 250-mL, round-bottomed flask, under an atmosphere of N2, was charged with sodium hydride (60% oil dispersion, 772 mg, 19.3 mmol). The sodium hydride was washed with 3 portions of hexanes to remove the oil and then 8 mL of anhydrous DMF was added followed by benzyl bromide (3.38 mL, 28.4 mmol). The solution was cooled to 0° C. and then a solution of methyl N-trityl-L-threoninate (4.83 g, 12.9 mmol) dissolved in 12 mL of DMF was added dropwise via cannula over 5 minutes. After stirring for 2 hours, the reaction mixture was treated with saturated aqueous Na2CO3 solution and 200 mL of Et2O and the layers were separated. The organic portion was washed successively with H2O (5×100 mL) and brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 5-10% ethyl acetate/hexanes) gave 4.61 g of methyl O-benzyl-N-trityl-L-threoninate as a colorless syrup.
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][C:6]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:7]=1[NH2:8].[CH:14](=O)[CH:15]([CH3:17])[CH3:16]>C(O)(C)C.[Pd]>[CH3:5][C:6]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:7]=1[NH:8][CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)C=O
Reactant: Cc1ccc(N)c(C)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)O
Product: Cc1ccc(NCC(C)C)c(C)c1
Reaction time: 1 h
Yield: 84.6 %

Procedure:
An aqueous solution of ammonium formate (3.15 g, 50.0 mmol, 10 mL) was diluted with isopropanol (80 mL) and added to palladium on carbon 10% wet (1.064 g, 10.00 mmol) under nitrogen. A solution of 2,4-dimethylaniline (1.212 g, 10 mmol) and isobutyraldehyde (1.004 mL, 11.00 mmol) in isopropanol (3 mL) was added and the mixture was stirred for 1 h. The mixture was filtered through celite, the celite cake washed with isopropanol and combined liquid phases concentrated in vacuo. The residue (1.8 g) was purified using a pre-conditioned aminopropyl solid phase extraction cartridge (NH2 SPE) (20 g) using methanol as an eluent. The methanolic organic phase was concentrated under vacuo to give a second residue which was further purified on a Biotage Flashmaster II using silica (Si) 10 g/mmol using a 0-100% dichloromethane-cyclohexane gradient over 40 mins. The fractions containing the expected product were combined and concentrated in vacuo to give the desired product 1.5 g as a yellow oil.
Reaction SMILES: [CH2:1]([N:5]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:7]=[N:6]1)[CH2:2][C:3]#[CH:4].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[CH:7]=[N:6][N:5]([CH2:1][CH2:2][C:3]#[C:4][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:9]=2)=[CH:15][CH:14]=1
Reactant: Brc1ccccn1
Reactant: C#CCCn1ncc(-c2ccc(F)cc2)n1
Product: Fc1ccc(-c2cnn(CCC#Cc3ccccn3)n2)cc1
Yield: 41.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-4-(4-fluorophenyl)-2H-1,2,3-triazole (150 mg, 0.70 mmol, Example 254(B)) and 2-bromopyridine (122 mg, 0.77 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 84 mg (0.29 mmol, 41%) of 2-(4-(4-(4-fluorophenyl)-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridine as a yellow solid (M.P.=83.5-84.5° C.).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]1([CH:18]([CH3:21])[CH:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>ClCCl>[OH:23][N:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:19](=[O:20])[CH:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:21]
Reactant: O=Nc1ccccc1
Reactant: CC(C=O)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C(=O)N(O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (30 mg, 0.2 mmol) was added under argon to a solution of 2-phenylpropanal (134 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (72.8 mg, 0.2 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1>>[C:20]1([CH3:24])[CH:21]=[CH:22][CH:23]=[C:18]([NH:17][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)[CH:19]=1
Reactant: Cc1cccc(N)c1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: Cc1cccc(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)c1
Yield: 22.4 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (100 mg, 0.43 mmol) and m-toluidine (0.07 mL, 0.65 mmol) to provide 241 (29 mg, 20% yield) as a black powder. LC-MS (M+H (parent)=302, obsd.=302).
Reaction SMILES: [CH2:1]([CH:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)=[CH:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].N.[CH3:20][N:21](C)C=O>>[CH2:1]([CH:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:20]#[N:21])=[CH:14][CH:13]=2)=[CH:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1C=CC(c2ccc(Br)cc2)=CC1
Reactant: CN(C)C=O
Agent: N
Product: CCCCCC1C=CC(c2ccc(C#N)cc2)=CC1

Procedure:
In 15 ml of N,N-dimethylformamide, 4 g of the 1-pentyl-4-(4-bromophenyl)dihydrobenzene, which had been obtained in Example 8, were dissolved, followed by the addition of 1.4 g of cuprous cyanide. The resulting mixture was reacted for 6 hours at reflux temperature. After the completion of the reaction, aqueous ammonia was added to the reaction mixture, followed by the extraction of the reaction mixture with toluene. The extract was washed with aqueous ammonia and then with saturated NaCl. Anhydrous sodium sulfate was thereafter added to dry the extract. The toluene was distilled off under reduced pressure. The reaction product so obtained was recrystallized twice from ethanol, whereby 0.8 g of 1-pentyl-4-(4-cyanophenyl)dihydrobenzene was obtained.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([NH:15][C@H:16]([CH3:52])[CH2:17][O:18][C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[N:26](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:25]2=[O:49])=[CH:21][CH:20]=1)=O)(C)(C)C>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:15][C@H:16]([CH3:52])[CH2:17][O:18][C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:49])=[CH:21][CH:20]=1
Reactant: C[C@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
500 ml of trifluoroacetic acid were added dropwise, whilst ice-cooling, to a solution of 85.5 g of 5-{4-[2(R)-t-butoxycarbonylaminopropoxy]benzyl}-3-triphenylmethylthiazolidine-2,4-dione [prepared as described in step (e) above] in 700 ml of methylene chloride, and the resulting mixture was stirred at room temperature for 4 hours. At the end of this time, the reaction mixture was freed from the methylene chloride solvent and the trifluoroacetic acid by distillation under reduced pressure, and a mixture of benzene and a small amount of ethyl acetate was added to the residue. The crystals which precipitated were collected by filtration and were recrystallized from a mixture of methanol and ethyl acetate, to give the title compound as crystals, melting at 162°166° C. [α]D23 -13.0° (c=0.885, methanol)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[S:36]([CH3:35])(=[O:38])=[O:37])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: CS(=O)(=O)Cl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)S(C)(=O)=O)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, methanesulfonyl chloride.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[C:5]([CH2:16][CH3:17])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2.[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[C:26]([CH2:32][CH2:33][CH3:34])=[N:25][C:24]([OH:35])=[CH:23]2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:2].[ClH:1].[CH2:16]([C:5]1[C:4]([CH2:3][C:23]2[C:22]3[C:27](=[CH:28][C:29]([O:30][CH3:31])=[C:20]([O:19][CH3:18])[CH:21]=3)[C:26]([CH2:32][CH2:33][CH3:34])=[N:25][C:24]=2[OH:35])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[N:6]=1)[CH3:17]
Reactant: CCc1nc2ccc(OC)cc2cc1CCl
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2CC)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 5 %

Procedure:
To a stirred solution of 3-(chloromethyl)-2-ethyl-6-methoxyquinoline hydrochloride SMA 44014 (183 mg, 0.67 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (166 mg, 0.67 mmol) followed by a 2 N aq. LiOH solution (0.67 mL, 1.34 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to room temperature, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided after evaporation 4-((2-ethyl-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.32 mL) and the mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((2-ethyl-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 66 as a yellow solid (17 mg, 5% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[Li]CCCC.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23]>C1COCC1>[F:18][C:19]1[CH:20]=[C:21]([CH:22]([OH:23])[C:11]2[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:7]([NH:9][CH3:10])=[O:8])[CH:24]=[CH:25][CH:26]=1
Reactant: CNC(=O)c1ccc(OC)cc1
Reactant: O=Cc1cccc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(OC)cc1C(O)c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a −78 C solution of 4-methoxy-N-methylbenzamide (2.0 g) in THF was added n-BuLi (10 mL, 2.5 M in hexanes). The reaction was stirred for 10 min at −78° C., warmed to 0 C, then cooled back to −78 C. 3-fluorobenzaldehyde (1.90 mL) was added as a solution in THF via cannula. The reaction was warmed to room temp, then quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc, concentrated, and purified by flash chromatography (5% MeOH in CH2Cl2) to give 2-[(3-fluorophenyl) (hydroxy)methyl]-4-methoxy-N-methylbenzamide.