Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3]I.[C:5]1([S:11]([NH:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[C:23]([SH:25])[N:22]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[CH:29][CH:28]=4)[C:21]=3[CH:39]=2)=[O:16])(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>CO.O>[C:5]1([S:11]([NH:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[C:23]([S:25][CH3:3])[N:22]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[CH:31][CH:32]=4)[C:21]=3[CH:39]=2)=[O:16])(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(NS(=O)(=O)c1ccccc1)c1ccc2nc(S)n(Cc3ccc(-c4ccccc4)cc3)c2c1
Reactant: CI
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
A 20% potassium hydroxide aqueous solution (0.323 g), 2 ml of water and 0.123 g of methyl iodide were added to a solution of 0.310 g of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-mercaptobenzimidazole in 5 ml of methanol in this order, and the mixture was stirred at room temperature for 2 hours. The reaction solution was adjusted to a pH of from 5 to 6 with 10% hydrochloric acid. The crystals precipitated were separated through filtration, and were dried to give 0.281 g of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methylthio-benzimidazole (237).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([OH:15])=[CH:9][CH:10]=3)[C:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]=2[CH:3]=1.Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:9][CH:10]=3)[C:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]=2[CH:3]=1
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCC1(CCCCCCCC)c2cc(O)ccc2-c2ccc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCOc1ccc2c(c1)C(CCCCCCCC)(CCCCCCCC)c1cc(Br)ccc1-2

Procedure:
A mixture of 2-bromo-9,9-dioctyl-7-hydroxyfluorene (6.00 g, 0.0124 mol), 1-bromooctane (3.104 g, 0.0161 mol), potassium carbonate (3.41 g, 0.0247 mol) and butanone (100 cm3) was heated under reflux overnight. The cooled mixture was filtered and evaporated down under reduced pressure. The crude product was purified by column chromatography [silica gel, dichloromethane: hexane: 1:1] and then used without further purification (yield 5.04 g, 68.3%), GC: 99%.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11](O)=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([N:20]=[N+:21]=[N-:22])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C=CC(=O)O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(=O)Oc1ccc(C=CC(=O)N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
41.2 g (0.02 mol) of p-acetoxy-cinnamic acid are suspended in 100 ml of benzene and 29 ml (0.4 mol) of thionyl chloride are added. The reaction mixture is heated to the boil under a reflux condenser for half an hour and thereafter the solvent and excess thionyl chloride are removed by distillation in vacuo. The crude p-acetoxy-cinnamic acid chloride which remains is dissolved in 200 ml of absolute dimethoxyethane, 39 g (0.6 mol) of sodium azide are added and thereafter the mixture is stirred for 48 hours at room temperature. The inorganic salts are then filtered off and the filtrate is concentrated in vacuo at 30° C. Hereupon, colourless crystals separate out. The crystallisation is completed by adding ether. p-Acetoxy-cinnamic acid azide of melting point 114° C. (decomposition) is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:22]([CH3:21])[CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCCOc1ccc(OC)c(OC)c1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Product: COc1ccc(OCCCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane and N-methyl-3-(3,4-dimethoxyphenyloxy)-propylamine analogously to Example 6.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].Br[C:8]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=1.C(N(CC)CC)C>O1CCOCC1.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:4][Si:3]([CH3:6])([CH3:5])[C:1]1[O:14][C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:2]=1
Reactant: Oc1cccnc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)c1cc2ncccc2o1
Temperature: 500 °C
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
Ethynyltrimethylsilane (32.5 ml, 0.2298 mol), copper(I)iodide (2.2 g, 0.0114 mol) and bis(triphenylphospine)palladium(II)chloride (4.1 g, 0.0057 mol) are added to a degassed solution of 2-Bromopyridine-3-ol (20 g, 0.1149 mol) in dioxane (20 ml). The mixture is stirred for 5 min under nitrogen and then triethyl amine (80 ml, 0.574 7 mol) is added. The mixture is heated to 500° C. for 18 h, cooled to RT, filtered through celite and the filtrate is concentrated under reduced pressure. The crude material is purified by column chromatography by using petrolether and ethyl acetate (90:10) as an eluent to afford (22 g, 56%) of the title compound as a brown liquid. TLC: hexane/ethyl acetate: (9/1): Rf=0.50; LCMS (method B): 4.875 min (purity 98.4%); M+H+ 192.1; 1H NMR (DMSO-d6, 400 MHz) δ [ppm] 8.50-8.48 (1H, dd, J1=1 Hz, J2=4.6 Hz), 8.015-7.9923 (1H, dd, J1=1 Hz, J2=8.32 Hz), 7.352-7.350 (1H, d, J1=0.8 Hz), 7.314-7.280 (1H, m), 0.372-0.355 (9H, s).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C@@H:13]12[C:21](=[O:22])[O:20][CH2:19][C@@H:18]1[CH2:17][CH2:16][CH2:15][CH2:14]2.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:23]([C@@:13]12[C:21](=[O:22])[O:20][CH2:19][C@@H:18]1[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1OC[C@@H]2CCCC[C@H]12
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C1OC[C@@H]2CCCC[C@]12Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Under argon, a solution of diisopropylamine (3.85 ml, 27.5 mmol) in 20 ml of dry THF is cooled to 0° C. and slowly admixed with butyllithium (11 ml, 27.5 mmol, 2.5M in hexane). With ice-cooling. This solution is stirred for 15 min and then cooled to −78° C. and a solution of cis-8-oxabicyclo[4.3.0]nonan-9-one (3.5 g, 25 mmol) in 10 ml of THF is added dropwise. The mixture is stirred at −78° C. for another 30 min and then mixed with benzyl bromide (3.27 ml, 27 mmol). The mixture is then slowly warmed to room temperature and stirred for another 16 h. The solvent is removed and the residue is taken up in 20 ml of dichloromethane and washed 2× with in each case 20 ml of 2 M HCl. The organic phase is dried over magnesium sulphate, filtered and concentrated. The residue is purified by column chromatography (mobile phase: cyclohexane:ethyl acetate 10:1).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[CH:13]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Cl>[OH-].[Na+]>[CH:13]1([C:19]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)NCCC[C@H](NC(=O)C1CCCCC1)C(=O)O
Temperature: 50 °C
Yield: 37.6 %

Procedure:
(L)-Arginine (103.2 g., 0.6 mole) was dissolved in 600 mL of 2N sodium hydroxide. Cyclohexanoyl chloride (87 mL, 0.6 mole) was added dropwise to the mixture. The reaction mixture was maintained at 50° C. for 2 hours. The mixture was then cooled to room temperature and acidified to pH 2.3 with aqueous (4:1) hydrochloric acid. The precipitate which formed was separated by decantation. The solids were dissolved in 2N sodium hydroxide and dried by Iyophilization to furnish 64.1 g of crude N-cyclohexanoyl-(L)-arginine. The product was purified by column chromatography on silica gel/using butanol/acetic acid/water as the eluent system. The products isolated were N-cyclohexanoyl-(L)-arginine and N(α)-N(γ)-dicyclohexanoyl-(L)-arginine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([OH:16])=O)[S:10][C:11]=1[CH2:12][CH3:13].C(N(CC)C(C)C)(C)C.[NH2:27][C@@H:28]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[C:48]([F:51])([F:50])[F:49])[CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([NH:27][C@@H:28]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48]([F:51])([F:49])[F:50])[CH2:29][N:30]2[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:40])=[O:16])[S:10][C:11]=1[CH2:12][CH3:13]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: CCc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (200 mg, 0.74 mmol), N,N-diisopropylethylamine (0.64 ml, 3.69 mmol) and 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (284 mg, 0.74 mmol)[prepared according to Preparation 6] in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (414 mg, 0.886 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide (316 mg, 0.526 mmol, 71% yield) as a white foam: LCMS (ES) m/e 601, 603 (M, M+2)+.
Reaction SMILES: C(O[CH:5]1[CH:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][CH:8]2[CH:7]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:6]1)(=O)C.I[Si](C)(C)C.[CH:25]([O:28][P:29]([O:34]C(C)C)[O:30][CH:31]([CH3:33])[CH3:32])([CH3:27])[CH3:26]>ClCCl>[CH:25]([O:28][P:29]([CH:5]1[CH:9]2[O:10][C:11]([CH3:13])([CH3:14])[O:12][CH:8]2[CH:7]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:6]1)([O:30][CH:31]([CH3:33])[CH3:32])=[O:34])([CH3:27])[CH3:26]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: CC(=O)OCC1OC(OC(C)=O)C2OC(C)(C)OC12
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: CC(=O)OCC1OC(P(=O)(OC(C)C)OC(C)C)C2OC(C)(C)OC12
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of acetic acid 6-acetoxy-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethyl ester (623 mg, 2.27 mmol) in dichloromethane (3 mL) was added iodotrimethylsilane (0.35 mL, 2.49 mmol) at −78° C. and the reaction mixture brought to RT. After confirming the disappearance of starting material by TLC, triisopropylphosphite (1.18 mL, 5.68 mmol) was added at −78° C. The reaction mixture was left to warm to RT and stirred overnight. The reaction was quenched with sodium bicarbonate, extracted with dichoromethane, the organic layers concentrated, dried and chromatographed. Elution with 50% ethylacetate/hexanes gave acetic acid 6-(diisopropoxy-phosphoryl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethyl ester as a colorless syrup (467 mg, 54%).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH:3]([CH2:6][SH:7])[CH2:4][OH:5].[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)#[CH:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:2]([CH:3]1[CH2:4][O:5][CH:16]([C:15]2[CH:18]=[CH:19][C:12]([C:10]#[CH:11])=[CH:13][CH:14]=2)[S:7][CH2:6]1)([CH3:9])([CH3:8])[CH3:1]
Reactant: CC(C)(C)C(CO)CS
Reactant: C#Cc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C#Cc1ccc(C2OCC(C(C)(C)C)CS2)cc1

Procedure:
A solution of 3,3-dimethyl-2-mercaptomethylbutan-1-ol (1.46 g), 4-ethynylbenzaldehyde (1.30 g) (W.B. Austin et al. J. Org. Chem., 1981, 46. 2280) and para-toluenesulphonic acid (10 mg) in benzene (50 ml) was heated to reflux overnight under Dean and Stark conditions. The resulting solution was evaporated under reduced pressure and the residue was purified on silica. Elution with 4:1 hexane: dichloromethane gave 5-t-butyl-2-(4-ethynylphenyl)-1,3-oxathiane as a mixture of isomers.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].C([Li])CCC.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1.O>[C:14]1([CH2:13][CH:3]2[CH2:4][CH2:5][CH2:6][NH:1][C:2]2=[O:7])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCCN1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1NCCCC1Cc1ccccc1
Temperature: -40 °C
Reaction time: 12 h
Yield: 53.9 %

Procedure:
To a stirred solution of 2-piperidone (40 g, 0.404 mol) in tetrahydrofuran (800 ml) at 0° C. was added, over a period of 2 hours, n-butyl lithium (2.5 M in hexane, 356 ml, 0.889 mol). The reaction was cooled to -40° C. and a solution of benzyl bromide (48 ml, 0.404 mol) in tetrahydrofuran (200 ml) was added dropwise over a period of 2 hours. The reaction was allowed to warm slowly to room temperature and stirred for 12 hours. Water (100 ml) and saturated aqueous ammonium chloride (100 ml) were added and the aqueous phase separated and extracted with ethyl acetate (3×100 ml). The combined organic phases were washed with brine (200 ml), dried with sodium sulphate and evaporated in vacuo. The resulting solid was recrystallised from toluene to give the desired product as white needles (41.2 g), m.pt. 120°-123° C. Low resolution mass spectroscopy revealed the mass/charge ratio of the parent molecule ion, M+, to be 190 thereby confirming the molecular of the product to be 190.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].C(N(CC)CC)C.Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>CCOCC>[CH3:4][C:3]([NH2:6])([CH3:5])[CH2:2][NH:1][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CC(C)(N)CN
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)NCC(C)(C)N
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
To a mixture of 88.2 g (1 mol) of 1,2-diamino-2-methylpropane, 50 ml of triethylamine and 500 ml of diethylether was added dropwise a solution of 27.1 g (0.25 mol) of ethyl chloroformate in 100 ml of ether. The reaction mixture was stirred for 16 hours at 25° C. and filtered. Evaporation of the filtrate to dryness gave 38 g (95%) of product which was identified by NMR and IR spectroscopy.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(OC([CH2:36][NH:37][C:38]([CH3:50])([CH3:49])[CH2:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](O)=O)=[CH:42][CH:41]=1)=O)(C)(C)C.[C:51](OC(CNC(C)(C)CC1C=CC(C(CCNC2C=C(OC)C=CC=2C2CCC3C=C(OC(=O)C(C)(C)C)C=CC=3C2)=O)=CC=1)=O)(C)(C)C>>[CH3:51][N:37]([CH3:36])[C:38]([CH3:49])([CH3:50])[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:44][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:47][CH:48]=1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCC(=O)c2ccc(CC(C)(C)NCC(=O)OC(C)(C)C)cc2)c1
Reactant: CC(C)(Cc1ccc(C(=O)O)cc1)NCC(=O)OC(C)(C)C
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(CC(C)(C)N(C)C)cc2)c1
Yield: 37 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (100 mg) and 4-[2-(tert-butoxycarbonylmethylamino)-2-methylpropyl]benzoic acid (120 mg) according to an analogous synthetic method to Preparation Example 86, pivalic acid 6-{2-{{4-[2-(tert-butoxycarbonylmethylamino)-2-methylpropyl]benzoyl}ethylamino}-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (67 mg) was used according to an analogous synthetic method to Example 337 to provide the title compound (18 mg).
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:20]([OH:22])[CH3:21].[CH2:23]([OH:25])[CH3:24].[CH2:26]([Cl:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[Cl-:33].[CH2:26]([NH2+:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH2:20]([OH:22])[CH3:21].[CH2:23]([OH:25])[CH3:24]
Reactant: ClCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCC[NH2+]Cc1ccccc1
Product: [Cl-]
Reaction time: 8 h

Procedure:
A 4-liter reaction vessel equipped with a reflux condenser and mechanical stirrer was charged with 719.6 gm. (2.0 mol) diethanol octadecylamine, 278.5 gm. (2.2 mol) benzyl chloride, 20 gm. of sodium bicarbonate and approximately 400 ml. isopropyl alcohol. The reaction mixture was heated under reflux overnight. An aliquot was removed, analyzed and found to contain 7.4% amine and 1.7% amine HCl. The mixture was allowed to continue reacting overnight. A second aliquot was analyzed and found to contain 4.1% amine and 3.7% amine HCl. An additional 20 gm. of sodium bicarbonate and 30 gm. benzyl chloride were added. After one week the reaction had not progressed any further. The mixture was placed in the autoclave and the quaternization was finished with methyl chloride. The final analyses showed amine 0.0%; amine HCl <1% and Effective gram MW 834.4.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:34])[C:12]1[CH:17]=[CH:16][C:15]([O:18]CC2C=CC=CC=2)=[C:14]([O:26]CC2C=CC=CC=2)[CH:13]=1.[H][H]>C(O)(C)C.O.[C].[Pd]>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:34])[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([OH:26])[CH:13]=1
Reactant: COc1ccc(CCNCC(O)c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(CCNCC(O)c2ccc(O)c(O)c2)cc1OC
Yield: 104.1 %

Procedure:
3.0 g of α-(3,4-dimethoxyphenethylaminomethyl)-3,4-dibenzyloxybenzylalcohol hydrochloride are suspended in a mixture of 80 ml of isopropanol and 20 ml of water. One g of 10 % palladium-carbon is added to the solution. Then, the mixture is subjected to catalytic hydrogenation in a hydrogen atmosphere at room temperature for 1 hour under atmospheric pressure. After the reaction is completed, the mixture is filtered to remove the catalyst. The filtrate is concentrated to dryness under reduced pressure, and the residue thus obtained is recrystallized from aqueous isopropanol. 2.1 g of α-(3,4-dimethoxyphenethylaminomethyl)-3,4-dihydroxybenzylalcohol hydrochloride are obtained. Yield: 90 % M.p. 98° - 109°C (decomp.)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1.O>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:32][C:31]3[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:36])[F:37])=[CH:35][CH:34]=3)[C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCc2c(n(Cc3ccc(C(F)(F)F)cc3)c3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
To a stirred solution of 2-benzyloxycarbonyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole (5.82 g, 19.0 mmole) in dry DMF (75 mL) at 5° C. was added 60% NaH (1.10 g, 28.5 mmole). After 10 min, 4-trifluoromethylbenzyl bromide (5.0 g, 20.9 mmole) was added and the reaction was allowed to warm to RT and stir for 12 hr. The reaction contents were poured into H2O (100 mL) and extracted with EtOAc (2×100 mL). The combined organic phases were washed sequentially with H2O and brine, thenwere dried over Na2SO4. Concentration under reduced pressure and purification on silica (hexanes/EtOAc, 4:1) afforded the title compound (8.73 g, 99%) as a white solid: MS (ES) m/e 465 (M+H)+.
Reaction SMILES: CC[O-].[Na+].Cl.[C:6]([NH2:9])(=[NH:8])[CH3:7].[C:10]([CH:13]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:14](OCC)=[O:15])(=O)[CH3:11]>CCO>[CH3:7][C:6]1[NH:9][C:14](=[O:15])[C:13]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:10]([CH3:11])[N:8]=1
Reactant: CCOC(=O)CCC(C(C)=O)C(=O)OCC
Reactant: CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCc1c(C)nc(C)[nH]c1=O
Yield: 51 %

Procedure:
A mixture of NaOEt (0.069 mol) in EtOH (prepared from 1.6 g of Na and 35 mL of EtOH), acetamidine hydrochloride (3.3 g, 0.035 mol), and diethyl acetylglutarate (8.0 g, 0.035 mol) was heated under reflux for 22 h. The mixture was concentrated, taken up in water, acidified to pH 4 with conc. HCl, and extracted with EtOAc. The extracts were washed with brine, dried (MgSO4), and concentrated. Trituration with hexane gave 4.0 g (51%) of product as a white solid. An analytical sample was crystallized from ether/hexane, mp 114°-116° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=3[F:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:33]1([CH2:38][CH2:39][C:40](Cl)=[O:41])[CH2:37][CH2:36][CH2:35][CH2:34]1>CN(C1C=CN=CC=1)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]([C:40](=[O:41])[CH2:39][CH2:38][CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[C:19]3[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=3[F:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3cc(C(=O)OCC)ccc3F)cc2)cc1
Reactant: O=C(Cl)CCC1CCCC1
Agent: CN(C)c1ccncc1
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)c3cc(C(=O)OCC)ccc3F)cc2)cc1

Procedure:
The titled compound was prepared following the procedure B using ethyl 3-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-4-fluorobenzoate and 3-cyclopentylpropionyl chloride in the presence of DMAP as a colorless oil (15%). M+ (ESI): 553.9. HPLC, Rt: 6.39 min (Purity: 93.6%).