Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][NH:9][S:10]([NH:13][C:14]2[S:18][C:17]([C:19]3[N:20]([CH2:26][C:27]([NH:29][CH:30]([CH:37]([CH3:39])[CH3:38])[C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[O:28])[C:21](=[O:25])[CH:22]=[CH:23][N:24]=3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[C:42](OC(=O)C)(=[O:44])[CH3:43].CO>C(O)(=O)C.[Fe]>[C:42]([NH:1][C:4]1[CH:41]=[CH:40][C:7]([CH2:8][NH:9][S:10]([NH:13][C:14]2[S:18][C:17]([C:19]3[N:20]([CH2:26][C:27]([NH:29][CH:30]([CH:37]([CH3:39])[CH3:38])[C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[O:28])[C:21](=[O:25])[CH:22]=[CH:23][N:24]=3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:44])[CH3:43]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccc(NS(=O)(=O)NCc3ccc([N+](=O)[O-])cc3)s2)nccc1=O)C(=O)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(CNS(=O)(=O)Nc2ccc(-c3nccc(=O)n3CC(=O)NC(C(=O)C(F)(F)F)C(C)C)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[5-(4-nitrobenzylaminosulfonylamino)-6-oxo-2-thienyl-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.431 g) in acetic acid (12 mL) was added acetic anhydride (0.265 mL), followed by iron powder (0.783 g). The reaction was stirred at room temperature overnight. Methanol was added and the reaction mixture filtered through diatomaceous earth to remove excess iron. Ethyl acetate was added and the resultant solution washed (water (twice), brine), dried (MgSO4) and evaporated. The crude material was purified by chromatography, with dichloromethane:methanol (gradient, 99.5:0.5, 98:2) as the eluent, to provide the title compound (0.247 g); TLC: Rf =0.27, dichloromethane:methanol (98:2); NMR: 0.87-0.97 (m,6), 2.17-2.30 (m,1), 3.32 (s,3), 4.02 (d,2), 4.73-4.77 (m,1) 4.77-4.93 (m,2), 7.13-7.20 (m,3), 7.33 (d,1), 7.47 (d,2), 7.80-7.87 (m,1), 7.91 (s,1), 7.97-8.03 (m,1), 9.04 (d,1), 9.09 (s,1), 9.87 (s,1); MS: m/z=629(M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[NH:16][C:15]=2[CH2:24][CH2:25][N:26]2C(=O)C3[C:28](=CC=CC=3)[C:27]2=[O:36])=[CH:7][CH:6]=1)[CH3:2].NN.C(OC(=O)C)(=O)C.O>CC(O)C>[CH2:1]([O:3][C:4](=[O:37])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[NH:16][C:15]=2[CH2:24][CH2:25][NH:26][C:27](=[O:36])[CH3:28])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(CCCc2c(CCN3C(=O)c4ccccc4C3=O)[nH]c3ccc(Cl)cc23)cc1
Agent: NN
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(C)O
Product: CCOC(=O)c1ccc(CCCc2c(CCNC(C)=O)[nH]c3ccc(Cl)cc23)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 87.6 %

Procedure:
A stirred mixture of 4-(3-{5-chloro-2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-1H-indol-3-yl}-propyl)-benzoic acid ethyl ester (415 g, 0.81 mol) and 55% hydrazine solution (141 g, 2.42 mol) in 2-propanol (4 L) is warmed to 80° C. for 3 h-4 h. The reaction is complete when the product/starting material ratio is greater than 99/1 by HPLC. The reaction mixture is cooled to room temperature. The byproduct is removed by filtration. The cake is washed with 2-propanol (400 mL×3). The filtrate and wash are combined and distilled to about half volume. Pyridine (830 mL×2) is added and the remainder of the 2-propanol is removed under reduced pressure. The stirred mixture is cooled to 5° C.-10° C. Acetic anhydride (90.4 g, 1.10 mol) is added dropwise to the reaction mixture at 5° C.-10° C. The reaction is complete when the product/starting material ratio is >99/1 by HPLC analysis. Water (5.0 L) is added to the reaction mixture, maintaining the temperature below 25° C. The reaction mixture is stirred at room temperature for 12 hours. The solid product is collected by filtration, washed with water (500 mL×3) and dried in vacuum oven (70° C.) to give 303 g (87.6%, 95.4% by HPLC) of 4-{3-[2-(2-Acetylamino-ethyl)-5-chloro-1H-indol-3-yl]-propyl}-benzoic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.[Sn](Cl)(Cl)(Cl)Cl.CN1CCNCC1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=1[CH3:1].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=2[CH3:1])=[CH:28][CH:27]=1
Reactant: Cc1c(CO)cccc1[N+](=O)[O-]
Reactant: Clc1ccccc1
Agent: CN1CCNCC1
Agent: Cl[Sn](Cl)(Cl)Cl
Product: Cc1c(Cc2ccc(Cl)cc2)cccc1[N+](=O)[O-]
Product: Cc1c(Cc2ccccc2Cl)cccc1[N+](=O)[O-]
Yield: 24 %
Yield: 41 %

Procedure:
A mixture of 25 g (0.15 mol) of 2-methyl-3-nitrobenzyl alcohol and 25 ml (0.22 mol) of tintetrachloride in 250 ml of chlorobenzene is refluxed for 3 hours with stirring. After cooling 50 ml of N-methylpiperazine is slowly instilled. The precipitate is suctioned off and washed several times with ethyl acetate. The combined filtrates are dried on sodium sulfate and concentrated by evaporation and the temperature must not rise above 160° C. The residue (39 g) with a mixture of 33 parts of cyclohexane and 1 part of ethyl acetate is subjected twice to a pressure column chromatography. Thus 9.3 g (24%) of 2-(2-chlorobenzyl)-6-nitrotoluene, melting point 54°-56° C., and 16 g (41%) of 2-(4-chlorobenzyl)-6-nitrotoluene, melting point 62°-63° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([CH2:7][CH2:8][OH:9])[CH2:4][O:3]1.O[N:12]1C(=O)C2C(=CC=CC=2)C1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.O.NN>C(Cl)Cl>[CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([CH2:7][CH2:8][O:9][NH2:12])[CH2:4][O:3]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC1(C)OC[C@@H](CCO)O1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC1(C)OC[C@@H](CCON)O1
Yield: 43.4 %

Procedure:
The title compound was prepared using the procedure described for Example 2K by using (R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol (4.28 mL, 30 mmol), CH2Cl2 (100 mL), 2-hydroxyisoindoline-1,3-dione (4.9 g, 30 mmol), triphenylphosphine (11.8 g, 45 mmol), diisopropylazodicarboxylate (8.8 ml, 45 mmol) and hydrazine hydrate (6.0 mL, 60 mmol) to afford 2.1 g (43%, over two steps) of (R)—O-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)hydroxylamine (2X) as a pale yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.13 (s, 3H), 1.18 (s, 3H), 1.53-1.71 (m, 2H), 3.53 (m, 2H), 3.79-3.89 (m, 1H), 3.89-4.01 (m, 1H), 4.63-4.81 (m, 1H). MS (ES) [M+H] calculated for C2H16NO3, 162.11; found 162.0.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17]CC=C)=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH:4]=1)#[N:2].N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:34])=[O:35])[CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(=O)(=O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC1=C(C(=O)O)C(c2ccc(C#N)cc2S(=O)(=O)c2ccccc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The reaction was carried out under argon. Allyl 4-[4-cyano-2-(phenylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (220 mg, 0.378 mmol) and morpholine (1.5 eq., 43 mg, 0.567 mmol) were initially charged in dry THF (6 ml) at RT. The reaction mixture was degassed repeatedly (evacuation followed by venting with argon). Under protective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 22 mg, 0.019 mmol) was added, and the reaction mixture was stirred at RT for 16 h (HPLC control). The mixture was then concentrated, and the residue was taken up in ethyl acetate (100 ml). The organic phase was washed successively with 0.1 N hydrochloric acid (6 ml), saturated ammonium chloride solution (3×50 ml), water (30 ml) and saturated sodium chloride solution (30 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→80:20).
Reaction SMILES: [C:1]1([CH:7]2[O:12][C:10](=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:13]>>[OH:12][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH2:9][C:10]([NH2:13])=[O:11]
Reactant: N
Reactant: O=C1CCC(c2ccccc2)O1
Product: NC(=O)CCC(O)c1ccccc1
Reaction time: 8 h
Yield: 75 %

Procedure:
A mixture of γ-phenyl-γ-butyrolactone (10.30 g, 63.5 mmol) and an excess of ammonia was stirred under nitrogen and a dry ice trap for 8 hours. The dry ice trap was removed and after evaporation of the ammonia 11.27 g of a tan solid remained. Recrystallization of the solid from ethyl acetate-hexane gave 4-hydroxy-4-phenyl-butyramide (8.56 g, 75%) as a white solid, mp 85-87° C.
Reaction SMILES: [ClH:1].C(O)(C(F)(F)F)=O.C(OC([N:16]1[C@@H:20]([CH3:21])[CH2:19][CH2:18][C@H:17]1[C:22]1[NH:23][C:24]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[CH:33]=[C:32]([C:37]#[C:38][C:39]2[NH:43][C:42]([C@@H:44]4[CH2:49][C@@H:48]5[C@@H:46]([CH2:47]5)[N:45]4C(OC(C)(C)C)=O)=[N:41][CH:40]=2)[CH:31]=[CH:30]3)=[CH:25][N:26]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[CH3:21][C@@H:20]1[NH:16][C@H:17]([C:22]2[NH:26][CH:25]=[C:24]([C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[CH:33]=[C:32]([C:37]#[C:38][C:39]3[N:43]=[C:42]([C@@H:44]5[CH2:49][C@@H:48]6[C@@H:46]([CH2:47]6)[NH:45]5)[NH:41][CH:40]=3)[CH:31]=[CH:30]4)[N:23]=2)[CH2:18][CH2:19]1
Reactant: C[C@H]1CC[C@@H](c2ncc(-c3ccc4cc(C#Cc5cnc([C@@H]6C[C@H]7C[C@H]7N6C(=O)OC(C)(C)C)[nH]5)ccc4c3)[nH]2)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CC[C@@H](c2nc(-c3ccc4cc(C#Cc5c[nH]c([C@@H]6C[C@H]7C[C@H]7N6)n5)ccc4c3)c[nH]2)N1
Reaction time: 2 h
Yield: 135.2 %

Procedure:
4M HCl (0.611 mL, 2.445 mmol) in dioxane was added to a mixture of a TFA salt of (1R,3S,5R)-tert-butyl 3-(5-((6-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (53.6 mg, 0.061 mmol) in dioxane (1.5 mL) and the reaction was vigorously stirred for 2 h. The reaction was concentrated under a steam of nitrogen overnight to yield an HCl salt of (1R,3S,5R)-3-(4-((6-(2-((2S,5S)-5-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (37 mg) which was used without further purification. LC-MS retention time 2.302 min; m/z 449.40 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.[S:9](Cl)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].CCOCC>C(N(CC)CC)C>[C:15]1([CH3:16])[CH:17]=[CH:18][C:12]([S:9]([C:5]2[NH:1][N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: NC(=O)c1nc[nH]n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)c2nc(C(N)=O)n[nH]2)cc1

Procedure:
To a cooled, stirred mixture of 3.0 g. of 1,2,4-triazole- 3-carboxamide and 5.1 g. of tosyl chloride in 125 ml. of anhydrous ether is added rapidly 2.75 g. of triethylamine. The cooling bath is removed and the mixture is stirred at room temperature for 23 hours. The heterogeneous mixture is filtered and washed successively with ether, cold water and then ether and dried in vacuo for 4.5 hours yielding a crude colorless solid. This solid is heated in about 50 ml. of acetonitrile and the hot mixture is filtered. The filtrate is concentrated to a smaller volume of about 20 ml. in vacuo. A colorless solid separates from the filtrate, which is collected and washed with acetonitrile and air dried for 10 minutes. The product is then dried overnight in vacuo, m.p. 148°-150° C.
Reaction SMILES: [C:1](OC)(=[O:3])C.[C:6](#[N:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[ClH:15].CC1CCCCC1>CO>[ClH:15].[C:6](=[NH:14])([O:3][CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCC#N
Reactant: COC(C)=O
Agent: Cl
Solvent: CO
Solvent: CC1CCCCC1
Product: CCCCCCCC(=N)OC
Temperature: 0 °C
Reaction time: 25 h
Yield: 93.4 %

Procedure:
Methanol (2.81 g) and methyl acetate (30 ml) were added to octanenitrile (10.00 g), and the mixture was cooled to 0° C. Hydrogen chloride (7.50 g) was added and the mixture was stirred for 25 hours at the same temperature. Methylcyclohexane (60 ml) was added to the reaction solution, and then the solvent was distilled off under reduced pressure. Methylcyclohexane (20 ml) was added to the residue, the mixture was stirred for 1.5 hours at room temperature, and then crystals were filtered. The crystals were washed with methylcyclohexane and dried under reduced pressure to give the title compound as a white solid (14.45 g, 93.4% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[C:21]([Cl:32])[N:20]=[C:19]2[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:13][CH:12]=1)=O.[NH2:37][NH2:38]>>[CH2:33]([C:19]1[N:18]([CH2:17][C:14]2[CH:13]=[CH:12][C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:3]([NH:37][NH2:38])=[O:2])=[CH:16][CH:15]=2)[C:22]([CH2:23][O:24][Si:25]([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:26])[CH3:27])=[C:21]([Cl:32])[N:20]=1)[CH2:34][CH2:35][CH3:36]
Reactant: NN
Reactant: CCCCc1nc(Cl)c(CO[Si](C)(C)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Product: CCCCc1nc(Cl)c(CO[Si](C)(C)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)NN)cc1
Yield: 60 %

Procedure:
According to the procedure of Example 2, 4'-[[2-butyl-4-chloro-5-(t-butyldimethylsilyloxymethyl)-1H-imidazol-1-yl]methyl][1,1'-biphenyl-2-yl]carboxylic acid methyl ester was treated with hydrazine to give 4'-[[2-butyl-4-chloro-5-(t-butyldimethylsilyloxymethyl)-1H imidazol-1-yl]methyl][1,1'-biphenyl-2-yl]carboxylic acid hydrazide (60%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][C:3]=1[O:19][CH3:20].[H][H]>C(O)C.[C].[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: CCCCCCCC(=O)/C=C/c1ccc(O)c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCC(=O)CCc1ccc(O)c(OC)c1
Yield: 55.9 %

Procedure:
Moreover, 10 g (36 mmol) of the resulting (E)-1-(4′-hydroxy-3′-methoxyphenyl)dec-1-en-3-one was dissolved in 100 mL of ethanol followed by the addition of 1 g of palladium carbon (5% palladium) to this solution and stirring overnight at normal temperature in a hydrogen atmosphere (normal pressure). After filtering the insoluble matter, the filtrate was concentrated under reduced pressure to obtain 9.8 g of crude product. This crude product was purified by column chromatography (SiO2/CHCl3) to obtain 1-(4′-hydroxy-3′-methoxyphenyl)-3-decanone (5.6 g, yield: 58%).
Reaction SMILES: [NH2-].[Na+].C1(C)C=CC=CC=1.[C:10]1([CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17]#[N:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:25][C:26]([CH2:28]Cl)=[CH2:27]>C(OCC)C.CN(C)C=O>[Cl:25][C:26](=[CH2:27])[CH2:28][C:16]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:17]#[N:18]
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: C=C(Cl)CCl
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=C(Cl)CC(C#N)(c1ccccc1)c1ccccc1
Temperature: 10 °C
Reaction time: 4 h

Procedure:
A 40.3 g. portion of sodium amide was suspended in 400 ml. of dry toluene at 70° C. and 199.6 g. of diphenylacetonitrile, dissolved in 600 ml. of hot dry toluene, was added dropwise. The mixture was stirred at 70°-100° C. for 4 hours, and an additional 500 ml. of dry toluene and 100 ml. of dimethylformamide were added. The mixture was stirred for 27 hours more. The slurry was cooled to 10° C., and 114.6 g. of 2,3-dichloropropene was added. The mixture was warmed to ambient temperature and stirred for 40 hours, and was then stirred at 90°-100° C. for one hour. The mixture was then cooled to ambient temperature, diluted with a large amount of diethyl ether, washed with water and dried over magnesium sulfate. The solution was evaporated to give 265 g. of crude liquid product.
Reaction SMILES: [Br-:1].[CH2:2]([N+:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:15]([N:17]([CH2:26][CH3:27])[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1)[CH3:16].N1CCCCC1>CO>[OH2:23].[Br-:1].[CH2:26]([N:17]([CH2:15][CH3:16])[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N+:8]=2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:20][CH:19]=1)[CH3:27].[CH2:15]([N:17]([C:18]1[CH:19]=[CH:20][C:21]([CH:22]=[CH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N+:8]=2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:24][CH:25]=1)[CH2:26][CH3:27])[CH3:16].[Br-:1]
Reactant: CCN(CC)c1ccc(C=O)cc1
Reactant: CCCCCC[n+]1ccccc1C
Agent: [Br-]
Solvent: CO
Solvent: C1CCNCC1
Product: CCCCCC[n+]1ccccc1C=Cc1ccc(N(CC)CC)cc1
Product: O
Yield: 45.3 %

Procedure:
1-Hexyl-2-methylpyridinium bromide (7.8 g, 0.03 mole) and 4-diethylaminobenzaldehyde (7.0 g, 0.04 mole) were refluxed in methanol (50 ml) in the presence of piperidine (1.0 ml) under nitrogen for four hours. The solution was evaporated and the resulting oil was redissolved in a small amount of isopropanol. Addition of twice the volume of ether gave a red crystalline solid which was collected and washed with isopropanol/ether to give 2-[4-(diethylamino)styryl]-1-hexylpyridinium bromide hemihydrate (5.8 g), melting point 222°-223° (decomposition).
Reaction SMILES: [Na+].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][S:17]([O-:20])(=O)=[O:18])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN(C)C=O.C(Cl)(=O)C([Cl:29])=O>C1COCC1.C(OCC)C>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][S:17]([Cl:29])(=[O:20])=[O:18])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)([O-])Cc1ccc(OCc2ccccc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=S(=O)(Cl)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
Under inert gas, 5.70 g of (4-benzyloxyphenyl)methanesulfonic acid sodium salt and 1.48 ml of N,N-dimethylformamide were initially charged in 110 ml of THF, then, at a temperature of −20° C., 4.17 ml of oxalyl chloride were added dropwise and the reaction solution was allowed to come to 0° C. within 15 minutes. The reaction solution was diluted with 100 ml of diethyl ether and washed with water, dilute aqueous sodium hydrogencarbonate solution and saturated sodium chloride solution. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. The residue (4.89 g) was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:28][C@H:29]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:30][C:31](O)=[O:32])(=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(Cl)CCl.CI>>[CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH:11][C:31](=[O:32])[CH2:30][C@H:29]([O:28][C:15](=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O
Reactant: N[C@@H](CO)C(=O)OCc1ccccc1
Solvent: ClCCCl
Solvent: CI
Product: CCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)N[C@@H](CO)C(=O)OCc1ccccc1
Yield: 89.4 %

Procedure:
In the same manner as described in Example 2-(5), L-serine benzyl ester (390 mg, 2.0 mmol) was acylated with (R)-3-dodecanoyloxytetradecanoic acid (935 mg, 2.2 mmol) in the presence of EDC·MeI (745 mg, 2.5 mmol) in CH2C2 to afford 1.08 g (90%) of N-[(R)-3-dodecanoyloxytetradecanoyl]-L-serine benzyl ester: mp 53-54° C. 1H NMR (CDCl3) δ 0.88 (t, 6H, J=6.5 Hz), 1.1-1.6 (m, 46H), 2.30 (t, 2H, J=7.7 Hz), 2.50 (d, 2H, 5.6 Hz), 2.62 (t, 1H, J=6.2 Hz), 3.97 (m, 2H), 4.65 (m, 1H), 5.19 (m, 3H), 6.63 (d, 1H, J=6.8 Hz), 7.35 (br s, 5H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[C:14]1(=[O:24])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[N:16][NH:15]1>>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]#[C:6][CH2:5][CH2:4][CH2:3][CH2:2][N:15]1[N:16]=[CH:17][C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]1=[O:24]
Reactant: BrCCCCC#Cc1ccccn1
Reactant: O=c1[nH]ncc2ccccc12
Product: O=c1c2ccccc2cnn1CCCCC#Cc1ccccn1

Procedure:
The title compound was prepared in accordance with the general method of Example 242(B), from 2-(6-bromohex-1-ynyl)pyridine (138 mg, 0.578 mmol) and phthalazin-1(2H)-one (80 mg, 0.55 mmol).
Reaction SMILES: [C:1]([C:3]1([C:6]([OH:8])=O)[CH2:5][CH2:4]1)#[N:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:43]([O:45][C:46]1[CH:51]=[CH:50][C:49]([CH:52]2[CH2:57][CH2:56][N:55]([C:58]3[CH:63]=[CH:62][C:61]([C@@H:64]([NH2:66])[CH3:65])=[CH:60][CH:59]=3)[CH2:54][CH2:53]2)=[CH:48][CH:47]=1)[CH3:44]>CN(C=O)C>[CH2:43]([O:45][C:46]1[CH:47]=[CH:48][C:49]([CH:52]2[CH2:53][CH2:54][N:55]([C:58]3[CH:59]=[CH:60][C:61]([C@@H:64]([NH:66][C:6]([C:3]4([C:1]#[N:2])[CH2:5][CH2:4]4)=[O:8])[CH3:65])=[CH:62][CH:63]=3)[CH2:56][CH2:57]2)=[CH:50][CH:51]=1)[CH3:44]
Reactant: CCOc1ccc(C2CCN(c3ccc([C@H](C)N)cc3)CC2)cc1
Reactant: N#CC1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ccc(C2CCN(c3ccc([C@H](C)NC(=O)C4(C#N)CC4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 14 mg (0.13 mmol) 1-cyano-cyclopropanecarboxylic acid in 1 mL DMF are added 52 μL (0.30 mmol) DIPEA and 49 mg (0.13 mmol) HATU. The mixture is stirred for 10 min at rt. Subsequently a mixture of 36 mg (0.10 mmol) (S)-1-{4-[4-(4-ethoxy-phenyl)-piperidin-1-yl]-phenyl}-ethylamine hydrochloride (XII.1) in 1 mL DMF is added and stirring is continued for 6 h at rt. The crude mixture is directly purified by HPLC (Sunfire, narrow gradients, water (+0.1% TFA)/methanol) to yield the desired product.