Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:10]=[N:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.C(OC([N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH:36]=[C:35]([NH2:37])[CH:34]=[N:33]2)[CH2:28][CH2:27]1)=O)(C)(C)C>COCCO>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[C:6]3[N:7]=[C:2]([NH:37][C:35]4[CH:34]=[N:33][N:32]([CH:29]5[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]5)[CH:36]=4)[N:3]=[CH:4][C:5]=3[N:10]=[N:9]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(N)cn2)CC1
Reactant: COc1ccc(-n2nnc3cnc(Cl)nc32)cc1
Solvent: COCCO
Product: COc1ccc(-n2nnc3cnc(Nc4cnn(C5CCNCC5)c4)nc32)cc1
Temperature: 25 °C

Procedure:
A solution of 183 mg (0.70 mmol) 5-chloro-3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (from example 2) and 186 mg (0.70 mmol) 4-(4-amino-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester in 1.8 ml 2-methoxy-ethanol is stirred for 4 hours at 100° C. The reaction mixture is cooled to room temperature, concentrated under vacuum and the residue is chromatographed on a silica gel column with dichloromethane/methanol as eluent giving two products:
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1/[CH:21]=[CH:22]/[C:23](O)=[O:24])([O-:14])=[O:13]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:23](=[O:24])/[CH:22]=[CH:21]/[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N+:12]([O-:14])=[O:13])[CH2:4]2
Reactant: O=C(O)/C=C/c1ccccc1[N+](=O)[O-]
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(/C=C/c1ccccc1[N+](=O)[O-])N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(2-nitrophenyl)propenoic acid; MS (ES+) 302 (MH+).
Reaction SMILES: [N:1]1([CH2:14][CH2:15][O:16][CH2:17][C:18]#[CH:19])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.C(N(CC)CC)C.I[C:28]1[S:29][CH:30]=[CH:31][CH:32]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C)C=O>[S:29]1[CH:30]=[CH:31][CH:32]=[C:28]1[C:19]#[C:18][CH2:17][O:16][CH2:15][CH2:14][N:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: C#CCOCCn1cnc2cnc3ccccc3c21
Reactant: Ic1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C(#Cc1cccs1)COCCn1cnc2cnc3ccccc3c21
Reaction time: 0.83 h
Yield: 60.8 %

Procedure:
A dried round bottom flask was charged with a stir bar, 2-(1H-imidazo[4,5-c]quinolin-1-yl)ethyl (2-propynyl)ether (11.78 g, 46.88 mmol), anhydrous triethylamine (14 mL, 121.9 mmol), 2-iodothiophene (5.7 mL, 51.57 mmol) and anhydrous dimethyl formamide(130 mL) under a nitrogen atmosphere and heated to 80° C. After 5 minutes dichlorobis(triphenylphosphine)palladium(II) (0.658 g, 0.937 mol) and copper(I) iodide (0.357 g, 1.875 mmol) were added neat to the solution. The reaction was judged complete after 50 minutes. The volatiles were removed under reduced pressure and the resulting solid partitioned between dichloromethane and 0.5N aqueous potassium hydroxide. The aqueous fraction was extracted with dichloromethane (3×); the combined organic fractions were dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide a brown solid. The glassy solid obtained from purification by chromatography over silica gel (98/2 dichloromethane/methanol) was triturated with ether to provide 9.5 g of 1-{2-[(3-thien-2-ylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin as a tan solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:39])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[CH:36][N:35]=[N:34]2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([NH:14][C:12]1[C:11]([C:19]([F:20])([F:21])[F:22])=[CH:10][C:9]2[NH:23][C:24](=[O:39])[CH2:25][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N:33]4[CH:37]=[CH:36][N:35]=[N:34]4)[CH:28]=3)=[N:7][C:8]=2[CH:13]=1)[CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CNc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {5-(isobutyl-amino)-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M128) (0.34 g, 0.61 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (150 mg, 56%).
Reaction SMILES: Cl.CO[C:4](=[O:9])[C@H:5]([CH3:8])NC.[C:10]([O:14][C:15](=[O:18])[CH2:16][CH3:17])(=O)CC.[CH2:19]([N:21](CC)CC)C.O>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:10][O:14][C:15](=[O:18])[C@H:16]([CH3:17])[N:21]([CH3:19])[C:4](=[O:9])[CH2:5][CH3:8]
Reactant: CCN(CC)CC
Reactant: CN[C@@H](C)C(=O)OC
Reactant: CCC(=O)OC(=O)CC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(=O)N(C)[C@@H](C)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 150 ml of chloroform was dissolved 28 g (0.18 mol) of N-methyl-L-alanine methyl ester hydrochloride, followed by addition of 27 g (0.21 mol) of propionic anhydride and 33 ml of triethylamine. The mixture was allowed to stand at room temperature overnight. With the addition of 100 ml of water, the reaction mixture was stirred at room temperature for 30 minutes. Thereafter, 600 ml of ethyl acetate was added and the organic layer was washed with aqueous sodium hydrogen carbonate and water in the order mentioned, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. In the above manner, N-methyl-N-propionyl-L-alanine methyl ester was obtained as a yellow oil. NMR spectrum (CDCl3) δ: 1.15(3H,t,J=7Hz), 1.40(3H,d,J=7Hz), 2.40(2H,q,J=7Hz), 2.93(3H,s), 3.70(3H,s), 5.27(1H,q, J=7Hz)
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]1[NH:16][N:15]=[CH:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1N=CN([C:22](N2C=NC=C2)=[O:23])C=1>O1CCOCC1>[CH2:1]([N:6]1[C:7]2[N:8]=[CH:9][NH:10][C:11]=2[C:12]2=[N:13][CH:14]=[N:15][N:16]2[C:22]1=[O:23])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNc1nc[nH]c1-c1ncn[nH]1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: CCCCCn1c(=O)n2ncnc2c2[nH]cnc21
Temperature: 110 °C
Reaction time: 2 h
Yield: 5.1 %

Procedure:
A mixture of N-pentyl-5-(1H-1,2,4-triazol-5-yl)-1H-imidazol-4-amine (0.52 g, 2.4 mmol) and N,N-carbonyldiimidazole (0.57 g, 3.5 mmol) in 1,4-dioxane (10 mL) was stirred at 110° C. for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative LCMS to yield the desire product (30 mg, 5% yield). LCMS calculated for C11H15N6O (M+H): 247.1. found: 247.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[C:21]([CH3:22])=[CH:20][S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([Cl:1])[CH:3]=2)[C:16]2[C:21]([CH3:22])=[CH:20][S:19][C:17]=2[N:18]=1
Reactant: COc1ccc(CN)cc1Cl
Reactant: Cc1csc2nc(Cl)nc(Cl)c12
Product: COc1ccc(CNc2nc(Cl)nc3scc(C)c23)cc1Cl

Procedure:
Following the procedure of Example 1, the reaction of 3-chloro-4-methoxybenzylamine with 2,4-dichloro-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-5-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][C:17]#[CH:18])[C:4]=2[CH:3]=1.[CH2:19]=O.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCOCC1>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][C:17]#[C:18][CH2:19][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:4]=2[CH:3]=1
Reactant: C#CCN1c2ccccc2Sc2ccc(Cl)cc21
Reactant: C1CCNC1
Reactant: C=O
Solvent: C1COCCO1
Product: Clc1ccc2c(c1)N(CC#CCN1CCCC1)c1ccccc1S2

Procedure:
Following the procedure given in Example 1B, 2-chloro-10-propargylphenothiazine (21.7 g.; 0.08 mole) was caused to react with 3.8 g of paraformaldehyde and 7.1 g. (0.1 mole) of pyrrolidine in the presence of a trace of cuprous chloride in dioxane. Recrystallized from ether-hexane, the pure 2-chloro-10-[4-(1-pyrrolidinyl)-2-butynyl]-phenothiazine thus obtained melted at 48.0°-50.0° C.
Reaction SMILES: [OH-:1].[Na+].C([O:5][C:6]([CH2:8][NH:9][C:10](=[O:29])[NH:11][C:12]1[CH:28]=[CH:27][C:26]2[C:17]3[NH:18][C:19](=[O:25])[C:20]4[N:21]([CH:22]=[CH:23][N:24]=4)[C:16]=3[CH2:15][C:14]=2[CH:13]=1)=[O:7])C>C(O)C>[OH2:5].[OH2:1].[C:6]([CH2:8][NH:9][C:10](=[O:29])[NH:11][C:12]1[CH:28]=[CH:27][C:26]2[C:17]3[NH:18][C:19](=[O:25])[C:20]4[N:21]([CH:22]=[CH:23][N:24]=4)[C:16]=3[CH2:15][C:14]=2[CH:13]=1)([OH:7])=[O:5]
Reactant: CCOC(=O)CNC(=O)Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: O
Product: O=C(O)CNC(=O)Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Temperature: 20 °C
Reaction time: 18 h

Procedure:
20 ml of 30% sodium hydroxide solution are added, at a temperature in the region of 20° C., to 1 g of 8-(3-ethoxycarbonylmethylureido)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one in suspension in 40 ml of ethanol. The reaction is continued for 18 hours at 50° C. After cooling to a temperature in the region of 20° C., the precipitate formed is filtered, then taken up in 20 ml of distilled water and the mixture is acidified using concentrated hydrochloric acid. The suspension is stirred for 2 hours at a temperature in the region of 20° C. and then filtered, washed with water and dried under partial vacuum (1 mm Hg, 0.13 kPa) at 100° C. After recrystallization from dimethylformamide, there is obtained 0.22 g of 8-(3-carboxymethylureido)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one dihydrate in the form of a beige solid, the melting point of which is greater than 260° C. (Analysis C16H12N5O4 2.0.H2O.0.1DMF, % calculated C: 56.64, H: 3.86, N: 20.64, % found C: 56.7, H: 3.8, N: 21.0).
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[CH2:15][CH2:16][C:17](=[O:18])[C:13]=3[CH:12]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[NH:11][C:10]2=[O:27])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>O1CCCC1.O>[F:28][CH:2]([F:1])[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[CH2:15][CH2:16][C:17](=[O:18])[C:13]=3[CH:12]([C:19]3[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=3)[N:11]([S:32]([CH3:31])(=[O:34])=[O:33])[C:10]2=[O:27])[CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)F)c3)C3=C2C(=O)CC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)N1C(=O)N(c2cccc(C(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 50 °C

Procedure:
4-(1-(3-(Difluoromethyl)phenyl)-2,5-dioxo-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)benzonitrile (example 11, 100 mg, 0.26 mmol) is added to a suspension of sodium hydride (60% in mineral oil, 30 mg, 0.74 mmol) in tetrahydrofuran (3.0 mL). After 10 min methanesulfonyl chloride (42 μL, 0.55 mmol) is added and the mixture is heated at 50° C. over night. The mixture is cooled at room temperature, diluted with water (0.5 mL) and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 74 mg; ESI mass spectrum [M+H]+=458; Retention time HPLC: 0.76 min (005_CA01).
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH3:12].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19](C#N)=[CH:18][CH:17]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:3]1[C:4]2[C:5](=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=2)[CH:12]=[C:1]([C:19]2[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[N:2]=1
Reactant: CNC(=O)c1ccc(OC)cc1C
Reactant: COc1ccc(C#N)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cc3cc(OC)ccc3c(Cl)n2)cc1

Procedure:
6-Methoxy-3-(4-methoxyphenyl)isoquinolin-1-one (0.40 g) obtained by reacting N-methyl-4-methoxy-2-methylbenzamide (1.0 g) and 4-methoxybenzonitrile (0.75 g) according to Example 10-1 was reacted with phosphorus oxychloride (10 ml) according to Example 10-2, to give 1-chloro-6-methoxy-3-(4-methoxyphenyl)isoquinoline.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14](Br)[CH2:15][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.O1CCCC1.C([Li])(C)(C)C.CCCCC.[B:42](OC(C)C)([O:47]C(C)C)[O:43]C(C)C>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12](=[CH:11][CH:10]=1)[CH:13]=[C:14]([B:42]([OH:47])[OH:43])[CH2:15][CH2:16]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: BrC1=Cc2ccc(OCc3ccccc3)cc2CC1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OB(O)C1=Cc2ccc(OCc3ccccc3)cc2CC1
Reaction time: 0.17 h

Procedure:
7-Benzyloxy-3-bromo-1,2-dihydro-naphthalene (21.75 g, 0.06900 mol) was azeotroped with toluene (100 mL, 0.9 mol) and dried on the high vacuum for 30 min. This was dissolved in tetrahydrofuran (200 mL, 2 mol), cooled with a dry ice-isopropanol bath under an atmosphere of nitrogen. 1.70 M tert-Butyllithium in pentane (89.3 mL, 0.152 mol) was added slowly, stirred for 10 min. Triisopropyl borate (79.1 mL, 0.345 mol) was added and the mixture was stirred for 1 hour with cooling then brought to r.t. The reaction was quenched with ice-water. The organic layer was separated and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered, concentrated and dried on the high vacuum to give a crude intermediate, 6-(benzyloxy)-3,4-dihydronaphthalen-2-ylboronic acid.
Reaction SMILES: [CH2:1]([C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14](=[O:21])[CH:15]=[C:16]([CH2:19][OH:20])[O:17][CH:18]=1)[CH2:2][CH3:3].CC(C)=[O:28].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[OH2:6].[O:21]=[C:14]1[C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:5]2[CH:22]=[CH:23][CH:24]=[CH:25][C:4]=2[CH2:1][CH2:2][CH3:3])=[CH:18][O:17][C:16]([C:19]([OH:28])=[O:20])=[CH:15]1
Reactant: CCCc1ccccc1OCCCCCOc1coc(CO)cc1=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCCc1ccccc1OCCCCCOc1coc(C(=O)O)cc1=O
Product: O
Yield: 93.3 %

Procedure:
To a stirred solution 3.53 g (10.2 mmole) of the title alcohol of Example 4 in 100 ml of acetone was added dropwise 22.7 ml (ca. 20.4 mmole) of 0.9M Jones reagent. The solution was warmed to 50° and an additional 11.4 ml (10.2 mmoles) of Jones reagent was added. After five hours at room temperature the reaction was quenched with 40 ml of isopropyl alcohol. The insolubles were removed by decanting and the supernatant was concentrated in vacuo. The residue was triturated with ethyl acetate and filtered, and the filtrate was reconcentrated. Recrystallization from ethyl acetate-hexane (2:1 by volume) afforded 1.8 g of the title compound as the monohydrate.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:11].[Li+].[O:13]1[CH2:17]CCC1>O>[C:1]1([CH2:7][C:8](=[O:9])[C:17]([OH:13])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([CH2:7][C:8]([OH:9])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Product: O=C(O)C(=O)Cc1ccccc1
Product: O=C(O)Cc1ccccc1
Temperature: 5 °C
Yield: 72.6 %
Yield: 0.76 %

Procedure:
A 20 mL aliquot of 0.15 mmoles/mL of potassium tricarbonyl [triphenylphosphine] cobaltate was charged to a 100 mL three-neck round bottom flask under nitrogen and cooled to 5° C. Phenylacetyl chloride (0.4 mL; 3.0 mmoles) was added to the flask. The solution containing the preformed cobaltate complex was then charged into a 300 mL autoclave by means of a transfer needle under nitrogen. The autoclave had previously been charged with 12 mmoles (0.287 g) of lithium hydroxide as a suspension in 22.5 mLs tetrahydrofuran and 5 mLs water. The vessel was sealed, flushed with carbon monoxide, pressurized to 900 psig and heated to 90° C. for nine hours. The autoclave was vented and the contents were poured into a 250 mL separatory funnel. The reaction mixture was acidified with 10% hydrochloric acid and then treated with an excess of iodine. The organic phase was diluted with 100 mLs of diethyl ether and the lower aqueous phase was discarded. The organic phase was washed with saturated sodium thiosulfate until the color of iodine was dispelled. The resultant light yellow diethyl ether phase was washed with 10% sodium hydroxide (3×25 mLs) and the organic phase discarded. Acidification of the combined aqueous sodium hydroxide solution followed by re-extraction with diethyl ether (2×75 mLs) gave a clear solution. The solution was dried over MgSO4 and evaporated to give 0.02 mmoles (0.76% yield) of phenylpyruvic acid and 2.18 mmoles (72.6% yield) of phenylacetic acid as identified by mass spectroscopy and comparison to an authentic sample.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:6][NH:7][CH:8]([CH3:10])[CH3:9].COC1C=C(C=CC=1OC)C=O.C(N)(C)C.[OH-].[Na+].[Cl:34][CH:35]([Cl:39])[C:36](Cl)=[O:37]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:6][N:7]([CH:8]([CH3:10])[CH3:9])[C:36](=[O:37])[CH:35]([Cl:39])[Cl:34]
Reactant: COc1ccc(CNC(C)C)cc1OC
Reactant: O=C(Cl)C(Cl)Cl
Agent: COc1ccc(C=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(C)N
Product: COc1ccc(CN(C(=O)C(Cl)Cl)C(C)C)cc1OC
Temperature: 0 °C

Procedure:
A mixture of 126 g N-(3,4-dimethoxybenzyl)-N-isopropyl amine (prepared by condensing 3,4-dimethoxybenzaldehyde and isopropylamine and hydrogenating the conversation product b.p. 77.5°-77.8°/0.03 mbar) and 250 ml of toluene is stirred in a 750 ml 4-neckflask until the amine is dissolved. Then 120 g of 20% sodium hydroxide is added thereto and the reaction-mixture is cooled in a CO2 /alcohol bath to a temperature of -10°/-15°. A mixture of 89 g of dichloroacetic acid chloride in 100 ml of toluene is then added dropwise while stirring to the cold reaction mixture. A white precipitate forms immediately. When everything is added, what takes about 11/2hours, the cooling bath is removed and the reaction mixtured is stirred until room temperature has been reached. Then it is poured into an ice-water mixture. The phases are separated and the water-phase is extracted with toluene. The organic layer is then washed twice with 1N hydrochloric acid and twice with water, dried and concentrated. There remain 176 g (91.7% of the theory) or a clear sticky oil with a refraction index of nD22 1.5495 which eventually crystallizes m.p. 69°-72°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=[CH:6][C:5]=1[OH:29].[C:31](=[O:34])([O-])[O-].[K+].[K+].[CH3:37][C:38]([CH3:40])=[O:39]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=[CH:6][C:5]=1[O:29][CH2:16][CH2:15][CH2:14][O:39][C:38]1[CH:40]=[CH:11][C:12]([O:34][CH2:31][C:9]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:13][CH:37]=1
Reactant: O=C([O-])[O-]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(O)c(C(=O)OC)c1
Reactant: CC(C)=O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(OCCCOc2ccc(OCc3ccccc3)cc2)c(C(=O)OC)c1
Yield: 76 %

Procedure:
A mixture of 1 g (2.4 mmol) of 2-hydroxy-5-(octadecyloxy) benzoic acid methyl ester, 0.85 g (2.6 mmol) of 3-[(4-phenylmethoxy)phenoxy]propyl bromide and 0.65 g (4.7 mmol) of potassium carbonate in 40 ml of acetone and 7 ml of DMF was stirred at reflux for 48 hours. The usual workup followed by recrystallization from ethyl acetate-hexane gave 1.2 g (76% yield, mp 81°-83°) of 5-(octadecyloxy)-2-[3-[4-(phenylmethoxy)phenoxy]propoxy]benzoic acid methyl ester.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH:29]1[CH2:44][CH2:45]O)=[O:26])([CH3:23])([CH3:22])[CH3:21].C1(P([N:61]=[N+:62]=[N-:63])(C2C=CC=CC=2)=O)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1>[N:61]([CH2:45][CH2:44][CH:29]1[CH:28]([NH:27][C:25]([O:24][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:26])[CH2:33][CH2:32][CH2:31][N:30]1[C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])=[N+:62]=[N-:63]
Reactant: CC(C)(C)OC(=O)NC1CCCN(C(=O)OCc2ccccc2)C1CCO
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCN(C(=O)OCc2ccccc2)C1CCN=[N+]=[N-]
Temperature: 0 °C

Procedure:
Triphenylphosphine (202 mg) was added to the compound 14 (146 mg), tetrahydrofuran (1 mL), diphenylphosphoryl azide (0.17 mL) and 2.2 mol/L of a solution (0.35 mL) of diethyl azodicarboxylate in toluene with stirring at 0° C. The reaction solution was stirred at room temperature for 1 hour and then concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:3) to obtain the title compound (136 mg) having the following physical properties.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[N:20]1([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[CH:24]=[N:23][CH:22]=[N:21]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)=[CH:33][CH:32]=1
Reactant: O=C(O)c1ccc(-n2cncn2)cc1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(-n2cncn2)cc1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-[1,2,4]triazol-1-yl-benzoic acid. MS: 431.3 (M+H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1.I[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:17]([OH:19])=[O:18])=[CH:14][CH:15]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (78.0 mL of a 0.91 M stock solution, 70.98 mmol) cooled to −78° C. was treated with (4-chloro-phenyl)-acetic acid (5.76 g, 33.8 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (84 mL, 3:1). The resulting solution was stirred at −78° C. for 1 h. Iodomethylcyclopentane (7.45 g, 35.49 mmol) was then added in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). This solution was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (20 mL). The excess solvent was removed in vacuo. The residue was acidified to pH=1 with a 1 N aqueous hydrochloric acid solution. The mixture was then poured into water (150 mL) and extracted with ethyl acetate (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid (6.76 g, 79.1%) as a yellow solid: mp 82-84° C.: EI-HRMS m/e calcd for C14H17ClO2 (M+) 252.0917, found 252.0906.