Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N:11]1([CH2:16][C:17]#[N:18])[CH:15]=[N:14][CH:13]=[N:12]1.O>C1(C)C=CC=CC=1.N1CCCCC1>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[C:16]([N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[C:17]#[N:18]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: N#CCn1cncn1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: O
Product: N#CC(=Cc1ccc(Cl)cc1Cl)n1cncn1
Yield: 30 %

Procedure:
138.9 g (790 millimoles) of 2,4-dichlorobenzaldehyde, 76.7 g (710 millimoles) of 2-(1,2,4-triazol-1-yl)-acetonitrile and 1 g of piperidine in 1 l of toluene are heated at the boil under a water separator until 1 equivalent of water has been separated off. The mixture is then left to cool, and the precipitated crystals are filtered off under suction. They can be purified by recrystallization from toluene. 56.5 g (30% of theory) of 3-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-acrylonitrile of melting point 156°-160° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([CH2:17][C:18]([OH:20])=O)[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:25]=1[NH:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([CH2:17][C:18]([N:26]([CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:25]2[C:35]([CH3:39])=[CH:36][CH:37]=[CH:38][C:24]=2[CH3:23])=[O:20])[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCNc1c(C)cccc1C
Reactant: Cc1cccc(C)c1N(CC(=O)O)C(=O)c1ccc(Cl)cc1
Product: CCOC(=O)CCCN(C(=O)CN(C(=O)c1ccc(Cl)cc1)c1c(C)cccc1C)c1c(C)cccc1C

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-2-(2,6-dimethylanilino)acetic acid and ethyl 4-(2,6-dimethylanilino)butyrate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-2-(2,6-dimethylanilino)acetyl]-4-(2,6-dimethylanilino)butyrate (M.P. 150° to 151°), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-2-(2,6-dimethylanilino)acetyl]-4-(2,6-dimethylanilino) butyric acid (M.P. 214° to 216°).
Reaction SMILES: O=[C:2]1[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH:2]2[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])[CH2:3]2)[CH2:19][CH2:18]1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: CN1CCN(C2CN(C(=O)OCc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
A mixture of benzyl 3-oxoazetidine-1-carboxylate (1.026 g, 5 mmol), 1-methylpiperazine (0.833 mL, 7.50 mmol) and acetic acid (0.429 mL, 7.50 mmol) in 1,2-dichloroethane (5 mL) was stirred at room temperature for 3 h. sodium triacetoxyborohydride (2.119 g, 10.00 mmol) was added and the reaction mixture was stirred at room temperature overnight. A small amount of water was added to the reaction mixture and the reaction mixture was directly loaded onto a 120 g ISCO column and eluted with 1-12% 2N ammonia in methanol/dichloromethane). benzyl 3-(4-methylpiperazin-1-yl)azetidine-1-carboxylate (1.45 g) was obtained as a brown oil.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][C:8]1[N:9]2[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[N:13]=[C:10]2[S:11][CH:12]=1.[CH2:19](O)[CH3:20]>C(Cl)Cl.O>[CH3:7][C:8]1[N:9]2[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:13]=[C:10]2[S:11][CH:12]=1
Reactant: CCO
Reactant: Cc1csc2nc(C(=O)O)cn12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cn2c(C)csc2n1

Procedure:
To a solution of 6.3 g of phosphorus pentachloride in 120 ml of dry methylene chloride, 5 g of 3-methyl-imidazo-(2,1-b)thiazole-6-carboxylic acid(prepared as described in Example 10) is added and the suspension obtained is refluxed for 3 hours. After vacuum evaporation of the solvent the residue obtained being 3-methyl-imidazo-(2,1-b)thiazole-6-carboxylchloride chlorohydrate is dissolved in 100 ml of abs.ethanol and the solution is refluxed for 4 hours. The solvent is removed and the residue obtained is dissolved in water. The solution obtained is neutralised to pH 7.5 to yield 5 g of 3-methyl-6-carboethoxyimidazo-(2,1-b)thiazole; m.p. 117°-119°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:15][C:16]([O:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C1COCC1>[C:20]1([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:18][C:16]([CH2:15][N:5]2[CH:6]=[CH:7][C:2](=[O:1])[CH:3]=[CH:4]2)=[O:17])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Oc1ccncc1
Reactant: O=C(CBr)OC(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Cn1ccc(=O)cc1)OC(c1ccccc1)c1ccccc1
Yield: 68.9 %

Procedure:
1.37 g of 4-hydroxypyridine was dissolved in 16 ml of THF, then 1.63 g of potassium tert-butoxide was added and reacted overnight. Thereafter, 3.12 g of diphenylmethyl bromoacetate was added and reacted for 6 hours. After the reaction, the solvent was removed, the residue was dissolved in chloroform and washed with water. This was dried over magnesium sulfate, the solvent was removed, and the residue was purified on silica gel chromatography using chloroform-methanol (20:1) to obtain 2.25 g of the title compound (55%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].[OH-].[K+].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>COCCOC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(C[C@H]3CCCN3C)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a stirred solution of (R)-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (10.0 g, 34.1 mmol) in ethyleneglycol dimethylether (50 ml) at 0° C. under a nitrogen atmosphere was added potassium hydroxide flake (9.58 g, 171 mmol) in one portion. Para-toluenesulfonyl chloride (6.83 g, 35.8 mmol) was then added portionwise to the brown slurry over a 5 min period, maintaining the temperature below 5° C. The brown slurry was then warmed to ambient temperature and stirred for a further 2 hr. The mixture was then filtered in vacuo and the filter cake washed with toluene (2×100 ml). The filtrate was then concentrated in vacuo to approximately 20 ml volume which resulted in precipitation of a cream solid. After stirring for 2 hr, the solid was filtered and dried in vacuo at 50° C. for 12 hr to give the title compound (9.91 g, 65%) as a beige solid. m.p. 98-104° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]([CH3:17])([O:11][O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:10])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26]>C(OCC)C>[C:25](=[O:26])([O:27][CH2:28][CH2:29][CH2:30][CH3:31])[O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][C:9]([CH3:17])([O:11][O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:10]
Reactant: CC(CCO)CCCC(C)(C)OOC(C)(C)C
Reactant: CCCCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCOC(=O)OCCC(C)CCCC(C)(C)OOC(C)(C)C

Procedure:
To a solution of 7.9 g (0.03 mole) of 3,7-dimethyl-7(t-butylperoxy)octyl alcohol and 2.4 g (0.03 mole) of pyridine in diethyl ether cooled at 10°±1° C was added a solution of 4.09 (0.03 mole) of n-butyl chloroformate in diethyl ether. The reaction temperature was maintained at 15°±1° C during the addition.
Reaction SMILES: NC1C=C2C(C=CN2)=CC=1.[CH3:11][NH:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][N:19]2[CH3:22])=[CH:15][CH:14]=1.C(N(CC)CC)C.[CH2:30]([O:37][C:38](Cl)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:11][NH:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][N:19]2[CH3:22])=[CH:15][CH:14]=1.[CH2:30]([O:37][C:38](=[O:39])[N:12]([CH3:11])[C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][N:19]2[CH3:22])=[CH:15][CH:14]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CNc1ccc2ccn(C)c2c1
Agent: Nc1ccc2cc[nH]c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)OCc1ccccc1)c1ccc2ccn(C)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
N-Methyl-(1-methyl-1H-indol-6-yl)-amine was prepared from 6-amino indole in a manner similar to that described in Example 1 a. c) Methyl-(1-methyl-1H-indol-6-yl)-amine (50 mg, 0.33 mmole) was dissolved in methylene chloride (2 mL) and cooled to 0° C. Triethylamine (55 μl, 0.39 mmole) was added followed by benzylchloroformate (52 μL, 0.39 mmnole). The reaction was stirred at room temperature for 1 hr. The reaction mixture was washed with 0.1 N hydrochloric acid and the organic was dried over magnesium sulfate, filtered and concentrated. The product was purified by column chromatography in 25% ethyl acetate/hexane to give methyl-(1-methyl-1H-indol-6-yl)-carbamic acid benzyl ester (67 mg, 73%).
Reaction SMILES: C([CH:3]1[CH2:29][CH2:28][CH2:27][CH:26]2[N:4]1[C:5](=[O:72])[C:6](=[O:71])[C:7]1([OH:70])[O:66][CH:11]([CH:12]([O:64][CH3:65])[CH2:13][CH:14]([CH3:63])[CH2:15][C:16]([CH3:62])=[CH:17][CH2:18][C:19](=[O:61])[CH2:20][CH:21]([O:53][Si:54]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55])[CH:22]([CH3:52])[CH:23]([C:31]([CH3:51])=[CH:32][CH:33]3[CH2:38][CH2:37][CH:36]([O:39][CH2:40][CH:41]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[OH:42])[CH:35]([O:49][CH3:50])[CH2:34]3)[O:24][C:25]2=[O:30])[CH:10]([O:67][CH3:68])[CH2:9][CH:8]1[CH3:69])C.C[N+]1([O-])CCO[CH2:76][CH2:75]1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:75]([CH:18]1[CH:17]=[C:16]([CH3:62])[CH2:15][CH:14]([CH3:63])[CH2:13][CH:12]([O:64][CH3:65])[CH:11]2[O:66][C:7]([OH:70])([CH:8]([CH3:69])[CH2:9][CH:10]2[O:67][CH3:68])[C:6](=[O:71])[C:5](=[O:72])[N:4]2[CH:26]([CH2:27][CH2:28][CH2:29][CH2:3]2)[C:25](=[O:30])[O:24][CH:23]([C:31]([CH3:51])=[CH:32][CH:33]2[CH2:38][CH2:37][CH:36]([O:39][CH2:40][C:41]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:42])[CH:35]([O:49][CH3:50])[CH2:34]2)[CH:22]([CH3:52])[CH:21]([O:53][Si:54]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:55])[CH3:56])[CH2:20][C:19]1=[O:61])[CH3:76]
Reactant: C[N+]1([O-])CCOCC1
Reactant: CCC1CCCC2C(=O)OC(C(C)=CC3CCC(OCC(O)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC(=O)CC=C(C)CC(C)CC(OC)C3OC(O)(C(=O)C(=O)N12)C(C)CC3OC
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(=O)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Yield: 77.1 %

Procedure:
To solution of 17 ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2"'-phenyl-2"'hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (13 mg in 0.3 mL methylene chloride) was added powdered 4A molecular sieves (10 mg), 4-methylmorpholine N-oxide (6.0 mg), tetrapropylammonium perruthenate (1.0 mg) and the reaction stirred at room temperature. After 30 minutes the mixture was filtered through a small diatomaceous earth/silica gel plug and the filtrate concentrated in vacuo. Purification by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (10 mg).
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][C:11](=[C:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]2)C=CC=CC=1>C(O)(=O)C>[NH:8]1[CH2:13][CH2:12][CH:11]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]1
Reactant: CCOC(=O)C(C)=C1CCN(Cc2ccccc2)CC1
Solvent: CC(=O)O
Product: CCOC(=O)C(C)C1CCNCC1
Reaction time: 18 h

Procedure:
Dissolve 2-[1-(phenylmethyl)-4-piperidinylidene]propanoic acid, ethyl ester (1.5 g, 5.5 mmol) in acetic acid (50 mL).and place in a Paar hydrogenation flask. Add 10% palladium(C) (500 mg). Charge the vessel to 50 psi and shake for 18 hours. Filter the solution through Celite and remove the solvent in vacuo to give 2-(4-piperidyl)propanoic acid, ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([C@@H:18]1[CH2:20][O:19]1)[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[CH3:22][NH2:23]>>[C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17])[C@@H:18]([OH:19])[CH2:20][NH:23][CH3:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)[C@@H]1CO1
Reactant: CN
Product: CNC[C@H](O)[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-(2,5-difluoro-phenyl)-ethyl]carbamic acid tert-butylester (0.17 g, 0.57 mmol) and methylamine (7 mL, 2M solution in methanol, 14 mmol; used as solvent) gives the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)=[O:6].[C:19](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(#N)C>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([O:16][CH3:19])=[O:15])=[CH:9][CH:8]=1)=[O:6]
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)CCCCl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: COS(=O)(=O)OC
Product: COC(=O)C(C)(C)c1ccc(C(=O)CCCCl)cc1
Yield: 89.5 %

Procedure:
Mix 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic acid (10.0 g, 37.3 mmol) and anhydrous potassium carbonate (3.5 g, 25.3 mmol). Heat to 40° C. in acetonitrile (100 mL) and stir under a nitrogen atmosphere. Add dimethyl sulfate (13.3 g, 105 mmol) and reflux for 45 minutes. Evaporate the solvent in vacuo, dissolve the residue in ethyl acetate (50 mL) and wash with water (4×50 mL). Dry (MgSO4), filter through silica gel and evaporate the solvent in vacuo to give the title compound (6.4 g, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[CH3:12].[CH2:13]([O:15][C:16](=[O:33])[CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24](SC2C=CC=CC=2)=[O:25])[CH2:20][CH2:19]1)[CH3:14]>COCCOC.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].S1C=CC=C1C([O-])=O.[Cu+]>[CH2:13]([O:15][C:16](=[O:33])[CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:25])[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:12])[CH:5]=2)[CH2:20][CH2:19]1)[CH3:14]
Reactant: CCOC(=O)CN1CCC(C(=O)Sc2ccccc2)CC1
Reactant: COc1ccc(B(O)O)cc1C
Agent: [Cu+]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CCC(C(=O)c2ccc(OC)c(C)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.2 %

Procedure:
To a mixture of 4-methoxy-3-methyl phenylboronic acid (0.32 g, 1.95 mmol), ligand TFP (0.06 g, 0.26 mmol), Pd2dba3 (0.12 g, 0.13 mmol), copper (I) thiophene-2-carboxylate (0.37 g, 2.0 mmol) was added a solution of (4-phenylsulfanylcarbonyl-piperidin-1-yl)-acetic acid ethyl ester (0.4 g, 1.3 mmol) in 6 mL of DME. It was stirred at RT for 16 hours, the reaction mixture was diluted with ethyl acetate, filtered through celite then concentrated in vacuo. Purification by flash chromatography gave the title compound (0.2 g, 0.6 mmol). MS (ESI) m/z 319.8 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.36 min.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[CH3:30])=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=1>>[C:10]1([C:1]2[CH:6]=[CH:5][CH:4]=[C:3]([C:17]3[CH:22]=[CH:21][C:20](/[C:23](/[CH3:30])=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=3)[CH:2]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Reactant: CCOC(=O)/C=C(\C)c1ccc(Br)cc1
Product: CCOC(=O)/C=C(\C)c1ccc(-c2cccc(-c3ccccc3)c2)cc1
Yield: 67.7 %

Procedure:
(E)-Ethyl 3-[1,1′;3′,1″]terphenyl-4″-yl-but-2-enoate (1.02 g, 68% yield) was prepared from 3-biphenylboronic acid (1.31 g, 6.60 mmol) and (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (1.0 g, 4.40 mmol) by a procedure analogous to that described in example 52 a.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[C:10](Cl)(=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].Cl>C1C=CC=CC=1>[CH3:9][O:8][C:6]([C:2]1[NH:1][CH:5]=[C:4]([C:10](=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:3]=1)=[O:7]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: COC(=O)c1ccc[nH]1
Agent: Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCC(=O)c1c[nH]c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.7 %

Procedure:
To a solution (5 ml) of 1.25 g (10 mmol) of methyl pyrrole -2-carboxylate in benzene was added 2.71 g (11 mmol) of tetradecanoyl chloride under ice-cooling, followed by adding 1.73 ml) (15 mmol) of stannic chloride dropwise thereto. The mixture was stirred for 2 hours at room temperature, treated with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the product was purified by subjecting it to column chromatography over silica gel (ethyl acetate/hexane=1/7) to obtain 1.80 g (54% yield) of methyl-4-tetradecanoylpyrrole-2-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4](O)[N:3]=1.P(Cl)(Cl)([Cl:12])=O>>[CH3:1][C:2]1[N:3]=[C:4]([Cl:12])[CH:5]=[C:6]([CH3:8])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)nc(C)n1
Product: Cc1cc(Cl)nc(C)n1

Procedure:
2,4-Dimethyl-6-hydroxypyrimidine (20 g) was added to phosphorus oxychloride (120 ml) and the mixture was refluxed for 2 hours. Excess phosphorus oxychloride was removed in vacuo, water was added and the product was extracted into dichloromethane (2×200 ml), dried (Na2SO4) and the solvent removed to give 2,6-dimethyl-4-chloropyrimidine as an oil (21 g) which slowly crystallised on standing; NMR (CDCl3): 2.52 (s, 3H), 2.71 (s, 3H), 7.05 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[CH:3]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([O-])(=O)C.[Na+]>CN(C=O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:16]([O:15][C:11](=[O:14])[CH:12]=[CH:13][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[CH:3]=1)[CH3:17]
Reactant: Brc1ccc2ccoc2c1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C=Cc1ccc2ccoc2c1
Temperature: 100 °C

Procedure:
A mixture of the 6-bromo-benzofuran 6-3 (1.74 g, 8.79 mmol), ethyl acrylate (1.09 g, 10.98 mmol), Pd(OAc)2 (0.099 g, 0.44 mmol), tri-o-tolylphosphine (0.268 g, 0.880 mmol), and sodium acetate (3.60 g, 43.9 mmol) in DMF (10 mL) was heated to 100° C. in a sealed tube for 4 h. The mixture was cooled to room temperature, diluted with water, and extracted with Et2O (2×40 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (10% ethyl acetate/hexanes) to give the ester 6-4 as an off-white solid.
Reaction SMILES: [BH4-].[Li+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:15]2[CH:33]=[CH:32][C:18]([O:19][C:20]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)([CH3:25])[C:21](OC)=[O:22])=[CH:17][CH:16]=2)([CH3:14])[CH:11]([CH3:13])[CH3:12])=[CH:6][CH:5]=1>C1COCC1>[I:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:15]2[CH:16]=[CH:17][C:18]([O:19][C:20]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)([CH3:25])[CH2:21][OH:22])=[CH:32][CH:33]=2)([CH3:14])[CH:11]([CH3:13])[CH3:12])=[CH:8][CH:9]=1
Reactant: COC(=O)C(C)(Oc1ccc(C(C)(c2ccc(I)cc2)C(C)C)cc1)c1ccccn1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C(C)(c1ccc(I)cc1)c1ccc(OC(C)(CO)c2ccccn2)cc1

Procedure:
Lithium borohydride (1 equiv) is added to a stirred solution of 5d (1 equiv) in THF at room temperature. After completion of reaction, the reaction mixture is quenched with 2 N HCl, poured into saturated aqueous sodium bicarbonate and extracted three times with EtOAc. The combined organic extracts are washed with water, brine, dried (Na2SO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel affords the title compound 5e.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[I:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[CH:38]=[CH:37][C:24]([O:25][CH:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=2)([CH3:20])[CH:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1.CN1CCCN(C)C1=O.IC>C1CCCCC1.C1COCC1>[I:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([C:21]2[CH:22]=[CH:23][C:24]([O:25][C:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)([CH3:1])[C:27]([O:29][CH3:30])=[O:28])=[CH:37][CH:38]=2)([CH3:20])[CH:17]([CH3:18])[CH3:19])=[CH:14][CH:15]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C(Oc1ccc(C(C)(c2ccc(I)cc2)C(C)C)cc1)c1ccccn1
Agent: [Li+]
Solvent: CI
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C(C)(Oc1ccc(C(C)(c2ccc(I)cc2)C(C)C)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide mono (THF) (1.2 equiv. of a 5M solution in cyclohexane) is added to a stirred solution of 5c (1 equiv.) in THF at −78° C. After 15 mins, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 equiv.) is added followed by iodomethane (1.5 equiv). After 1 h, the reaction mixture is warmed to room temperature and aged until the reaction is deemed complete. The reaction mixture is quenched with saturated aqueous ammonium chloride, poured into saturated aqueous sodium bicarbonate and extracted three times with EtOAc. The combined organic extracts are washed with water, brine, dried (Na2SO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel affords the title compound 5d.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:21])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:20])=[CH:17]/[CH:18]=O.Cl>O1CCCC1>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:21])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:20])=[CH:17]/[CH:18]=[CH:18]/[CH:17]=[C:16](\[CH3:20])/[CH:15]=[CH:14]/[CH:13]=[C:12](\[CH3:21])/[CH:11]=[CH:10]/[C:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=O)C(C)(C)CCC1
Agent: Cl
Solvent: C1CCOC1
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)CCCC2(C)C)C(C)(C)CCC1
Yield: 19.4 %

Procedure:
A slurry of titanium trichloride (770 mg, 5.0 mmol) in 20 ml dry tetrahydrofuran was prepared under an inert atmosphere (nitrogen or argon), and magnesium turnings (120 mg, 5.0 mmol) were added. The resulting mixture was refluxed overnight to form the Ti(II) reagent, and a solution of retinal (710 mg, 2.5 mmol) in 5 ml dry tetrahydrofuran was added. After refluxing for two hours, the solution was poured into 50 ml 2 N aqueous hydrochloric acid and extracted several times with ether. The ether extracts were combined, washed with saturated aqueous sodium chloride solution, dried sulfate, and concentrated by solvent removal at the rotary evaporator. The residue was purified by chromatography over silica gel. Elution with hexane gave 130 mg (20% yield) beta-carotene identified by thin-layer chromatographic comparison with an authentic sample, and by its characteristic ultraviolet spectrum.