Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(O)O.[C:4]([CH:7]([CH:9](C(O)=O)O)O)(O)=O.[CH:14]([C:16]1[C@H:21]([C:22]([O:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[N:20]2[C:38](=[O:50])[C@@H:39]([NH:40][C:41](=[O:49])[CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@H:19]2[S:18][CH:17]=1)=[O:15].O.C(OCC)(=O)C>O1CCCC1>[OH:15][CH:14]([C:16]1[C@H:21]([C:22]([O:24][CH:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:23])[N:20]2[C:38](=[O:50])[C@@H:39]([NH:40][C:41](=[O:49])[CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C@H:19]2[S:18][CH:17]=1)[CH2:9][CH:7]=[CH2:4]
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: O=CC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Agent: OBO
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C=CCC(O)C1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
via a tartrate boronate. A mixture of dimethyl (R,R)-2-allyl-1,3,2-dixoaborolane-4,5-dicarboxylate (0.67M in toluene, 1.8 ml, 1.2 mmol) and 0.4 nm molecular sieves (50 mg) was stirred at 20° C. for 10 minutes and then cooled to −70° C., and then a solution of diphenylmethyl (4R, 6R, 7R)-3-formyl-7-phenylacetamidoceph-2-em-4-carboxylate (100 mg, 0.2 mmol) in tetrahydrofuran (0.5 ml) was added dropwise. After 2 h at −70° C. the mixture was warned to 20° C. and water and ethyl acetate were added. The organic layer was dried (MgSO4) and evaporated and the residue purified by chromatography as in part a to give the title compound S-diastereomer, 45 mg (43%), and the R-diastereomer 8 mg (8%).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[N:6]=1.[Cl:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[Cl:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:18]
Reactant: Cc1nc(-c2ccc(N)cc2)cs1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccc(NC(=O)c3ccc(Cl)cc3Cl)cc2)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(2-methylthiazol-4-yl)aniline (0.05 g, 0.26 mmol) and 2,4-dichlorobenzoic acid (0.05 g, 0.26 mmol) in dimethylformamide (20 mL) and diisopropylethylamine (0.067 g, 0.09 mL, 0.52 mmol) at room temperature was added HATU (0.148 g, 0.39 mmol) in one portion. The reaction was stirred at room temperature for 4 hours, then poured in to water (200 mL) and stirred for 20 minutes. The product (0.094 g, 100%) as a light yellow solid was collected via filtration. LC-MS (M+H): 364. 1H NMR (400 MHz, dmso-d6): 10.67 (s, 1H), 7.95 (d, 2H), 7.87 (s, 1H), 7.80-7.77 (m, 3H), 7.69-7.58 (m, 2H), 2.74 (s, 3H).
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][CH2:5]NN1.C(N)CCC.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1CCN>CN(C)C=O>[ClH:1].[S:13]1[C:14]2[CH2:15][CH2:16][NH:2][CH2:7][C:6]=2[CH:5]=[CH:17]1
Reactant: C1CNNNC1
Reactant: NCCc1cccs1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCCCN
Product: c1cc2c(s1)CCNC2
Temperature: 45 °C
Yield: 65 %

Procedure:
To 73 ml dimethylformamide heated at 45° C. in which are dissolved 0.45 mole gaseous hydrochloric acid, is added, over 25 minutes, a mixture of 17 g (0.2 M) s.hexahydrotriazine of n. n.butylamine/and 26 g 2-(2-thienyl)ethylamine. The temperature of the medium is maintained at 45° C. throughout the addition by means of a cold water bath. The desired product precipitates out at the end of the addition. Filtration gives 22.16 g 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (Yield: 65%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11](Cl)=[O:12])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].[CH3:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>N1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([N:22]2[CH2:23][CH2:24][CH:19]([CH3:18])[CH2:20][CH2:21]2)=[O:12])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: COc1cc(C=CC(=O)Cl)ccc1OC(C)=O
Reactant: CC1CCNCC1
Solvent: c1ccncc1
Product: COc1cc(C=CC(=O)N2CCC(C)CC2)ccc1OC(C)=O

Procedure:
Using 5.09 g of 4-acetoxy-3-methoxycinnamoyl chloride, 2.4 ml of 4-methylpiperidine, and 100 ml of pyridine, a reaction similar to that conducted in Example 53 was carried out. As a result, 5.2 g of 1-(4-acetoxy-3-methoxycinnamoyl)-4-methylpiperidine (a compound of the present invention) was obtained as an orange-yellow oil, which had the following physiochemical properties:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[CH2:9][CH:10]=[CH2:11])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([O:12][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24])[CH2:9][CH:10]=[CH2:11])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(O)c1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCC(O[Si](C)(C)C(C)(C)C)c1cccc(Br)c1

Procedure:
A solution of 1-(3-bromophenyl)but-3-en-1-ol (17.0 g, 74.9 mmol), 1H-imidazole (11.8 g, 172.2 mmol) and tert-butyldimethylchlorosilane (13.9 g, 89.8 mmol) in DMF (40 mL) is stirred at room temperature for 2 hours. The mixture is diluted with dichloromethane and is washed sequentially with water and saturated ammonium chloride aqueous solution. The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The crude product is purified by silica gel chromatography eluting with 5% ethyl acetate in hexanes to give the title compound as racemic mixture (23.9 g, 94%). 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.34 (d, 1H, J=7.5 Hz), 7.24-7.14 (m, 2H), 5.78-5.70 (m, 1H), 5.02-4.97 (m, 2H), 4.65-4.62 (m, 1H), 2.45-2.31 (m, 2H), 0.87 (s, 9H), 0.02 (s, 3H), 0.12 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[C:32]=3[NH:31][CH:30]=[C:29]4[CH2:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[C:32]=3[NH:31][CH:30]=[C:29]4[CH2:33][CH2:34][C:35]([OH:37])=[O:36])[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)c[nH]c34)no2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Yield: 84.9 %

Procedure:
Trifluoroacetic acid (0.32 mL) was added to a solution of 1,1-dimethylethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D7) (40 mg) in dichloromethane (0.5 mL) at RT for 1 hour. The reaction mixture was concentrated. The residue was recrystallized from dichloromethane/ether to afford 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E1) (30 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 2.65 (2H, q), 3.01 (2H, t), 4.91 (1H, m), 7.22 (1H, t), 7.28 (1H, d), 7.46 (1H, d), 7.83 (1H, d), 7.95 (1H, dd), 8.21 (1H, dd), 8.39 (1H, d), 10.86 (1H, s), 12.12 (1H, br s). MS (ES): C22H20ClN3O4 requires 425; found 425.9 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[C:19]([NH:27][C:28]2[N:37]=[CH:36][C:35]3[N:34]([CH3:38])[C:33](=[O:39])[CH2:32][N:31]([CH:40]([CH3:42])[CH3:41])[C:30]=3[N:29]=2)[CH:20]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:22]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C:13](=[O:15])[NH:16][C:17]2[CH:22]=[C:21]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:20]=[C:19]([NH:27][C:28]3[N:37]=[CH:36][C:35]4[N:34]([CH3:38])[C:33](=[O:39])[CH2:32][N:31]([CH:40]([CH3:42])[CH3:41])[C:30]=4[N:29]=3)[CH:18]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(N)cc(S(C)(=O)=O)c3)nc21
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)C1
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(NC(=O)[C@H]4CCN(C(=O)OC(C)(C)C)C4)cc(S(C)(=O)=O)c3)nc21
Yield: 32 %

Procedure:
The (S)-enantiomer was prepared with the same procedure used for the (R)-enantiomer and described in Scheme 12 starting from (S)pyrrolidine-1,3-dicarboxylic acid tert butyl ester (33 mg; 0.154 mmol) and 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (40 mg; 0.102 mmol), 19 mg (0.032 mmol; 32% yield) of the desired compound were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[N+:22]([O-])([OH:24])=[O:23]>>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[N:5]=[C:6]([OH:8])[C:7]([N+:22]([O-:24])=[O:23])=[C:2]([OH:1])[N:3]=2)=[CH:10][CH:11]=1
Reactant: Oc1cc(O)nc(-c2ccc(F)cc2)n1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1c(O)nc(-c2ccc(F)cc2)nc1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 68 %

Procedure:
4,6-dihydroxy-2-(4-fluorophenyl)pyrimidine (11 g, 53 mmol) described in European patent No. 136976A was gradually added to fuming nitric acid (100 mL) at 0° C. The reaction temperature was raised to room temperature, and the mixture was stirred for 15 hours. The reaction mixture was poured onto ice-water (150 mL), and then neutralized with sodium carbonate at 0° C. The resulting precipitate was collected by filtration and dried to give the objective compound as a solid (9.2 g, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](=[O:9])N[C:5](=[O:6])[C:4]=1[O:10][CH3:11].[OH-:12].[Na+]>>[CH3:1][O:2][C:3]1=[C:4]([O:10][CH3:11])[C:5]([O:9][C:8]1=[O:12])=[O:6]
Reactant: [OH-]
Reactant: COC1=C(OC)C(=O)NC1=O
Agent: [Na+]
Product: COC1=C(OC)C(=O)OC1=O

Procedure:
555 g of dimethoxymaleimide in 2 l of 5% strength NaOH were stirred for 2 days at room temperature. Thereafter, the mixture was acidified and extracted thoroughly with methylene chloride. After the organic phase had been separated off and the solvent removed in a rotary evaporator, 486 g of a product of melting point 41°-43° C. remained.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[CH2:18][CH2:17][C:16]2[C:7](=[C:8]([N:19]=CN(C)C)[C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]1=O)C.[CH3:25][NH:26]N>CCO>[NH2:19][C:8]1[C:9]2[C:14]([N:15]=[C:16]3[C:7]=1[C:6]1[N:26]([CH3:25])[N:2]=[CH:4][C:5]=1[CH2:18][CH2:17]3)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CNN
Reactant: CN(C)C=Nc1c2c(nc3ccccc13)CCC(=CN(C)C)C2=O
Solvent: CCO
Product: Cn1ncc2c1-c1c(nc3ccccc3c1N)CC2

Procedure:
3,4-Dihydro-2-[(dimethylamino)methylene]-9-[[(dimethylamino)methylene]amino]acridin-1-(2H)-one (3.0 g) was refluxed for 60 min in 150 mL of EtOH containing 8.0 g of methylhydrazine. At the end of this time the solvent was evaporated under reduced pressure and then the residue was adhered to silica with MeOH. Purification by flash chromatography (toluene:MeOH:Et3N, 19:1:1) gave 1.71 g of material which was pure to TLC. This was combined with the product of another run of smaller size and recrystallized from toluene to give analytically pure product, mp 240° (d).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([O:15]C)[C:9]([O:13]C)=[CH:10][CH:11]=2)[C:6](=[O:17])[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:4]1)[CH3:2].B(Br)(Br)Br.CCO>ClCCl>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([OH:15])[C:9]([OH:13])=[CH:10][CH:11]=2)[C:6](=[O:17])[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2ccc(OC)c(OC)c2c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2ccc(O)c(O)c2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a brown solution of ethyl 1-ethyl-5,6-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (6 g, 19.65 mmol) in Dichloromethane (DCM) (100 mL) was added BBr3 (6.13 mL, 64.8 mmol) dropwise and the mixture was stirred at r.t. overnight. The resulting mixture was carefully poured into EtOH (50 mL) at −40° C. and the mixture was stirred at r.t. over the weekend. The precipitates were collected by filtration and washed with DCM and MeOH. The filtrate was concentrated a bit, the precipitates were collected and washed by DCM. The solids were combined to afford ethyl 1-ethyl-5,6-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (5 g, 9.02 mmol, 45.9% yield) as a yellow solid that contained also some 1-ethyl-5,6-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. This mixture was directly used in the next step without further purification. LCMS: (M+H)+: 278.4 (ester); 250.3 (acid).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[C:7]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)=[C:6]([O:19][CH2:20][CH3:21])[CH:5]=1.Cl>CO.C1COCC1.[OH-].[Na+]>[CH2:20]([O:19][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][CH3:12])[C:7]=1[C:13]1[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=1)[C:3]([OH:22])=[O:2])[CH3:21]
Reactant: CCOc1cc(C(=O)OC)cc(OCC)c1-c1cnn(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc(C(=O)O)cc(OCC)c1-c1cnn(C)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
3,5-Diethoxy-4-(1-methyl-1H-pyrazol-4-yl)-benzoic acid methyl ester (895 mg) was dissolved in a mixed methanol/THF solution (16 mL, 5/3), aqueous 1 M NaOH solution (6 mL) was added to it, and stirred at 50° C. for 5 hours. The reaction liquid was cooled to room temperature, and aqueous 1 M HCl solution (6 mL) was added to it, and the solvent was evaporated away under reduced pressure. The resulting solid was taken out through filtration, washed with water and ether, and dried under reduced pressure to obtain the title compound as a pale yellow solid.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[N:10]=[CH:9][C:8]([C:12]#[N:13])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C>CS(C)=O>[O:1]=[C:2]1[C:11]2[N:10]=[CH:9][C:8]([C:12]#[N:13])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: N#Cc1cnc2c(c1)CCCC2O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: N#Cc1cnc2c(c1)CCCC2=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of 8-hydroxy-5,6,7,8-tetrahydroquinoline-3-carbonitrile (555 mg, 3.19 mmol) in DMSO (15 ml) at 23° C. was added triethylamine (1.93 g, 2.66 ml, 19.1 mmol) and sulphur trioxide-pyridine complex (1.52 g, 9.56 mmol). The brown solution was stirred at 23° C. for 2 hours. The reaction mixture was poured on water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give of a light brown solid, which was purified by silica gel flash chromatography with dichloromethane/methanol to give the 8-oxo-5,6,7,8-tetrahydroquinoline-3-carbonitrile (286 mg, 1.66 mmol, 52.1% yield) as a light yellow solid. MS (ISP): m/z=173.1 [(M+H)+].
Reaction SMILES: P(OCCCC)(OCCCC)OCCCC.[Cl-].[Cl-].C([Al+2])C.[CH:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:28]=[CH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>ClC1C=CC=CC=1.C(C(CCCC)C([O-])=O)C.C(C(CCCC)C([O-])=O)C.[Ni+2]>[CH2:39]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH3:28]
Reactant: C=CCCCCCCCCCC
Reactant: c1ccccc1
Agent: [Ni+2]
Agent: CCCCC(CC)C(=O)[O-]
Agent: CCCCOP(OCCCC)OCCCC
Solvent: Clc1ccccc1
Product: CCCCCCCCCCCCc1ccccc1

Procedure:
8.4 Grams of hexenes (containing 90% n-hexenes and 10% methyl-pentenes) was reacted with 17 mgs of nickel bis(2-ethyl hexanoate), 13 mgs of tributyl phosphite and 64 mgs of ethyl aluminum dichloride in 0.8 g of chlorobenzene. After two hours of reaction at between 35 and 45C, 57% of the hexenes were converted to products which contained 90% dodecenes. 78% of those dodecenes had linear or mono-branched structures. The unreacted starting material consisted of 86% n-hexenes and 14% methyl-pentenes, indicating only a very slight preference by the catalyst for dimerizing the linear olefins. As in Example 1, alkylation of benzene with this dodecene mixture using HF catalyst resulted in a 95+ % yield of dodecylbenzene, with less than 1% loss due to olefin fragmentation.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:15]([CH3:31])[C:16](=[O:30])[CH2:17][N:18]([CH2:27][C:28]#[N:29])[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[Li+].[OH-].FC(F)(F)C(O)=[O:37]>O1CCCC1.O>[NH2:29][C:28](=[O:37])[CH2:27][N:18]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[CH2:17][C:16]([N:15]([C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:31])=[O:30]
Reactant: CN(C(=O)CN(CC#N)c1ccc(Cl)c(Cl)c1)[C@@H](CN1CCCC1)c1ccc(Br)cc1
Reactant: O=C(O)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)CN(CC(N)=O)c1ccc(Cl)c(Cl)c1)[C@@H](CN1CCCC1)c1ccc(Br)cc1
Temperature: 77 °C
Reaction time: 0.08 h

Procedure:
N1-[(1R)-1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethyl]-N2-(cyanomethyl)-N2-(3,4-dichlorophenyl)-N1-methylglycinamide (6.1 g, crude) was dissolved in 25 mL of tetrahydrofuran and treated with a solution of LiOH (3.14 g, 74.9 mmol) suspended in 10.8 mL of water. The reaction was stirred vigorously and allowed to reflux at 77° C. for 24 hours before it was determined to be complete by LCMS (Eclipse XDB C18 (4.6×250 mm); trifluoroacetic acid: 1-99% B for 10 min, ES) Rt=7.8 min and m/e 543 [M+1]+. The solvent was removed by rotary evaporation and the crude residue was purified by silica gel chromatography (330 g Redisep column, silica, 40 um, 60 Å, 90 mL/min, A: methylene chloride, B: methanol, B: 0% for 5 min, 10% for 60 min; detection at 214 nm) to give 2-[(2-amino-2-oxoethyl)(3,4-dichlorophenyl)amino]-N-[(1R)-1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethyl]-N-methylacetamide (2.82 g, 5.2 mmol). MS (ES) m/e 543 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15].[CH:20]([O:23][C:24]1[C:31]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:30][C:27]([CH:28]=[O:29])=[C:26]([N+:36]([O-:38])=[O:37])[CH:25]=1)([CH3:22])[CH3:21].C(O)(=O)C>O1CCCC1.O>[CH:20]([O:23][C:24]1[C:31]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:30][C:27]([CH:28]([OH:29])[C:15]#[C:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])=[C:26]([N+:36]([O-:38])=[O:37])[CH:25]=1)([CH3:21])[CH3:22]
Reactant: CC(C)Oc1cc(C=O)c([N+](=O)[O-])cc1OC(C)C
Reactant: C#CC(=O)OCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C#CC(O)c1cc(OC(C)C)c(OC(C)C)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 114.2 %

Procedure:
To a solution of diisopropylamine (5.0 ml, 36.0 mmol) in tetrahydrofuran (75 ml) was added, at -78° C. under an argon atmosphere, a 1.5 N butyllithium (22.6 ml, 33.8 mmol). The mixture was stirred for one hr. Ethyl propiolate (2.9 ml, 28.2 mmol) and a solution of 4,5-diisopropoxy-2-nitrobenzaldehyde (5.0 g, 18.7 mmol) in tetrahydrofuran (50 ml) were added in that order, and the mixture was stirred at -78° C. for additional 1.5 hr. A solution of acetic acid (5.9 ml, 102 mmol) in tetrahydrofuran (20 ml) was then added to the reaction mixture, water was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, water, a saturated aqueous sodium bicarbonate solution, and saturated brine in that order. It was then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The resultant mixture was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give ethyl 4-(4,5-diisopropoxy-2-nitrophenyl)-4-hydroxy-2-butynoate (7.80 g). Ethyl 4-(4,5-diisopropoxy-2-nitrophenyl)-4-hydroxy-2-butynoate thus obtained was dissolved in toluene (60 ml), 4-methoxybenzylazide (10.5 g, 64.4 mmol) was added thereof, and the mixture was stirred at 100° C. for 9 hr. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give a 1:1 mixture of ethyl 4-(1-hydroxy-(4,5-diisopropoxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate (a-1: low polar product (LP)) and ethyl 5-(1-hydroxy-(4,5-diisopropoxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate (a-2: high polar product (MP)) (5.34 g, 54%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([NH:21][OH:22])([CH3:20])([CH3:19])[CH3:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[N+:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[O-:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)NO
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)[N+]([O-])=Cc1ccc(OCc2ccccc2)cc1
Yield: 89.3 %

Procedure:
A mixture of 4-benzyloxybenzaldehyde, N-tert-butylhydroxylamine and catalytic amount of p-toluenesulfonic acid monohydrate in benzene was refluxed under argon atmosphere with a Dean-Stark trap to remove generated water. The mixture was then rotary evaporated to give a residue which was purified by recrystallization. The title compound was obtained in 89.3% yield as a white powder, m.p. 111.0° C. (Rf=0.66 on a silica gel plate using EtOAc as an eluant).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][C:4]=1F.[C:17](=O)(O)[O-:18].[Na+]>CO>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][C:4]=1[O:18][CH3:17]
Reactant: O=C([O-])O
Reactant: O=S(=O)(c1ccc(Br)c(F)c1)C1CCC1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1cc(S(=O)(=O)C2CCC2)ccc1Br
Temperature: 60 °C
Reaction time: 10 h
Yield: 87 %

Procedure:
Sodium (235 mg, 10.2 mmol) was added to MeOH (6 mL) under nitrogen and the mixture stirred until all the sodium had reacted. 1-bromo-4-(cyclobutylsulfonyl)-2-fluorobenzene (Preparation 28, 300 mg, 1.02 mmol) was added and the mixture stirred at 60° C. for 10 hours. 2% aqueous sodium bicarbonate (36 mL) was added and the mixture extracted with EtOAc (2×36 mL), the organic layers dried over sodium sulphate and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography eluting with CH2Cl2/EtOAc 3:1 to provide the title compound as a white solid 87% yield, 270 mg.