Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[Cl:13][C:14]1[CH:40]=[CH:39][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[C:20]2[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]2)=[O:29])=[CH:16][CH:15]=1.N1(O)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[CH3:60][N:61]1[CH:65]=[CH:64][C:63]([CH2:66][NH2:67])=[N:62]1>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:13][C:14]1[CH:40]=[CH:39][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[C:20]2[C:28]([N:30]2[CH2:31][CH2:32][CH:33]([C:36]([NH:67][CH2:66][C:63]3[CH:64]=[CH:65][N:61]([CH3:60])[N:62]=3)=[O:37])[CH2:34][CH2:35]2)=[O:29])=[CH:16][CH:15]=1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reactant: Cn1ccc(CN)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1ccc(CNC(=O)C2CCN(C(=O)c3cc4ccccc4n3Cc3ccc(Cl)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (259 mg, 1.350 mmol), 1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (428 mg, 1.080 mmol), and 1H-benzo[d][1,2,3]triazol-1-ol (182 mg, 1.350 mmol) were dissolved in 4.0 mL of DCM. The reaction was stirred at room temperature for ten minutes before Hunig's Base (0.236 ml, 1.350 mmol) and (1-methyl-1H-pyrazol-3-yl)methanamine (100 mg, 0.900 mmol) as a 1.0 mL DCM solution was added. The reaction was allowed to stir at room temperature overnight. The reaction was diluted with water and ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate (twice), and saturated sodium chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated. The resulting material was triturated with ethyl acetate to obtain white solid as the product. 1H-NMR (400 MHz, DMSO-d6) 8.18, 7.66-7.51, 7.35, 7.22, 7.12, 6.73, 6.05, 5.49, 4.40, 4.18, 3.96, 3.77, 2.93, 2.41, 1.69, 1.44
Reaction SMILES: [C:1]([O:4][C:5]1[CH:18]=[C:17]2[C:8]([NH:9][C:10]3[C:15]([S:16]2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]2[CH:19]=[CH:20][CH:21]=[CH:22][C:6]=12)(=[O:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:28]>ClCCl.CO>[C:1]([O:4][C:5]1[CH:18]=[C:17]2[C:8]([NH:9][C:10]3[C:15]([S:16]2=[O:28])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]2[CH:19]=[CH:20][CH:21]=[CH:22][C:6]=12)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)Oc1cc2c(c3ccccc13)Nc1ccccc1S2=O

Procedure:
To a suspension of 5-acetoxy-12H-benzo[a]phenothiazine (10 g) in dichloromethane (125 cc) there was rapidly added a solution of 85% m-chloroperoxybenzoic acid (6.61 g) in methanol (125 ml). At first the solids dissolved, then after a few minutes a new solid separated out of solution. After 1 and 1/2 hours the mixture was filtered and the solid washed with dichloromethane. The title compound was thus obtained pure (8.76 g), m.p. 179°-181° C.
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:15]([O:14][C:12]([N:10]1[CH2:11][CH:8]([C:3]2[C:2]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:26]=3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2Cl)C1
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2nccnc2C2CN(C(=O)OC(C)(C)C)C2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (7) (540 mg, 2.0 mmol, Preparation 2), 3-methoxy-phenylboronic acid (29) (334.4 mg, 2.2 mmol), K3PO4 (818 mg, 4.0 mmol), in dioxane (20 mL) and water (4 mL) was added Pd(dppf)Cl2 (73.2 mg, 0.1 mmol) then the reaction mixture was stirred at 90° C. under nitrogen atmosphere overnight. The reaction mixture was filtered through CELITE® and washed with EtOAc (50 mL). The filtrate was concentrated and the crude product was purified by silica gel column to give compound (33) (627.4 mg, 1.84 mmol, yield 91.85%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([CH3:11])[CH:3]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[NH2:27][CH2:28][CH:29]1[CH2:31][CH2:30]1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)=[O:10])[CH:5]=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Cl)nc(C(=O)O)c1
Reactant: NCC1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(Cl)nc(C(=O)NCC2CC2)c1
Reaction time: 3 h
Yield: 89.4 %

Procedure:
6-Chloro-4-methylpyridine-2-carboxylic acid (422 mg, 2.46 mmol) was dissolved in DCM (10 mL) and oxalyl chloride (422 μL, 4.92 mmol) and DMF (100 μL) were added. The reaction mixture was stirred for 3 h, the solvents were removed in vacuo and the residue was azeotroped with DCM. The residue was dissolved in DCM (10 mL), DIPEA (1.63 mL, 9.84 mmol) and aminomethylcyclopropane (427 μL, 4.92 mmol) were added and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with DCM (40 mL), washed with sat aq NaHCO3 (50 mL), 1 M aq HCl (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (494 mg, 69%) as a yellow liquid. LCMS (ES+): 225.5 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:23])=[C:4]([NH:10][S:11]([N:14]2[CH2:18][C@@H:17]([OH:19])[CH2:16][C@H:15]2[C:20](O)=[O:21])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C1CCC(N=C=NC2CCCCC2)CC1.C1C([N+]([O-])=O)=CC=C(O)C=1>C(#N)C>[OH:19][C@@H:17]1[CH2:18][N:14]2[C@H:15]([C:20](=[O:21])[N:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=3[CH3:23])[S:11]2(=[O:13])=[O:12])[CH2:16]1
Reactant: Cc1c(NS(=O)(=O)N2C[C@@H](O)C[C@H]2C(=O)O)ccc(C#N)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: CC#N
Product: Cc1c(N2C(=O)[C@@H]3C[C@H](O)CN3S2(=O)=O)ccc(C#N)c1Cl
Temperature: 25 °C
Yield: 51.9 %

Procedure:
To a solution of 4B (57 mg, 0.158 mmol) in 5 mL of acetonitrile at rt was added DCC (33 mg, 0.158 mmol) followed by p-nitrophenol (44 mg, 0.317 mmol). The suspension was refluxed for 1 h, cooled to rt and filtered. The filtrate was concentrated under reduced pressure and the residue dissolved in EtOAc, washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, EtOAc/Hexanes, 50:50 and 75:25) to afford the title compound (28 mg) as a beige solid. 1H NMR (DMSO-d6) δ 2.25, 2.28 (s, 3H), 2.31-2.38 (m, 2H), 3.46-3.50 (m, 1H), 3.86 (d, J=12.1, 1H), 4.24 (s, 1H), 4.93, 5.07 (d, J=7.2, 1H), 5.42, 5.51 (s, 1H), 7.27, 7.50 (d, J=8.2, 1H), 7.98, 8.03 (d, J=8.3, 1H); 13C NMR (DMSO-d6) δ 15.06, 15.74, 37.57, 60.55, 60.72, 64.84, 65.37, 68.30, 114.37, 115.61, 128.85, 129.59, 132.65, 132.79, 134.96, 136.96, 138.35, 139.36, 169.16; HPLC column: Phenominex LUNA C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA; 1 min hold, 4 mL/min UV detection at 220 nm, 2.62 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/rein, UV detection at 254 nm, 2.45 min retention time (100%); HPLC c) column: Daicel Chiralcel OD 4.6×250 mm, Isocratic 25% Isopropanol/Hexanes, 30 min, 1 mL/min, UV detection at 220 nm, 12.65 min retention time (99%); MS (ES) m/z 340 [M−H]−.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CCCCCC.C(OCC)(=O)C.O.CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([N:24]3[CH2:23][CH2:22][N:21]([CH2:20][C:19]4[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:17]([O:16][CH3:15])[CH:18]=4)[CH2:26][CH2:25]3)=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(CN2CCN(C(=O)c3ccc4[nH]ccc4c3)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
To a mixture of indole-5-carboxylic acid (1 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (2.2 g), triethylamine (1.9 g) and N,N-dimethylformamide (20 ml) is added dropwise under ice-cooling diethyl cyanophosphonate (1.5 ml), followed by stirring for 30 minutes under ice-cooling and for further one hour at room temperature. After addition of water (200 ml), ethyl acetate (200 ml) and hexane (50 ml), the reaction mixture is extracted with ethyl acetate. The extract is washed with water, dried, and concentrated. The residue is purified by means of a silica gel column chromatography(hexane:acetone=1:1) to give 1-(5-indolylcarbonyl)-4-(3,4,5-trimethoxybenzyl)piperazine (1.9 g) as a colorless oily product. This product (0.3 g) is led to its fumarate in ethyl ether to obtain colorless powder (0.25 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[NH:10][C:6]=2[CH:5]=[C:4]([C:14]([OH:16])=O)[CH:3]=1.[NH2:17][C@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:19][C:20]([NH:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(Cl)Cl.C(N(CC)CC)C>[CH2:31]([C@@H:18]([NH:17][C:14]([C:4]1[CH:3]=[C:2]([CH3:1])[C:7]2[N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[NH:10][C:6]=2[CH:5]=1)=[O:16])[CH2:19][C:20](=[O:21])[NH:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: N[C@@H](CC(=O)NOCc1ccccc1)Cc1ccccc1
Reactant: CCCc1nc2c(C)cc(C(=O)O)cc2[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCc1nc2c(C)cc(C(=O)N[C@@H](CC(=O)NOCc3ccccc3)Cc3ccccc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.2 %

Procedure:
To a solution of 7-methyl-2-propyl-3H-benzoimidazole-5-carboxylic acid (164 mg, 752 μmol) and (R)-3-amino-N-benzyloxy-4-phenylbutyramide (TFA salt: 300 mg, 754 μmol) in DMF (10 mL) containing triethylamine (210 μL), was added HOBt (151 μg, 755 μmol) and EDC (151 mg, 788 μmol). The mixture was stirred at room temperature overnight and concentrated in vacuo, yielding a pale brown residue. The residue was dissolved in DCM (100 mL) and washed sequentially with 1M H3PO4, a saturated NaHCO3 solution, and saturated aqueous NaCl. The organic layer was collected, dried over MgSO4, and concentrated to afford the title compound as a pale yellow oil (150 mg; 41% yield), which was used without further treatment. ESMS [M+H]+ calcd for C29H32N4O3, 485.26. found 485.5.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[Ca+2].[OH-].Cl[CH:13]([CH3:21])[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15]>CS(C)=O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH:13]([CH3:21])[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])=[CH:4][CH:3]=1
Reactant: CCCCOC(=O)C(C)Cl
Reactant: Oc1ccc(O)cc1
Agent: [Ca+2]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCOC(=O)C(C)Oc1ccc(O)cc1
Reaction time: 1 h
Yield: 46.2 %

Procedure:
121 g (1.1 moles) of hydroquinone were dissolved in 500 ml of dimethylsulfoxide, 37 g (0.5 mole) of calcium hydroxide were added to the solution, and the mixture was stirred for 1 hour at 45°-50° C. Thereafter, 82.3 g (0.455 mole) of optically active n-butyl 2-chloropropionate (αD20 =-13.0°) were added dropwise in the course of 1 hour at the same temperature. The mixture was stirred for a further 3 hours at 45°-50° C., cooled, and worked up as described in Example 1. 49.7 g (0.21 mole) of optically active n-butyl 2-(4-hydroxyphenoxy)-propionate were obtained. Yield: 46.2%; bp. =150°-152° C./0.22 mbar; αD20 =+11.8° ##STR7##
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C@@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[N:9]2)[CH2:4][O:3]1.[H][H]>CO.[Pd]>[CH3:1][C:2]1([CH3:16])[O:6][C@@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)[CH2:4][O:3]1
Reactant: [H][H]
Reactant: CC1(C)OC[C@H](Cn2ccc([N+](=O)[O-])n2)O1
Agent: [Pd]
Solvent: CO
Product: CC1(C)OC[C@H](Cn2ccc(N)n2)O1
Yield: 78.4 %

Procedure:
A solution of 1-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-3-nitro-1H-pyrazole (348.4 mg, 1.53 mmol) in methanol (10 mL, 0.15M) in a high pressure reaction bottle was treated with 10% palladium on activated carbon (19.5 mg). The mixture was placed on a Parr shaker and exposed to hydrogen (40 psi) overnight. After this time, the reaction mixture was filtered through a pad of diatomaceous earth and rinsed with ethanol. The filtrate was concentrated in vacuo to afford 1-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (237.4 mg, 1.20 mmol) as a viscous, yellow oil. The material was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:23]=[N:24][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:26][CH:27]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[N:24][C:25]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)nc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(N4CCOCC4)nc3)o2)cc(OC)c1Br

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(6-morpholinopyridin-3-yl)ethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(6-morpholinopyridin-3-yl)acetamide according to the procedure used in Example 30. Purification by chromatography (60% EtOAc/hexanes) gave the product as a pale yellow solid (0.04 g, 11% yield). MS: m/z 517.3 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:54][CH2:55][C:56]1[O:60][C:59]([C:61]2[CH:66]=[CH:65][C:64]([C:67]3[C:72]([CH3:73])=[CH:71][CH:70]=[C:69]([C:74]([NH:76][CH:77]4[CH2:79][CH2:78]4)=[O:75])[CH:68]=3)=[CH:63][CH:62]=2)=[N:58][N:57]=1>CN(C=O)C>[CH:77]1([NH:76][C:74]([C:69]2[CH:68]=[C:67]([C:64]3[CH:65]=[CH:66][C:61]([C:59]4[O:60][C:56]([CH2:55][NH:54][C:8](=[O:10])[CH2:7][C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[N:57][N:58]=4)=[CH:62][CH:63]=3)[C:72]([CH3:73])=[CH:71][CH:70]=2)=[O:75])[CH2:79][CH2:78]1
Reactant: O=C(O)Cc1ccccc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CNC(=O)Cc3ccccc3)o2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Phenylacetic acid (12 mg) and HATU (33 mg) in DMF (1 ml) were stirred for 10 minutes at room temperature. To this solution was added HOBt (11.6 mg), DIPEA (.0.45 ml) and 4′-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Example 53) (30 mg) in DMF (2 ml) and the reaction stirred at room temperature for 18 hours. The solvent was evaporated under vacuum and the residue dissolved in DMSO (0.25 ml), methanol (0.25 ml) was added and the precipitate produced isolated by filtration to give N-cyclopropyl-6-methyl-4′-(5-{[(phenylacetyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:13][C:12]([CH3:14])=[C:11]2[C:7]=1[CH2:8][C@H:9]1[C:15]([CH3:17])([CH3:16])[C@H:10]12)=[O:5])C.[Li+].[OH-]>CCO.O>[CH3:16][C:15]1([CH3:17])[C@@H:9]2[CH2:8][C:7]3[C:11]([C@H:10]12)=[C:12]([CH3:14])[S:13][C:6]=3[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Temperature: 70 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of crude (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (10.3 g, 41.2 mmol) in EtOH (200 mL) a solution of 2N aq. LiOH (300 mL) is added. The resulting mixture is stirred at 70° C. for 1 h, cooled to rt and diluted with water (250 mL). The aq. solution is extracted three times with DCM (125 mL) before it is acidified to pH 3 by adding citric acid. The acidified solution is extracted twice with DCM (2×250 mL), These second extracts are combined, dried over Na2SO4, filtered and evaporated to give (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (7.0 g) as a yellow solid. LC-MS: tR=0.95 min, [M+1]+=223.00. 1H NMR (CDCl3): δ 3.04-2.92 (m, 1H), 2.83 (d, J=19.3 Hz, 1H), 2.39 (s, 3H), 1.91-1.87 (m, 2H), 1.13 (s, 3H), 0.73 (s, 3H).
Reaction SMILES: [OH-].[Na+].[CH2:3](Br)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][CH2:24][OH:25])[CH:19]=[CH:20][CH:21]=1>C(O)C>[CH2:3]([O:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][CH2:24][OH:25])[CH:19]=[CH:20][CH:21]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: OCCCc1cccc(O)c1
Reactant: CCCCCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCOc1cccc(CCCO)c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 80.3 %

Procedure:
A 15 N aqueous sodium hydroxide solution (2 ml) and a solution (10 ml) of 8.0 g of undecyl bromide in ethanol was added to a solution (30 ml) of 4.56 g of 3-(3-hydroxyphenyl)propanol in ethanol and the mixture was stirred at 70° C. for 12 hours. The solvent was distilled away and the residue was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogencarbonate and brine, and dried over magnesium sulfate. The solvent was distilled away and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:20-1:3) to give 7.37 g of 3-(3-undecyloxyphenyl)propanol as a colorless, oily substance.
Reaction SMILES: [CH2:1]([C:5]([NH2:7])=[O:6])[C:2]([NH2:4])=[O:3].C1(C)C=CC(S([N:17]=[N+:18]=[N-])(=O)=O)=CC=1>C(O)C>[OH:3][C:2]1[N:4]=[N:17][NH:18][C:1]=1[C:5]([NH2:7])=[O:6]
Reactant: NC(=O)CC(N)=O
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCO
Product: NC(=O)c1[nH]nnc1O
Yield: 70.3 %

Procedure:
To a solution of sodium ethoxide obtained from sodium (2.3 g, 0.10 mole) and absolute ethanol (150 ml) was added malondiamide (10.2 g, 0.10 mole). The mixture was stirred until most of the malondiamide dissolved. p-Toluenesulfonyl azide (19.7 g, 0.10 mole) was dissolved in ethanol (20 ml) and added dropwise with stirring. The thick mixture was stirred at room temperature for 30 min and heated under reflux in an oil bath for an additional 30 min. The mixture was cooled and the sodium salt was removed by filtration and washed with ethanol followed by ether. The salt was dissolved in a minimum of hot water and the solution was acidified to pH 2 with dilute hydrochloric acid. Upon cooling, the product crystallized. The compound was recrystallized from water to give 9.0 g of the known compound 4-hydroxy-1,2,3-triazole-5-carboxamide, m.p. 191°-192°.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:20][C:21]([CH:23]1[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[CH2:25][O:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:31](=[O:33])[CH3:32]>O1CCCC1>[CH2:13]([O:20][C:21]([C:23]1([CH:31]([OH:33])[CH3:32])[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[CH2:25][O:24]1)=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1(C)COC(C(=O)OCc2ccccc2)CO1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)C1(C(=O)OCc2ccccc2)COC(C)(C)CO1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of N,N-diisopropylamine (530 mg, 0.73 mL, 5.25 mmol) in anhydrous tetrahydrofuran (4 mL) was stirred at −78° C. under nitrogen. n-Butyl lithium (2.1 mL, 5.25 mmol, 2.5 M solution in hexane) was added dropwise and the reaction mixture was stirred at −78° C. for 30 min. A solution of 5,5-dimethyl-[1,4]dioxane-2-carboxylic acid benzyl ester (870 mg, 3.5 mmol) in tetrahydrofuran (8 mL) was added and the reaction mixture was stirred at −78° C. for 20 min. Acetaldehyde (462 mg, 0.6 mL, 10.5 mmol) was added in one portion. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0° C. and ice-cold hydrochloric acid (2 M) was added to acidify the reaction mixture to pH 2. Sodium chloride was added to saturate the aqueous phase and the mixture was extracted with diethyl ether. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 6:1 to 0:1 followed by silica gel chromatography using iso-hexanes/ethyl acetate 3:1 to 0:1 to the title compound (400 mg, 40%) as an oil and as a 2:1 mixture of diastereoisomers. LCMS (m/z) 295.1 [M+H], Tr=2.11 min.
Reaction SMILES: [CH2:1]([CH:7]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:8]#[C:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([C:18]#[C:19][CH:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:12][C:11]=1[O:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>O1CCCC1.[Pd]>[CH2:1]([CH:7]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH2:18][CH2:19][CH:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:12][C:11]=1[O:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCC(C#Cc1cc(OC)c(C#CC(CCCCCC)CCCCCCCC)cc1OC)CCCCCC
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCC(CCCCCC)CCc1cc(OC)c(CCC(CCCCCC)CCCCCCCC)cc1OC
Temperature: 30 °C
Reaction time: 2.5 h
Yield: 94.1 %

Procedure:
1,4-Bis-(3-hexyl-undec-1-ynyl)-2,5-dimethoxy-benzene (4.3) (7.70 g, 12.1 mmol) is dissolved in tetrahydrofuran (200 cm3) under an atmosphere of Argon. 10% Pd/C (1.25 g) is added, the mixture warmed to 30° C. (oil bath temperature) and stirred under an atmosphere of hydrogen for 2.5 hours. The reaction mixture is filtered through a plug of celite and the plug washed through with ethyl acetate (2×50 cm3), and the filtrate is concentrated in vacuo. The crude oil is purified by column chromatography eluting with 2 to 5% ethyl acetate in petroleum ether (40-60° C.). A second purification by column chromatography is carried out, eluting with 3% ethyl acetate in petroleum ether (40-60° C.) to give the title product as a colourless oil (7.00 g, 90%). NMR (1H, 400 MHz, CDCl3): δ 6.65 (s, 2H); 3.78 (s, 6H); 2.53 (m, 4H); 1.51 (m, 4H); 1.28 (m, 50H); 0.89 (m, 12H)