Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])[C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[OH:19])[CH2:15][CH2:14][CH2:13]2)=O)([CH3:4])([CH3:3])[CH3:2].[C:28](OCC)(=[O:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C1CCN2C(=NCCC2)CC1>>[C:24]([C:21]1[CH:20]=[C:7]([C:8]2[C:10]3[CH:11]=[C:12]4[CH2:13][CH2:14][CH2:15][C:16]4=[CH:17][C:18]=3[O:19][C:28](=[O:35])[C:29]=2[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:22]=1[OH:23])([CH3:26])([CH3:27])[CH3:25]
Reactant: CC(C)(C)c1cc(C(=O)c2cc3c(cc2O)CCC3)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1c(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cc3c(cc2oc1=O)CCC3
Yield: 87.7 %

Procedure:
A mixture of 5-(3,5-di-tert-butyl-4-hydroxybenzoyl)-6-hydroxyindan (2.8 g), diethyl malonate (3.6 g) and DBU (0.12 ml) was heated at 160°-170° C. for 2 hours. After cooling, the resulting crystals were collected by filtration and washed with ethanol to give ethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta[g][1]benzopyran-3-carboxylate (3.1 g, 87.8%). Recrystallization from ethanol gave colorless prisms, m.p. 208°-209° C.
Reaction SMILES: S([O-])(O)=O.[Na+].[NH2:6][C:7]1[C:12]([CH:13]=O)=[CH:11][C:10]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)=[CH:9][N:8]=1.[NH2:21][C:22]1[CH:23]=[C:24]([C:29]2[CH:30]([CH3:36])[CH2:31][C:32](=[O:35])[NH:33][N:34]=2)[CH:25]=[CH:26][C:27]=1[NH2:28].O>CN(C=O)C>[NH2:6][C:7]1[C:12]([C:13]2[NH:21][C:22]3[CH:23]=[C:24]([C:29]4[CH:30]([CH3:36])[CH2:31][C:32](=[O:35])[NH:33][N:34]=4)[CH:25]=[CH:26][C:27]=3[N:28]=2)=[CH:11][C:10]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)=[CH:9][N:8]=1
Reactant: Cn1cc(-c2cnc(N)c(C=O)c2)cn1
Reactant: CC1CC(=O)NN=C1c1ccc(N)c(N)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc2nc(-c3cc(-c4cnn(C)c4)cnc3N)[nH]c2c1
Temperature: 25 °C

Procedure:
1.2 300 μl (1.485 mmol) of 38-40% sodium hydrogensulfite solution are added to a solution of 100 mg (0.495 mmol) of 2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carbaldehyde and 108 mg (0.495 mmol) of 6-(3,4-diaminophenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one in 4 ml of DMF, and the resultant suspension is stirred at 50° C. for 72 hours. The reaction mixture is cooled to RT, water is added, and the precipitated product is filtered off with suction, washed with water and dried, giving 6-{2-[2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl]-3H-benzimidazol-5-yl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one as yellow solid; APCI-401;
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=1[O:22][CH3:23].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:36][C:37]#[N:38])[CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33].CC(C)([O-])C.[K+].Cl>COC(C)(C)C.O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17](/[CH:18]=[C:36](/[C:28]2[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[CH:27]=2)\[C:37]#[N:38])=[CH:16][C:15]=1[O:22][CH3:23]
Reactant: COc1cc(CC#N)cc(OC)c1OC
Reactant: COc1cc(C=O)ccc1OCCCCCCCCCCCO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Product: COc1cc(/C=C(\C#N)c2cc(OC)c(OC)c(OC)c2)ccc1OCCCCCCCCCCCO
Temperature: 54 °C
Reaction time: 18 h
Yield: 75.5 %

Procedure:
7.1 g (22 mmol) of 4-[(11-hydroxyundecyl)oxy]-3-methoxybenzaldehyde, 5.0 g (24 mmol) of (3,4,5-trimethoxyphenyl)acetonitrile are dissolved in 50 mL of tert-butyl methyl ether. 0.49 g of potassium tert-butoxide are added under stirring and the mixture is heated to 54° C. After 18 h at 54° C., the reaction mixture is poured on 75 mL icy water under stirring. The pH is adjusted to 7 with 25% HCl. After 1 h stirring, the precipitate is filtered off, washed with water and dried at 40° C. under vacuum. 8.5 g of (2Z)-3-{4-[(11-hydroxyundecyl)oxy]-3-methoxyphenyl}-2-(3,4,5-trimethoxyphenyl)prop-2-enenitrile are obtained as a yellow solid (76% yield). This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[CH:13]([C:14]([NH:16][C@H:17]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[CH3:18])=[O:15])[CH:12]3[CH2:29][CH2:30][CH:9]2[CH2:10][CH2:11]3)=[CH:5][CH:4]=1.O[Li].O>>[F:33][C:2]([F:1])([F:34])[C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[CH:13]([C:14]([NH:16][C@H:17]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[CH3:18])=[O:15])[CH:12]3[CH2:11][CH2:10][CH:9]2[CH2:30][CH2:29]3)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)C2C3CCC(CC3)N2Cc2ccc(C(F)(F)F)cc2)cc1
Agent: [Li]O
Solvent: O
Product: C[C@H](NC(=O)C1C2CCC(CC2)N1Cc1ccc(C(F)(F)F)cc1)c1ccc(C(=O)O)cc1
Yield: 100.7 %

Procedure:
The title compound (E39) (11.04 mg) was prepared according to the general procedure for esters hydrolysis (Method C) starting from methyl 4-((1S)-1-(2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[2.2.2]octane-3-carboxamido)ethyl)benzoate (D155) (11.3 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:25](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:17][C@@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:25])[C@@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CNCc1ccccc1
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](N[C@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-3-Methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5.4 g, 25.3 mmol) was dissolved in dichloromethane (75 mL). R-(+)-□-Methylbenzylamine (3.1 g, 3.2 mL, 25.3 mmol) was added followed by sodium triacetoxyborohydride (10.7 g, 50.6 mmol). The reaction was stirred overnight at room temperature. LC/MS analysis revealed four components, with only one component clearly separated. The reaction was diluted with dichloromethane (150 mL) and extracted twice with water, once with brine and dried over MgSO4. Filtration and concentration in vacuo afforded a white foam that was purified by flash column chromatography (84.5:15:0.5 CH2Cl2:acetonitrile:NH4OH) to afford a clear oil. The material was rechromatographed (89.5:10:0.5 CH2Cl2:acetonitrile:NH4OH) to afford the title compound as a clear oil. Wt.: 547 mg (7%). 1H NMR (300 MHz, CDCl3) δ 7.31 (m, 3H), 7.22 (m, 2H), 3.85 (m, 3H), 2.68 (m, 1H), 2.46 (m. 1H), 2.17 (m, 1H), 1.67 (m, 1H), 1.40 (s, 9H), 1.30 (d, 3H), 1.08 (m, 2H), 0.97 (d, 3H); LC/MS m/z 319 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=1[CH2:10][OH:11].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:20]([O:7][C:8]1[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][C:9]=1[CH2:10][OH:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCc1cc(C(F)(F)F)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCc1cc(C(F)(F)F)ccc1OCc1ccccc1
Temperature: 50 °C
Yield: 100.1 %

Procedure:
Cesium carbonate (2.24 g, 6.9 mmol) was added to a solution of 2-hydroxy-5-trifluoromethyl-benzyl alcohol (885 mg, 4.6 mmol) and benzyl bromide (547 μL, 4.6 mmol) in anhydrous DMF (8 mL) at room temperature. The reaction was heated to 50° C. for 2 hours, cooled, diluted with ethyl acetate (25 mL) and washed with water (3×25 mL), brine (1×25 mL), and dried (Na2SO4), filtered and concentrated to afford 1.3 g of the title compound as a colorless solid. 1H NMR (400 MHz. CDCl3) δ 7.6-7.3 (m, 7H); 7.01 (d, 1H, J=9.1 Hz); 5.18 (s, 2H); 4.79 (s, 2H); 2.8 (bs, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH2:12][S:13][CH:14]([CH3:16])[CH3:15])[C:9]2[N:17]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:19][C:8]=2[C:7]=1[O:24]C(=O)C(C)(C)C)=[O:5])[CH3:2].[O-]CC.[Na+]>C(O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH2:12][S:13][CH:14]([CH3:15])[CH3:16])[C:9]2[N:17]=[C:18]([C:20]([CH3:22])([CH3:21])[CH3:23])[S:19][C:8]=2[C:7]=1[OH:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(CSC(C)C)c2nc(C(C)(C)C)sc2c1OC(=O)C(C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1nc(CSC(C)C)c2nc(C(C)(C)C)sc2c1O
Yield: 65.8 %

Procedure:
A solution of 2-tert-butyl-7-(2,2-dimethyl-propionyloxy)-4-isopropylsulfanylmethyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (150 mg, 0.33 mmol) and sodium ethoxide (215 mg of 21% sodium ethoxide in ethanol) in 0.6 mL of ethanol was heated at 90° C. for 2 h. The reaction mixture was diluted with ethyl acetate and washed with 1 N HCl and brine. The organic fraction was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography, eluting the desired product from silica gel with a gradient of 0-40% ethyl acetate in hexanes to give 80 mg of a clear oil. MS (ESI+): m/z 368.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[C:44]1([CH:50]2[CH2:54][CH2:53][CH:52]([NH2:55])[CH2:51]2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([NH:55][CH:52]4[CH2:53][CH2:54][CH:50]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[CH2:51]4)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: NC1CCC(c2ccccc2)C1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(NC4CCC(c5ccccc5)C4)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 27 %

Procedure:
In a manner analogous to that described in Example 3 a), the amination of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-4-(5-bromo-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.1) with (RS)-3-phenyl-cyclopentylamine (CAS [103858-37-3]; WO2007135026) yielded the title compound (27% yield) as a yellow solid. MS (ISP): m/z=734.5 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH2:3][CH2:4][N:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][C:7]=1[CH:8]=O.C(N(CC)CC)C.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:23][SH:24].[OH-].[K+]>N1C=CC=CC=1.O>[S:24]1[C:2]2[CH2:3][CH2:4][N:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][C:7]=2[CH:8]=[C:23]1[C:22]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)CS
Reactant: CCOC(=O)N1CCC(Cl)=C(C=O)C1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2c(s1)CCN(C(=O)OCC)C2
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-chloro-5-formyl-3,6-dihydropyridine-1(2H)-carboxylate (1 eq) obtained from step II in pyridine was added triethyl amine (1.5 eq.), ethyl thioglycolate (1 eq.) at 0° C. and the reaction mixture was stirred for overnight. A solution of KOH (1.5 eq) in water was added at 0° C. and further stirred at room temperature for 1 h Water was added and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the desired diethyl 6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[C:8]([N:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([OH:23])[C:20]([OH:24])=C(O)C=2)[N:14]([CH2:26][C:27]([OH:29])=[O:28])[C:13](=[O:30])[CH:12]1[CH:31]([CH3:33])[CH3:32])(=[O:10])[CH3:9]>CC(C)=O>[C:8]([N:11]1[CH:16]=[C:15]([C:17]2[CH:6]=[C:5]([O:4][C:1](=[O:3])[CH3:2])[C:20]([O:24][C:1](=[O:3])[CH3:2])=[C:21]([O:23][C:5](=[O:4])[CH3:6])[CH:22]=2)[N:14]([CH2:26][C:27]([OH:29])=[O:28])[C:13](=[O:30])[CH:12]1[CH:31]([CH3:33])[CH3:32])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N1C=C(c2cc(O)c(O)c(O)c2)N(CC(=O)O)C(=O)C1C(C)C
Solvent: CC(C)=O
Product: CC(=O)Oc1cc(C2=CN(C(C)=O)C(C(C)C)C(=O)N2CC(=O)O)cc(OC(C)=O)c1OC(C)=O

Procedure:
Acetic anhydride is added to a suspension of {(3RS)-4-acetyl-3-isopropyl-2-oxo-6-(3,4,5-trihydroxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}acetic acid (630 mg, Reference compound No. 62-2) in acetone (10 ml), and the mixture is stirred for one week. The reaction mixture is concentrated under reduced pressure to give the titled reference compound (790 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][C:10](=O)[CH2:9]2)=[CH:4][CH:3]=1.Cl.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]([NH2:24])[CH3:23])=[CH:18][C:17]=1[O:25][CH3:26]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][C@H:10]([NH:24][C@@H:22]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[C:17]([O:25][CH3:26])[CH:18]=3)[CH3:23])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CC[C@@H](c2ccc(Br)cc2)C1
Reactant: COc1cc([C@@H](C)N)ccc1F
Agent: Cl
Product: COc1cc([C@@H](C)N[C@H]2CC[C@@H](c3ccc(Br)cc3)C2)ccc1F

Procedure:
General procedure B was followed using (3R)-3-(4-Bromo-phenyl)-cyclopentanone as the ketone and (1R)-1-(4-fluoro-3-methoxyphenyl)ethylamine hydrochloride as the amine. The product was purified by flash chromatography (gradient of 20-80% EtOAc in heptane containing 2.5% NEt3), and the faster eluting peaks were collected to afford the title compound. 1H NMR (300 MHz, CDCl3) δ 7.37 (d, J=8.4 Hz, 2H), 7.10-6.94 (m, 4H), 6.85-6.78 (m, 1H), 3.90 (s, 3H), 3.83 (q, 1H), 3.12-3.00 (m, 1H), 2.96-2.81 (m, 1H), 2.24-2.13 (m, 1H), 2.08-1.91 (m, 2H), 1.80-1.29 (m, 6H).
Reaction SMILES: Cl.[C:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])(=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(C)C=CC=CC=1>O.CCOCC.[Zn]>[C:3]1([CH2:2][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)CCCCCCCCCCC(=O)c1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: O=C(O)CCCCCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.7 %

Procedure:
To a solution of 1 gm Hg2Cl2 in 30 ml H2O was added 1 ml of concentrated HCl followed by 24 gms powdered Zn (portion wise) with mechanical stirring. The resulting mixture was stirred together for 5 minutes, then the liquid phase was decanted off, and 15 ml H2O was added, followed by 36 ml concentrated HCl. This mixture was cooled to room temperature (the reaction to this point is exothermic), then 5.4 gms 11-benzoylundecanoic acid was added followed by 25 ml toluene. The resulting mixture was stirred and refluxed for 20 hours; 12 ml concentrated HCl was added during the first 6 hours of the reflux. The reaction mixture was cooled, the liquid was decanted, the phases were separated and the solid was three times triturated with 25 ml ether. The aqueous phase was 3×15 ml ether extracted; all organic phases were combined, washed with water and brine and dried over MgSO4. The drying agent was filtered off, and the solvents were removed in vacuo to give a solid residue. This residue was dissolved in ether, extracted with dilute NaOH, and the organic layer was discarded. The aqueous layer was acidified with concentrated HCl, then extracted with ether. This ether solution was washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo to give 4.2 gms title product which was used without further purification.
Reaction SMILES: C(O[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14](C(=O)C)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=O)C.C([O:23][C:24](=[O:26])[CH3:25])(=O)C.[C:27]([OH:31])(=[O:30])CC>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C([O-])(=O)C.[Mn+2].C([O-])(=O)C>[C:24]([O:23][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([C:8]2[CH:7]=[CH:6][CH:5]=[CH:10][CH:9]=2)[C:16]=1[C:27]([OH:31])=[O:30])(=[O:26])[CH3:25]
Reactant: CCC(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Oc1ccc(-c2ccc(C(C)=O)cc2)cc1
Agent: [Co+2]
Agent: [Mn+2]
Agent: CC(=O)[O-]
Product: CC(=O)Oc1cccc(-c2ccccc2)c1C(=O)O
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
345 g of 4-acetoxy-4'-acetylbiphenyl were suspended in 2.6 l of propionic acid. 2.6 g of cobalt(II) acetate, 10.1 g of manganese(II) acetate and 375 g of acetic anhydride were added to this suspension, and the mixture was heated to 110° C. The mixture was stirred for 15 minutes at 110° C., after which it was gassed with air via a valve in the base. After gassing had been carried out for 90 minutes at 110° C., the reaction was complete; the reaction mixture was discharged through the valve in the base, and the product was filtered off under suction and washed with petroleum ether. 291.3 g (84% yield) of acetoxybiphenylcarboxylic acid having a purity of 99.9% (HPLC) were obtained.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([B:15]([OH:17])[OH:16])=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O:19]([NH2:21])[CH3:20]>N1C=CC=CC=1.CCO>[CH3:20][O:19][N:21]=[C:1]([C:9]1[CH:14]=[CH:13][C:12]([B:15]([OH:17])[OH:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON
Reactant: O=C(c1ccccc1)c1ccc(B(O)O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C(c1ccccc1)c1ccc(B(O)O)cc1

Procedure:
A solution of 4-benzoyl phenyl boronic acid (226.00 mg, 1.00 mmol) and methoxyl amine hydrochloride (101.00 mg, 1.20 mmol) in pyridine (5 mL) and EtOH (5 mL) was refluxed at 125° C. for 24 h. Reaction was then concentrated in vacuo to give a crude product which was used for next step without further purification. MS (ES+): m/z 256.00 (100)[MH+]. HPLC: tR=3.17 min (Open Lynx polar—5 min).
Reaction SMILES: [CH3:1][C:2]([CH3:17])=[CH:3][CH2:4][CH2:5][C:6]1[CH2:7][CH:8]2[C:13](=[O:14])[O:12][C:10](=[O:11])[CH:9]2[CH2:15][CH:16]=1.B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:17])[CH2:3][CH2:4][CH2:5][C:6]2[CH2:7][CH:8]3[C:13]([O:12][C:10](=[O:11])[CH:9]3[CH2:15][C:16]1=2)=[O:14]
Reactant: CC(C)=CCCC1=CCC2C(=O)OC(=O)C2C1
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC1(C)CCCC2=C1CC1C(=O)OC(=O)C1C2

Procedure:
1,2,3,6-tetrahydro-4-(4-methyl-3-pentenyl)phthalic anhydride (VIII, Z=O) (1000g) and boron trifluoride etherate (100 g.) in 1 liter of benzene was refluxed for one and one-half hours. Work-up, using standard techniques, gave in almost quantitative yield crude 1,2,3,4,5,6,7,8-octahydro-5,5-dimethyl-2,3-naphthalenedicarboxylic acid anhydride (VII, X=O; R is the radical C). The cyclized anhydride (1 mole) was heated slowly to 250° C. with 200 ml. of ammonium hydroxide (s.g. 0.91) until ammonia no longer was liberated, using a condenser of a length which allowed ready evaporation of water. The resulting 1,2,3,4,5,6,7,8-octahydro-5,5-dimethyl-2,3-naphthalenedicarboximide (VII, X=NH; R is the radical C) was dissolved in 500 ml. of 2N sodium hydroxide in ethyl alcohol with warming, the solution was evaporated to dryness in vacuo, and the resulting sodium salt of the imide was suspended in 500 ml. of dioxane and treated with trichloromethanesulfenyl chloride (1.1 moles) in 200 ml. of dioxane with gentle stirring. The reaction was completed by heating at 80° C. for thirty minutes. The mixture was allowed to stand overnight, concentrated in vacuo, and the residue was crystallized from ethyl alcohol (or benzene) to give a yield of 91% of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH2:26])[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[ClH:27]>ClCCl.O1CCOCC1>[ClH:27].[CH2:1]([O:3][C:4]([C:6]1([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH2:26])[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(Cc2ccccc2N)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)C1(Cc2ccccc2N)CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 4-(2-amino-benzyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (1.29 g, 4.102 mmol) in dichloromethane (15 mL) was added a 4.0M solution of hydrogen chloride in dioxane (5 mL). The resulting solution was stirred at room temperature overnight. The concentration of the solution under vacuum provided the title compound (1.23 g, 100%) as white solid, which was used in the next step without purification. Mass spec.: 263.40 (MH)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([NH:12]C(OC(C)(C)C)=O)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>>[F:20][C:21]([F:26])([F:25])[C:22]([O-:24])=[O:23].[C:9]([O:8][CH2:7][CH:6]([NH3+:12])[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)OCC(COC(C)=O)NC(=O)OC(C)(C)C
Product: CC(=O)OCC([NH3+])COC(C)=O
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetic acid 3-acetoxy-2-tert-butoxycarbonylamino-propyl ester (7.2 g) was dissolved in trifluoroacetic acid (40 ml) and stirred at ambient temperature. Effervescence was rapid at the start and had stopped after 1 h when the volatiles were removed at reduced pressure to give the product as a viscous oil in quantitative yield. The structure was confirmed 1H NMR (300 MHz, CDCl3): 2.12 (s, 9H), 3.83-3.91 (m, 1H), 4.27-4.46 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:13][C@H:14]([C:19]([NH:21][CH2:22][C:23]#[N:24])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.BrC1C=C(C(N[C@H:38]([C:43]([NH:45][CH2:46][C:47]#N)=O)[CH2:39]C(C)C)C(F)(F)F)C=CC=1>>[C:23]([CH2:22][NH:21][C:19](=[O:20])[C@H:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:13][CH:8]([C:5]1[CH:6]=[CH:7][CH:2]=[C:3]([C:39]2[CH:38]=[CH:43][N:45]=[CH:46][CH:47]=2)[CH:4]=1)[C:9]([F:12])([F:11])[F:10])#[N:24]
Reactant: CC(C)C[C@H](NC(c1cccc(Br)c1)C(F)(F)F)C(=O)NCC#N
Reactant: CC(C)C[C@H](NC(c1ccc(Br)cc1)C(F)(F)F)C(=O)NCC#N
Product: CC(C)C[C@H](NC(c1cccc(-c2ccncc2)c1)C(F)(F)F)C(=O)NCC#N

Procedure:
Using the procedure described for example 8, where N2-[1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N1-(cyanomethyl)-L-leucinamide was substituted for N2-[1-(3-bromophenyl)-2,2,2-trifluoroethyl]-N1-(cyanomethyl)-L-leucinamide, the title compound was obtained as a colorless gum.
Reaction SMILES: [CH2:1]1[CH2:8][C:6](=O)[C:4](=O)[CH2:3][CH2:2]1.Cl.[C:10]1([N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)N)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(=O)C>[C:6]1([N:16]2[C:18]3[C:23](=[CH:22][CH:21]=[C:20]4[C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=5[N:16]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[C:19]4=3)[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:4]=[CH:3][CH:2]=[CH:1][CH:8]=1
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: O=C1CCCCC1=O
Agent: Cl
Solvent: CC(=O)O
Product: c1ccc(-n2c3ccccc3c3ccc4c5ccccc5n(-c5ccccc5)c4c32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
1,2-Cyclohexadione (98%; 5.0 g, 1 eq.) is dissolved in acetic acid (100%; 30 ml). 1,1-Diphenylhydrazine hydrochloride (98%; 19.68 g, 2 eq.) is slowly added thereto. The suspension is stirred at room temperature overnight. Subsequently, the reaction is stirred at reflux for 54 h. After cooling to room temperature, the suspension is filtered with suction and washed with a little acetic acid. The residue is suspended in hot distilled water, filtered off with suction and washed to neutrality. The solid is dried under reduced pressure overnight. Subsequently, the solid is dissolved in toluene (300 ml) and Pd/C (10%; 2 g) is added; the mixture is stirred at reflux overnight. The solution was filtered through Celite (super standard) and washed with toluene and methylene chloride. The clear solution is concentrated and the residue is dried at 100° C. under reduced pressure. This gives 5.11 g of compound 4, 57.2% yield.