Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([C:10]2[O:11][C:12]([CH3:15])=[N:13][N:14]=2)=[CH:8][C:7]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[NH:18][C:17]2=[O:27])=[C:6]([F:28])[CH:5]=1.[H][H].[CH3:31]OS(=O)(=O)OC>CN(C)C=O>[Cl:3][C:4]1[C:9]([C:10]2[O:11][C:12]([CH3:15])=[N:13][N:14]=2)=[CH:8][C:7]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[N:18]([CH3:31])[C:17]2=[O:27])=[C:6]([F:28])[CH:5]=1
Reactant: [H][H]
Reactant: COS(=O)(=O)OC
Reactant: Cc1nnc(-c2cc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c(F)cc2Cl)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnc(-c2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.1 %

Procedure:
To a suspension of 0.31 g of sodium hydride (oil, purity: 55%) in 13 ml of dimethylformamide, a solution of 2.5 g of 3-(4-chloro-2-fluoro-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione in 20 ml of N,N-dimethylformamide was added dropwise at 25° C. After evolution of hydrogen ceased, 1.02 g of dimethylsulfuric acid was added over a period of 15 minutes. The mixed solution was stirred at room temperature for 2 hours and extracted with ethyl acetate by adding water. The extract was dried over anhydrous sodium sulfate. Then the solvent was distilled off and the residue was purified by preparative high performance liquid chromatography using acetonitrile/water (5:1) as eluent to obtain 0.78 g of the objective compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH2:11][CH3:12])(=[O:9])[C:4]([O:6]CC)=O.[CH3:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:23][CH2:24][N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28]>C1COCC1>[CH2:11]([O:10][C:3](=[O:9])[C:4]([CH2:13][C:14]1[C:15]([CH2:23][CH2:24][N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])=[CH:16][CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])=[O:6])[CH3:12]
Reactant: CCCN(CCC)CCc1cccc([N+](=O)[O-])c1C
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCN(CCC)CCc1cccc([N+](=O)[O-])c1CC(=O)C(=O)OCC
Reaction time: 0.33 h

Procedure:
Sodium hydride (7.5 g) is added to Tetrahydrofuran (125 ml) at ambient temperature under Nitrogen atmosphere and stirred for 10-30 minutes. Diethyl oxalate (20 ml) is added to reaction mixture and at 25-45° C. and stirred the solution for 15 minutes. 2-Methyl-3-nitro-N, N-Di-n-propyl phenyl ethyl amine free base as generated above is added to reaction mixture and stirred slowly under nitrogen atmosphere at 25-30° C. for 36-72 hours. After completion of reaction THF is distilled out from the reaction mixture under vacuum at 35-70° C. and Ethyl acetate (250 ml) is added to reaction mass. Further, 3N HCl (approx. 30 ml) is added to adjust the pH of reaction mass to 7.5-8.0. Organic layer is separated out and dried over sodium sulphate. Ethyl acetate is distilled out to obtain Ethyl-6-(2-di-n-propylaminoethyl)-2-nitrophenylpyruvate.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH2:13]([O:15][C:16]([Sn](CCCC)(CCCC)CCCC)=[CH2:17])[CH3:14]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([O:15][C:13]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1)=[CH2:14])[CH3:17]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: C=C(OCC)c1nc(OC)ccc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a suspension of 2-chloro-6-methoxy-3-nitropyridine (600 g) and PdCl2(PPh3)2 (33.5 g) in acetonitrile (4200 ml) at 65° C. under N2 was added dropwise over 2 h (1-ethoxyvinyl)-tributyl-stannane (1182 ml). The resulting suspension was stirred at 65° C. for 4 h then left to cool to room temperature overnight. The reaction mixture was quenched with 10% KF aqueous solution (3600 ml) with vigorous stirring and stirred for 1 h. The resulting solid was removed by vacuum filtration and washed with acetonitrile (7×1000 ml). The layers were separated and the organic layer was evaporated to 3000 ml. This was filtered through Whatman, GF/B glass microfibre filter paper and the small amount of brown solid removed was washed with MeCN (1800 ml). EtOAc (3600 ml) was added and the volume reduced to 1800 ml. Cyclohexane (3600 ml) was added and the volume reduced to 3000 ml. Cyclohexane (2400 ml) and silica gel (600 g, 1 wt) were added and allowed to stir at room temperature for 1.5 h. The solid was removed by vacuum filtration and washed with EtOAc/cyclohexane, 1:8 (4200 ml). The filtrate was reduced to 1800 ml. Cyclohexane (2400 ml) was added and the volume reduced to 1800 ml. Cyclohexane (3600 ml) and EtOAc (600 ml) and silica gel (600 g, 1 wt) were added and stirred for 1.5 h. The solid was removed by vacuum filtration and washed with EtOAc/cyclohexane 1:8 (4200 ml). The solvents were evaporated to dryness. MeCN (2000 ml) was added and evaporated to give an orange coloured oil.
Reaction SMILES: [C:1](O)(=O)/[CH:2]=[CH:3]\[C:4](O)=O.CN1C[C@@H:13]2[C:15]3[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=3O[C:18]3[CH:23]=[CH:22]C=C[C:19]=3[C@@H:12]2C1.[CH3:28][N:29]1C[C@@H]2C3C=C(C)C=CC=3OC3C=CC=CC=3[C@@H]2[CH2:30]1.C(O)(=O)/C=C\C(O)=O.CN1C[C@@H]2C3C=C(Cl)C=CC=3OC3C=CC=CC=3[C@@H]2C1.C(O)(=O)/C=C\C(O)=O.CN1CC[C@@H]2C3C=CC=CC=3OC3C=CC=CC=3[C@@H]2C1.C(O)(=O)/C=C\C(O)=O.CN1CC[C@@H]2C3C=CC=CC=3CC3C=CC=CC=3[C@@H]2C1>>[CH3:28][N:29]1[CH2:30][CH:3]2[C:4]3[CH:22]=[CH:23][CH:18]=[CH:19][C:12]=3[CH2:13][C:15]3[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=3[CH:2]2[CH2:1]1
Reactant: CN1C[C@@H]2c3ccccc3Oc3ccccc3[C@@H]2C1
Reactant: O=C(O)/C=C\C(=O)O
Reactant: Cc1ccc2c(c1)[C@H]1CN(C)C[C@H]1c1ccccc1O2
Agent: CN1CC[C@@H]2c3ccccc3Cc3ccccc3[C@@H]2C1
Agent: CN1CC[C@@H]2c3ccccc3Oc3ccccc3[C@@H]2C1
Agent: CN1C[C@@H]2c3cc(Cl)ccc3Oc3ccccc3[C@@H]2C1
Product: CN1CC2c3ccccc3Cc3ccccc3C2C1

Procedure:
cis-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3;6,7] oxepino[4,5-c]pyrrole maleate, m.p. 143-144° C.; cis-2,5-dimethyl-2,3,3a,12b-tetrahydro-1H-dibenz[ 2,3;6,7]oxepino[4,5-c]pyrrole, m.p. 99-101° C.; cis-2-methyl-5-chloro-2,3,3a,12b-tetrahydro-1H-dibenz[ 2,3;6,7]oxepino[4,5-c]pyrrole maleate, m.p. 116-169° C.; cis-2-methyl-1,2,3,4,4a,13b-hexahydro-dibenz[2,3;6,7] oxepino[4,5-c]pyridine maleate, m.p. 174-1750° C.; cis-2-methyl-2,3,4,4a,9,13b-hexahydro-1H-dibenzo[1,2;5,6] cyclohepta[3,4-c]pyridine maleate, m.p. 207-209° C. and the corresponding trans isomer (maleate salt), m.p. 175-176° C.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][NH:12][CH2:11][CH2:10]2.CO>ClCCl>[CH2:13]1[C:14]2[C:9](=[CH:8][C:7]([OH:6])=[CH:16][CH:15]=2)[CH2:10][CH2:11][NH:12]1
Reactant: COc1ccc2c(c1)CCNC2
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc2c(c1)CCNC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of boron tribromide (1.2 mL, 12.5 mmol) in dichloromethane (12.5 mL) was added dropwise to a −78° C. solution of 6-methoxytetrahydroisoquinoline (1.0 g, 5.0 mol, prepared as described in Org. Synth 1988, 67, 60) in dichloromethane (38 mL). The mixture was stirred for 1 hour, warmed to 0° C., stirred for 1 hour, warmed to room temperature, and stirred for 1 hour. The mixture was cooled to −78° C., treated dropwise with methanol (20 mL), warmed to room temperature, stirred for 1 hour, and concentrated to provide the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]2=[N:17][CH:18]=[C:19]([CH2:21]O)[N:20]=[C:15]2[CH:14]=1.C(Cl)Cl.S(Cl)(Cl)=O.[N-:39]=[N+:40]=[N-:41].[Na+]>O>[N:39]([CH2:21][C:19]1[N:20]=[C:15]2[CH:14]=[C:13]([C:6]3[C:5]4[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=4)[N:8]([CH3:12])[CH:7]=3)[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:16]2=[N:17][CH:18]=1)=[N+:40]=[N-:41]
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CO)cnc3n1COCC[Si](C)(C)C)cn2C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc2c(c1)c(-c1cc3nc(CN=[N+]=[N-])cnc3n1COCC[Si](C)(C)C)cn2C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 100 %

Procedure:
A flask was charged with (6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanol (4.00 g, 9.12 mmol, Preparation #F.1), DCM (90 mL) and thionyl chloride (0.732 mL, 10.0 mmol). The mixture was stirred at rt for about 40 min and concentrated under reduced pressure. The residue was dissolved in DMF (90 mL) and treated with NaN3 (1.48 g, 22.8 mmol). The mixture was stirred overnight at rt. The solution was diluted with water (150 mL). The suspension was extracted with EtOAc (3×125 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give 2-(azidomethyl)-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (4.23 g, 100%): LC/MS (Table 2, Method b) Rt=3.16 min; MS m/z 464 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]([CH3:21])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[CH:10]=[C:9]([C:17]#[CH:18])[CH:8]=[C:7]([O:19][CH3:20])[C:6]2=3)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:18]#[C:17][C:9]2[CH:8]=[C:7]([O:19][CH3:20])[C:6]3[CH:5]([N:4]([CH:1]4[CH2:3][CH2:2]4)[CH3:21])[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]=3[CH:10]=2)=[CH:30][CH:31]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1cc(OC)c2c(c1)C(C)(C)CCC2N(C)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1

Procedure:
Following General Procedure B and using 5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 81, 0.065 g, 0.23 mmol), methyl-4-iodophenylacetate (0.063 g, 0.23 mmol), triethyl amine (8 mL), copper(I)iodide (0.018 g, 0.093 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.065 g, 0.093 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-20% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow solid (0.09 g, 90%).
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.[F:13][C:14]([F:21])([F:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18].C(I)C>C1COCC1>[CH2:1]([CH:16]([CH2:15][C:14]([F:21])([F:20])[F:13])[C:17]([OH:19])=[O:18])[CH3:2]
Reactant: O=C(O)CCC(F)(F)F
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCI
Product: CCC(CC(F)(F)F)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (17.1 g, 169 mmol) in THF (180 mL) was stirred under nitrogen at 0° C. n-Butyl lithium (n-BuLi-67.6 mL, 2.5 M in hexane) was added dropwise over 15 min and the resulting solution stirred for 0.5 h at 0° C. After this time period, the reaction was cooled to −78° C., and 4,4,4-trifluorobutyric acid (10.0 g, 70.4 mmol) in THF (20 mL) was added dropwise over 0.5 h. The resulting solution was stirred for an additional 0.5 h at −78° C. After this time period, ethyl iodide (6.19 mL, 77.4 mmol) was added dropwise over 15 min. The resulting solution was stirred for 15 min. at −78° C. then warmed to 25° C. for 24 h. After this time period, the reaction mixture was quenched by slow addition of H2O (˜20 mL). After concentration, the residue was acidified to pH 1 with 2 N aq. HCl and then extracted with Et2O (400 mL). The organic layer was then dried using MgSO4. After concentration, the resulting residue was used directly in the next reaction without further purification.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:8]=[CH:7][NH:6][N:5]=1)[CH3:2].[CH2:9]([N:13]([CH2:17][CH2:18][CH3:19])[C:14](Cl)=[O:15])[CH2:10][CH2:11][CH3:12].O1CCCC1>C(N(CC)CC)C>[CH2:9]([N:13]([CH2:17][CH2:18][CH3:19])[C:14]([N:6]1[CH:7]=[N:8][C:4]([S:3][CH2:1][CH3:2])=[N:5]1)=[O:15])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCN(CCC)C(=O)Cl
Reactant: CCSc1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCN(CCC)C(=O)n1cnc(SCC)n1

Procedure:
A mixture of 5.16 g. 3-ethylthio-1,2,4-triazole, 7.8 g. N-n-butyl-N-propylcarbamoyl chloride, 35 ml. dry tetrahydrofuran and 8 ml. dry triethylamine was refluxed under anhydrous conditions for 24 hours. The reaction mixture was worked up as described in Example 1 to give a residual oil. This oil was distilled under reduced pressure to give 1-(N-n-butyl-N-propylcarbamoyl)-3-ethylthio-1,2,4-triazole, b.p. 127°C./0.2 mm. (91.2% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: [I:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.IC.[C:12](=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[I:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([O:9][CH3:12])=[O:8])[CH:3]=1
Reactant: O=C(O)c1csc(I)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1csc(I)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.6 %

Procedure:
A mixture of 5-iodothiophene-3-carboxylic acid (3.48 g), iodomethane (2.92 g), potassium carbonate (2.84 g) and DMF (35 ml) was stirred at room temperature for 1 day. The reaction mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (3.62 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([O:16]C)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.O.O.[OH-].[Li+]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]2)=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
Methyl 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylate (3.28 g, 14.00 mmol) was dissolved in THF (23.34 mL), water (11.67 mL) was added, followed by lithium hydroxide monohydrate (1.763 g, 42.0 mmol), and the mixture stirred at room temperature for 30 minutes. After this time the THF was removed under reduced pressure and the pH of the water layer was adjusted to ˜5 with 2 M HCl while the solution was cooled in an ice bath. The precipitate that formed was dissolved in ethyl acetate (125 mL) and the layers were separated. The organic layer was washed with water (100 mL) and brine (100 mL) and then dried over magnesium sulfate. Evaporation of the solvent yielded 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (2.952 g, 94% yield) as an off white powder. 1H NMR (400 MHz, DMSO-d6): δ 13.06 (broad s, 1H), 10.56 (s, 1H), 7.60 (m, 2H), 7.12 (m, 2H), 1.39 (s, 4H); MS (ESI) m/z: 224.1 (M+H+).
Reaction SMILES: [CH3:1]O.S(=O)(=O)(O)O.[CH2:8]([C@H:11]1[CH2:16][CH2:15][C@H:14]([C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)[CH2:9][CH3:10].O>C1(C)C=CC=CC=1>[CH3:1][O:24][C:23]([C@H:20]1[CH2:21][CH2:22][C@H:17]([C@H:14]2[CH2:15][CH2:16][C@H:11]([CH2:8][CH2:9][CH3:10])[CH2:12][CH2:13]2)[CH2:18][CH2:19]1)=[O:25]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)O)CC2)CC1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)OC)CC2)CC1

Procedure:
Methyl alcohol (200 ml) and conc. sulfuric acid (15 ml) were added to trans-4-(trans-4'-propylcyclohexyl)cyclohexanecarboxylic acid (68.2 g, 0.27 mol) and the mixture was heated under reflux for 4 hours, followed by cooling, adding water (200 ml) and toluene (100 ml), transferring the resulting mixture to a separating funnel, three times washing the toluene layer with water (each time 100 ml), distilling off toluene, adding ethyl alcohol (40 ml) to the residue, recrystallizing, filtering off and drying to obtain the objective trans-4-(trans-4'-propylcyclohexyl)cyclohexanecarboxylic acid methyl ester (65 g) (yield: 90.2%).
Reaction SMILES: N[C@H:2]([CH3:13])[CH2:3][C:4]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].Cl.[OH-:15].[Na+]>>[Br:12][C:10]1[CH:11]=[C:4]2[C:5](=[CH:8][CH:9]=1)[C:6](=[O:15])[NH:7][C@H:2]([CH3:13])[CH2:3]2
Reactant: [OH-]
Reactant: C[C@@H](N)Cc1cc(Br)ccc1C#N
Agent: Cl
Agent: [Na+]
Product: C[C@@H]1Cc2cc(Br)ccc2C(=O)N1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
480 mg (1.7 mmol) (R)-2-(2-amino-propyl)-4-bromo-benzonitrile (as hydrochloride salt) are dissolved in 5 ml 10 N sodium hydroxide solution and stirred for 16 hours at 80° C. Then the reaction mixture is acidified with hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac. The residue is purified by RP-HPLC.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][NH2:7])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[F:17][C:18]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[CH:20][C:19]=1[S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH:2]1([CH2:5][O:6][NH:7][S:26]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[C:23]([F:24])[C:18]=2[F:17])(=[O:28])=[O:27])[CH2:4][CH2:3]1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1F
Reactant: NOCC1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(NOCC1CC1)c1ccc(F)c(F)c1F
Reaction time: 0.2 h
Yield: 67.9 %

Procedure:
To a stirring suspension comprised of O-cyclopropylmethyl-hydroxylamine hydrochloride (5.40 g, 0.0437 mol) in dichloromethane (20 ml) at ambient temperature under a nitrogen atmosphere was added diisopropylethylamine (10.8 ml, 0.062 mol). A solution comprised of 2,3,4-trifluorobenzenesulfonyl chloride (Oakwood Products, Inc., 1.00 g, 4.34×10−3 mol) in dichloromethane (120 ml) was added dropwise to the reaction vessel containing the stirring suspension over a 12 minute period. The reaction mixture was stirred for another 12 minutes and was quenched with 10% aqueous hydrochloric acid (140 ml). The biphasic mixture was stirred vigorously for 16 hours. The layers were separated and the organic phase was dried (MgSO4) and concentrated to 6 ml volume. The concentrated solution was administered to a flash silica column (Biotage, 90 g of silica gel). Elution with dichloromethane afforded 0.8283 g of a white amorphous solid; 68% yield; 1H-NMR (400 MHz; CDCl3 signal offset to δ 7.03; values reported are uncorrected) δ 7.50 (m,1H), 7.10 (s,1H), 6.95 (m,1H), 3.59 (d, 2H, J═7.2 Hz), 0.80 (m, 1H), 0.31 (m, 2H), 0.02 (m, 2H); 19F-NMR (376 MHz; CDCl3) δ−122.65 (m, 1F), −129.37 (m, 1F), −156.20 (m, 1F); MS (APCl−) 280 (M−1, 100), 210 (55), 195 (45).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH:21]1(C2C=CC(C(O)=O)=NC=2OCC2CCCO2)CC1.[NH2:40][C@@H:41]([CH2:45][CH:46]([CH3:48])[CH3:47])[C:42]([NH2:44])=[O:43]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([NH:40][C@@H:41]([CH2:45][CH:46]([CH3:48])[CH3:47])[C:42]([NH:44][CH3:21])=[O:43])=[O:20])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCOCC2)n1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: CNC(=O)[C@H](CC(C)C)NC(=O)c1ccc(C2CC2)c(OCC2CCOCC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (which can e.g. be prepared in a similar manner than 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 b)) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=404.2 [M+H]+.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[CH2:5]([C:7]([CH2:20]C)(P(O)(O)=O)/[C:8](/C)=C(\CC)/C([O-])=O)[CH3:6].[CH3:22][C:23]([CH3:37])=[CH:24][CH2:25][CH2:26]/[C:27](/[CH3:36])=[CH:28]/[CH2:29][CH2:30]/[C:31](/[CH3:35])=[CH:32]/[CH:33]=[O:34].C(O)(=O)C>CN(C)C=O>[CH2:2]([O:1][C:33](=[O:34])/[CH:32]=[C:31](\[CH3:35])/[CH:30]=[CH:29]/[CH:28]=[C:27](\[CH3:36])/[CH2:26][CH2:25]/[CH:24]=[C:23](\[CH3:37])/[CH2:22][CH2:6][CH:5]=[C:7]([CH3:20])[CH3:8])[CH3:3]
Reactant: CC/C(C(=O)[O-])=C(/C)C(CC)(CC)P(=O)(O)O
Reactant: CC[O-]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)/C=C(C)/C=C/C=C(\C)CC/C=C(\C)CCC=C(C)C
Temperature: -10 °C
Yield: 88 %

Procedure:
Under argon atmosphere, sodium ethoxide (2.16 g, 1.26 equivalents) was suspended in 20 ml of dimethylformamide, and the suspension was added dropwise with 5 ml dimethylformamide solution of triethyl-3-methyl-4-phosphonocrotonate (7.87 g, 1.2 equivalents, 23.28 mmol) at room temperature. The reaction mixture was then added dropwise with 5 ml dimethylformamide solution of farnesal (5.0 g, 22.7 ml) under stirring at −10° C., and further stirred at the same temperature for 30 minutes. The reaction mixture was added to ice-water. The solution was neutralized with acetic acid and extracted with n-heptane. The resulting organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 6.6 g of the title compound (yield 88%, 2E:2Z=86:14) as a yellow oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([OH:19])=O)=[O:7])(C)(C)C.[N:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=C=O.[N:28]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[NH2:39])[CH:32]=[CH:31][CH:30]=[CH:29]1>>[CH2:15]([O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([NH:20][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:7])[C@H:9]([C:17]([NH:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:28]2[CH:29]=[CH:30][CH:31]=[CH:32]2)=[O:19])[CH2:10]1)[CH3:16]
Reactant: Nc1ccccc1-n1cccc1
Reactant: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCCCCN=C=O
Product: CCCCCNC(=O)N1CC(=NOCC)C[C@H]1C(=O)Nc1ccccc1-n1cccc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, 1-isocyanatopentane, and 2-(1H-pyrrol-1-yl)phenylamine the title compound was obtained in 83% purity by LC/MS. MS(ESI+): m/z=426.2.