Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][NH2:14])=[C:11]([CH3:15])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:18]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:24][O:23][C:21](=[O:22])[C:20]1[CH:25]=[CH:26][C:17]([NH:14][CH2:13][C:12]2[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][O:10][C:11]=2[CH3:15])=[N:18][CH:19]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cc1onc(-c2cccc(F)c2)c1CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc(NCc2c(-c3cccc(F)c3)noc2C)nc1
Temperature: 160 °C
Yield: 37.7 %

Procedure:
A mixture of C-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methylamine (530 mg, 2.6 mmol), methyl 6-chloronicotinate (440 mg, 2.6 mmol), N,N-diisopropyl ethyl amine (880 μL, 5.1 mmol) and DMSO (5.1 mL) was heated in the microwave to 160° C. for 2×0.5 h and 1 h. The mixture was then diluted with ice-water and extracted with ethyl acetate. The combined organic extracts were then washed with brine and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (335 mg, 38%) as a yellow gum. MS: m/e=342.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[Cl:26][C:27]1[CH:28]=[C:29]([C:33](=[N:35]O)[NH2:34])[CH:30]=[CH:31][CH:32]=1>>[Cl:26][C:27]1[CH:28]=[C:29]([C:33]2[N:35]=[C:23]([CH:11]3[CH2:10][CH:9]([C:6]4[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=4)[CH2:14][N:13]([C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:16])[CH2:12]3)[O:24][N:34]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: NC(=NO)c1cccc(Cl)c1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4cccc(Cl)c4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 38 mg (0.22 mmol, 1.1 eq.) of 3-chloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 40 mg (42% of theory)
Reaction SMILES: [Br-].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[NH:11][CH3:12])=[CH:6][CH:5]=1)#[N:3].C([Li])CCC.CI.[OH-].[Na+]>O1CCCC1>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][NH:11][CH3:12])=[CH:8][CH:9]=1)#[N:3]
Reactant: CNN(c1ccc(C#N)cc1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CNNc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a mixture of 260 g of (1-(4-cyanophenyl)-2-methylhydrazino)triphenylphosphonium bromide and 2,000 ml of tetrahydrofuran, 347 ml of n-butyllithium (1.66 M, hexane solution) was added at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. 85.6 g of methyl iodide was added thereto, and the resulting mixture was stirred for 20 hours. Then, 1,400 ml of 2N aqueous sodium hydroxide was added. The mixture was stirred at 50° C. for another 1 hour. After the mixture was allowed to separate, the aqueous layer was extracted with benzene. The organic layers were combined and extracted with 1N hydrochloric acid, and the extract was washed with chloroform. The resulting acidic aqueous solution was adjusted to pH 10-12 with 2N aqueous sodium hydroxide and then extracted with benzene. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After the insolubles were filtered off, the solvent was removed by evaporation under reduced pressure to leave 60.8 g of the title compound as a pale yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:19][C:20](=[O:22])[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[N+:16]([O-])=O.[NH4+].[Cl-]>[Fe]>[NH2:16][C:10]1[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=1[S:8][C:7]1[CH:6]=[CH:5][C:4]([NH:19][C:20](=[O:22])[CH3:21])=[CH:3][C:2]=1[F:1]
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2[N+](=O)[O-])c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)c(F)c1

Procedure:
The product from Example 39d was reduced with Fe and NH4Cl following the procedure from Example 237E to give the title compound.
Reaction SMILES: [CH2:1]=[C:2]([OH:10])[CH:3]([OH:9])[CH:4]([OH:8])[C:5]([OH:7])=[CH2:6].CC([O-:15])(C)C.[K+].C1COCC1.CO.C(=O)=O>C1COCC1>[CH2:6]([OH:15])[C@H:5]([C@H:4]([C@@H:3]([C@@H:2]1[O:10][CH2:1]1)[OH:9])[OH:8])[OH:7]
Reactant: C=C(O)C(O)C(O)C(=C)O
Reactant: CC(C)(C)[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H]1CO1
Reaction time: 30 h
Yield: 17 %

Procedure:
To a solution of 1,2:5,6-dianhydro-D-mannitol (0.50 g) in dry THF (3.4 mL) was added t-BuOK/THF solution (0.17 mL, 1.0 mol·L−1) under a nitrogen atmosphere. After 30 hours, the reaction mixture was poured into a large amount of methanol and neutralized with aqueous dry ice. The solvent was evaporated, and the residue was purified using a permeable membrane in water to give the polymer 0.085 g (17.0% yield); a specific rotation+19.6f (c 1.0, H2O, 23 fC). The Mw,SEC and Mw/Mn were 1,600 and 5.07, respectively, and the Mw,SLS was 13.1×105 in aqueous sodium nitrate solution (0.2 mol·L−1). The inertial and hydrodynamic radii of the polymer were 131 nm (SLS) and 132 nm (DLS), respectively, at 40° C. in aqueous sodium nitrate solution (0.2 mol·L−1). The 1H NMR and 13C NMR spectra of the polymer are shown in FIG. 3 and FIG. 4, respectively.
Reaction SMILES: CN1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36](Br)=[N:35][CH:34]=1.[N:43]1([CH2:49][CH2:50][O:51][C:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[CH:54][CH:53]=2)[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1.C(N(CC)C(C)C)(C)C>CC(O)C>[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36]([NH:58][C:55]2[CH:56]=[CH:57][C:52]([O:51][CH2:50][CH2:49][N:43]3[CH2:44][CH2:45][O:46][CH2:47][CH2:48]3)=[CH:53][CH:54]=2)=[N:35][CH:34]=1
Reactant: Brc1ncc(Br)n2ncnc12
Reactant: Nc1ccc(OCCN2CCOCC2)cc1
Agent: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Brc1cnc(Nc2ccc(OCCN3CCOCC3)cc2)c2ncnn12
Temperature: 95 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
According to the procedure described for Compound 6, step 1, 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (0.5 g, 1.799 mmol), 4-(2-morpholin-4-yl-ethoxy)-phenylamine (0.6 g, 4.5 mmol) and N,N-diisopropylethylamine (0.47 mL, 2.7 mmol) in 2-propanol (6 mL) are stirred at 95° C. overnight. After evaporation of the solvent the residue is dissolved in DCM and washed with water (2×) and brine. The organic layer is dried over MgSO4, filtered and concentrated in vacuo to afford an oil purified by silica gel column chromatography. Elution with a 97:3 mixture DCM:MeOH gives the title compound (650 mg 86%) as a light yellow solid. LCMS: Rt 2.06 nm in (97.7%).
Reaction SMILES: C(OC([N:8]1[CH2:18][CH2:17][C:11]2([CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)S(O[C:25]1[CH2:26][O:27][C:28](=[O:31])[C:29]=1C)(=O)=O.CC1C(=O)OCC=1N1CCCC2(CCNCC2)C1=O>>[O:31]=[C:28]1[O:27][CH2:26][C:25]([N:14]2[C:13](=[O:16])[CH2:12][C:11]3([CH2:10][CH2:9][NH:8][CH2:18][CH2:17]3)[CH2:15]2)=[CH:29]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)C2
Reactant: CC1=C(OS(=O)(=O)C(F)(F)F)COC1=O
Agent: CC1=C(N2CCCC3(CCNCC3)C2=O)COC1=O
Product: O=C1C=C(N2CC3(CCNCC3)CC2=O)CO1

Procedure:
The title compound was prepared from 3-oxo-2,8-diaza-spiro[4,5]decane-8-carboxylic acid tert-butyl ester and 4-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate in two steps in an analogous fashion to that described for 2-(4-Methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,9-diazaspiro[5.5]undecan-1-one (I-19) above.
Reaction SMILES: NN.[CH3:3][O:4][C:5](=[O:17])[CH2:6][N:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[CH:10]=1)[NH2:8].[O-:18][C:19]#[N:20].[Na+].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.CCOCC>[NH2:20][C:19]([NH:8][N:7]([CH2:6][C:5]([O:4][CH3:3])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[CH:10]=1)=[O:18]
Reactant: CCc1cccc(N(N)CC(=O)OC)c1
Reactant: N#C[O-]
Agent: NN
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCc1cccc(N(CC(=O)OC)NC(N)=O)c1
Reaction time: 3 h
Yield: 49 %

Procedure:
To the hydrazine (Intermediate 39; 3.75 g; 0.018 mol) and sodium cyanate (3.54 g; 0.054 mol) in toluene (30 ml) was added, dropwise, trifluoroacetic acid (5.82 g; 3.93 ml; 0.051 mol). This mixture was stirred for 3 h. and was then quenched with sodium bicarbonate and extracted into ethyl acetate. The organic extract was washed with sodium bicarbonate, water and brine and then dried (Na2SO4). Filtration and evaporation gave a cream solid which, on trituration with ether, afforded the title compound as a white solid (2.21 g; 49%), m.p. 128°-130° C.
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:35])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].[NH2:36][C@H:37]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[OH:41]>C1COCC1.CN(C=O)C.O>[C:46]([O:45][C:43](=[O:44])[C@@H:37]([NH:36][C:9](=[O:35])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Eicosanedioic acid tert-butyl ester 2,5-dioxo-pyrrolidin-1-yl ester (6.01 g, 12.124 mmol) was dissolved in THF (150 mL) and mixed with a slurry of H-Glu-OtBu (2.71 g, 13.33 mmol) in DMF/water (1/1, 40 mL). This resulted in a gel-like solution which was heated to give a clear solution that was stirred at RT for 3 h. Then the solution was evaporated, 100 mL of water was added and the mixture was heated to 60° C. which resulted in a solution which crystallised on cooling. The precipitate was recrystallised from acetonitrile and the crystals were dried in vacuum. Yield 6.82 g (96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:35])[C:6]=1[C:7]1[CH:21]=[C:20]([NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH:19]=[CH:18][C:8]=1[O:9][CH2:10][C:11]([O:13]C(C)(C)C)=[O:12].O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:35])[C:6]=1[C:7]1[CH:21]=[C:20]([NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=2)[CH:19]=[CH:18][C:8]=1[O:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(=O)O
Reaction time: 18 h
Yield: 70.8 %

Procedure:
To a solution of tert-butyl 2-(2-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-(3-(trifluoromethyl)benzamido)phenoxy)acetate (0.460 g, 0.902 mmol) in CH2Cl2 (5 mL) was added water (0.5 mL) and trifluoroacetic acid (5 mL, 56 mmol). The resulting solution was stirred for 18 hours, reduced under vacuum, azeotroped with toluene, and triturated in ether to give the title compound as a white solid (0.290 g, 70.8%). LCMS m/z (%)=454 (M+H, 35Cl, 100), 456(M+H, 37Cl, 30). 1H NMR (400 MHz, DMSO-d6) δ 3.72 (s, 3H) 4.70-4.84 (m, 2H) 7.11 (d, J=9.09 Hz, 1H) 7.63 (s, 1H) 7.72 (d, J=2.53 Hz, 1H) 7.79 (t, J=7.83 Hz, 1H) 7.87 (dd, J=9.22, 2.65 Hz, 1H) 7.97 (d, J=8.34 Hz, 1H) 8.26 (d, J=8.08 Hz, 1H) 8.29 (s, 1H) 10.52 (s, 1H) 13.10 (br. s., 1H).
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[OH-].[K+].C(OP([CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1)(OCC)=O)C>CO>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([CH:21]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([CH:1]=[O:10])=[CH:3][CH:4]=2)=[CH:23][CH:24]=1)#[N:27]
Reactant: O=Cc1ccc(C=O)cc1
Reactant: CCOP(=O)(Cc1ccc(C#N)cc1)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(C=Cc2ccc(C=O)cc2)cc1
Yield: 91 %

Procedure:
With stirring, cooling and blanketing with nitrogen, 6.7 g of terephthalaldehyde are added in portions to a mixture of 6.2 ml of aqueous potassium hydroxide solution 50% w/v and 40 ml of methanol, such that the temperature does not exceed 22° C. The resultant solution is then treated dropwise at 10° C. over 1/2 hour with a solution of 12.7 g of p-diethylphosphonomethylbenzonitrile (99.5%) in 10 ml of methanol, whereupon the reaction product soon precipitates. After stirring overnight at 10° C., the thick suspension is neutralised with 3 ml of glacial acetic acid, diluted with 40 ml of water, and filtered with suction. The filter residue is washed repeatedly with a 3:2 mixture of methanol/water and then with water until salt-free and dried under vacuum at 80° C., affording 10.6 g of 4-cyanostilbene-4'-aldehyde as a pale yellow powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:38])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([O:27]CC4C=CC(OC)=CC=4)=[C:22]([O:24][CH2:25][CH3:26])[CH:23]=3)=[CH:14][C:13]=2[F:37])=[CH:5][C:4]=1[C:39]([F:42])([F:41])[F:40])#[N:2].Cl>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:38])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[C:22]([O:24][CH2:25][CH3:26])[C:21](=[O:27])[NH:20][CH:19]=3)=[CH:14][C:13]=2[F:37])=[CH:5][C:4]=1[C:39]([F:41])([F:42])[F:40])#[N:2]
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(C#N)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: Cl
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(C#N)c(C(F)(F)F)c3)c(F)c2)c[nH]c1=O
Yield: 24.6 %

Procedure:
A solution of N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (15 mg, 0.026 mmol) in HCl (MeOH (solvate), 5 mL, 0.026 mmol) was stirred at 20° C. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The crude product was purified by preparative HPLC to yield a white solid of N-(4-cyano-3-(trifluoro-methyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide (3 mg, 6.39 μmol, 24.7% yield): 1H NMR (400 MHz, CD3OD) δ 8.23 (s, 1H), 7.99 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.41 (m, 1H), 7.37-7.34 (m, 3H), 7.29 (d, J=2.0 Hz, 1H), 4.17-4.11 (m, 2H), 3.84 (s, 2H), 1.46 (t, J=6.8 Hz, 3H); ES-LCMS m/z 460.1 (M+H).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:37]=[CH:36][C:21]([O:22][CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[CH:20][CH:19]=3)[C:10]2=[S:38])=[CH:5][C:4]=1[CH3:39])#[N:2]>Cl.CO>[CH3:39][C:4]1[C:3]([C:1]#[N:2])=[N:8][CH:7]=[C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:13][CH2:14][CH2:15]3)[N:11]([C:18]3[CH:19]=[CH:20][C:21]([O:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:36][CH:37]=3)[C:10]2=[S:38])[CH:5]=1
Reactant: Cc1cc(N2C(=O)C3(CCC3)N(c3ccc(OC4CCN(C(=O)OC(C)(C)C)CC4)cc3)C2=S)cnc1C#N
Agent: Cl
Solvent: CO
Product: Cc1cc(N2C(=O)C3(CCC3)N(c3ccc(OC4CCNCC4)cc3)C2=S)cnc1C#N
Yield: 93.4 %

Procedure:
Tert-butyl 4-(4-(7-(6-cyano-5-methylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenoxy)piperidine-1-carboxylate (prepared by reaction of 5-(5-(4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methylpicolinonitrile (Compound 77) with tert-butyl 4-hydroxypiperidine-1-carboxylate, according to Example 16, 300 mg, 0.55 mmol) was stirred in 2M HCl/methanol (1.5 mL) at room temperature overnight. The mixture was concentrated and purified by column chromatography, eluting with 10% MeOH/DCM to provide 230 mg of 3-methyl-5-(8-oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)picolinonitrile as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.72 (d, 1H), 8.14 (d, 1H), 7.30 (d, 2H), 7.13 (d, 2H), 4.53-4.42 (m, 1H), 3.94-3.86 (m, 1H), 3.02-2.83 (m, 3H), 2.66-2.50 (m, 5H), 2.49-2.33 (m, 3H), 2.11-1.80 (m, 3H), 1.60-1.33 (m, 3H). LCMS [M+1]+ 448.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:3]=1.[SH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][S:18][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:3]=1)[CH3:24]
Reactant: Clc1ccc(CNc2nc(Cl)cc(Cl)n2)cc1
Reactant: CCOC(=O)CS
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1cc(Cl)nc(NCc2ccc(Cl)cc2)n1

Procedure:
A stirred mixture of 3.25 g. of 4,6-dichloro-2-(p-chlorobenzylamino)pyrimidine, 1.35 g. of ethyl mercaptoacetate and 0.95 g. of sodium bicarbonate in 50 ml. of ethanol was heated under reflux overnight. The reaction mixture was filtered. A crystalline material was deposited which amounted to 2.7 g., m.p. 122°-125°C. The analytical sample was obtained by recrystallization from ethanol, m.p. 122°-125°C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[C:5](/[O:16][CH2:17][CH3:18])=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)[CH3:2].[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)/C(=C/c1ccc2[nH]ccc2c1)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Reaction time: 2 h
Yield: 89 %

Procedure:
A suspension of 9.7 g of (Z)-2-ethoxy-3-(1H-indol-5-yl)-acrylic acid ethyl ester in 100 ml of EtOH and 1.0 g of Pd/C (10%) was hydrogenated at 22° C. for 2 h after which time hydrogen uptake ceased. The suspension was filtered, the filtrate evaporated and the residue chromatographed on silica (n-hexane/AcOEt, 2:1) to give 8.7 g of the title compound as a white solid. MS: (M)+ 261.2.
Reaction SMILES: C([Li])(C)(C)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.[N:14]1[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][CH:15]=1.O>CCOCC.CO.C(Cl)Cl>[Cl:13][C:10]1[C:9]([CH:20]([C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)[OH:21])=[N:8][C:7]([Cl:6])=[CH:12][CH:11]=1
Reactant: O=Cc1ccncc1
Reactant: Clc1ccc(Cl)nc1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: OC(c1ccncc1)c1nc(Cl)ccc1Cl
Temperature: -78 °C
Yield: 46.6 %

Procedure:
Under stirring at −78° C., tert-butyl lithium (1.51M pentane solution: 4.6 ml) was added dropwise to a solution of 2,5-dichloropyridine (1.02 g, 6.89 mmol) in ether (20 ml). After stirring at −78° C. for 2 hours, pyridin-4-carbaldehyde (0.65 ml, 6.89 mmol) was added to the reaction mixture. The resulting mixture was stirred at −78° C. for 1 hour. Water was added to the reaction mixture and the temperature was raised to room temperature. The mixture was extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The residue thus obtained was subjected to chromatography on a silica gel column. A fraction obtained from the eluate with methanol:methylene chloride (1:50) was concentrated under reduced pressure. The solid thus obtained was washed with ether and collected by filtration, whereby the title compound (819 mg, 3.21 mmol, 47%) was obtained as a white powder.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:16])[CH2:14][OH:15])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H][H]>>[CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:16])[CH2:14][OH:15])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(CO)CCCc1ccc(C(C)C)cc1
Product: CC(CO)CCCC1CCC(C(C)C)CC1
Reaction time: 15 h
Yield: 97.3 %

Procedure:
100 g of 5-(4-Isopropylphenyl)-2-methyl-1-pentanol (obtained as described in EP 0 908 439) combined with 1.5 g Ru on aluminium oxide (Ru content 5 wt. %) were hydrogenated at a hydrogen pressure of 25 bar and at a temperature of 110° C. After 15 hours the reaction was finished. The catalyst was removed and the product distilled. 100 g (content 99.7%) of 5-(4-isopropylcyclohexyl)-2-methyl-1-pentanol were obtained.
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.C[C:53]1[CH:60]=[C:59]([CH2:61]Br)[CH:58]=[CH:57][C:54]=1[C:55]#[N:56].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[C:55]([C:54]1[CH:57]=[CH:58][C:59]([CH2:61][O:51][C:42]2[CH:41]=[C:40]([CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=2)[CH2:39][N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])=[CH:60][CH:53]=1)#[N:56]
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Reactant: Cc1cc(CBr)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCc2ccc(C#N)cc2)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (3R,4 S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.05 M) was added methyl 4-(bromomethyl)benzonitrile (1.6 eq.) and cesium carbonate (1.3 eq.). The reaction was heated to 80° C. and stirred for 16 h. After cooling to rt, the reaction was diluted with ether and quenched with water. The aqueous layer was extracted with ether. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 5% EtOQc in Hex→100% EtOAc) to afford the title compound as a oil
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([OH:27])[CH:26]=1)[CH:22]=[O:23]>>[CH2:2]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:27][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2])[CH:26]=1)[CH:22]=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: O=Cc1cc(O)cc(O)c1
Product: CCCCCCCCCCCCCCCCOc1cc(C=O)cc(OCCCCCCCCCCCCCCCC)c1

Procedure:
The title compound was prepared according to the method described in Example 9 above from 1-bromohexadecane and 3,5-dihydroxy-benzaldehyde. The solid reaction product was collected by filtration and washed with methyl ethyl ketone (Soxhlet). The filtrate was evaporated under reduced pressure to give the title compound as a red oil which was crystallised from acetone.