Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N:16]3[C:20](=[O:21])[NH:19][C:18]([C:22]([CH3:27])([CH3:26])[CH2:23][O:24][CH3:25])=[N:17]3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][O:24][CH2:23][C:22]([C:18]1[NH:19][C:20](=[O:21])[N:16]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:32]4[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=4)[CH:7]=3)=[C:14]([CH3:15])[N:13]=2)[N:17]=1)([CH3:27])[CH3:26]
Reactant: COCC(C)(C)c1nn(-c2ccc(Oc3ccnc(Cl)c3)c(C)n2)c(=O)[nH]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COCC(C)(C)c1nn(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(=O)[nH]1
Temperature: 85 °C
Reaction time: 12 h
Yield: 75.1 %

Procedure:
1-(5-((2-Chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-(1-methoxy-2-methylpropan-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.10 g, 0.26 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.07 g, 0.33 mmol), and K2CO3 (0.09 g, 0.66 mmol) were suspended in a solution of dioxane (2.0 mL) and water (0.4 mL). The suspension was sonicated and sparged with Ar for 10 min followed by the addition of Pd(PPh3)4 (0.03 g, 0.026 mmol). The reaction mixture was stirred at 85° C. for 12 h, allowed to cool to RT, diluted with water (2.0 mL), and extracted with EtOAc (5×3 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford an orange oil. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 3-(1-methoxy-2-methylpropan-2-yl)-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.085 g, 76%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.93 (s, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 6.65 (dd, J=5.7, 2.5 Hz, 1H), 3.84 (s, 3H), 3.39 (s, 2H), 3.25 (s, 3H), 2.33 (s, 3H), 1.24 (s, 6H); MS (ESI) m/z: 436.2 (M+H+).
Reaction SMILES: [Na].[CH:2]1([C:5](=[N:7][OH:8])[NH2:6])[CH2:4][CH2:3]1.[CH3:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]2[CH:20]=[N:21][C:22]([C:23](OCC)=O)=[C:12]2[C:11]1=[O:28]>C(O)C>[CH:2]1([C:5]2[N:6]=[C:23]([C:22]3[N:21]=[CH:20][N:13]4[C:14]5[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=5)[N:10]([CH3:9])[C:11](=[O:28])[C:12]=34)[O:8][N:7]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ncn2c1c(=O)n(C)c1ccccc12
Reactant: NC(=NO)C1CC1
Agent: [Na]
Solvent: CCO
Product: Cn1c(=O)c2c(-c3nc(C4CC4)no3)ncn2c2ccccc21

Procedure:
50 mg of sodium was dissolved in 25 ml of dry ethanol containing 3 g of molecular sieves (4 Å) and 0.5 g of cyclopropylcarboxamide oxime was added to this mixture and thereupon 0.6 g of ethyl 4,5-dihydro-5-methyl-4-oxo-imidazo(1,5-a)quinoxaline-3-carboxylate. The resulting mixture was refluxed for 2 hours, whereafter the molecular sieves were filtered off. The title compound was isolated after evaporation of the solvent in vacuo, followed by addition of icewater and filtration. Yield 0.4 g of title compound. M.p. 224.7-225.6° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH-].[Na+].S(OC)(O[CH3:23])(=O)=O>C(O)C>[CH3:23][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCC(=O)c1cc(C)ccc1O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(=O)c1cc(C)ccc1OC
Temperature: 0 °C
Yield: 57 %

Procedure:
1-(2-Hydroxy-5-methylphenyl)heptan-1-one (127 g, 0.61 mol), a 2.5N aqueous sodium hydroxide solution (250 ml) and ethanol (250 ml) were mixed, and this solution was cooled to 0° C. Dimethyl sulfate (60 ml) was added, and the mixture was refluxed under heating for 2 hours. Dimethyl sulfate (40 ml) and a 2.5N aqueous sodium hydroxide solution (170 ml) were further added, and the mixture was refluxed under heating for 2 hours. The reaction mature was concentrated under reduced pressure and the obtained residue was extracted twice with ether (200 ml). The organic layers were combined, washed twice with a 2.5N aqueous sodium hydroxide solution and saturated brine (100 ml1 each), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane/ethyl acetate=95/5) to give 1-(2-methoxy-5-methylphenyl)heptan-1-one (82 g, 57%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:13])[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH3:12])[C:6]=2[N:7]=1.[H-].[Na+].I[CH3:17]>CN(C)C=O.O>[NH2:1][C:2]1[N:3]([CH3:17])[C:4](=[O:13])[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH3:12])[C:6]=2[N:7]=1
Reactant: Cn1cc(I)c2c(=O)[nH]c(N)nc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(N)nc2c(c(I)cn2C)c1=O
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a solution of 2-amino-5-iodo-7-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (15.4 g, 53.1 mmol) in N,N-dimethylformamide (150 ml) was added sodium hydride (66% dispersion in oil, 1.93 g, 53.1 mmol) and iodomethane (3.31 ml, 53.1 mmol) at 0° C., and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate (×2) and ethyl acetate-tetrahydrofuran (×2). The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 50-100% hexane/ethyl acetate gradient mixture, and the desired fractions were concentrated in vacuo. The residual crystals were washed with diethyl ether to give 12.3 g (76%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([OH:42])[CH:34]=[C:35]([S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:42][C:33]2[CH:34]=[C:35]([S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])[CH:36]=[C:31]([Br:30])[CH:32]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCS(=O)(=O)c1cc(O)cc(Br)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(S(=O)(=O)CC)c2)c1CCC(=O)OCC
Yield: 94.9 %

Procedure:
A similar procedure as described in Example 40, step 6 was used, starting from 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.13 g, 2.39 mmol), 3-bromo-5-ethanesulfonyl-phenol (576 mg, 2.17 mmol), and potassium carbonate (600 mg, 4.34 mmol) to afford 4-[3-[6-(3-bromo-5-ethanesulfonyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.35 g, 95%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C31H43BrO8S (M+Na)+ 677.1754, found 677.1756.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:16][CH:15]([CH2:17][OH:18])[CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C1COCC1>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:14][CH:15]([CH2:17][O:18][C:20]4[N:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:16]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CC(c2ccc(CN3CCCC3)cc2)C1
Reactant: Clc1ncccn1
Solvent: C1CCOC1
Product: c1cnc(OCC2CC(c3ccc(CN4CCCC4)cc3)C2)nc1

Procedure:
To a stirring solution of [3-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutyl]-methanol (38.0 mg, 0.16 mmol) prepared above (Step F) in 1.5 mL of THF was added 2-chloropyrimidine (21.3 mg, 0.19 mmol) followed by a solution of KotBu (310 uL, 0.31 mmol, 1 M THF). The reaction immediately turned to a dark pink/milky solution. When mass spectral analysis indicated complete consumption of starting alcohol (15 minutes) the reaction was quenched with an aqueous solution of NH4Cl. The reaction was diluted with a 3:1 mixture of chloroform/isopropyl alcohol. The layers were separated and the organic layer was dried over MgSO4, filtered through a fritted glass filter, and concentrated under reduced pressure to yield the title compound as a mixture of cis:trans isomers. Conversion to the HCl salt was accomplished by dissolving the free base in EtOAc, and then adding 1 eq of a solution of HCl (1 M THF). The colorless solid was collected and dried under reduced pressure to yield 45 mg of a colorless solid, and as a mixture of isomers.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH:19]=[C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28]>>[CH:30]([O:29][C:27]([N:23]1[CH2:24][CH2:25][CH:20]([C:18]2[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=4)[CH:12]=[C:13]3[CH:19]=2)[CH2:21][CH2:22]1)=[O:28])([CH3:32])[CH3:31]
Reactant: CS(=O)(=O)N1CC=C(c2cc3cc(C4CCNCC4)oc3cn2)CC1
Reactant: CC(C)OC(=O)Cl
Product: CC(C)OC(=O)N1CCC(c2cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3o2)CC1

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-furo[2,3-c]pyridine and isopropyl chloroformate following a procedure analogous to that described for Example 19. LC (method 6): tR=1.45 min; Mass spectrum (ESI+): m/z=448 [M+H]+.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH2:35])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Product: COc1cc(C(N)=O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and ammonium chloride. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.41 (m, 3H) 1.54-1.86 (m, 7H) 3.32 (s, 3H) 3.93 (s, 3H) 4.17 (t, J=12.5 Hz, 2H) 4.44-4.55 (m, 1H) 7.33 (s, 1H) 7.55 (d, J=8.3 Hz, 1H) 7.59 (s, 1H) 7.99 (s, 1H) 8.13 (d, J=8.1 Hz, 1H) 8.24 (s, 1H) 8.61 (s, 1H). [M+H] calc'd for C22H26F2N6O3 461. found 461.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:42])=[C:9]([CH2:11][O:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26](N(OC)C)=[O:27])=[CH:22][N:21]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:20]=3)=[CH:15][C:14]=2[O:40][CH3:41])[N:10]=1.[CH2:43]([Mg]Br)[CH3:44].Cl>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:42])=[C:9]([CH2:11][O:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26](=[O:27])[CH2:43][CH3:44])=[CH:22][N:21]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:20]=3)=[CH:15][C:14]=2[O:40][CH3:41])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)N(C)OC)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCC(=O)/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
To a mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-N-methoxy-N-methyl-2-propenamide (0.40 g) and tetrahydrofuran (30 mL) was added dropwise ethylmagnesium bromide (1M tetrahydrofuran solution, 4.2 mL) at 0° C. and the mixture was stirred at room temperature for 2 hrs. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give (1E)-1-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-1-penten-3-one as colorless crystals (0.13 g, yield 34%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 167-168° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].Br[CH2:9][CH:10](OCC)OCC.Br>C(O)C>[N:7]1[CH:9]=[CH:10][N:1]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=12
Reactant: CCOC(CBr)OCC
Reactant: Nc1cnccn1
Agent: Br
Solvent: CCO
Product: c1cn2ccnc2cn1
Yield: 24 %

Procedure:
2-Pyrazinamine (9.51 g, 100 mmol) was dissolved in ethanol (300 ml) and 2-bromo-1,1-bis(ethyloxy)ethane (21.06 ml, 140 mmol) was added. 48% hydrobromic acid (33.3 ml) was added and the mixture heated at reflux for 24 hr. The solution was concentrated in vacuo to a crude solid that was basified with 10% ammonia-ice (300 ml). The solution was extracted in to ethyl acetate (3×300 ml), the combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude solid, (4.76 g). The solid was purified by flash chromatography (Biotage SP4, 40+M, eluting with a 0-100% [25% 2M ammonmia/methanol in dichloromethane] in dichloromethane gradient) to afford imidazo[1,2-a]pyrazine (2.86 g, 24.01 mmol, 24.01% yield).).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](#[N:18])[CH:16]=[CH2:17].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CO.O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:17][CH2:16][C:15]#[N:18])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC#N
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#CCCOc1ccc(Oc2ccccc2)cc1
Yield: 34.6 %

Procedure:
3-(p-Phenoxyphenoxy)propionitrile was prepared by heating under reflux for 18 hours a mixture of 25 g of p-phenoxyphenol, 28.4 g of acrylonitrile and 5 ml of a 40% solution of benzyltrimethylammonium hydroxide in methanol. It was worked up by cooling, diluting with 400 ml water, extracting using ethyl acetate; washing the organic layer with 5% aqueous sodium hydroxide, drying, evaporating the solvent, and recrystallizing from hexane to yield 11.1 g of 3-(p-phenoxyphenoxy)propionitrile m.p. 81-3° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]2)=[CH:9][C:5]=1[CH:6]=[N:7]O)[CH3:2].NO.C(OC(=O)C)(=O)C>O>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:14][CH2:15][C@H:16]([CH2:19][CH2:20][CH3:21])[CH2:17][CH2:18]2)=[CH:9][C:5]=1[C:6]#[N:7])[CH3:2]
Reactant: CCC[C@H]1CC[C@H](c2ccc(OCC)c(C=NO)c2)CC1
Agent: NO
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCC[C@H]1CC[C@H](c2ccc(OCC)c(C#N)c2)CC1
Reaction time: 0.33 h

Procedure:
A mixture of 28.9 g of 2-ethoxy-5-(trans-4-propyl-cyclohexyl)-benzaldoxime (obtainable from the aldehyde and hydroxylamine) and 40 ml of acetic anhydride is heated until the exothermic reaction starts, and is then boiled for 20 minutes and poured into water to give 2-ethoxy-5-(trans-4-propyl-cyclohexyl)-benzonitrile of m.p. 32°.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:28][CH2:27][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH2:14][N:13]([CH2:23][CH2:24]O)[C:12]2=[O:26])[CH2:10][CH2:9]1)=[O:7].[CH:38]([NH2:41])([CH3:40])[CH3:39]>>[F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH2:14][N:13]([CH2:23][CH2:24][NH:41][CH:38]([CH3:40])[CH3:39])[C:12]2=[O:26])[CH2:27][CH2:28]1)=[O:7]
Reactant: Cc1ccccc1N1CN(CCO)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: CC(C)N
Product: Cc1ccccc1N1CN(CCNC(C)C)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=571.1 (M+H+), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-hydroxy-ethyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and isopropylamine.
Reaction SMILES: [C:1]1([N:7]2[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)(=O)C.O.Cl>[C:1]1([N:7]2[CH2:8][CH2:9][C:10](=[O:11])[CH2:15][CH2:16]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCN(c2ccccc2)CC1
Temperature: 50 °C

Procedure:
8-Phenyl-1,4-dioxa-8-azaspiro[4.5]decane (18.1 g, 82.5 mmol) was dissolved in a mixture of acetic acid (150 mL), water (150 mL), and conc. hydrochloric acid (38 mL) and the resulting solution was heated to 50° C. for 18 hrs. The reaction mixture was cooled in an ice-water bath, and sodium hydroxide pellets were added in portions until the mixture was neutralized. This mixture was extracted with dichloromethane (3×300 mL) and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give a dark oil. Chromatography on silica gel, eluting with hexane--10% ethyl acetate gave the product as a pale yellow oil.
Reaction SMILES: C1COCC1.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26]CC2C=CC=CC=2)=[CH:22][CH:21]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>CCO.[Pd]>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 250 mL round bottomed flask which contained a suspension of Pd—C (10% wt, 3 g) in EtOH (70 mL) and THF (30 mL) was added (R)-2-(4-benzyloxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.5 g, 9 mmol). The stirred solution was flushed with a H2 balloon. This process was repeated 3 times. The resulting solution was stirred at rt under hydrogen atmosphere overnight. The reaction mixture was then filtered, washed with THF (30 ml), EtOH (25 ml) and dried in vacuo to provide the crude product which was further purified by recrystallization with ether-EtOAc-hexane to yield the title product, (2.5, 90%); MS; APCI+, Calcd: 293.5; Found m/z: 294.2 (M+1); 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.80-2.10 (m, 4H), 3.40 (br, 2H), 3.69-3.89 (m, 1H), 4.00-4.18 (m 2H), 6.71-6.76 (m, 4H).
Reaction SMILES: [F-].[K+].[CH:3]1([O:8][C:9]2[CH:10]=[C:11]([C:17]3([C:24]#[C:25][Si](C)(C)C)[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH2:18]3)[CH:12]=[CH:13][C:14]=2OC)CCCC1.CN(C)[CH:32]=[O:33]>>[CH:32]1([O:33][CH2:3][O:8][C:9]2[CH:10]=[C:11]([C:17]3([C:24]#[CH:25])[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH2:18]3)[CH:12]=[CH:13][CH:14]=2)[CH2:13][CH2:14][CH2:9][CH2:10]1
Reactant: CN(C)C=O
Reactant: COc1ccc(C2(C#C[Si](C)(C)C)CCCC(=O)C2)cc1OC1CCCC1
Agent: [F-]
Agent: [K+]
Product: C#CC1(c2cccc(OCOC3CCCC3)c2)CCCC(=O)C1
Reaction time: 18 h

Procedure:
A mixture of potassium fluoride (900 mg, 15.6 mmol) and 3-(3-cyclopentyloxy-4-methoxyphenyl)3-trimethylsilylethynyl cyclohexan-1-one (0.3 g, 0.78 mmol) was stirred in dry N,N-dimethylformamide (3 mL) under an argon atmosphere. After 18 h, the solvent was removed in vacuo, the residue was partitioned between water and ethyl acetate, the aqueous layer was extracted twice with ethyl acetate, the combined extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 4:1 hexanes/ethyl acetate provided a clear colorless oil . Anal. (C20H24O3 ·1/10H2O) calcd: C 76.45,H 7.76; found: C 76.32,H 7.60.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Br:29][C:30]1[CH:31]=[CH:32][C:33]2[C:39](=O)[CH2:38][CH2:37][CH2:36][S:35][C:34]=2[CH:41]=1>C1COCC1>[Br:29][C:30]1[CH:31]=[CH:32][C:33]2[C:39](=[CH:2][O:3][CH3:4])[CH2:38][CH2:37][CH2:36][S:35][C:34]=2[CH:41]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCCSc2cc(Br)ccc21
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC=C1CCCSc2cc(Br)ccc21
Temperature: -75 °C
Reaction time: 1.25 h
Yield: 85.2 %

Procedure:
16.68 g (1.6 eq.) of (methoxymethyl)triphenylphosphonium chloride was suspended in 75 ml of abs. THF and deprotonated between −15° C. and −5° C. by adding via syringe 29.5 ml of 1.6 M n-butyllithium (hexane, 1.55 eq.). The resultant red ylide solution was cooled to −75° C. and treated with 7.82 g (30.4 mmol) of 8-bromo-3,4-dihydro-2H-benzo[b]thiepin-5-one, dissolved in 15 ml of abs. THF. The mixture was then kept for 0.3 h at −78° C. and for 1.25 h at room temperature. Pouring onto crushed ice, twofold extraction with diethylether, washing the organic phase with water, drying over magnesium sulfate, filtration and evaporation of the solvents yielded a crude product which was purified by flash chromatography (SiO2, hexane/ethylacetate 95/5); thereby, 7.39 g of 8-bromo-5-methoxymethylene-2,3,4,5-tetrahydrobenzo[b]thiepine was obtained as E/Z-mixture which was hydrolyzed as follows:
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:9]=[C:8]2[C:18](=[O:20])[CH3:19])=[CH:4][CH:3]=1.C1COCC1.[C:28](OCC)(=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].CC[O-].[Na+]>CCOC(C)=O>[CH2:32]([O:31][C:29](=[O:30])[C:28](=[O:34])[CH2:19][C:18]([C:8]1[N:7]([CH2:6][C:5]2[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=2)[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=1)=[O:20])[CH3:33]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(-c2ccccc2)n1Cc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)CC(=O)c1ccc(-c2ccccc2)n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added 1-[1-(4-fluorobenzyl)-5-phenyl-1H-pyrrol-2-yl]ethanone AV-8-1 (0.628 g, 2.14 mmol), dry THF (10 mL), diethyl oxalate (0.41 mL, 3.00 mmol) and NaOEt (0.204 g, 3.00 mmol). The resulting mixture was stirred 1 h at ambient temperature. The mixture was diluted with EtOAc and washed with 1N HCl, H2O (2×) and brine. Drying (MgSO4) filtration and removal of the solvent in vacuo gave 4-[1-(4-fluorobenzyl)-5-phenyl-1H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AV-9-1 as an oil. This material was used without further purification. 1H NMR (CDCl3) δ 1.38 (3H, t, j=7.1 Hz), 4.38 (2H, q, j=7.1 Hz), 5.65 (2H, s), 6.38 (1H, d, j=4.1 Hz), 6.79 to 6.94 (4H, m), 7.29 (2H, m), 7.39 (3H, m).