Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:16]([CH2:20][C:21](=O)[CH3:22])[C:17]([CH3:19])=O>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH3:22][C:21]1[N:1]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=2)[C:12]([O:14][CH3:15])=[O:13])[C:17]([CH3:19])=[CH:16][CH:20]=1
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(=O)OC)cc(-n2c(C)ccc2C)c1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of dimethyl 5-aminoisophthalate (8, 10.5 g, 50 mmol) in toluene (50 mL) was added acetonylacetone (6.18 mL, 52.5 mmol) and p-TsOH (95 mg, 0.5 mmol). The reaction mixture was heated in a Dean-Stark apparatus under reflux for 12 h. After cooling to room temperature, the mixture was concentrated with a rotary evaporator, and the resulting brown oil was purified by flash column chromatography (EtOAc/hexanes, 1:19-1:9) to give 9 (13.2 g, 46 mmol, 92%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 2.05 (s, 6H), 3.99 (s, 6H), 5.95 (s, 2H), 8.11 (s, 2H), 8.74 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 13.3, 52.9, 106.8, 128.9, 130.0, 132.0, 133.6, 139.9, 165.7; LC-MS (M +H+) calcd for C16H18NO4 288, found 288.
Reaction SMILES: [CH2:1]([C:8]1([N:29]([CH3:31])[CH3:30])[CH2:13][CH2:12][C:11]([C:14]2[NH:15][C:16]3[C:21]([C:22]=2[CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[CH2:1]([C:8]1([N:29]([CH3:31])[CH3:30])[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][C:16]3[C:21]([C:22]=2[CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C1(Cc2ccccc2)CC=C(c2[nH]c3ccccc3c2CCCC(=O)O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)C1(Cc2ccccc2)CCC(c2[nH]c3ccccc3c2CCCC(=O)O)CC1

Procedure:
Palladium as the catalyst (Pd/C, 5%, 120 mg) was added to 4-[2-(4-benzyl-4-dimethylaminocyclohex-1-enyl)-1H-indol-3-yl]butanoic acid (300 mg, 0.7 mmol) in abs. methanol (30 ml) and hydrogenation was carried out at RT for 6 h (hydrogen pressure: 3 bar). The catalyst was removed with the aid of a frit provided with a layer of Celite 1 cm high. The residue was rinsed thoroughly with methanol (500 ml). The solvent was distilled off in vacuo. 4-(2-(4-Benzyl-4-(dimethylamino)cyclohexyl)-1H-indol-3-yl)butanoic acid was obtained in a yield of 260 mg (86%) as a yellow solid (one of the two possible diastereoisomers).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][C:33]=1[N+:40]([O-:42])=[O:41].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([OH:31])=[C:33]([N+:40]([O-:42])=[O:41])[CH:34]=2)[CH2:21][CH2:20]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(O)c([N+](=O)[O-])c2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.35 mmol), 4-hydroxy-3-nitrobenzaldehyde (1.22 mmol), methanol (3.8 mL), and acetic acid (0.175 mL) was added NaBH3CN (1.58 mmol) in methanol (3.2 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Variant™ SCX column, and washed with CH3OH. Product was eluted off using 2 N NH3 in CH3OH and concentrated. The resulting material was dissolved into ethyl acetate/methanol=5/1, loaded onto Varian™ Si column, eluted off using ethyl acetate/methanol 5/1 (10 mL), and concentrated to give 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-hydroxy-3-nitrobenzyl)piperidine (175 mg, 87%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[N:18][C:19]2[CH:20]=[CH:21][C:22]([OH:28])=[C:23]([CH:27]=2)[C:24]([OH:26])=[O:25])=[CH:13][CH:12]=1.[N-:29]=[N+:30]=[N-:31].[Na+]>CS(C)=O.CCOC(C)=O>[N:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[N:18][C:19]2[CH:20]=[CH:21][C:22]([OH:28])=[C:23]([CH:27]=2)[C:24]([OH:26])=[O:25])=[CH:13][CH:12]=1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1cc(N=Nc2ccc(OCCCCCCCCBr)cc2)ccc1O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCCCCCCCOc1ccc(N=Nc2ccc(O)c(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.1 %

Procedure:
5-((4-(8-Bromooctyloxy)phenyl)diazenyl)-2-hydroxybenzoic acid (2.50 g, 5.6 mmol) was dissolved in DMSO (40 mL) and NaN3 (1.10 g, 16.9 mmol) was added slowly to the reaction mixture with stirring at room temperature. After 48 h, the mixture was diluted with EtOAc (100 mL), washed with water (4×20 mL), brine (20 mL), dried over Na2SO4, and filtered. Volatiles were removed in vacuo and the residue subjected to column chromatography on silica gel 60 (230-400 mesh) using EtOAc and methanol (98:2) as the elutant to give 2.10 g (5.1 mmol, 91%) of the product as a red-brown solid, mp 54-56° C. 1H NMR (500 MHz, CDCl3) δ 1.27-1.58 (m, 8H), 1.62-1.64 (m, 2H), 1.81-1.86 (m, 2H), 3.31 (t, J=5 Hz, 2H), 4.06 (t, J=6.5 Hz, 2H), 6.88-7.01 (m, 3H), 7.84 (d, J=10 Hz, 2H), 7.91 (dd, J=15 Hz, 2.5 Hz, 1H), 8.47 (d, J=2.5 Hz, 1H); 13C NMR (125 MHz, CDCl3+CD3OD) δ 22.0, 25.3, 25.4, 28.5, 28.6, 28.8, 31.2, 50.8, 67.7, 114.1, 116.5, 117.5, 123.6, 126.2, 144.6, 146.2, 160.7, 175.0; HRMS (ESI) calculated for C21H26N5O4 (M+H)+412.1979, observed 412.1971.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([OH:10])[CH:5]=1.[CH3:11]I>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][N:7]([CH3:11])[C:6](=[O:10])[CH:5]=1
Reactant: Oc1cc(Br)ccn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc(Br)cc1=O
Reaction time: 1 h
Yield: 48.9 %

Procedure:
To a suspension of NaH (80 mg, 2 mmol) in THF (10 mL) was added 4-bromopyridin-2-ol (80 mg, 0.46 mmol) at 0° C. The resulting mixture was stirred for 1 h. Then CH3I (355 mg, 2.5 mmol) was added to the above mixture, and the mixture was stirred overnight. The reaction was quenched with aqueous NH4Cl solution. The organic phase was concentrated to give the crude product, which was purified by column to give 4-bromo-1-methylpyridin-2(1H)-one (42.3 mg, 50%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:15](Br)=[CH:14][C:13]2[C:12]([CH3:18])([CH3:17])[CH2:11][CH2:10][C:9]([CH3:20])([CH3:19])[C:8]=2[CH:7]=1.[Cl-].[CH3:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][Zn+])=[CH:25][CH:24]=1>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:15]([CH2:22][C:23]2[CH:30]=[CH:29][C:26]([CH3:27])=[CH:25][CH:24]=2)=[CH:14][C:13]2[C:12]([CH3:18])([CH3:17])[CH2:11][CH2:10][C:9]([CH3:20])([CH3:19])[C:8]=2[CH:7]=1
Reactant: CC1(C)CCC(C)(C)c2cc(C3OCCO3)c(Br)cc21
Reactant: Cc1ccc(C[Zn+])cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccc(Cc2cc3c(cc2C2OCCO2)C(C)(C)CCC3(C)C)cc1
Yield: 89 %

Procedure:
To a mixture of 2-(1,3-dioxolan-2-yl)-3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (250 mg, 0.74 mmol) and tetrakis(triphenylphospine)palladium(0) (21 mg, 0.018 mmol) under an argon atmosphere was added a 0.5 M tetrahydrofuran solution of 4-methylbenzylzinc chloride (7.3 mL, 3.68 mmol). The reaction mixture was stirred at reflux overnight and partitioned between saturated ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel (5% ethyl acetate/hexane) to give 2-(1,3-dioxolan-2-yl)-3-(4-methylbenzyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene as a white crystalline solid (240 mg, 89%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][Si:20]([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-bromo-3,5-dimethylphenol (2.1 g, 10 mmol) and imidazole (1.50 g, 22 mmol) in DMF (15 mL) was cooled to 0° C. then TBDMSCl (1.66 g, 11 mmol) was added. After the addition, the solution was warmed up to ambient temperature and was stirred for 10 min. The solution was recooled to 0° C. and the reaction was quenched with water. The aqueous layer was extracted with Et2O and the organic layer was washed with water, brine, dried with MgSO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (10:1) to give (4-bromo-3,5-dimethylphenoxy)-tert-butyl-dimethylsilane as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:15])=[CH:6][C:7]=1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[NH2:16][NH2:17]>CCO>[Cl:15][C:5]1[N:4]=[N:3][C:2]([NH:16][NH2:17])=[C:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:6]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nnc1Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)c1cc(Cl)nnc1NN
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a solution of tert-butyl 3,6-dichloropyridazine-4-carboxylate (66A) (3.9 g, 15.6 mmol) in EtOH (20 mL) was added anhydrous hydrazine (2 mL). The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. The crude product was triturated with 80% EtOH in H2O to afford 1.58 g (40%) of the title compound as a yellow solid. HPLC/MS (Method B): retention time=1.77 min, [M+H]+=189.3.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][Si:8]([CH2:20][CH2:21][C:22](OCC)=[O:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:5])[CH3:2].[H-].[Na+].C1(C)C=CC=CC=1>C(O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][Si:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][C:22]1=[O:23])=[O:5])[CH3:2]
Reactant: CCCCC[Si](CCC(=O)OCC)(CCC(=O)OCC)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCC[Si]1(c2ccccc2)CCC(=O)C(C(=O)OCC)C1
Yield: 88 %

Procedure:
194 g of di(2-ethoxycarbonylethyl)phenyl-n-pentylsilane was added to a suspension of 18.5 g sodium hydride and 800 ml of toluene, and the mixture was stirred for 3 hours at 100 ° C. while ethanol was distilled away. After cooling, 500 ml of 20% hydrochloric acid was added to the reaction mixture to make it neutral, and then the toluene layer was concentrated to obtain 150 g of 2-ethoxycarbonyl-4-n-pentyl-4-phenyl-4-silacyclohexanone.
Reaction SMILES: [CH3:1][CH:2]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][NH:4][CH2:3]1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:4]2[CH2:3][CH:2]([CH3:1])[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[NH:8][C:7]=3[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)C1=CNCC(C)c2c1[nH]c1ccccc21
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)c2c1[nH]c1ccccc21

Procedure:
In a manner similar to Example 2, the title compound was prepared from ethyl 1-methyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and 4-fluorobenzoyl chloride. 1H-NMR (CDCl3): δ 10.54 (1H, br s), 7.97 (1H, s), 7.63-7.68 (2H, m), 7.58 (1H, d), 7.39 (1H, d), 7.09-7.23 (4H, m), 5.28 (1H, dd), 4.25 (2H, m), 3.85 (1H, m), 3.18 (1H, d), 1.34 (3H, d), 1.22 (3H, t); MS(ESI): 393 (MH+).
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][CH:6]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:32]#[N:33])=[C:25]([CH:31]=1)[O:26][CH2:27][CH:28]1[O:30][CH2:29]1>C(O)(C)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:32]#[N:33])=[C:25]([CH:31]=1)[O:26][CH2:27][CH:28]([OH:30])[CH2:29][NH:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(N)CNc1ccc(C2=NNC(=O)CC2)cc1
Reactant: N#Cc1ccc(Cl)cc1OCC1CO1
Solvent: CC(C)O
Product: CC(C)(CNc1ccc(C2=NNC(=O)CC2)cc1)NCC(O)COc1cc(Cl)ccc1C#N
Reaction time: 20 h
Yield: 87.4 %

Procedure:
5.2 g of 6-[4-(2-amino-2-methylpropylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone obtained in Example 1, (3) and 4.4 g of 1-(5-chloro-2-cyanophenoxy)-2,3-epoxypropane were dissolved in 30 ml of isopropyl alcohol, and the solution was heated with stirring for 20 hours. The solution was then worked up as in Example 1, (5) to give 8.2 g of 6-[4-[2-[3-(5-chloro-2-cyano-phenoxy)-2-hydroxypropylamino]-2-methylpropylamino]-pheyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:4][CH:3]=1.[Li]CCCC.C([C:22]([O:24][CH2:25][CH3:26])=[O:23])#N>C1COCC1.CCOC(C)=O>[CH2:25]([O:24][C:22]([C:5]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:13])([CH3:12])[CH3:14])[C:2]([CH3:1])=[CH:3][N:4]=1)=[O:23])[CH3:26]
Reactant: Cc1cncn1COCC[Si](C)(C)C
Reactant: CCOC(=O)C#N
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ncc(C)n1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a solution of 5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (as prepared in the previous step, 0.320 g, 1.50 mmol) in 5 mL of THF at −78° C. was added n-BuLi (0.80 mL, 2 M in cyclohexane) and the mixture was allowed to attain RT and stirred for 30 min. The mixture was cooled to −78° C. and ethyl cyanoformate (0.160 g, 1.65 mmol) was added and the mixture allowed to stir for 10 h at RT. The reaction was diluted with 15 mL of EtOAc and washed with NaHCO3 (2×15 mL) and brine (15 mL). The title compound was eluted from a 20-g SPE with 50% EtOAc/hexanes to give 0.160 g (38%) of a light brown oil: Mass spectrum (ESI, m/z): Calcd. for C13H24N2O3Si, 285.2 (M+H). found 284.9.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5]([C:7]1[S:11][CH:10]=[C:9]([C:12]#[N:13])[CH:8]=1)=[O:6].O.Cl>CN(C=O)C>[NH:1]1[C:12]([C:9]2[CH:8]=[C:7]([CH:5]=[O:6])[S:11][CH:10]=2)=[N:13][N:3]=[N:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1csc(C=O)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(-c2nnn[nH]2)cs1
Temperature: 25 °C
Yield: 20 %

Procedure:
Sodium azide (2.9 g, 44.6 mmol) and TEA hydrochloride (4.13 g, 30 mmol) were added to a solution of 5-formyl-thiophene-3-carbonitrile (2 g, 15 mmol, prepared according to Intern. application WO 02126718) in DMF (50 ml). The solution was refluxed for 12 h. After cooling to RT, water was added and the solution was carefully acidified with HCl. The solution was extracted 3 times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to yield the desired product as a brown solid (540 mg) which was used without further purification.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2.C[O:11][C:12]([C:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=O>C1(C)C=CC=CC=1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:12]([C:14]1([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)=[O:11])[CH2:2]2
Reactant: COC(=O)C1(c2ccccc2)CCCCCC1
Reactant: O[C@H]1CN2CCC1CC2
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A solution of (R)-(3)-quinuclidinol (10.13 g) and 1-phenyl-cycloheptanecarboxylic acid methyl ester (Example 14d) (9.25 g) in toluene (90 mL) was heated to reflux with a Dean-Stark trap for 30 min. The reaction mixture was allowed to cool to room temperature and the trap was removed. Sodium hydride (60% dispersion in mineral oil) (3.19 g) was added portionwise under nitrogen and the reaction mixture was heated to reflux overnight under nitrogen. The reaction mixture was cooled in an ice bath and diluted with ethyl acetate (200 mL) and water (200 mL). The mixture was filtered and the layers separated. The aqueous layer was extracted with ethyl acetate (2×250 mL) and the combined organic layers were washed with brine, dried over magnesium sulfate and evaporated to give the crude product which was purified by silica gel chromatography eluting with EtOAc containing 1% triethylamine to give the sub-titled compound as a colourless oil (7.63 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:25](Cl)=[O:26])[C:6]2[CH2:7][CH:8]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:9]3[CH:14]([C:15]=2[CH:16]=1)[CH2:13][CH2:12][CH2:11][CH2:10]3.[NH4+:28].[OH-].C(OCC)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:25]([NH2:28])=[O:26])[C:6]2[CH2:7][CH:8]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:9]3[CH:14]([C:15]=2[CH:16]=1)[CH2:13][CH2:12][CH2:11][CH2:10]3
Reactant: [NH4+]
Reactant: COc1ccc(C2Cc3c(C(=O)Cl)cc(OC)cc3C3CCCCC23)cc1
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1ccc(C2Cc3c(C(N)=O)cc(OC)cc3C3CCCCC23)cc1

Procedure:
Combine 3-Methoxy-9-(4-methoxy-phenyl)-4b,5,6,7,8,8a,9,10-octahydro-phenanthrene-1-carbonyl chloride (0.08 g, 0.18 mmol), NH4OH (2 ml), and diethyl ether (1 ml) at 0-5° C. and stir as such 2 hours. Dilute with ethyl acetate and wash with water. Dry over anhydrous sodium sulfate, and remove solvent in vacuo at 40° C. to yield preparation 121 (0.069 g, 100%). MS m/z 366 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=[O:18])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])([CH3:9])[CH3:8])[CH3:2].[F:20][C:21]([Si](C)(C)C)([F:26])[C:22]([F:25])([F:24])[F:23].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:3][C:4](=[O:19])[C:5]([OH:18])([C:21]([F:26])([F:20])[C:22]([F:25])([F:24])[F:23])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(C)(C)c1ccccc1OC
Reactant: C[Si](C)(C)C(F)(F)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(CC(C)(C)c1ccccc1OC)C(F)(F)C(F)(F)F

Procedure:
Analogously to Example 7, 687 mg of ethyl-4-(2-methoxyphenyl)-4-methyl-2-oxopentanoate (WO 00/32584) is reacted with 1 g of (pentafluoroethyl)trimethylsilane and 0.5 ml of (tetrabutylammonium fluoride solution (1 M in THF)) in 18 ml of THF to form g of ethyl-4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)-pentanoate. 450 mg of the obtained ester in 12 ml of diethyl ester is mixed in portions at 0° C. with 66 mg of lithium aluminum hydride. After stirring for 11 hours, it is added to saturated bicarbonate solution and filtered through diatomaceous earth. The phases are separated, and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by evaporation. 420 mg of diol is obtained as a yellow oil. 400 mg of the diol is oxidized to the corresponding aldehyde with 0.11 ml of oxalyl chloride, 0.21 ml of DMSO and 1 ml of triethylamine. It is washed with water and brine, dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 0->5%), 268 mg of the title compound is obtained as a yellow oil.
Reaction SMILES: O.O.[NH2:3][C:4]1[S:5][CH:6]=[C:7](/[C:9](=[N:13]/[O:14][C:15](=[O:17])[CH3:16])/[C:10]([OH:12])=[O:11])[N:8]=1.N12CCN(CC1)CC2.[P:26](Cl)([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[S:27]>CC(N(C)C)=O>[CH2:29]([O:28][P:26]([O:11][C:10](=[O:12])/[C:9](/[C:7]1[N:8]=[C:4]([NH2:3])[S:5][CH:6]=1)=[N:13]\[O:14][C:15](=[O:17])[CH3:16])([O:31][CH2:32][CH3:33])=[S:27])[CH3:30]
Reactant: CCOP(=S)(Cl)OCC
Reactant: CC(=O)O/N=C(\C(=O)O)c1csc(N)n1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOP(=S)(OCC)OC(=O)/C(=N\OC(C)=O)c1csc(N)n1
Temperature: -20 °C
Reaction time: 3.5 h
Yield: 86 %

Procedure:
To a stirred solution of 134.9 g (Z)-(2-aminothiazol4-yl)-acetoxyiminoacetic acid dihydrate (508.6 mmol) and 570 mg 1,4-diazabicyclo[2.2.2]octane (DABCO) (5.09 mmol) in 1500 ml dimethylacetamide was added under argon 158 ml tributylamine (661 mmol). The yellowish solution was cooled to -20° C. and over 30 min was added dropwise 104 ml diethyl chlorothiophosphate (661 mmol). Stirring was continued at -20° C. for 3.5 h. The reaction was followed by HPLC. After 3 h, all starting material was consumed. The reaction mixture was allowed to warm up to 0° C. and over 1.0 h was added dropwise 2200 ml water. The precipitated product was filtered, washed with water and dissolved in 800 ml dichloromethane. The aqueous layer was back-extracted with 300 ml dichloromethane. The combined organic layers were dried over 70 g sodium sulfate and concentrated under reduced pressure until the product started to crystallize. The residual solution was cooled to 2° C. and 1200 ml n-hexane was added dropwise over 1 h. The resulting suspension was stirred for 1 h at 2° C. and then filtered. The crystalline product was washed with n-hexane and dried to constant weight. (Z)-(2-aminothiazol-4-yl)-acetoxyiminoacetic acid diethoxythiophosphoryl ester was obtained as a white solid (166.9 g, yield=86%, mp 128-130° C. and was stored under argon at -20° C. No further purification was necessary and the product was used as isolated for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[CH2:25]([C:27]1[N:32]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:31](=[O:40])[C:30]([C:41](O)=[O:42])=[CH:29][CH:28]=1)[CH3:26].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:41]([C:30]5[C:31](=[O:40])[N:32]([C:33]6[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=6)[C:27]([CH2:25][CH3:26])=[CH:28][CH:29]=5)=[O:42])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: CCc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccc(F)cc1
Yield: 36.8 %

Procedure:
Using N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.306 mmol), 6-ethyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (95.9 mg, 0.367 mmol), N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (105 μL, 0.612 mmol) and HATU (151 mg, 0.40 mmol) and in the same manner as in Example 68, the title compound (64.1 mg, 37%) was obtained as a white solid.