Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7]/[CH:8]=[C:9](/[CH3:16])\[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3]/[CH2:4][OH:5].[C:17]1(C)C=[CH:21][C:20](S(O)(=O)=O)=[CH:19][CH:18]=1.[OH2:28]>O1C=CCCC1>[CH3:1]/[C:2](/[CH2:6][CH2:7]/[CH:8]=[C:9](/[CH3:16])\[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3]/[CH2:4][O:5][CH:21]1[CH2:20][CH2:19][CH2:18][CH2:17][O:28]1
Reactant: CC(C)=CCC/C(C)=C\CC/C(C)=C\CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Agent: C1=COCCC1
Product: CC(C)=CCC/C(C)=C\CC/C(C)=C\COC1CCCCO1
Reaction time: 2 h

Procedure:
A solution of 1 g (0.0045 mol) of (2Z,6Z)-3,7,11-trimethyl-2,6,10-dodecatrien-1-ol in 32 ml of 3,4-dihydro-2H-pyran is treated at 0° with 91 mg of p-toluenesulfonic acid. The solution is stirred at the same temperature for 2 hours under argon. After the addition of 100 ml of water the mixture is extracted with ether. The organic phase is washed with sodium bicarbonate solution. After drying and removing the solvent the residue is chromatographed on silica gel with ether-hexane 1:1. There is obtained tetrahydro-2-[[(2Z,6Z)-3,7,11-trimethyl-2,6,10-dodecatrienyl]oxy]-2H-pyran which has the following bands in the IR spectrum: 1668 cm-1, 1444 cm-1, 1378 cm-1, 1118 cm-1, 1075 cm-1, 1023 cm-1.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:15]([CH2:21]OC)[CH2:16][Si](C)(C)C)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:24][N:25]1[C:29](=[O:30])[CH:28]=[CH:27][C:26]1=[O:31]>ClCCl>[CH2:8]([N:15]1[CH2:16][CH:27]2[C:26](=[O:31])[N:25]([CH3:24])[C:29](=[O:30])[CH:28]2[CH2:21]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN1C(=O)C=CC1=O
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)C2CN(Cc3ccccc3)CC2C1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Trifluoroacetic acid (2.4 g) was added dropwise to a solution of benzyl-methoxymethyltrimethylsilanylmethylamine (5.1 g) and 1-methylpyrrole-2,5-dione (2.98 g) in dichloromethane (50 ml) at 0° C. Stirring at 0° C. for 15 minutes was followed by further stirring at room temperature for one hour. The reaction mixture was diluted with dichloromethane, washed with sodium bicarbonate solution and water, dried over magnesium sulfate and concentrated. The product with the molecular weight of 244.30 (C14H16N2O2); MS (ESI): 245 (M+H+) was obtained in this way.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([N+:11]([O-:13])=[O:12])[C:5]([O:9][CH3:10])=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[Ca+2].Cl[C:22]([O:24][CH2:25][CH2:26][Cl:27])=[O:23]>O1CCOCC1>[Cl:27][CH2:26][CH2:25][O:24][C:22]([NH:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([N+:11]([O-:13])=[O:12])[C:5]([O:9][CH3:10])=[C:6]([Cl:8])[CH:7]=1)=[O:23]
Reactant: O=C(Cl)OCCCl
Reactant: COc1c(N)cc(Cl)c(OC)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Product: COc1c(Cl)cc(NC(=O)OCCCl)c(OC)c1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
0.05 mole (11.7 g) of 5-amino-2,4-dimethoxy-3-nitrochlorobenzene was dissolved in 50 ml of dioxane. 5 g of calcium carbonate were added, then the temperature was raised to the region of 90° C. 0.05 mole (7.2 g) of β-chloroethyl chloroformate was then introduced with stirring. Upon completion of the addition, stirring was maintained for 30 additional minutes at 90° C. The inorganic salts present in the reaction mixture were removed by filtration while hot. After addition of iced water to the filtrate, the expected product crystallized. The product obtained was thoroughly drained and washed with water. After drying, it was recrystallized from ethanol. It melted at 93° C.
Reaction SMILES: FC1C=C(F)C=CC=1NC1C=CC(C(C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=O)=C(C)C=1.Br[C:35]1[CH:40]=[CH:39][C:38]([C:41]([C:43]2[CH:48]=[C:47]([N:49]3[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]3)[CH:46]=[CH:45][C:44]=2[CH3:57])=[O:42])=[C:37]([Cl:58])[CH:36]=1.[F:59][C:60]1[CH:61]=[C:62]([NH2:67])[CH:63]=[C:64]([F:66])[CH:65]=1>>[Cl:58][C:37]1[CH:36]=[C:35]([NH:67][C:62]2[CH:61]=[C:60]([F:59])[CH:65]=[C:64]([F:66])[CH:63]=2)[CH:40]=[CH:39][C:38]=1[C:41]([C:43]1[CH:48]=[C:47]([N:49]2[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]2)[CH:46]=[CH:45][C:44]=1[CH3:57])=[O:42]
Reactant: Nc1cc(F)cc(F)c1
Reactant: Cc1ccc(-n2cc(CCO)nn2)cc1C(=O)c1ccc(Br)cc1Cl
Agent: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Product: Cc1ccc(-n2cc(CCO)nn2)cc1C(=O)c1ccc(Nc2cc(F)cc(F)c2)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 471 (0.13 mmol) and 3,5-difluoro-phenylamine (0.13 mmol). The crude product was purified by flash chromatography using MeOH/DCM 1:20 as the eluent to afford the title compound. 13C NMR (CDCl3) δ 195.0, 163.8 (dd), 146.6, 146.4, 143.1 (t), 140.5, 138.4, 135.2, 134.8, 133.6, 132.7, 132.6, 132.3, 129.4, 122.5, 121.0, 120.1, 118.1, 114.5, 102.2 (m), 98.2 (t), 61.5, 28.8, 20.0
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[CH3:19][N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1>>[CH3:19][N:20]1[CH2:25][CH2:24][CH:23]([O:14][C:13]([C:11]2[S:12][C:8]([C:5]3[C:4]([CH3:16])=[C:3]([C:2]([F:17])([F:1])[F:18])[O:7][N:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:22][CH2:21]1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: CN1CCC(O)CC1
Product: Cc1c(-c2ccc(C(=O)OC3CCN(C)CC3)s2)noc1C(F)(F)F

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 1-methyl-piperidin-4-ol by the method described in Example 41. Colorless solid (51 mg, 75%). 1H NMR (CD3OD) 1.85-1.98 (m, 2H), 2.03-2.15 (m, 2H), 2.38 (s, 3H), 2.43 (br q, J=1.3, 3H), 2.40-2.56 (m, 2H), 2.73-2.86 (m, 2H), 5.02-5.14 (m, 1H), 7.69 (d, J=4.0, 1H), 7.90 (d, J=4.0, 1H). 13C NMR 7.9, 31.4, 46.2, 53.5 (br), 71.9 (br), 116.8 (br), 120.3 (q, J=270), 130.7, 135.1, 136.0, 137.5, 159.4, 162.3. 19F NMR −64.8. LC/MS 4.75 min, [M+1]+ 375.
Reaction SMILES: [CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][NH:14][CH:13]([C:16]([NH2:18])=[O:17])[C:12]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:8][N:9]1[C:38](=[O:40])[N:14]2[CH2:15][C@H:10]1[CH:11]=[C:12]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])[C@H:13]2[C:16]([NH2:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)OCC1=C[C@@H](NOCc2ccccc2)CNC1C(N)=O
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCC1=C[C@@H]2CN(C(=O)N2OCc2ccccc2)[C@@H]1C(N)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 110 %

Procedure:
To a solution of (5R)-5-((benzyloxy)amino)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 163, 0.562 g, 1.44 mmol) and diisopropylethyl amine (1.000 mL, 5.74 mmol) in acetonitrile (200 mL) at 0° C. was added triphosgene (0.145 g, 0.49 mmol) as a solution in acetonitrile (6 mL). The triphosgene solution was added at a rate of 4 mL/hour. Once addition was complete the reaction was stirred at 0° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate. The aqueous layer was extracted again with EtOAc and then DCM. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-100, ethyl acetate/hexanes) afforded the title compound (0.225 g, 37.5%) as a colorless film.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH:26]=O)=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:29][OH:30].CO.C(Cl)Cl>CO.C([O-])(O)=O.[Na+]>[C:1]([NH:5][C:6]1[C:7](/[CH:26]=[N:29]/[OH:30])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1/C=N/O
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A solution of 3-(tert-butylamino)-5-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxaline-2-carbaldehyde (307b) (44.0 mg, 0.12 mmol), hydroxylamine hydrochloride (11.7 mg, 0.17 mmol), and TEA (0.024 mL, 0.17 mmol) in MeOH (5.0 mL) was stirred at 60° C. for 1.5 h. The reaction mixture was subsequently cooled to RT, diluted with saturated aq. NaHCO3 (20 mL), and extracted with 5% MeOH/DCM (2×30 mL). The combined extracts were sequentially washed with water (30 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished (E)-3-(tert-butylamino)-5-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxaline-2-carbaldehyde oxime (31.0 mg, 0.082 mmol, 68% yield) as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.34 (1H, br. s.), 11.86 (1H, br. s.), 8.34 (1H, s), 8.31 (1H, s), 7.91 (1H, dd, J=7.3, 1.1 Hz), 7.67 (1H, dd, J=8.0, 1.0 Hz), 7.40 (1H, t, J=7.8 Hz), 7.09 (1H, d, J=2.2 Hz), 6.95 (1H, br. s.), 3.43 (2H, td, J=6.8, 2.2 Hz), 2.86 (2H, t, J=6.8 Hz), 1.57 (9H, s). m/z (ESI, +ve) 379.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]1([C:16]2[CH:20]=[C:19]([NH2:21])[NH:18][N:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O=[C:23]([CH3:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1.CCCCCCC.N1CCCCC1>[CH3:29][C:23]1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:6]([C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:18]2[N:17]=[C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=[C:19]2[N:21]=1
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Reactant: COC(=O)CC(C)=O
Reactant: Cc1ccc(C=O)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCCCCCC
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: COC(=O)c1c(C)nc2cc(-c3ccccc3)nn2c1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a stirred solution of 4-methylbenzaldehyde (1.2 g, 9.99 mmol), 3-phenyl-1H-pyrazol-5-amine (1.6 g, 9.99 mmol), and methyl 3-oxobutanoate (1.3 g, 10.99 mmol) in THF (80 mL) and heptane (20 mL) was added piperidine (30 mL, 0.303 mmol). The reaction mixture was heated at reflux for 20 h. The solvent was evaporated and the crude material was dissolved in CH2Cl2. DDQ (2041 mg, 8.99 mmol) was added and the mixture was stirred at room temperature for 1 h. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (2.3 g, 64.4%). 1H-NMR (500 MHz, CDCl3) δ ppm 2.47 (3H, s), 2.65 (3H, s), 3.64 (3H, s), 6.93 (1H, s), 7.31-7.47 (5H, m), 7.63 (2H, d, J=7.9 Hz), 7.86-7.99 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH:10][CH2:11][C@H:12]1[C@H:18]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([F:26])[CH:20]=2)[O:17][CH2:16][CH2:15][N:14]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13]1)=[O:9].C(N(CC)CC)C.[C:41](=O)(OC(Cl)(Cl)Cl)[O:42]C(Cl)(Cl)Cl.O>C1COCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@@H:18]2[O:17][CH2:16][CH2:15][N:14]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13][C@H:12]2[CH2:11][N:10]2[C:8](=[O:9])[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[NH:1][C:41]2=[O:42])=[CH:20][C:21]=1[F:26]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNC(=O)c2ccccc2N)C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](Cn2c(=O)[nH]c3ccccc3c2=O)C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-({[(2-aminophenyl)carbonyl]amino}methyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate (191.1 mg) and triethylamine (167 μL) in THF (5 mL) was added bis(trichloromethyl) carbonate (142 mg) at 0° C., and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was allowed to cool to room temperature, and poured into water, and the mixture was partitioned twice with ethyl acetate. The organic layers were combined, and the mixture was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (193.8 mg).
Reaction SMILES: [P:1]([OH:4])([OH:3])[OH:2].O1C[CH2:9][CH2:8][O:7]O1.P(Cl)(Cl)Cl.[C:15](#[N:17])C>>[C:8]([NH:17][CH2:15][P:1]([OH:4])(=[O:3])[OH:2])(=[O:7])[CH3:9]
Reactant: CC#N
Reactant: OP(O)O
Reactant: C1COOOC1
Solvent: ClP(Cl)Cl
Product: CC(=O)NCP(=O)(O)O

Procedure:
82 g of aqueous phosphorous acid and 32 g of trioxane are dissolved in 200 cc of acetonitrile. 5 cc of phosphorus trichloride are added to said solution. The resulting mixture is heated to boiling under reflux for about two hours. A highly viscous oil separates as a result of the reaction. Unreacted acetonitrile is distilled off. The residue is dissolved in a small amount of water. Addition of acetone precipitates therefrom a white crystalline product which is filtered off and dried at 60° C. in a water jet vacuum. About 100 g of N-acetylaminomethane phosphonic acid are obtained. By thin layer chromatographic investigation of the filtrate it was found that, in addition to phosphorous acid, the solution still contained some additional N-acetylaminomethane phosphonic acid and also another phosphonic acid which apparently is N-acetylimino-bis-methane phosphonic acid.
Reaction SMILES: [Cl:1][C:2]1[O:11][C:5]2=[C:6]([OH:10])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>CN(C=O)C>[Br:19][C:9]1[CH:8]=[N:7][C:6]([OH:10])=[C:5]2[O:11][C:2]([Cl:1])=[CH:3][C:4]=12
Reactant: Oc1nccc2cc(Cl)oc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Oc1ncc(Br)c2cc(Cl)oc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
A 0.15 M solution of 2-chlorofuro[2,3-c]pyridin-7-ol (113 mg, 0.7 mmol) in DMF stirred in the dark at 0° C. under an atmosphere of nitrogen was treated with NBS (120 mg, 0.7 mmol) in three equal portions. The ice bath was removed; the mixture was stirred at rt for 3 h. The reaction mixture was treated with a 10% aqueous solution of sodium thiosulfate (5 ml) and was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (15 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexanes/EtOAc=4:1) to afford the title compound (145 mg, 87%) as a white solid. LCMS (M+H)+=249.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[NH:7]1)=[O:5])[CH3:2].[H-].[Na+].I[CH:19]([Cl:22])[CH2:20][CH3:21].O>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]1[CH2:21][CH2:20][CH2:19][Cl:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)n1[nH]c(=O)c2ccccc21
Reactant: CCC(Cl)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)n1c2ccccc2c(=O)n1CCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
To a solution of 3-oxo-2,3-dihydro-indazole-1-carboxylic acid ethyl ester (410 mg, 2 mmol) dissolved in dry DMF (10 ml) is added sodium hydride (60% w/w in oil, 120 mg, 3 mmol). The resulting cloudy solution is allowed to stir for 1 h at rt and is added dropwise under inert atmosphere via a syringe onto a solution of iodochloropropane (268 μl, 2.5 mmol) in dry DMF (2 ml). The resulting solution is allowed to stir at rt overnight. By addition of water and evaporation under reduced pressure most of the DMF is removed from the crude mixture. The residue is dissolved in AcOEt (25 ml) and the resulting organic phase is washed 3 times with water and once with brine. The crude product is purified by chromatography on silica gel (AcOEt/heptane, 2:3), yielding the title compound (78 mg) in 15% as a colourless oil: tR=2.17 min (LC-2), ESI-MS (pos.): m/z 283.05 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 1.38 (t, 3H, CH3), 2.08 (quint., 2H, CH2CH2N), 3.42 (t, 2H, CH2Cl), 4.25 (t, 2H, NCH2), 4.39 (q, 2H, OCH2CH3), 7.22 (t, 1Harom), 7.53 (t, 1Harom), 7.79 (t, 2Harom), and 3-(3-chloro-propoxy)-indazole-1-carboxylic acid ethyl ester (125 mg) in 24% as a colourless oil: tR=2.49 min (LC-2), ESI-MS (pos.): m/z 283.05 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 1.44 (t, 3H, CH3), 2.26 (quint., 2H, CH2CH2N), 3.71 (t, 2H, CH2Cl), 4.49 (q, 2H, OCH2CH3), 4.59 (t, 2H, OCH2CH2), 7.20 (t, 1H, m), 7.46 (t, 1Harom), 7.59 (d, 1 Harom), 8.02 (d, 1Harom). 3-(3-Chloro-propoxy)-indazole-1-carboxylic acid ethyl ester is used as alkylating agent D-06d in the preparation of Precursor D-06b.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.Cl[C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+].CC(N(C)C)=O>C1(C)C=CC=CC=1>[O:12]=[C:9]1[C:10]2[CH:11]=[C:2]([O:1][C:22]3[CH:14]=[N:15][CH:16]=[C:17]([CH:21]=3)[C:18]([NH2:20])=[O:19])[CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: O=C1CCCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: NC(=O)c1cncc(Oc2ccc3c(c2)C(=O)CCC3)c1
Temperature: 25 °C

Procedure:
Combine 7-hydroxy-1-tetralone (J. Med. Chem. (1998), 41(7), 1068-1083), (3.37 g, 20.7 mmol), 6-chloronicotinamide (available from Aldrich Chemical Company, Milwaukee, USA) (2.95 g, 18.8 mmol, K2CO3 (3.91 g, 28.3 mmol), DMA (dimethylacetamide) (45 ml) and toluene (25 ml) in a round bottom flask, equipped with Dean-Stark trap, condenser, and nitrogen inlet. Reflux the suspension for 2-3 hours before cooling to ambient temperature. Remove the solids via filtration, wash solids with EtOAc, and concentrate the filtrate/wash on a rotary evaporator. Dissolve the remaining oil in EtOAc, wash with water (2×) and brine, dry (MgSO4) and concentrate. Triturate the resulting brown solid with boiling EtOAc, cool, and collect solid via filtration to give 4.76 g of the title compound as a yellow solid. Mass Spectrum (ion spray): m/z=283 (M+1); 1HNMR (DMSO-d6): 8.56 (s, 1H), 8.25 (d, 1H), 8.02 (s, 1H), 7.52 (s, 1H), 7.48 (s, 1H), 7.42 (d, 1H), 7.35 (d, 1H), 7.12 (d, 1H), 2.95 (t, 2H), 2.60 (t, 2H), 2.05 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(OCC)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([N:10]2[CH2:11][CH:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9]2)=[O:28])=[CH:22][CH:21]=1
Reactant: Clc1ccc(C2=NNCC2c2ccccc2)cc1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CCOCC
Product: O=C(Nc1ccc(Cl)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Reaction time: 8 h
Yield: 88.7 %

Procedure:
In a 500 ml round bottomed flask was suspended 55 g of 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole in 250 ml of diethyl ether. The suspension was warmed to reflux and 33 g of 4-chlorophenyl isocyanate was added at a rate to maintain reflux. After cooling and standing overnight the precipitated product was filtered yielding 78 g of white solid. mp 173°-175° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:28])[C@H:4](CC1C=CC=CC=1)[NH:5][C:6](=[O:20])[C:7]1[C:12]([I:13])=[C:11]([NH2:14])[C:10]([I:15])=[C:9]([C:16]([OH:18])=[O:17])[C:8]=1[I:19].[C:29](Cl)(=[O:31])[CH3:30].[CH3:33]C(N(C)C)=O>>[CH3:33][N:2]([CH3:1])[C:3](=[O:28])[CH2:4][NH:5][C:6](=[O:20])[C:7]1[C:12]([I:13])=[C:11]([NH:14][C:29](=[O:31])[CH3:30])[C:10]([I:15])=[C:9]([C:16]([OH:18])=[O:17])[C:8]=1[I:19]
Reactant: CC(=O)N(C)C
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: CC(=O)Cl
Product: CC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NCC(=O)N(C)C)c1I

Procedure:
Analogously to Example 1, N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-glycine dimethylamide (IV n), m.p. 239°-241° C. (under decomposition) is acetylated with acetyl chloride in dimethylacetamide.
Reaction SMILES: [N:1]1([CH:16]2[CH2:22][CH:21]3[N:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:18]([CH2:19][CH2:20]3)[CH2:17]2)[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][NH:8][CH2:7]2)[CH2:3][CH2:2]1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C.Cl>ClCCl.CCOC(C)=O>[C:29]([N:8]1[CH2:7][C:4]2([CH2:5][CH2:6][N:1]([CH:16]3[CH2:17][CH:18]4[N:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]([CH2:20][CH2:19]4)[CH2:22]3)[CH2:2][CH2:3]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)(=[O:31])[CH3:30]
Reactant: CCOC(=O)N1C2CCC1CC(N1CCC3(CC1)CNCc1ccccc13)C2
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)N1C2CCC1CC(N1CCC3(CC1)CN(C(C)=O)Cc1ccccc13)C2

Procedure:
Crude ethyl 3-(2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate 5c (1.00 g, 2.6 mmol) was dissolved in anhydrous dichloromethane (12 mL), cooled in an ice/H2O bath and treated dropwise with a solution of acetyl chloride (214 mg, 2.73 mmol) in anhydrous dichloromethane (2 mL). The reaction was then treated dropwise with a solution of 1.1 eq triethylamine (289 mg, 2.86 mmol) in anhydrous dichloromethane (2 mL) and stirred in the ice/H2O bath for 30 min. The reaction was diluted with EtOAc (50 mL) and washed with 50% saturated NaHCO3 (3×20 mL), saturated brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 1.063 g crude product as a pale yellow oil. The crude product was purified by reverse-phase HPLC (2-99% CH3CN—H2O gradient with 0.03% TFA, 15 min). The combined pure fractions were concentrated under reduced pressure and treated with 1 N NaOH (25 mL). The product was extracted with dichloromethane (2×50 mL) and the combined extracts washed with saturated brine, dried (Na2SO4) and filtered and concentrated. The free base was dissolved in anhydrous diethyl ether (˜10 mL) and treated with 1.0 eq HCl (500 μL 2 N ethereal HCl). The suspension was cooled in an ice/H2O bath, filtered, rinsed with Et2O (3×10 mL) and dried to provide ethyl 3-(2-acetyl-2,3-dihydro-1H -spiro[isoquinoline-4,4′-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate. LC/MS m/z [M+H]+ 426.2 retention time 1.89 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min). 1H-NMR (400 MHz, DMSO-d6) δ 10.88 (br s, 1H), 7.46 (d, J=7.5 Hz, 1H), 7.23 (m, 3H), 4.70 (s, 2H), 4.25 (br s, 2H), 4.05 (br q, 2H), 3.81 (s, 2H), 3.78 (m, 1H), 3.46 (m, 3H), 3.12 (br m, 2H), 2.46 (br m, 1H), 2.13 (s, 3H), 2.12 (br s, 2H), 1.87 (br m, 4H), 1.69 (br m, 4H), 1.21 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10]S(C)=O.C([Cl:17])(=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][Cl:17]
Reactant: CC(=O)Cl
Reactant: CS(=O)COc1ccc(Cl)cc1Cl
Solvent: ClCCl
Product: ClCOc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
To an ice-water cooled solution of 2,4-dichloro-1-methanesulfinylmethoxy-benzene (8 g, 33.46 mmol) in DCM (100 mL) was added dropwise a solution of acetylchloride (2.6 mL, 36.80 mmol) in DCM (10 mL). The reaction mixture was allowed to reach room temperature during 2 hrs at which time the volatiles were evaporated in vacuo affording ˜7 g of crude 2,4-dichloro-1-chloromethoxy-benzene which was used without further purification.