Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[NH2:9].[C:10](OC(=O)C)(=O)[CH3:11]>>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:9]=[C:10]1[CH3:11]
Reactant: CNc1ccncc1N
Reactant: CC(=O)OC(C)=O
Product: Cc1nc2cnccc2n1C
Yield: 64 %

Procedure:
The solution of N4-methylpyridine-3,4-diamine (2.5 g, 20.3 mmol) in acetic anhydride (25 mL) was refluxed overnight. Then acetic anhydride was evaporated under reduced pressure and 1 N hydrochloride acid was added. Then the mixture was extracted with dichloromethane (50 mL×3). The aqueous layer was neutralized with sodium bicarbonate, and extracted with dichloromethane (50 mL×3). The organic layers were concentrated to give the title compound (1.9 g, yield 64%). LC-MS (ESI) m/z: 148 (M+1)+. 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.64 (s, 3H), 3.74 (s, 3H), 7.23-7.24 (d, J=5.2 Hz, 1H), 8.39-8.41 (d, J=5.2 Hz, 1H), 8.98 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:16])[C:7]2=[O:15].[C:17](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:17][O:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:16])[C:7]2=[O:15]
Reactant: O=C([O-])[O-]
Reactant: CN1CCc2c(O)ccc([N+](=O)[O-])c2C1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c2c1CCN(C)C2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a stirring solution of 5-Hydroxy-2-methyl-8-nitro-3,4-dihydro-2H-isoquinolin-1-one (444 mg, 2.0 mmol) and in DMF (5 mL) is added potassium carbonate (553 mg, 4.0 mmol.) and the solution cooled to 0° C. Iodomethane (0.25 mL, 4.0 mmol.) is added and the reaction mixture allow to warm to room temperature and then stirred for 1 hour. The mixture is quenched with a cold water and then the precipitate is filtered, washed with water and dried under vacuum to give a white solid corresponding to 5-methoxy-2-methyl-8-nitro-3,4-dihydro-2H-isoquinolin-1-one (336 mg, 71%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](I)=[N:9][N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:4]=2[CH:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>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>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)=[N:9][N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:4]=2[CH:3]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1cc2c(cn1)c(I)nn2C1CCCCO1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2nn(C3CCCCO3)c3cc(Cl)ncc23)cn1
Temperature: 85 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
A mixture of 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (120 mg, 0.33 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.50 mmol), tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol) and cesium carbonate (320 mg, 0.99 mmol) in 1,4-dioxane (1 mL) and water (0.12 mL) was degassed and sealed. It was stirred at 85° C. for 3 h. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.10 g). LCMS (M+H)+=318.1.
Reaction SMILES: [C:1]1([C@@H:7]([NH:10][C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:30]Br)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][NH:33][CH3:34]>>[C:1]1([C@@H:7]([NH:10][C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:30][N:33]([CH3:34])[CH3:32])=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNC
Reactant: CC[C@H](NC(=O)c1c(CBr)n(-c2ccccc2)c(=O)c2ccccc12)c1ccccc1
Product: CC[C@H](NC(=O)c1c(CN(C)C)n(-c2ccccc2)c(=O)c2ccccc12)c1ccccc1
Reaction time: 0.17 h

Procedure:
A mixture of 3-bromomethyl-1-oxo-2-phenyl-1,2-dihydro-isoquinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide (70 mg, 0.147 mmol) and dimethylamine (1 ml of 33% solution in abs. ethanol, excess) was kept at 50° C. for 10 min and then evaporated in vacuo. The residue was dissolved in methanol and passed through SCX cation exchange column (1 g, RSO3H form). Uncharged impurities were eluted with methanol and the product was eluted with 4M NH3 in methanol to give 53 mg of colourless glass-like solid. It was further purified by flash chromatography on SiO2 (5 g, gradient 1,2-dichloroethane—10% ethyl acetate in 1,2-dichloroethane) to give 45 mg of colourless solid. Yield 70%. LC-MS (m/z) 440.1 (MH+); tR=0.88. 1H NMR (250 MHz, DMSO-d6, T=333 K): 0.92 (t, 2H), 1.83 (two overlapping m, 2H), 1.66 (s, 6H), 2.96 and 3.08 (two d of CHAHBN, 2H), 4.96 (q, 1H), 7.19-7.56 (m, 12H), 7.68 (t, 1H), 8.21 (d, 1H), 8.75 (d, 1H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Br:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([NH2:17])[CH:11]=[C:10]([Br:18])[N:9]=1.C(N(CC)CC)C>O>[CH2:5]([O:4][C:2](=[O:3])[NH:17][C:12]1[CH:11]=[C:10]([Br:18])[N:9]=[C:8]([Br:7])[C:13]=1[N+:14]([O-:16])=[O:15])[CH3:6]
Reactant: Nc1cc(Br)nc(Br)c1[N+](=O)[O-]
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)Nc1cc(Br)nc(Br)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
A solution of ethyl chloroformate (5.96 g) in anhydrous 2-methyl THF (50 ml) was added drop-wise to a solution of 2,6-dibromo-3-nitro-pyridin-4-ylamine (15.00 g) and triethylamine (10.1 g) in anhydrous 2-methyl THF (100 ml) at 0° C., keeping the addition rate such that the reaction temperature did not rise above 5° C. The reaction mixture was allowed to warm to room temperature then left to stir under nitrogen for 1 hour. A further portion of ethyl chloroformate (0.54 g) was added and the mixture was left to stir for a further 1 hour. Water (50 ml) was added and the layers separated. The aqueous layer was extracted with EtOAc (50 ml) and the combined organics were dried (MgSO4) and evaporated to a brown solid. This solid was pre-absorbed onto silica (˜19 g) then columned on Isco Companion on a silica column (330 g, Redisep), eluting with EtOAc:heptane. The gradient was kept isocractic at 10:90 for 1 column volume (CV), then increased linearly from 10:90 to 30:70 over 6 CVs. This provided the title compound (12.6 g) as a pale yellow foamy solid.
Reaction SMILES: [F:1][C:2]([F:15])([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](OCC)=[O:4].[BH4-].[Na+].O>CO.C(OCC)(=O)C>[F:1][C:2]([F:15])([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][OH:4]
Reactant: CCOC(=O)C(F)(F)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: OCC(F)(F)Cc1ccccc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
To a cooled solution of Intermediate 90 (2.2 g, 10.3 mmol) in methanol (30 mL) was added sodium borohydride (1.94 g, 51 mmol). The mixture was stirred at 5° C. for 20 minutes and at room temperature for 2 hours. To the crude reaction was added water (1 mL) and the solvents reduced under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed with brine (2×25 mL), dried (Na2SO4), and concentrated. Purification by column chromatography with silica gel eluting with ethyl acetate/n-hexane 1:5 gave the title compound (0.75 g, 42%) as oil
Reaction SMILES: [CH:1]([O:14][C:15]1[C:16]2[C:34](=[O:35])[N:33]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[CH2:32][C:17]=2[C:18]([O:25]CC[Si](C)(C)C)=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N(CC)CC)C>C1COCC1>[CH:1]([O:14][C:15]1[C:16]2[C:34](=[O:35])[N:33]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[CH2:32][C:17]=2[C:18]([OH:25])=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)CCOc1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1c2c(c(O)c3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the compound 44 (350.0 mg, 0.592 mmol) in anhydrous THF (20 mL), was added tetrabutylammonium fluoride (1M in THF, 651 μl, 0.651 mmol) and triethylamine (330 μl, 2.37 mmol). The reaction mixture turned to red and was stirred at room temperature under nitrogen for 1 hour. The reaction forming 45 was monitored by TLC (EtOAc/Hexane=3/7).
Reaction SMILES: [Na:1].[NH2:2][C:3]([P:9]([OH:12])(=[O:11])[OH:10])([P:5]([OH:8])(=[O:7])[OH:6])[CH3:4].[C:13](OC(=O)C)(=[O:15])[CH3:14]>O>[Na:1].[C:13]([NH:2][C:3]([P:5]([OH:8])(=[O:6])[OH:7])([P:9]([OH:12])(=[O:10])[OH:11])[CH3:4])(=[O:15])[CH3:14]
Reactant: CC(N)(P(=O)(O)O)P(=O)(O)O
Reactant: CC(=O)OC(C)=O
Agent: [Na]
Solvent: O
Product: CC(=O)NC(C)(P(=O)(O)O)P(=O)(O)O

Procedure:
22.7 g. (0.1 mole) of the mono-sodium salt of 1-amino ethane-1,1-diphosphonic acid are boiled under reflux in 30.6 g. (0.3 moles) of acetic acid anhydride for about 30 minutes. A clear solution is obtained. On cooling, a viscous yellowish sirup is produced. The sirup can be diluted with water and the aqueous solution can be used directly. In order to recover the crystalline reaction product, the sirup is added with stirring to 40 cc. of glacial acetic acid and the resulting crystalline product is filtered off by suction. After drying, 20.3 g. of the mono-sodium salt of N-acetyl-1-amino ethane-1,1-diphosphonic acid, corresponding to 75.4 % of the theoretical yield, are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([CH:11]=[N:12][OH:13])=[CH:9][CH:8]=1.ClN1C(=O)CCC1=O.[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[C:28]#[CH:29].C(N(CC)CC)C>CN(C=O)C.CCOCC>[CH2:32]([O:31][C:27]([C:28]1[O:13][N:12]=[C:11]([C:10]2[CH:14]=[CH:15][C:7]([O:6][CH2:5][C:4]3[CH:16]=[CH:17][CH:18]=[C:2]([F:1])[CH:3]=3)=[CH:8][CH:9]=2)[CH:29]=1)=[O:30])[CH3:33]
Reactant: C#CC(=O)OCC
Reactant: ON=Cc1ccc(OCc2cccc(F)c2)cc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccc(OCc3cccc(F)c3)cc2)no1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 5.7 %

Procedure:
4-(3-Fluoro-benzyloxy)-benzaldehyde oxime (which may be prepared as described in Preparation of Intermediate 3; 2 g, 8.2 mmol) was dissolved in DMF (4.8 mL) and the solution was cooled to 0° C. in an ice-water bath. N-Chlorosuccinimide (1.09 g, 8.2 mmol) was added slowly. The reaction mixture was stirred at 0° C. for 30 min, allowed to warm to room temperature and stirred at room temperature for 1 h. The reaction mixture was poured into ice-water (125 mL) and the resulting suspension was extracted with EtOAc (200 mL). The organic extract was dried over Na2SO4, filtered, and evaporated. The residue was dissolved in Et2O (20 mL). A mixture of ethyl propiolate (1.1 mL, 10.9 mmol) and triethylamine (1.5 mL) in Et2O (20 mL) was added dropwise, and the mixture was stirred at room temperature for 9 days. Silica gel was added and the solvent was evaporated. The resulting mixture was purified by chromatography (5-15% EtOAc/hexane) to give 3-[4-(3-fluoro-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid ethyl ester (160 mg, 6%) as a white crystalline solid, which contained some of the undesired 4-carboxylic acid ethyl ester regioisomer.
Reaction SMILES: [NH:1]1[CH:5]=[C:4](/[CH:6]=[C:7]2\[C:8](=[O:33])[C:9]3[C:14]([CH2:15][CH2:16]\2)=[C:13]([O:17][CH2:18][C@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24]2[N:32]=[CH:31][N:30]=[C:29]4[C:25]=2[N:26]=[CH:27][NH:28]4)[CH:12]=[CH:11][CH:10]=3)[N:3]=[CH:2]1.[OH-].[Na+]>C(O)(=O)C.O.[Zn]>[NH:1]1[CH:5]=[C:4]([CH2:6][CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[O:17][CH2:18][C@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:24]3[N:32]=[CH:31][N:30]=[C:29]4[C:25]=3[N:26]=[CH:27][NH:28]4)[C:8]2=[O:33])[N:3]=[CH:2]1
Reactant: O=C1/C(=C\c2c[nH]cn2)CCc2c(OC[C@H]3CCCN3c3ncnc4[nH]cnc34)cccc21
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2cccc(OC[C@H]3CCCN3c3ncnc4[nH]cnc34)c2CCC1Cc1c[nH]cn1

Procedure:
13.5 100 mg of 2-[1-(1H-imidazol-4-yl)meth-(Z)-ylidene]-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-3,4-dihydro-2H-naphthalen-1-one are heated at 80° C. for 30 min. together with 50 mg of zinc powder in 10 ml of conc. acetic acid and 5 ml of water. During this, the colour changes from greenish to yellowish. The batch is adjusted to pH 7 using conc. NaOH solution and extracted to exhaustion with ethyl acetate. The organic phase is dried over magnesium sulfate and freed from solvent in vacuo, giving 50 mg of 2-(1H-imidazol-4-yl-methyl)-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-3,4-dihydro-2H-naphthalen-1-one (“A15.1”) as colourless oil. Rt.: 1.405 min; [M+H]+444.2.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[CH3:3].Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[C:6](=[O:15])[N:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]([C@@H:2]([NH:1][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][N:27]3[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1)[CH3:3])=[CH:13]2
Reactant: C[C@H](N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1

Procedure:
3-(1-Aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (Compound 9) (0.72 mmol), 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) (344 mg, 1.44 mmol) and DIPEA (279 mg, 2.16 mmol) were dissolved in n-BuOH (20 mL), and the resulting mixture was stirred at reflux for 16 h. The reaction mixture was concentrated in vacuo and purified by flash column chromatography on silica gel (eluting with 30% to 50% Hex/EA) to afford the product, 8-chloro-2-phenyl-3-((1S)-1-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)isoquinolin-1(2H)-one (Compound 10), as a white solid (60% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28]O)=[CH:22][N:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:44]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.F.F.F.C(N(CC)CC)C>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][F:44])=[CH:22][N:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(CCCO)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: F
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(CCCF)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-{[5-(3-hydroxypropyl)pyridin-2-yl]methyl}-L-glutamate (68 mg, 0.13 mmol) was dissolved in 2 ml tetrahydrofuran, and cooled to 0° C. Triethylamine (280 μl, 2.01 mmol), 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (162 mg, 0.53 mmol), and triethylamine trihydrofluoride (86 mg, 0.53 mmol) were added, and the reaction was stirred at room temperature for 24 h. The same amounts of triethylamine, 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride and triethylamine trihydrofluoride were added again and the reaction was continued for 1 h. Water (10 ml) was added, and the mixture was extracted with dichloromethane (3×10 ml). The organic phases were dried over magnesium sulfate and concentrated. The so derived material was used without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]1[C:15](=[O:16])[O:14][CH2:13][C:11]1=O.[CH2:17]1[O:26][C:25]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=2[O:18]1>C(O)C>[CH2:7]([CH:8]1[C:23]2[CH:24]=[C:25]3[O:26][CH2:17][O:18][C:19]3=[CH:20][C:21]=2[NH:22][C:11]2[CH2:13][O:14][C:15](=[O:16])[C:10]1=2)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: O=C1COC(=O)C1
Reactant: O=CCc1ccccc1
Solvent: CCO
Product: O=C1OCC2=C1C(Cc1ccccc1)c1cc3c(cc1N2)OCO3

Procedure:
10 mmol of phenylacetaldehyde and 10 mmol of tetronic acid are added to 10 mmol of 3,4-methylenedioxyaniline dissolved in ethanol, then the reaction mixture is heated at reflux for the night. After returning to ambient temperature, the precipitate obtained is filtered and then washed with ethanol to yield the expected product.
Reaction SMILES: [OH:1]C(CC)CN1C=C([N+]([O-])=O)N=C1[N+]([O-])=O.[CH2:17](N=C=O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C[N:29]([CH:31]=[O:32])C>C(OCC)C.[Cu]I>[C:31](=[O:32])([O:1][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[NH2:29]
Reactant: CCCCCCCCN=C=O
Reactant: CCC(O)Cn1cc([N+](=O)[O-])nc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: [Cu]I
Solvent: CCOCC
Product: CCCCCCCCOC(N)=O
Reaction time: 2 h
Yield: 60 %

Procedure:
To a green heterogeneous mixture of 1-(2'-hydroxybutyl)-2,4-dinitroimidazole (500 mg, 2.17 mmol, Eur. J. Med. Chem. 24:631-633 (1989)) and 258 mg (2.60 mmol) of CuI in 10 mL of dry DMF was added 767 μL (4.34 mmol) of octyl isocyanate. The mixture was stirred for two hours, diluted with 40 mL of ethyl ether and the organic solution was washed with water, dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel (hexane:ethyl acetate, 6:1) to give 502 mg (60%) of n-octyl carbamate. 1H NMR (CDCl3) δ0.86 (t, 3H), 1.11 (t, 3H), 1.28(m, 10H), 1.40 (m, 2H), 1.75 (m, 2H), 3.05 (m, 2H), 4.42 (q, 1H), 4.75 (t, 1H), 4.90 (q, 1H), 5.10 (m, 1H), 7.88 (s, 1H); 13C NMR (CDCl3) δ9.32, 14.01, 22.54, 25.10, 26.54, 29.06, 29.63, 31.69, 40.04, 41.08, 54.28, 72.65, 124.14, 155.20: MS 386 (M+)
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@@:21]3([NH:25][CH2:24][CH2:23][CH:22]3[C:26]([O:28]C)=[O:27])[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O[Li:44].O.O1CCCC1>CO.O>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@@:21]3([NH:25][CH2:24][CH2:23][C@@H:22]3[C:26]([O-:28])=[O:27])[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1.[Li+:44]
Reactant: [Li]O
Reactant: COC(=O)C1CCN[C@@]12CCN(C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H](c1ccc(F)cc1C)C2
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)NCC[C@@H]2C(=O)[O-]
Product: [Li+]
Temperature: 50 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Methyl (5R,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-4-carboxylate (Intermediate 41, 12 mg, 0.020 mmol) was dissolved in Methanol (0.3 ml) and Water (0.3 ml). To the mixture was added LiOH.H2O (0.918 mg, 0.022 mmol) and the reaction mixture was left stirring overnight at 50° C. To the solution was added Tetrahydrofuran (THF) (0.3 ml) and it was heated at 70° C. for 1 more hour. The solvent was removed in vacuo obtaining the title compound (11.2 mg, 0.019 mmol, 96% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 7.98 (s, 1H) 7.69 (s, 2H) 7.07-7.15 (m, 1H) 6.84-6.91 (m, 1H) 6.69-6.79 (m, 1H) 5.25-5.38 (m, 1H) 4.43 (d, 1H) 2.98-3.23 (m, 2H) 2.69 (s, 3H) 2.60-2.92 (m, 2H) 2.31 (s, 3H) 1.56-2.04 (m, 5H) 1.48 (d, 3H) 1.40-1.54 (m, 1H) 1.33 (d, 1H). Stereochemistry consistent with the following data:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:11][C:12]([O:14][C:15](C)(C)C)=[O:13])[CH:5]([O:7][CH:8]([F:10])[F:9])[CH3:6].Cl.C(N(C(C)C)CC)(C)C.ClC(OC)=O>CO.ClCCl>[CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH:11][C:12]([O:14][CH3:15])=[O:13])[C@H:5]([O:7][CH:8]([F:10])[F:9])[CH3:6]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)C(C)OC(F)F
Agent: COC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)OC)[C@@H](C)OC(F)F
Temperature: 50 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
To a solution of 2-tert-Butoxycarbonylamino-3-difluoromethoxy-butyric acid methyl ester (3 g, 10.6 mmol) in methanol (40 mL) was added concentrated HCl solution (10 mL) and the reaction was stirred at 50° C. for 1 hour. The reaction was concentrated on a rotary evaporator and the resulting residue was basified with saturated NaHCO3 solution. The aqueous layer was extracted twice with ethyl acetate. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. To a solution of the crude material in dichloromethane (50 mL) was added diisopropylethylamine (4.2 mL, 24.2 mmol), followed by methyl chloroformate (0.95 mL, 12.3 mmol). The reaction was stirred at room temperature for 2 hours, quenched by the careful addition of saturated NH4Cl solution and diluted with ethyl acetate. The organic layer was separated, washed with water and brine, dried (MgSO4) and concentrated. The crude material was purified by flash chromatography to yield (2S,3R)-methyl-3-(difluoromethoxy)-2-(methoxycarbonylamino)butanoate (1.2 g, 47%).
Reaction SMILES: C1(C(N2C3C=C(F)C(F)=CC=3N=C2C2C(OC)=NC(OC)=CC=2)C(O)=O)CCCCC1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[N:43]([CH:44]([CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)[C:45](O)=[O:46])[C:42]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:41]=3[N:40]=2)=[CH:35][CH:34]=1.Cl.N[C@H]1CC[C@H](O)CC1.Cl.[CH2:70]([O:72][C:73](=[O:82])[CH2:74][C@H:75]1[CH2:80][CH2:79][C@H:78]([NH2:81])[CH2:77][CH2:76]1)[CH3:71]>>[CH2:70]([O:72][C:73](=[O:82])[CH2:74][CH:75]1[CH2:76][CH2:77][CH:78]([NH:81][C:45](=[O:46])[CH:44]([N:43]2[C:42]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:41]=3[N:40]=[C:39]2[C:36]2[CH:35]=[CH:34][C:33]([Cl:32])=[CH:38][CH:37]=2)[CH:48]2[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]2)[CH2:79][CH2:80]1)[CH3:71]
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: CCOC(=O)C[C@H]1CC[C@H](N)CC1
Agent: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)O)C2CCCCC2)c(OC)n1
Agent: Cl
Agent: N[C@H]1CC[C@H](O)CC1
Product: CCOC(=O)CC1CCC(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)CC1

Procedure:
The title compound was prepared in analogy to example 8 replacing cyclohexyl-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetic acid with [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid (example 22, intermediate c) and trans-4-amino-cyclohexanol hydrochloride with trans-(4-amino-cyclohexyl)-acetic acid ethyl ester hydrochloride ([CAS RN 76308-26-4]). MS (ES+): 572 (M+H).