Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.CS(C)=O.[CH2:18]([O:25][N:26]=[C:27]1[CH2:36][CH2:35][CH:34]([O:37][C:38](=[O:43])[CH:39]([CH3:42])[CH2:40][CH3:41])[CH:33]2[C:28]1=[CH:29][C:30](=[O:59])[CH:31]([CH3:58])[CH:32]2[CH2:44][CH2:45][CH:46]([OH:57])[CH2:47][CH:48]([OH:56])[CH2:49][C:50]([O:52][CH2:53][CH:54]=[CH2:55])=[O:51])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[CH2:18]([O:25][N:26]=[C:27]1[CH2:36][CH2:35][CH:34]([O:37][C:38](=[O:43])[CH:39]([CH3:42])[CH2:40][CH3:41])[CH:33]2[C:28]1=[CH:29][C:30](=[O:59])[CH:31]([CH3:58])[CH:32]2[CH2:44][CH2:45][C:46](=[O:57])[CH2:47][CH:48]([OH:56])[CH2:49][C:50]([O:52][CH2:53][CH:54]=[CH2:55])=[O:51])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=CCOC(=O)CC(O)CC(O)CCC1C(C)C(=O)C=C2C(=NOCc3ccccc3)CCC(OC(=O)C(C)CC)C21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C=CCOC(=O)CC(O)CC(=O)CCC1C(C)C(=O)C=C2C(=NOCc3ccccc3)CCC(OC(=O)C(C)CC)C21
Temperature: -78 °C
Reaction time: 0.05 h
Yield: 36.6 %

Procedure:
182 μl (1.3 mmole) of trifluoroacetic anhydride were dissolved in 2 ml of anhydrous toluene, and the resulting solution was cooled to -78° C. 1 ml of anhydrous toluene in which 121 μl (1.71 mmole) of dimethyl sulfoxide had been dissolved was then added dropwise under an atmosphere of nitrogen to the cooled solution over a period of 5 minutes. After the addition was complete, the mixed solution was stirred for 3 minutes, and then 3 ml of anhydrous toluene, in which 500 mg (0.86 mmole) of allyl 7-[5-benzyloxyimino-2-methyl-8-(2-methylbutyryloxy)-3-oxo-1,2,3,5,6,7,8,8a-octahydro-1-naphthyl]-3,5-dihydroxyheptanoate (prepared as described in Preparation 1) had been dissolved, were added dropwise over a period of 15 minutes. The solution was stirred for 15 minutes at -78° C., and then 0.6 ml (4.3 mmole) of triethylamine was added dropwise over a period of 5 minutes. The resulting reaction mixture was stirred for 20 minutes at -78° C. and for a further 40 minutes at 0° C. At the end of this time, 30 ml of a 10% w/v aqueous solution of citric acid was added to the reaction mixture, and the mixture was extracted at room temperature with ethyl acetate. The ethyl acetate extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate, filtered and condensed by evaporation under reduced pressure. The resulting oily residue was purified by flash column chromatography through silica gel, using a 2:1 by volume mixture of ethyl acetate and hexane as the eluent, to obtain 183 mg (yield 48%) of the title compound. At that time, 166 mg of unreacted starting material was also recovered.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[O:31]1[CH2:33][C@@H:32]1[CH2:34][O:35][C:36]1[CH:37]=[CH:38][C:39]2[S:43][C:42]([CH3:44])=[N:41][C:40]=2[CH:45]=1>C(O)C>[OH:31][C@@H:32]([CH2:34][O:35][C:36]1[CH:37]=[CH:38][C:39]2[S:43][C:42]([CH3:44])=[N:41][C:40]=2[CH:45]=1)[CH2:33][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][CH:13]=2)=[O:11])[CH2:2][CH2:3]1
Reactant: Cc1nc2cc(OC[C@H]3CO3)ccc2s1
Reactant: O=C(NCCN1CCNCC1)c1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCNC(=O)c4ccc(C(F)(F)F)cc4)CC3)ccc2s1

Procedure:
To a solution of N-(2-piperazinylethyl)[4-(trifluoromethyl)phenyl]carboxamide (0.2 g, 0.38 mmol) in ethanol was added diisopropyl ethylamine (0.25 ml, 1.5 mmol) and 5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole (0.09 g, 0.42 mmol). The reaction was heated to 85 degrees for four hours. The mixture was then concentrated in vacuo and purified using preparative thin layer chromatography (10:1 DCM:MeOH) to yield N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[4-(trifluoromethyl)phenyl]carboxamide (M+1=523.0).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([CH3:12])[CH:6]=1.C(N(CC)CC)C.C(#N)C.[O:24]([CH:31]([CH3:35])[C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C.O.C1C=CC=CC=1>[CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:32](=[O:33])[CH:31]([O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH3:35])=[C:7]([CH3:12])[CH:6]=1
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Reactant: CC(Oc1ccccc1)C(=O)Cl
Solvent: O
Solvent: c1ccccc1
Solvent: CCO
Product: CNC(=O)Oc1ccc(NC(=O)C(C)Oc2ccccc2)c(C)c1

Procedure:
3-methyl-4-aminophenyl N-methylcarbamate (1.8g., 0.01 mole), triethylamine (1.31g., 0.013 mole), and a solvent mixture of acetonitrile (20 ml.) and benzene (20 ml.) was stirred while a benzene solution of α-phenoxypropionyl chloride was added dropwise. The resulting mixture was refluxed for a short time, cooled, and solvents removed under reduced pressure to yield a tacky residue. This residue was dissolved in a minimum of hot 50% aqueous ethanol. Addition of more water and cooling produced a white precipitate of the desired product (3 grams, m.p. 123°-25° C.).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12](=[S:16])[NH:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:17][CH3:18])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:21]I.O>CN(C=O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([S:16][CH3:21])=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:17][CH3:18])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(=S)[nH]c(=O)c1-2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1[nH]n(C2CCCC2)c2nc(SC)nc(=O)c1-2
Reaction time: 3 h
Yield: 74.2 %

Procedure:
Alternatively, the product can be prepared as follows: To a stirred mixture of 1-cyclopentyl-3-ethyl-6-(thioxo)pyrazolo[3,4-d]pyrimidin-4-one (23.4 g, 0.09 mol) in DMF (250 mL) was added NaH (4.0 g, 0.1 mol., 60% dispersion in mineral oil) over 15 minutes. The resulting mixture was cooled in an ice bath, then methyl iodide (6.3 mL, 0.1 mol) was added over 20 minutes and the resulting mixture was stirred for 3 hours. The reaction mixture was poured into water (400 mL) and the precipitate which formed was collected by filtration, washed with water, then hexane and then was dried at 80°-85° C. in a vacuum oven to afford 18.6 g (74%) of 1-cyclopentyl-3-ethyl-6-(methylthio)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 203°-205° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]([CH3:16])[CH:14]=[O:15])[CH:10]=[CH:11][CH:12]=2)=[C:4]([CH3:19])[CH:3]=1.CC[O:22]C(CCl)=O>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]([CH3:16])[C:14]([OH:22])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[C:4]([CH3:19])[CH:3]=1
Reactant: CCOC(=O)CCl
Reactant: Cc1cc(Cl)ccc1Oc1cccc(C(C)C=O)c1
Product: Cc1cc(Cl)ccc1Oc1cccc(C(C)C(=O)O)c1

Procedure:
2-[m-(p-chloro-o-methyl-phenoxy)phenyl]propionaldehyde, which has been synthesized in accordance with Example 1 from 3-(p-chloro-o-methyl-phenoxyphenyl)acetophenone having the melting point of 148° - 156° C./0.5 mmHg and ethyl ester of chloroacetic acid, is subjected to oxidative treatment in the manner of Example 1 to obtain the contemplated product.
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[S:13][S:12][C:11](=S)[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.O1CCCC1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(N(CC)CC)C>[CH3:2][C:1]([NH:5][C:6]([N:8]=[C:9]1[N:10]=[C:11]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)[S:12][S:13]1)=[O:7])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NC(=O)Nc1nc(=S)ss1
Reactant: CN1CCNCC1
Solvent: CI
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(c2nc(=NC(=O)NC(C)(C)C)ss2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2.63 parts of 1-t-butyl-3(-3-thioxo-3H-1,2,4-dithiazol-5-yl)urea and 1.42 parts of methyl iodide in 50 parts of tetrahydrofuran was stirred for 1 hour at room temperature and refluxed with stirring for 1 hour. After cooling to room temperature 3.0 parts of triethylamine and 1.0 parts of N-methyl piperazine were added to the suspension and the mixture was stirred at room temperature overnight. The mixture was filtered to remove triethylamine hydroiodide and the solvent was removed from the filtrate under reduced pressure. The filtrate residue was triturated with water and recrystallized from methanol to afford 1.0 part of the title compound, m.p. 169°-172°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.C[O-].[Na+].CN(C)C=O.Br[CH:29]([CH2:34][CH2:35][CH3:36])[C:30]([O:32][CH3:33])=[O:31]>O.C1(C)C=CC=CC=1>[CH3:33][O:32][C:30](=[O:31])[CH:29]([CH2:34][CH2:35][CH3:36])[N:11]1[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:19][C:6]=2[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:8][CH2:9][C:10]1=[O:12]
Reactant: O=C1CN=C(c2ccccn2)c2cc(Br)ccc2N1
Reactant: CCCC(Br)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC(C(=O)OC)N1C(=O)CN=C(c2ccccn2)c2cc(Br)ccc21
Reaction time: 0.33 h

Procedure:
A mixture of 0.1 mole of 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one and 0.11 mole of sodium methoxide in about 200 ml. of dimethylformamide is heated at about 95° c. for about 20 minutes. To the mixture is added a solution of 0.11 mole of methyl 2-bromovalerate in about 200 ml. of toluene over a period of about 1 hour at about 95° C., and heating is continued for an additional period of about 6 hours. The reaction mixture is then evaporated in vacuo and the residue thus obtained is stirred with about 500 ml. of water. The resulting suspension is filtered and the solids thus obtained are crystallized from a suitable organic solvent such as ether, methanol, methylene chloride, methylene chloride-methanol and the like to obtain 7-bromo-2,3-dihydro-2-oxo-α-propyl-5-(2-pyridyl)-1H-1,4-benzodiazepine-1-acetic acid methyl ester.
Reaction SMILES: CC1C=CC(S([O:11][C:12]2[CH:13]=[CH:14][C:15]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:16]([CH:21]=2)[C:17]([O:19]C)=[O:18])(=O)=O)=CC=1.[OH-].[K+]>C(O)C.O>[OH:11][C:12]1[CH:13]=[CH:14][C:15]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([CH:21]=1)[C:17]([OH:19])=[O:18]
Reactant: COC(=O)c1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(O)ccc1OCc1ccccc1

Procedure:
Methyl 5-{[(4-methylphenyl)sulfonyl]oxy}-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 75; 9.0 g, 21.82 mmol) was boiled with potassium hydroxide (8.57 g, 153 mmol) in a mixture of ethanol (160 ml) and water (40 ml) for 3 h. After the ethanol had been evaporated, the aqueous solution was washed with ethyl acetate (250 ml), and then acidified with concentrated HCl. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over Na2SO4, and evaporated in vacuo to yield the title compound as a yellow oil. 5.2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[C:10]([N+:16]([O-])=O)[CH:9]=2)=[CH:4][CH:3]=1.O.[Cl-].[NH4+]>CO.[Zn]>[NH2:16][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:13]=[CH:12][C:11]=1[CH2:14][CH3:15]
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1N
Temperature: 25 °C
Yield: 75.3 %

Procedure:
4′-Chloro-4-ethyl-3-nitrobiphenyl (22.6 g, 0.086 mol) is suspended in methanol (250 ml) and the reaction mixture is stirred at room temperature. Distilled water (100 ml) is added, followed by zinc dust (39.0 g, 0.60 mol) and ammonium chloride (13.8 g, 0.26 mol) and the mixture is heated to reflux for 1 hour. The reaction mixture is cooled to room temperature, filtered through diatomaceous earth and the filtrate is evaporated in vacuo to remove most of the methanol. The residue is partitioned between ethyl acetate (200 ml) and water and the aqueous phase is re-extracted with ethyl acetate (200 ml). The organic extracts are combined, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated in vacuo to give 3-amino-4′-chloro-4-ethylbiphenyl (15.0 g) as a colourless solid. The product is used directly without further purification in Step 5.
Reaction SMILES: [F:1][CH:2]1[CH2:5][N:4]([C:6]([C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[C:32]5[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=5)[N:26]([CH3:34])[N:25]=4)[N:22]=3)[N:17](COCC[Si](C)(C)C)[CH:16]=2)=[O:14])[CH2:9][CH2:10][CH3:11])=[O:7])[CH2:3]1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[F:1][CH:2]1[CH2:5][N:4]([C:6]([C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[C:32]5[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=5)[N:26]([CH3:34])[N:25]=4)[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH2:9][CH2:10][CH3:11])=[O:7])[CH2:3]1
Reactant: CCC[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(=O)N1CC(F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: CCC[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(=O)N1CC(F)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 49.9 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(3-fluoro-azetidine-1-carbonyl)-butyl]-amide (126 mg, 0.21 mmol) was dissolved in dichloromethane (1.1 ml) and trifluoroacetic acid (0.65 ml, 8.4 mmol) was added. The reaction mixture was stirred at room temperature for 2.5 h then concentrated. The residue was dissolved in dichloromethane (1.1 ml) and ethylenediamine (0.85 ml, 12.7 mmol) was added. The reaction was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 49 mg (50%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(3-fluoro-azetidine-1-carbonyl)-butyl]-amide as an off-white powder. MS: (M+H)+=468; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.84 (br. s, 1H), 9.15 (s, 1H), 8.74 (dt, J=9.3, 4.6 Hz, 1H), 8.41-8.52 (m, 2H), 7.68 (d, J=7.9 Hz, 1H), 7.02-7.17 (m, 1H), 5.29-5.61 (m, 1H), 4.18-4.84 (m, 4H), 4.16 (s, 3H), 3.87-4.09 (m, 1H), 1.62-1.91 (m, 2H), 1.41 (d, J=7.2 Hz, 2H), 0.82-0.97 (m, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:17])[CH2:14][S:15][CH3:16])[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:20][C:21]1[CH:22]=[CH:23][C:24](F)=[C:25]([CH3:27])[CH:26]=1.CCO>CN(C=O)C.Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:17][C@H:13]([C@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:14][S:15][CH3:16])=[C:25]([CH3:27])[CH:26]=1
Reactant: Cc1cc(Cl)ccc1F
Reactant: CSC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CSC[C@H](Oc1ccc(Cl)cc1C)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-1-Hydroxy-2-methylsulfanylethyl)pyrrolidine-1-carboxylic acid t-butyl ester (20 mg, 80 μmol) was dissolved in DMF (367 μL). NaH (3.7 mg, 153 μmol) was added and the mixture was stirred at room temperature for 15 minutes. 5-Chloro-2-fluorotoluene (33.2 mg mg, 230 tμmol) was added and the mixture was stirred at 100° C. for 1 hour. The mixture was cooled to room temperature, concentrated then dissolved in 1.2M HCl in EtOH (2.2 mL, 2.7 mmol) and stirred overnight at room temperature. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (0.6 mg, purity 85%). MS m/z: [M+H]+ calcd for C14H20ClNOS, 286.10. found 286.0.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:4].C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:15][C:13]1[CH:12]=[C:7]([CH:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: CNC(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CNC(=O)c1cc(N)cc(C(=O)OC)c1
Temperature: 40 °C
Yield: 48.1 %

Procedure:
To a solution of methyl 3-[(methylamino)carbonyl]-5-nitrobenzoate (Intermediate 29) (1.33 g, 5.59 mmol), in ethanol (30 mL) were added ammonium formiate (3.52 g, 1 eq.) and Pd/C (catalytic quantity). The reaction was stirred at 40° C. for one night. After filtration on celite, the solvent was evaporated in vacuo. The residue was dissolved in DCM, washed with water, dried over sodium sulfate and concentrated to give the title compound as a white solid (0.56 g, 48.3%). LC/MS: m/z 209 (M+H)+, Rt: 1.50 min.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:13]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[F:24])=[N:14][CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[F:24][C:17]1[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=1[C:13]1[N:14]=[CH:15][C:10]([CH2:9][OH:8])=[CH:11][C:12]=1[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: COc1ccc(F)c(-c2ncc(CO[Si](C)(C)C(C)(C)C)cc2CC(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ncc(CO)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(2-fluoro-5-methoxyphenyl)-3-neopentylpyridine in THF (25 mL) was added a 1 M solution of tetrabutylammonium fluoride in THF (10 mL), and the mixture was stirred at room temperature for 5 min. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.50 g) as a pale-yellow oil.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([NH:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][C:64]([P:67](=[O:74])([O:71][CH2:72][CH3:73])[O:68][CH2:69][CH3:70])([F:66])[F:65]>>[CH2:69]([O:68][P:67]([C:64]([F:66])([F:65])[CH2:63][CH2:62][O:61][CH2:60][CH2:59][O:58][CH2:57][CH2:56][NH:55][C:20](=[O:21])[C@@H:19]([NH:18][C:16]([O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:17])[CH2:23][S:24][CH2:25][C@H:26]([NH:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=[O:74])[O:71][CH2:72][CH3:73])[CH3:70]
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(=O)CCCCCCCCCCC
Reactant: CCOP(=O)(OCC)C(F)(F)CCOCCOCCN
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCOCCOCCC(F)(F)P(=O)(OCC)OCC)NC(=O)CCCCCCCCCCC

Procedure:
The title compound was prepared from (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-((R)-2-dodecanamido-3-(dodecyloxy)propylthio) propanoic acid (1.0 eq, from example 26, step 8) and diethyl 3-(2-(2-aminoethoxy)ethoxy)-1,1-difluoropropylphosphonate (1.2 eq, from example 22, step 3) by following the procedure described for example 26, step 9.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[CH:20]=[CH:19][N:18]2[CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=[C:17]2[CH:16]=1)(C)(C)C>C(Cl)Cl>[C:24]1([C:22]2[N:23]=[C:17]3[CH:16]=[C:15]([NH2:14])[CH:20]=[CH:19][N:18]3[CH:21]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)Nc1ccn2cc(-c3ccccc3)nc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccn2cc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
Trifluoroacetic acid (30 ml) was added to a solution of (2-phenyl-imidazo[1,2-a]pyridin-7-yl)-carbamic acid tert-butyl ester (4.81 g, 15 mmol) in CH2Cl2 (30 ml), and the mixture was stirred at r.t. overnight. The mixture was then washed (water, 2×50 ml), dried (Na2SO4), and the solvent was evaporated. The title compound (2.25 g, 73%) was obtained from the residue by column chromatography (silica gel, CH2Cl2: MeOH=100:0-60:40). MS (m/e)=210.1 [M+H+].
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([C:15](OC)=[O:16])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:15][OH:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCCCN(Cc2ccccc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCCCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
Methyl 1-benzyl-2-oxoperhydroazepine-3-carboxylate (2.39 g, 9.15 mmol) was dissolved in tetrahydrofuran (50 mL). To this solution, lithium aluminum hydride (868 mg, 18.3 mmol) was added and the mixture was stirred for 2 hours while being refluxed. Subsequently, ice water and a 10% aqueous sodium hydroxide solution were added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then filtered through Celite. The filtrate was extracted with ethyl acetate and the extract washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the residue by silica gel column chromatography (Chromatorex NH-DM2035 (Fuji Sylysia Chemical Co., Ltd.) hexane:ethyl acetate=20:1->3:1) gave 1.30 g (65%) of the desired compound as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N(I)[C:17](=[O:18])C1.C([O-])([O-])=O.[K+].[K+].CO.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(#N)C>[C:1]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]([O:18][CH3:17])=[O:12])=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=Cc1ccc(-c2ccccc2)nc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: COC(=O)c1ccc(-c2ccccc2)nc1

Procedure:
To a solution of 43b (350 mg, 1.91 mmol) in acetonitrile (20 mL) were added NIS (1.29 g, 5.73 mmol), K2CO3 (787 mg, 5.73 mmol) and CH3OH (0.39 mL, 9.55 mmol). After stirring the reaction mixture for 15 h aqueous Na2S2O3-solution (1 g Na2S2O3 in 10 mL water) was added. The resultant mixture was extracted with a solution of 50% ether in hexane (4×20 mL). The combined organic phases were washed with brine and solvent was removed under vacuum. The crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (6:1) as eluent. White solid. Yield: 297 mg, 73%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=3.75 (s, 3H), 7.22-7.30 (m, 3H), 7.59 (dd, J=8.5, 0.9 Hz, 1H), 7.82-7.86 (m, 2H), 8.12 (dd, J=8.5, 2.2 Hz, 1H), 9.06 (dd, J=2.2, 0.9 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=52.3, 119.8, 124.2, 127.3, 128.9, 129.9, 137.8, 138.3, 150.9, 160.9, 165.9; (ESI): m/z=214.02 [M+H]+.