Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:4]=2[CH2:3]1.[N:20]1([CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][O:30][C:29]2=[O:33])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[OH-].[Na+]>>[F:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:4]=3[CH2:3][CH:2]([N:23]3[CH2:24][CH2:25][N:20]([CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][O:30][C:29]4=[O:33])[CH2:21][CH2:22]3)[C:8]=2[CH:9]=1
Reactant: O=C1OCCN1CCN1CCNCC1
Reactant: COc1ccc2c(c1)Sc1ccc(F)cc1C(Cl)C2
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(c1)Sc1ccc(F)cc1C(N1CCN(CCN3CCOC3=O)CC1)C2

Procedure:
15.4 g. of 10-chloro-8-fluoro-10,11-dihydro-3-methoxy-dibenzo[b,f]thiepin are treated with 41 g. of 3-[2-(1-piperazinyl)ethyl]-2-oxazolidinone and stirred at 120°-130° C. (internal temperature) for 10 minutes. The cooled mixture is treated with 2N sodium hydroxide and extracted with chloroform. The chloroform solution is washed to neutrality with water and shaken out with dilute methanesulfonic acid. The acid solution is made alkaline with sodium hydroxide and the base extracted with chloroform. The organic solution is washed with water, dried over magnesium sulfate and concentrated. The residue is recrystallized from acetone, whereby there is obtained 3-{2-[4-(8-fluoro-10,11-dihydro-3-methoxy-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone of melting point 177°-179° C. The corresponding maleate melts at 212°-214° C.
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[S:6][C:5]([C:7]([Cl:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(F)s1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)s1
Yield: 81.2 %

Procedure:
A mixture of the title compound of Example 2 (200 mg, 1.37 mmol), thionyl chloride (500 μl, 6.85 mmol) and DMF (20 μl) in dry methylene chloride was refluxed for 2 hours. The solvents were evaporated and the residue dried in vacuo to give 183 mg (81%) of the title product as a brown solid, mp 123-5 C. 1H-NMR (CDCl3): δ7.74 (m, 1 H), 6.64 (m, 1H),). GC-MS (m/e, %) 166/164 (M+, 11), 129(100).
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]#N)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[OH-:14].[K+].[OH2:16].N>C(O)C>[CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([OH:16])=[O:14])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: O
Reactant: [OH-]
Reactant: CCCC[C@H]1CC[C@H](CC#N)CC1
Agent: N
Agent: [K+]
Solvent: CCO
Product: CCCC[C@H]1CC[C@H](CC(=O)O)CC1

Procedure:
34 g (0.19 mol) of trans-4-butylcyclohexylacetonitrile, 43 g (0.76 mol) of KOH, 34 cm3 of water and 190 cm3 of ethanol were refluxed on a hot water bath until formation of ammonia gas stopped. The ethanol in the reactant was removed, the residue was dissolved in 100 cm3 of water, it was poured into a beaker containing 100 cm3 of concentrated HCl and 100 g of ice, and the deposited crystals were filtered and washed in water. The crystals were recrystallized from a solvent mixture of methanol and water to obtain 37 g (0.19 mol) of trans-4-butylcyclohexylacetic acid.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[NH:18][C:19](=[O:27])[C:20]4[CH:25]=[CH:24][N:23]([CH3:26])[C:21]=4[N:22]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C.[OH-].[Na+]>O1CCCC1.CO.O>[CH3:26][N:23]1[C:21]2[N:22]=[C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:28])=[O:3])=[CH:6][CH:7]=4)[CH2:12][CH2:13]3)[NH:18][C:19](=[O:27])[C:20]=2[CH:25]=[CH:24]1
Reactant: CCOC(=O)c1ccc(N2CCN(c3nc4c(ccn4C)c(=O)[nH]3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cn1ccc2c(=O)[nH]c(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 127.9 %

Procedure:
A solution of 4-[4-(7-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-piperazin-1-yl]-benzoic acid ethyl ester (163 mg, 427 μmol) in tetrahydrofuran (1.6 mL) and methanol (0.8 mL) was treated with a 1N aqueous sodium hydroxide solution (748 μL, 748 μmol). The resulting yellow solution was stirred for 3 h at room temperature. At this point, another aliquot of a 1N aqueous sodium hydroxide solution (748 μL, 748 μmol) was added. At this time, the reaction was heated to 75° C. where it was stirred for 1.5 h. The reaction was then diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The aqueous layer was acidified to pH 2 with a 1N aqueous hydrochloric acid solution and further extracted with ethyl acetate (20 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL). Since product was not soluble in the organic layer, all of the layers were combined and concentrated in vacuo and dried to afford 4-(4-(7-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)piperazin-1-yl)benzoic acid (193 mg, 128%) as a light grey solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.41 (br. s., 4H) 3.57 (s, 3H) 3.71 (br. s., 4H) 6.25 (d, J=3.39 Hz, 1H) 6.78 (d, J=3.39 Hz, 1H) 7.02 (d, J=9.23 Hz, 2H) 7.79 (d, J=8.85 Hz, 2H) 10.89 (s, 1H) 12.29 (s, 1H). LC-MS calcd. for C18H20N5O3 [(M+H)+] 354, obsd. 354.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10]Cl)=[C:4]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>CC(C)=O.C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10][N:37]2[CH2:38][CH2:39][N:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)[CH2:35][CH2:36]2)=[C:4]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH:3]=1
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Yield: 85.4 %

Procedure:
To a compound of N1-[4-chloro-2-(2-chlorobenzoyl)phenyl]-2-chloroacetamide (500 mg, 1.46 mmol) in dry acetone (20 mL) was added anhydrous potassium carbonate (1 g, 7.30 mmol) and 1-(2-pyridyl)piperazine (238 mg, 1.46 mmol). The reaction mixture was refluxed for 24 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. The potassium carbonate was then removed by suction filtration and the solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product 6a (585 mg, 86% yield).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:27])[C@H:10]([CH2:16][NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:11](OCC)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(C)C=C(C)C=C(C)C=1[Mg]Br.O>O1CCCC1>[Si:1]([O:8][C@@H:9]([C@@H:10]1[CH2:16][N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:11]1=[O:12])[CH3:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](CNCc1ccc(OC)cc1)[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: Cc1cc(C)c([Mg]Br)c(C)c1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2C[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C2=O)cc1
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
To a solution of ethyl (2S*,3R*)-3-(t-butyldimethylsilyloxy)-2-(4-methoxybenzylaminomethyl)butanoate (6 g) in tetrahydrofuran (303 ml) was added dropwise a solution of mesitylmagnesium bromide (1M, 24.3 ml) in tetrahydrofuran at room temperature. After stirring for 30 minutes, water (10 ml) was added dropwise to the reaction mixture and the solvent was removed under reduced pressure. To the residue were added ethyl acetate and water, then the aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate, water and an aqueous sodium chloride in turn and then dried over magnesium sulfate. The resultant solution was evaporated under reduced pressure and the residue was column-chromatographed on silica gel (eluent : a mixture of hexane and ethyl acetate, 3:1) to give (3S*)-3-[(1R*)-1-(t-butyldimethylsilyloxy)ethyl]-1-(4-methoxybenzyl)azetidin-2-one (4.8 g), which contained about 2% of the corresponding (3R*), (1R*)-isomer.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.[NH2:54][C@H:55]([CH2:59][CH3:60])[CH2:56][C:57]#[N:58]>CN(C=O)C>[C:57]([CH2:56][C@H:55]([NH:54][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([N:12]2[C:13]([OH:14])=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[CH:10]=[N:11]2)=[N:16][CH:17]=1)[CH2:59][CH3:60])#[N:58]
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Reactant: CC[C@@H](N)CC#N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](CC#N)NC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.1 %

Procedure:
Combined 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (29 mg, 0.095 mmol), EDCI (27.2 mg, 0.142 mmol), HOBT (19.2 mg, 0.142 mmol) in DMF (1 mL) and added N,N-diisopropyl ethylamine (66.0 μL, 0.379 mmol). Then (R)-3-aminopentanenitrile (13.9 mg, 0.142 mmol) was added and the reaction was stirred at room temperature for 16 hours. The reaction mixture was purified by preparative HPLC (SunFire™ C18, 5 μm, ID 30 mm×75 mm) using a gradient of 40-65% ACN (with 0.035% TFA) in water (with 0.05% TFA) to give the title compound (16.2 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.33 Hz, 3 H) 1.67 (quin, J=7.20 Hz, 2 H) 2.70-2.95 (m, 2 H) 4.05-4.22 (m, 1 H) 7.80 (d, J=8.34 Hz, 2 H) 8.15 (br. s., 2 H) 8.41-8.86 (m, 4 H) 8.94 (s, 1H). MS m/z [M+H]+ 387.2.
Reaction SMILES: [CH3:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11][CH3:12])[CH:8]=2)[C:3]1=[O:15].[N+:22]([O-])([O:24]CCCCC)=[O:23]>>[CH3:1][C:2]1([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11][CH3:12])[CH:8]=2)[C:3]1=[O:15]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccccc1)C2
Reactant: CCCCCO[N+](=O)[O-]
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccc([N+](=O)[O-])cc1)C2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Amyl nitrate (40 ml.) is added in 10 ml. increments at two hour intervals to 2-methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone (9.36 g., 0.03 mole) in polyphosphoric acid (150 g.) at 50°-60° C. with stirring. The total heating period is 8 hours. The reaction mixture is treated with crushed ice-water to precipitate 4.82 g. of 2-methyl-2-(4-nitrophenyl)-5-methoxy-6,7-dichloro-1-indanone which melts at 179°-180° C. after crystallization from butyl chloride.
Reaction SMILES: [H-].[Na+].[CH2:3]([P:14]([O:20][CH:21]([CH3:23])[CH3:22])(=[O:19])[O:15][CH:16]([CH3:18])[CH3:17])[P:4]([O:10][CH:11]([CH3:13])[CH3:12])(=[O:9])[O:5][CH:6]([CH3:8])[CH3:7].C([O:26][C:27](=[O:30])[CH2:28]Br)C.O>C1(C)C=CC=CC=1>[CH:16]([O:15][P:14]([O:20][CH:21]([CH3:23])[CH3:22])([CH:3]([P:4]([O:10][CH:11]([CH3:12])[CH3:13])([O:5][CH:6]([CH3:8])[CH3:7])=[O:9])[CH2:28][C:27]([OH:30])=[O:26])=[O:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)OP(=O)(OC(C)C)C(CC(=O)O)P(=O)(OC(C)C)OC(C)C
Reaction time: 0.25 h
Yield: 13.7 %

Procedure:
Sodium hydride (700 mg, 0.29 mmol) was added in small portions under a stream of dry nitrogen to a vigorously stirred solution of tetraisopropyl methane-1,1-bisphosphonate (1) (5.0 gm, 14.5 mmol) in dry toluene (25 ml). After the effervescence had stopped, stirring was continued for 15 minutes. Ethylbromoacetate (3.2 gm, 19.2 mmol) was then added dropwise over a period (2 min) whereupon the flask became warm and a white precipitate began to form. Stirring was continued for a further 2 hours at room temperature. Water (20 ml) was added then carefully and the mixture vigorously stirred. The toluene layer was separated and extracted with water (20 ml). The aqueous extracts were combined, washed with ether (50 ml), acidified to pH 1 and re-extracted with dichloromethane (2×25 ml). The dichloromethane extracts were combined, dried (MgSO4), filtered and solvent evaporated under reduced pressure to leave the acid (3) as a pale yellow liquid (800 mg). The toluene layer was also dried (MgSO4), filtered, and solvent evaporated to leave an oil which was found to be the ethyl ester (2) and unreacted starting material. This oil was dissolved in a methanol:water mixture (20 ml, 3:1) containing lithium hydroxide (1 g, 24 mmol) and the solution stirred at room temperature for 16 h. The methanol was removed by evaporation and water (20 ml) was then added. This aqueous solution was washed with ether (2×20 ml), acidified to pH 1 with dilute HCl and then extracted with dichloromethane (2×25 ml). The dichloromethane extracts were combined, dried (MgSO4), filtered and volatile components removed under reduced pressure to leave the acid (3) (2.77 g) as a pale yellow liquid. The combined product (3) (3.57 g, 61%) was sufficiently pure to be used in subsequent reactions without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@H:13]([OH:31])[CH2:14][C@H:15]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:16]([O:18]C(C)(C)C)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(CC)CC)C>ClCCl.FC(F)(F)C(O)=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][C@H:13]1[CH2:14][C@H:15]([NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[C:16](=[O:18])[O:31]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@@H](O)CNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](CNC(=O)OCc2ccccc2)OC1=O
Temperature: 0 °C
Reaction time: 15 h

Procedure:
A solution of 7.60 g (17.3 mmol) of tert-butyl 5-benzyloxycarbonylamino-2(S)-tert-butoxycarbonylamino-4(R)-hydroxypentanoate (Org. Lett. (2001) 3, 20:3153-3155) in 516 ml of dichloromethane and 516 ml of trifluoroacetic acid is stirred at RT for 2 h. The solvent is evaporated. The remaining crude product is dissolved in 2.6 l of anhydrous methanol and, while stirring at 0° C., 6.3 g (28.8 mmol) of di-tert-butyl dicarbonate and 7.3 ml (52.43 mmol) of triethylamine are added. After 15 h, the reaction solution is evaporated and the residue is taken up in 1 l of ethyl acetate. After the phases have separated, the organic phase is extracted twice with a 5% citric acid solution, twice with water and once with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated. The crude product is purified by chromatography on silica gel with toluene/acetone (5/1). 4.92 g (78% of theory) of product are obtained.
Reaction SMILES: [NH2:1][C@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([F:18])[CH:10]=2)=[N:5]1.[C:20]([C:23]1[O:27][N:26]=[C:25]([C:28](O)=[O:29])[CH:24]=1)(=[O:22])[CH3:21]>>[C:20]([C:23]1[O:27][N:26]=[C:25]([C:28]([NH:1][C@H:2]([CH3:19])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:10]=[C:11]([F:18])[C:12]([C:13]#[N:14])=[C:15]([F:17])[CH:16]=3)=[N:5]2)=[O:29])[CH:24]=1)(=[O:22])[CH3:21]
Reactant: C[C@@H](N)Cn1ccc(-c2cc(F)c(C#N)c(F)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)no1
Product: CC(=O)c1cc(C(=O)N[C@H](C)Cn2ccc(-c3cc(F)c(C#N)c(F)c3)n2)no1

Procedure:
The title compound was prepared from (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (0.214 g, 0.81 mmol) and 5-acetylisoxazole-3-carboxylic acid (0.127 g, 0.81 mmol) using the method of Example 34(d). Yield 0.166 g. 1H NMR (400 MHz; MeOD): δ 1.28 (d, 3H), 2.59 (s, 3H), 4.37 (m, 2H), 4.60 (m, 1H), 6.80 (d, 1H), 7.27 (s, 1H), 7.64 (m, 2H), 7.72 (d, 1H).
Reaction SMILES: [CH2:1]([N:7]([CH3:13])[C:8](=[O:12])[O:9][CH2:10]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH:14][C@@H:15]([C@H:17]1[C:37](=[O:38])[N:19]2[C:20]([C:34]([O-:36])=[O:35])=[C:21]([S:24]/[CH:25]=[CH:26]\[C:27]3[S:31][CH:30]=[N:29][C:28]=3[CH2:32][OH:33])[C@H:22]([CH3:23])[C@H:18]12)[CH3:16].[Na+]>>[OH:14][C@@H:15]([C@H:17]1[C:37](=[O:38])[N:19]2[C:20]([C:34]([O:36][CH2:10][O:9][C:8]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH3:13])=[O:12])=[O:35])=[C:21]([S:24]/[CH:25]=[CH:26]\[C:27]3[S:31][CH:30]=[N:29][C:28]=3[CH2:32][OH:33])[C@H:22]([CH3:23])[C@H:18]12)[CH3:16]
Reactant: CCCCCCN(C)C(=O)OCCl
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CCCCCCN(C)C(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 69.3 %

Procedure:
In the same manner as in step b) in Example 125, 206 mg of the title compound was prepared from 134 mg of chloromethyl N-n-hexyl-N-methylcarbamate and 217 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)[CH:12]([C:15]1[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][N:17]2[N:16]=1)[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NCCCN(C(C1N(CC2C=CC(F)=CC=2)C(=O)C2=CC=CN2N=1)CC)C(=O)C1C=CC(C)=CC=1)(C)(C)C.Br[CH2:78][C:79]([O:81][CH3:82])=[O:80]>>[CH3:82][O:81][C:79](=[O:80])[CH2:78][N:20]1[C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][N:17]2[N:16]=[C:15]1[CH:12]([N:11]([CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:34])[C:25](=[O:33])[C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)[CH2:13][CH3:14]
Reactant: CCC(c1nn2cccc2c(=O)[nH]1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Reactant: COC(=O)CBr
Agent: CCC(c1nn2cccc2c(=O)n1Cc1ccc(F)cc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Product: CCC(c1nn2cccc2c(=O)n1CC(=O)OC)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Yield: 30.9 %

Procedure:
(±)-(3-{(4-Methylbenzoyl)-[1-(4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4] triazin-2-yl)-propyl]amino}propyl)carbamic acid tert-butyl ester (Example 3 A, 100 mg, 0.21 mmol) was converted to the title compound (35 mg, 31%) in a manner similar to the preparation of (±)-{3-[{1-[3-(4-fluorobenzyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl]-propyl}-(4-methylbenzoyl)-amino]-propyl}-carbamic acid tert-butyl ester, except that methyl bromoacetate (42 mg, 0.27 mmol) was used instead of 4-fluorobenzyl bromide: 1H NMR (CDCl3) δ 7.43 (m, 1H), 7.26–7.21 (m, 4H), 7.07 (m, 1H), 6.58 (m, 1H), 5.84 (m, 1H), 5.10 (m, 1H), 4.78 (m, 1H), 3.91 (m, 1H), 3.78 (m, 3H), 3.71 (m, 1H), 3.31 (m, 2H), 2.74 (m, 2H), 2.40 (s, 3H), 2.21 (m, 1H), 2.05 (m, 1H), 1.52 (m, 1H), 1.39 (s, 9H), 1.04 (t, 3H, J=7.15 Hz); MS (ESI+) 540.21 (M++H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1>CN(C=O)C.CO>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[N:3][CH:4]=1)[CH3:10]
Reactant: CCOc1ccc(Br)nc1
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: CCOc1ccc(N2CCC(c3ccc([C@H](C)NC(C)=O)cc3)CC2)nc1
Temperature: 180 °C

Procedure:
250 mg (1.24 mmol) 2-Bromo-5-ethoxy-pyridine are added to 250 mg (1.02 mmol) (S)-N-[1-(4-piperidin-4-yl-phenyl)-ethyl]-acetamide (V.1). The mixture is heated at 180° C. for 1 h. Subsequently the residue is taken up in DMF/methanol and the mixture is purified using reversed phase HPLC (column: Waters XBridge 5 μM; eluent A: water+0.3% NH4OH, eluent B: MeOH+0.3% NH4OH) to yield the desired product.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2.C([O-])(O)=O.[Na+].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20]>CC#N>[CH:10]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]([CH2:5]3)[CH:3]1[NH:2][C:19](=[O:20])[O:21][C:22]1[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=1)[CH2:9]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C(NC1C2CC3CC(C2)CC1C3)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.6 %

Procedure:
To a stirred mixture of 2-aminoadamantane HCl salt (1.24 g, 6.61 mmol) and powdered NaHCO3 (1.17 g, 13.9 mmol) in MeCN (40 mL) was added p-nitrophenyl chloroformate (1.40 g, 6.9 mmol). The mixture was stirred at rt for 1 d. The mixture was concentrated and the residue was taken up in ether (150 mL), washed with 5% aq HCl (50 mL) and brine (50 mL), and dried over MgSO4. Removal of the solvent left a white solid (1.81 g). Chromatography on a 40-g silica cartridge eluted with a 30-100% EtOAc in hexanes gradient to afford 4-nitrophenyl (2-adamantyl)carbamate (1.33 g, 63%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:46])[NH:25][CH:26]([C:32]3[CH:33]=[C:34]([C:39]4[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=4)[CH:35]=[C:36]([F:38])[CH:37]=3)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:53]1([CH3:76])[CH:58]=[CH:57][C:56]([S:59]([O:62][CH2:63][CH2:64]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:61])=[O:60])=[CH:55][CH:54]=1>CN(C)C=O>[F:38][C:36]1[CH:37]=[C:32]([CH:26]([NH:25][C:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)[CH2:19]2)=[O:46])[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:33]=[C:34]([C:39]2[CH:40]=[CH:41][C:42]([O:45][CH2:64][CH2:63][O:62][S:59]([C:56]3[CH:57]=[CH:58][C:53]([CH3:76])=[CH:54][CH:55]=3)(=[O:61])=[O:60])=[CH:43][CH:44]=2)[CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cc(F)cc(-c2ccc(O)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cc(F)cc(-c2ccc(OCCOS(=O)(=O)c3ccc(C)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 70 h
Yield: 11.5 %

Procedure:
178.0 mg (0.28 mmol) 4-(3-{(R)-3-[1-(5-fluoro-4′-hydroxy-biphenyl-3-yl)-2-methoxycarbonyl-ethylcarbamoyl]-piperidin-1-yl}-3-oxo-propyl)-piperidine-1-carboxylic acid tert-butyl ester (example 17d) were dissolved in 10.7 ml N,N-dimethylformamide. 272 mg (0.84 mmol) cesium carbonate and 154.6 mg (0.42 mmol) ethylene glycol bis-p-toluenesulfonate were added. The mixture was stirred at room temperature for 70 hours and concentrated. The remainder was taken up with saturated ammonium chloride solution and ethyl acetate. The aqueous phase was extracted with 3×20 ml ethyl acetate. The extracts were dried over sodium sulfate and concentrated. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-95/5) gave 167 mg which were further purified by HPLC to yield 27 mg (11%) tert-butyl 4-{3-[(3R)-3-({1-[5-fluoro-4′-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)biphenyl-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.