Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[N:18]=[CH:19][N:20]=[C:21]3[C:28]=2[C:27]2[C@@H:26]([CH2:29][CH:30]=[O:31])[CH2:25][CH2:24][C:23]=2[S:22]3)[CH2:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].B([CH2:37][CH3:38])(CC)CC.[C:39]([O:43]O)(C)(C)[CH3:40].O=O.[NH4+].[OH-]>C1COCC1>[OH:31][C@H:30]([C@@H:38]1[CH2:37][CH2:40][CH2:39][O:43]1)[CH2:29][C@H:26]1[CH2:25][CH2:24][C:23]2[S:22][C:21]3[C:28](=[C:17]([O:16][CH:13]4[CH2:14][CH2:15][CH:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7])[CH2:11][CH2:12]4)[N:18]=[CH:19][N:20]=3)[C:27]1=2
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC=O)CC4)CC1
Reactant: CCB(CC)CC
Reactant: CC(C)(C)OO
Agent: O=O
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](O)[C@@H]2CCCO2)CC4)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
For the preparation of the starting material compound 43.1, please refer to Example 43. A 50-mL three necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with a solution of tert-butyl N-methyl-N-(4-[[(3R)-3-(2-oxoethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]oxy]cyclohexyl)carbamate (500 mg, 1.12 mmol, 1.00 equiv) in 10 mL of distilled THF. Et3B (11.2 mL, 1N) was added slowly at 0° C. over 20 min. Then t-BuOOH (1.225 mL) was added dropwise to the mixture at the same temperature. After being stirred for 10 min, the mixture was allowed to warmed to room temperature and stirring was continued for an additional period during which the reaction proceeded to completion (Caution: Triethylborane, a liquid pyrophoric toward oxygen, should be handled so as to avoid exposure to air. The addition of tert-butyl hydroperoxide to trialkylboranes may lead to highly exothermic reactions and gas evolution. We encountered no violent reaction with the present procedures, but special care is advised.) The reaction mixture was treated with 28% NH4OH and extracted with CH2Cl2. (A 28% NH4OH solution allows the removal of unidentified polar materials possibly derived from Et3B. Removal of polar byproducts in the crude mixture, detectable on an iodine/silica gel TLC plate, may otherwise be difficult. The crude mixture must thus be washed with 28% NH4OH for adequate purification.) The extracts were washed with saturated aqueous NaHSO3 and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to provide tert-butyl N-(4-[[(3R)-3-[(2S)-2-hydroxy-2-[(2S)-oxolan-2-yl]ethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (230 mg, 40%) as a colorless oil. MS (ES): m/z 518 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1)#[CH:10].O>C(N(CC)CC)C.[Cu](I)I>[CH3:19][CH:17]([C:14]1[CH:13]=[CH:12][C:11]([C:9]#[C:10][C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:15]=1)[CH3:18]
Reactant: Nc1ncccc1Br
Reactant: C#Cc1ccc(C(C)C)cc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)c1ccc(C#Cc2cccnc2N)cc1
Yield: 46.6 %

Procedure:
A mixture of bis(triphenylphosphine)palladium(0)dichloride (0.811 g), 3-bromopyridin-2-amine (2 g), 1-ethynyl-4-isopropylbenzene (1.667 g) and copper iodide (I) (0.22 g) in triethylamine (38.6 mL) was heated under reflux. Water was added to the reaction mixture, the mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1273 mg) as a pale-yellow solid.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][CH2:10]1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.CCOCC>[NH2:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][C:16]([O:18][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:17])[CH2:13][CH2:14]1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCC(CC(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@H](CC(=O)OCc2ccccc2)CC1
Reaction time: 16.75 h

Procedure:
To a solution of 2-[4-(tert-butoxycarbonylamino)cyclohexyl]acetic acid (1.0 g, 4 mmol) in DMF (10 mL) was added K2CO3 (600 mg, 4 mmol) followed by benzyl bromide (0.5 mL, 4.2 mmol). The resulting mixture was stirred for 16.75 hours, diluted with ether, washed with water (2×) followed by brine, dried over magnesium sulfate and concentrated. The residue was taken up in dichloromethane (12 mL). To this solution was added TFA (3 mL). The resulting solution was stirred for 2.5 hours then concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed with saturated sodium bicarbonate solution followed by brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:31]([CH3:33])[CH3:32])[C:6]2[O:10][C:9]([C:11]3[CH:29]=[CH:28][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:30]=1)#[N:2].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:65][C:66](O)([C:71]([F:74])([F:73])[F:72])[C:67]([F:70])([F:69])[F:68]>C1(C)C=CC=CC=1.O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:31]([CH3:33])[CH3:32])[C:6]2[O:10][C:9]([C:11]3[CH:29]=[CH:28][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([CH2:25][CH2:26][O:27][C:66]([CH3:65])([C:71]([F:74])([F:73])[F:72])[C:67]([F:70])([F:69])[F:68])[CH2:23][CH2:24]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:30]=1)#[N:2]
Reactant: CC(O)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CCO)CC4)cc3)oc12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CCOC(C)(C(F)(F)F)C(F)(F)F)CC4)cc3)oc12
Reaction time: 0.17 h

Procedure:
To a solution of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[trans-4-(2-hydroxyethyl)cyclohexyl]methyl}benzamide (50 mg, 0.112 mmol, EXAMPLE 43, Step A) and 1,1′-(azodicarbonyl)dipiperidine (57 mg, 0.226 mmol) in toluene (2 ml) was added tri-n-butylphosphine (0.06 ml, 0.241 mmol). After stirring for 10 min, hexafluoro-2-methylisopropanol (0.03 ml, 0.245 mmol) was added. Tetrahydrofuran (2 ml) was added to solubilize starting material, and the mixture was stirred overnight at room temperature. The mixture was concentrated and the residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes to provide the title compound (8.7 mg, 0.014 mmol, 12.72% yield). Mass spectrum (ESI) 610.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.33 (d, J=8.5 Hz, 2H); 7.94 (d, J=8.5 Hz, 2H), 7.94 (d, J=1.5 Hz, 1H); 7.51 (s, 1H), 6.27 (br s, 1H), 3.72 (t, J=6.5 Hz, 2H), 3.46 (septet, J=6.5 Hz, 1H), 3.36 (t, J=6.0 Hz, 2H), 1.83 (m, 4H), 1.50-1.65 (m, 5H), 1.46 (d, J=7.0 Hz, 6H), 1.40-1.50 (m, 2H), 0.85-1.22, (m, 6H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:24])[NH:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:12]([OH:14])=O)[N:3]=[CH:2]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:56]([NH:60][C:61]([C:63]1([CH:69]2[CH2:74][CH2:73][CH2:72][CH2:71][CH2:70]2)[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)=[O:62])([CH3:59])([CH3:58])[CH3:57]>ClCCl.CN(C)C=O>[C:56]([NH:60][C:61]([C:63]1([CH:69]2[CH2:74][CH2:73][CH2:72][CH2:71][CH2:70]2)[CH2:64][CH2:65][N:66]([C:12](=[O:14])[CH:11]([NH:10][C:9]([NH:8][CH2:7][CH2:6][C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)=[O:24])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:67][CH2:68]1)=[O:62])([CH3:59])([CH3:57])[CH3:58]
Reactant: CC(C)(C)NC(=O)C1(C2CCCCC2)CCNCC1
Reactant: COc1ccc(CC(NC(=O)NCCc2c[nH]cn2)C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CC(NC(=O)NCCc2c[nH]cn2)C(=O)N2CCC(C(=O)NC(C)(C)C)(C3CCCCC3)CC2)cc1
Reaction time: 3 h
Yield: 11.1 %

Procedure:
To 150 mg (0.45 mmol) of 2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxy-phenyl)propanoic acid dissolved in 3 ml of dichloromethane and 0.5 ml of dimethylformamide are added 0.16 ml (0.90 mmol) of diisopropylethylamine, 161 mg (0.50 mmol) of TBTU and 133 mg (0.50 mmol) of 4-tert-butylcarbamoyl-4-cyclohexylpiperidine. After 3 hours, the solution is washed with 1N sodium hydroxide solution and the organic products are extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude product obtained is purified by preparative TLC (eluent: dichloromethane/methanol 85/15). 29 mg of 4-tert-butylcarbamoyl 4-cyclohexyl-1-[2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)propionyl]-piperidine in the form of a white powder are obtained in a yield of 11%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH3:27])=[CH:20][CH:19]=1)=[O:17].[OH-].[Na+].Cl[C:31]([O:33][CH2:34][C:35]([Cl:38])([Cl:37])[Cl:36])=[O:32]>C(Cl)Cl.O>[CH2:2]([N:1]([CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH3:27])=[CH:20][CH:19]=1)=[O:17])[C:31]([O:33][CH2:34][C:35]([Cl:38])([Cl:37])[Cl:36])=[O:32])[CH2:3][CH3:4]
Reactant: CCCOc1ccc(C(=O)CBr)cc1
Reactant: CCCN
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCOc1ccc(C(=O)CN(CCC)C(=O)OCC(Cl)(Cl)Cl)cc1
Reaction time: 0.15 h

Procedure:
To 250 ml of methylene chloride was added 44 g (750 mmole) of 1-aminopropane and 107 g (830 mmole) of N,N-diisopropylethylamine. The resulting mechanically stirred mixture was cooled to +5° C. (internal) and a solution of 2-bromo-4'-propoxyacetophenone (Example 585b) (≤750 mmole) in 250 ml of methylene chloride was added over 6 minutes while strictly maintaining the internal temperature between +5° C. and +15° C. as a moderate exotherm occurred. Toward the end of the addition, the internal temperature was allowed to rise to +20° C. After the addition was complete, the mixture was stirred at +20° C. for 9 minutes and then rapidly cooled to -5° C. whereon a total of 120 g (1500 mmole) of 50% aqueous sodium hydroxide dissolved in 500 ml of water and 159 g (750 mmole) of 2,2,2-trichloroethyl chloroformate were added in alternate aliquots, roughly one eighth of the total for each aliquot, to the stirred reaction mixture. The internal temperature was maintained at between -5° C. and +5° C. during the additions. After stirring an additional 15 minutes, the organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo at 20 torr. The lower boiling impurities were then removed by distillation at 0.2 torr with the bath temperature rising to 200° C. and head temperature up to 130° C. The undistilled pot residue was dissolved in 300 ml of diethyl ether and 300 ml of hexane, filtered through silica gel and concentrated in vacuo to yield 123 g of the desired compound, an oil. An analytical sample was isolated by column chromatography on silica gel eluting with diethyl ether and hexanes.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C[NH:22][CH2:23][CH2:24][NH:25][CH3:26].[CH3:27]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:22][CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Reactant: CNCCNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1cccc(-c2ccc3ncnc(N)c3n2)c1

Procedure:
Following the same reaction and purification procedure, the acid 14 (100 mg, 0.38 mmol) was reacted with N,N′-dimethylethane-1,2-diamine (CAS 5752-40-9) (0.08 mL, 0.75 mmol), HATU (177 mg, 0.45 mmol) and DIPEA (0.33 mL, 1.9 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-(2-(dimethylamino)ethyl)benzamide 23. LC/MS (ESI+): m/z 337 (M+H). 1H NMR (400 MHz, DMSO) δ 8.74 (s, 1H), 8.60 (d, J=6.6 Hz, 2H), 8.50 (d, J=8.9 Hz, 1H), 8.43 (s, 1H), 8.28-8.14 (m, 1H), 8.06 (d, J=19.6 Hz, 2H), 7.97 (d, J=7.8 Hz, 1H), 7.64 (t, J=7.8 Hz, 1H), 3.44 (dd, J=12.9, 6.6 Hz, 2H), 2.47 (d, J=6.9 Hz, 2H), 2.22 (s, 6H).
Reaction SMILES: [N:1]([O-])=O.[Na+].Cl.[N+:6]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)([O-:8])=[O:7].[CH3:16][O:17][C:18]1[C:26]2[O:25][C:24]([CH3:28])([CH3:27])[CH2:23][C:22]=2[C:21]([CH3:29])=[CH:20][C:19]=1[CH3:30]>C(O)(=O)C.O>[CH3:16][O:17][C:18]1[C:26]2[O:25][C:24]([CH3:27])([CH3:28])[CH2:23][C:22]=2[C:21]([CH3:29])=[C:20]([N:1]=[N:13][C:12]2[CH:14]=[CH:15][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=2)[C:19]=1[CH3:30]
Reactant: O=N[O-]
Reactant: COc1c(C)cc(C)c2c1OC(C)(C)C2
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(C)c(N=Nc2ccc([N+](=O)[O-])cc2)c(C)c2c1OC(C)(C)C2
Temperature: 10 °C

Procedure:
A solution of water (100 mL) containing sodium nitrite (61.8 g, 895 mmol) was added dropwise to a suspension of 6N hydrochloric acid (1.74 L) containing p-nitroaniline (129 g, 933 mmol) under ice-cooling condition, with the inner temperature thereof being maintained at 10° C. or lower. The reaction solution was stirred under ice-cooling condition for 1 hour, and after that, a solution of acetic acid (1.74 L) containing 7-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran (crude, calculated as 746 mmol) synthesized in Reference Example 93 was added dropwise thereto. The obtained mixture was stirred at 45° C. for 4 hours. After cooled to room temperature, the precipitated solid was collected by filtration, and it was washed with 50% acetic acid aqueous solution (500 mL), water (500 mL) and cold methanol (500 mL) to give 1-(7-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-2-(4-nitrophenyl)diazene as wet crystal. Sodium hydrosulfite (519 g, 2.98 mol) was added to a suspension of methanol (1.74 L)/water (580 mL) containing the obtained wet crystal (calculated as 746 mmol), and the mixture was refluxed for 2 hours. After cooled to room temperature, the precipitate was filtered. Saturated saline was added to the filtrate, and extraction was performed using ethyl acetate (1.5 L, 1 L). The organic layer was washed with saturated saline (1 L) and dried using anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 85:15-70:30). The obtained crude product was dissolved in ethyl acetate (1.74 L), and 4N hydrochloric acid/ethyl acetate (100 mL) was added thereto for conversion into hydrochloride salt. The obtained white solid was collected by filtration, and it was washed with ethyl acetate to give 87.7 g of the title compound as a white solid (yield: 46%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][C:6]([OH:14])([P:10]([OH:13])([OH:12])=[O:11])[C:7]([OH:9])=[O:8])[CH3:3].[OH-].[Na+].[C:17]([S:20][CH2:21][CH2:22][Br:23])(=[O:19])[CH3:18]>O.C(O)C>[Br-:23].[C:17]([S:20][CH2:21][CH2:22][N+:2]([CH2:4][CH2:5][C:6]([C:7]([OH:9])=[O:8])([OH:14])[P:10]([OH:13])([OH:12])=[O:11])([CH3:1])[CH3:3])(=[O:19])[CH3:18]
Reactant: CN(C)CCC(O)(C(=O)O)P(=O)(O)O
Reactant: CC(=O)SCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)SCC[N+](C)(C)CCC(O)(C(=O)O)P(=O)(O)O
Product: [Br-]

Procedure:
A solution of 2.27 g (0.01 mole) of 4-(N,N-dimethylamino)-2-hydroxy-2-phosphonobutanoic acid (prepared as described in Method 1) in 20 ml water and 40 ml ethanol is adjusted to pH 7.0 by addition of 1N aqueous NaOH. To this is added 9.16 g (0.05 mole) of S-acetyl-2-bromoethanethiol, and the reaction is heated at 40°-80° for several hours. The reaction is evaporated to dryness under reduced pressure. The resulting residue is triturated with acetone several times (acetone extracts are discarded). The remaining solid is dissolved in distilled water, and is treated with cation exchange resin in H+ form. The resin is filtered off, the aqueous solution is concentrated to a few ml, and acetone is added dropwise to precipitate the product. This is purified by recrystallization from water/acetone to give N-(2-(acetylthio)ethyl)-N-(3-carboxy-3-hydroxy-3-phosphonopropyl)-N,N-dimethylammonium bromide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:36]1([CH2:42][C:43]([NH2:45])=[O:44])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:39]3[CH2:40][CH2:41][N:36]([CH2:42][C:43]([NH2:45])=[O:44])[CH2:37][CH2:38]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NC(=O)CN1CCNCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1
Product: Cl

Procedure:
2-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetamide hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 2-piperazin-1-yl-acetamide (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 636.4 [(M+H)+]
Reaction SMILES: [F:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[F:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:16])=[O:6]
Reactant: O=C(O)c1cccc(F)c1O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(F)c1O
Temperature: 40 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a solution of 3-fluoro-2-hydroxy-benzoic acid (5.0 g, 32 mmol) in methanol (20 mL) was added thionyl chloride (5.0 g, 42 mmol) dropwise and the reaction mixture was stirred at 40° C. for 3 hours, then heated at 50° C. for 16 hours. The reaction mixture was cooled and concentrated in vacuo and resulting residue was purified by silica gel column chromatography using 0-50% ethyl acetate/hexanes mixtures as eluant to give methyl 3-fluoro-2-hydroxy-benzoate (5.1 g, 94%) as white crystals. ESI-MS m/z calc. 170.0. found 170.9 (M+1)+; Retention time: 1.33 minutes (3 min run).
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br.CCO.O.[K+].[Br-]>O>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:15]1[C:14]2[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:13]=2[O:12][CH:11]([CH2:10][CH2:9][OH:1])[C:16]1=[O:17]
Reactant: COc1ccc2c(c1)NC(=O)C(CCO[Si](C)(C)C(C)(C)C)O2
Reactant: Clc1cccc(CBr)c1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)N(Cc1cccc(Cl)c1)C(=O)C(CCO)O2

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-6-methoxy-3-oxo-2H-1,4-benzoxazine by methods F and G, alkylating with 3-chlorobenzyl bromide, in 80% overall yield. Isolated by crystallization from EtOH/water to afford a white powder, MS (CI) 348 (MH+); IR (KBr) 3501, 3053, 3021, 2959, 2933, 2876, 2838, 1664, 1618, 1600, 1575, 1512, 1466, 1445, 1435, 1390, 1361, 1337, 1313, 1272, 1237, 1201, 1173, 1107, 1078, 1049, 1030 cm-1 ; 1H NMR (CDCl3) δ7.27-7.20 (m, 3H), 7.13 (m, 1H), 6.94 (d, J=8.8 Hz, 1H), 6.52 (dd, J=9.1, 2.7 Hz, 1H), 6.41 (d, J=2.7 Hz, 1H), 5.12 (d, J=16.2 Hz, 1H), 4.79 (dd, J=8.2, 5.4 Hz, 1H), 3.92 (m, 2H), 3.68 (s, 3H), 3.39-2.16 (m, 2H), 2.17 (t, J=5.9 Hz, 1H). Anal. Calc'd for C18H18ClNO4.0.25 H2O: C 61.37, H 5.29, N 3.98. Found: C 61.35, H 5.14, N 3.95.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:23]([CH3:33])[CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].ON1C(=O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([N:23]([CH3:33])[CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CNCCC(=O)OC(C)(C)C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: ClCCl
Product: CN(CCC(=O)OC(C)(C)C)C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 20 h
Yield: 96.7 %

Procedure:
Z-Phe-OH (29.9 g, 100 mmol), MeβAla-O-t-Bu (16.0 g, 110 mmol), and 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (17.9 g, 110 mmol) was dissolved in methylene chloride (200 ml). This solution was cooled to −10° C., added with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21.1 g, 110 mmol), and then stirred at −10° C. for one hour and further at room temperature for 20 hours. After the solvent was evaporated under reduced pressure, the reaction mixture was added with ethyl acetate (100 ml), and washed with 1N hydrochloric acid and then with saturated aqueous sodium hydrogencarbonate. The solvent was concentrated under reduced pressure to obtain an oily product, which was purified by silica gel column chromatography (benzene: ethyl acetate=10:1 (v/v)) to obtain 42.6 g of Z-Phe-MeβAla-O-t-Bu as a colorless oily product.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.O[CH2:13][CH:14]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15]1.[O:22]1[C:27]2[CH:28]=[CH:29][C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>C(C(C)=O)C(C)C>[CH:14]1([CH2:13][N:35]2[CH2:36][CH2:37][N:32]([C:30]3[CH:29]=[CH:28][C:27]4[O:22][CH2:23][CH2:24][O:25][C:26]=4[CH:31]=3)[CH2:33][CH2:34]2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15]1
Reactant: c1cc2c(cc1N1CCNCC1)OCCO2
Reactant: OCC1Cc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: c1ccc2c(c1)CC2CN1CCN(c2ccc3c(c2)OCCO3)CC1
Temperature: 100 °C

Procedure:
2.26 g (7.8×10-3 mol) of 1-hydroxymethylbenzocyclobutane tosylate, 1.7 g (7.8×10-3 mol) of 4-(2,3-dihydrobenzo-1,4-dioxin-6-yl)piperazine and 2.16 g (15.6×10-3 mol) of K2CO3 in 50 ml of methyl isobutyl ketone are mixed together. That mixture is heated at 100° C. for 8 hours and then cooled. The mixture is concentrated and the residue is taken up in water and ethyl acetate. Separation is carried out and the organic phase then extracted with 1N HCl. The aqueous phase is rendered basic with 1N NaOH and then extracted with methylene chloride and dried over MgSO4. The oil obtained is purified by flash chromatography (eluant CH2Cl2/CH3OH: 95/5). 1 g (yield=38%) of an oil that corresponds to the title compound is obtained, the dihydrochloride of which is prepared in acetonitrile. M.p. 242°-245° C.