Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].N1C=CC=CC=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.O>ClCCl>[CH2:4]=[CH:3][CH2:2][CH2:1][O:5][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCCO
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: C=CCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 5 °C
Reaction time: 3.5 h
Yield: 94.2 %

Procedure:
In a reactor 3-buten-1-ol (33.2 g) and pyridine (230 ml) were charged and p-toluene sulfonyl chloride (96.7 g) was added thereto over 3.5 hours, while maintaining the internal temperature not higher than 5° C. under cooling in an ice bath. After stirring for 30 minutes, the reaction mixture was added to water (250 ml). Dichloromethane (250 ml) was added thereto and subjected to liquid separation. A saturated aqueous sodium carbonate solution (250 ml) and water (200 ml) were added to wash the lower layer, followed by liquid separation and washing with water (200 ml) twice, and dried over magnesium sulfate. After filtration followed by distillation to remove the solvent, 98.1 g of CH2═CH(CH2)2OTs was obtained.
Reaction SMILES: [C:1]12([OH:13])[CH2:10][C:5]3([OH:11])[CH2:6][CH:7]([CH2:9][C:3]([OH:12])([CH2:4]3)[CH2:2]1)[CH2:8]2.C[N:15]([CH:17]=[O:18])[CH3:16]>>[CH3:16][NH:15][C:17]([O:13][C:1]12[CH2:10][C:5]3([O:11][C:17](=[O:18])[NH:15][CH3:16])[CH2:6][CH:7]([CH2:9][C:3]([O:12][C:17](=[O:18])[NH:15][CH3:16])([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:18]
Reactant: CN(C)C=O
Reactant: OC12CC3CC(O)(C1)CC(O)(C3)C2
Product: CNC(=O)OC12CC3CC(OC(=O)NC)(C1)CC(OC(=O)NC)(C3)C2
Temperature: 60 °C
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1,3,5-adamantanetriol obtained by the method of Example 32 and one drop of pyridine were dissolved in 10 mL of DMF. To the mixture, 30 mmole of methylisocyanato was added dropwise with stirring. Cooling of the resultant mixture with ice was started at about the time exothermic reaction began. When the exothermic reaction is completed, the mixture was heated to 60° C. and then stirred for one hour. As a result, the conversion of 1,3,5-adamantanetriol was 99% and 1,3,5-tris(methylcarbamoyloxy)adamantane (yield 95%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9]P(=O)(OCC)OCC)[CH:6]=[CH:5][CH:4]=1.[Li]CCCC.[CH:23]([C:25]1[N:26]=[C:27]2[C:32]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:31][CH:30]=[C:29]([C:39]3[CH:51]=[CH:50][C:42]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[CH:41][CH:40]=3)[N:28]2[CH:52]=1)=O>C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:23]/[C:25]2[N:26]=[C:27]3[C:32]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[N:31][CH:30]=[C:29]([C:39]4[CH:51]=[CH:50][C:42]([C:43]([O:45][C:46]([CH3:49])([CH3:47])[CH3:48])=[O:44])=[CH:41][CH:40]=4)[N:28]3[CH:52]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CCOP(=O)(Cc1cccc(OC)n1)OCC
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(C=O)cn23)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(/C=C/c2cn3c(-c4ccc(C(=O)OC(C)(C)C)cc4)cnc(N4CCOCC4)c3n2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of diethyl ((6-methoxypyridin-2-yl)methyl)phosphonate (76.2 mg, 0.29 mmol, prepared according to literature procedure: J. Med. Chem. 2005, 48, 5884-5887), n-BuLi (0.184 mL, 0.29 mmol, 1.6 M in hexanes) was added dropwise. After stirring the resulting mixture for 15 min at rt, it was slowly added to a suspension of compound 67a (100 mg, 0.25 mmol) in THF (5 mL). The resulting mixture was stirred at rt for 30 min and quenched with saturated NH4Cl (2 mL). The reaction mixture was treated with water (20 mL) and extracted with EtOAc (2×40 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (0-100% EtOAc/heptanes) to give (E)-tert-butyl 4-(2-(2-(6-methoxypyridin-2-yl)vinyl)-8-morpholinoimidazo[1,2-a]pyrazin-5-yl)benzoate, which was subjected to TFA deprotection using the methods described in Example 57, Step A to yield the title compound 7 containing 0.1 eq. of TFA. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.25 (s, 1H), 8.11 (m, J=7.8 Hz, 2H), 7.83 (m, J=7.8 Hz, 2H), 7.63-7.69 (m, 1H), 7.69-7.75 (m, 1H), 7.49 (s, 1H), 7.40 (d, J=15.7 Hz, 1H), 7.08 (d, J=7.1 Hz, 1H), 6.70 (d, J=8.1 Hz, 1H), 4.29 (br. s., 4H), 3.92 (s, 3H), 3.80 (br. s., 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C25H23N5O4: 458.2 [M+H]. found 458.4.
Reaction SMILES: CC[O:3][C:4]([C:6]1[N:7](C(OC(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH2:16][C:17]1[C:21]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=3[O:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5].[OH-].[K+]>C1COCC1.O.C(O)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]2[O:19][CH:18]=[C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:13]=3[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]4)[C:21]=2[CH:22]=1
Reactant: CCOC(=O)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2n1C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
101 (7.7 g, 16.3 mmol) is dissolved in 15 ml of a 1:1:1 mixture of THF/water/ethanol and after addition of KOH pellets (5.4 g, 81.9 mmol) the mixture is stirred for 2 h at 85° C. Then the organic phase is evaporated under reduced pressure. The residue is dissolved in ethyl acetate, acidified with 2M HCl and filtered off. The crude product is purified by crystalisation from ethyl acetate.
Reaction SMILES: COCCCCCCCCCCC[C:14]([NH:16][C@@H:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:18])=[O:15].[C:24]([O:28]C(N[C@@H](C(O)=O)C)=O)([CH3:27])([CH3:26])[CH3:25].O.O.O.O.O.[OH-].C[N+](C)(C)C.C(I)C>C(#N)C>[C:24]([O:28][C:14]([NH:16][C@@H:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:18])=[O:15])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCOC(=O)[C@@H](C)NC(=O)CCCCCCCCCCCOC
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CCI
Product: CCOC(=O)[C@@H](C)NC(=O)OC(C)(C)C

Procedure:
Reaction Scheme 6 illustratively shows the preparation of N-(12-methoxy-1-oxododecyl)-D-alanine, ethyl ester wherein N-(t-butyloxycarbonyl)-D-alanine (16) is treated with tetramethylammonium hydroxide pentahydrate in acetonitrile followed by the addition of ethyl iodide to form N-(t-butyloxycarbonyl)-D-alanine, ethyl ester (17) which in turn reacts with trifluoroacetic acid in methylene chloride to give the trifluoroacetate salt of D-alanine ethyl ester (18) which, when treated with 2-methoxydodecanoyl chloride (9) in methylene chloride, gives the desired fatty acid amino ester (19).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=N2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:16][C:17]1C=CNN=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH:17]=[CH:16][C:14]([CH3:13])=[N:15]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1cc[nH]n1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Product: Cc1ccc(-n2ccc(C)n2)c(C(=O)O)c1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A11 using 3-methyl-1H-pyrazole. MS (ESI) 217 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]([CH2:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[N:20]=[CH:21][N:22](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:23]=2)=[O:10])[C:6](=[O:43])[C:5]([NH:44][CH2:45][C:46]([F:54])([F:53])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=2)=[N:4][CH:3]=1.C([SiH](CC)CC)C.[F:62][C:63]([F:68])([F:67])[C:64]([OH:66])=[O:65]>>[OH:66][C:64]([C:63]([F:68])([F:67])[F:62])=[O:65].[Cl:1][C:2]1[N:7]([CH2:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[N:20]=[CH:21][NH:22][CH:23]=2)=[O:10])[C:6](=[O:43])[C:5]([NH:44][CH2:45][C:46]([F:53])([F:54])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=2)=[N:4][CH:3]=1
Reactant: O=C(Cn1c(Cl)cnc(NCC(F)(F)c2ccccn2)c1=O)NCc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cn1c(Cl)cnc(NCC(F)(F)c2ccccn2)c1=O)NCc1ccccc1-c1c[nH]cn1

Procedure:
To a solution of 2-[6-chloro-3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2-oxo-2H-pyrazin-1-yl]-N-[2-(1-trityl-1H-imidazol-4-yl)-benzyl]-acetamide (47 mg, 0.058 mmol) in trifluoroacetic acid (1.5 ml) was added triethylsilane (excess) until completion of the reaction. Concentration and purification by reverse phase preparative HPLC (5% to 95% CH3CN in water containing 0.1% TFA, C18 PRO YMC 20×150 mm) gave 2-[6-chloro-3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2-oxo-2H-pyrazin-1-yl]-N-[2-(1H-imidazol-4-yl)-benzyl]-acetamide TFA salt; 1H NMR (CD3OD, 400 MHz) δ 8.95 (d, 1H, J=1.3 Hz), 8.63 (d, 1H, J=4.1 Hz), 7.94 (dt, 1H, J=7.7 Hz, J=1.6 Hz), 7.70 (m, 2H), 7.51 (m, 6H), 6.83 (s, 1H), 4.80 (s, 2H), 4.46 (s, 2H), 4.28 (t, 2H, J=14.1 Hz); MS (ES+) M+1 500.4 for C23H20ClF2N7O2.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[OH:26].C(=O)([O-])[O-].[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O>[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[O:26][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12
Reactant: Clc1ccnc2cc(-c3nccs3)sc12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4nccs4)sc23)c(F)c1
Temperature: 180 °C
Yield: 66.1 %

Procedure:
To a suspension of 10 (194 mg, 0.77 mmol) in Ph2O (10 mL) was added 2-fluoro-4-nitrophenol (240 mg, 1.53 mmol) and potassium carbonate (425 mg, 3.08 mmol) and the reaction mixture was heated at 180° C. for 4 hrs. The reaction mixture was cooled to room temperature and diluted with EtOAc. The resultant solution was washed with water and the organic layer was collected, dried over anhydrous sodium sulfate and filtered. The solvents were removed under reduced pressure; the residue was dissolved in DCM, and purified by column chromatography (eluent EtOAc-hexane 4:1) to afford 11 (190 mg, 66% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) ppm: 8.61 (d, J=5.5 Hz, 1H), 8.46 (dd, J=2.74 and 10.37 Hz), 8.24 (s, 1H), 8.20-8.10 (m, 1H), 7.95 (s, 2H), 7.73 (t, J=8 Hz, 1H), 6.98 (d, J=5.3 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[F:1][C:2]1[C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(F)ccc1F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(F)cc([N+](=O)[O-])c1F
Temperature: 28 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a stirred solution of 2,5-difluorotoluene (0.544 g, 4.25 mmol, Aldrich, used as received) in conc. H2SO4 (5.0 mL) at 0° C., KNO3 (0.430 g, 4.25 mmol) was added in one portion. The resulting pale yellow solution was warmed to 28° C. and stirred at that temperature overnight. It was then poured into ice (25 g) and extracted with ethyl acetate (40 mL). The extract was dried over Na2SO4 and evaporated to afford 0.555 g (91%) of the title compound as a light red oil; 1H NMR (CDCl3): 2.369 (d, 3H, J=1.8 Hz), 7.127 (dd, 1H, J1 =8.1 Hz, J2 =6.0 Hz), 7.734 (dd, 1H, J1 =8.4 Hz, J2 =6.3 Hz).
Reaction SMILES: COC(=O)CO[C:6]1[N:11]=[C:10]2[S:12][C:13]([C:16](=[O:18])[NH2:17])=[C:14]([NH2:15])[C:9]2=[C:8](C)[CH:7]=1.[N+:21]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)([O-:23])=[O:22]>O1CCOCC1>[NH2:15][C:14]1[C:9]2[C:10](=[N:11][CH:6]=[CH:7][C:8]=2[NH:28][C:27]2[CH:29]=[CH:30][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)[S:12][C:13]=1[C:16]([NH2:17])=[O:18]
Reactant: COC(=O)COc1cc(C)c2c(N)c(C(N)=O)sc2n1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: C1COCCO1
Product: NC(=O)c1sc2nccc(Nc3ccc([N+](=O)[O-])cc3)c2c1N
Yield: 9.9 %

Procedure:
A solution of 20 mg trifluoromethanesulfonic acid 3-amino-2-carbamoyl-thieno[2,3-b]pyridin-4-yl ester (see Example 19) and 40.5 mg 4-nitroaniline in 1 mL of dry dioxane was heated at 95° C. overnight under N2. The reaction was concentrated and applied to a 2 mm silica gel prep plate that was developed twice in 7.5% MeOH—CH2Cl2. The band was eluted with 20% MeOH—CH2Cl2, concentrated in vacuo, re-dissolved in 5% MeOH—CH2Cl2, filtered, concentrated, and dried in vacuo at 60° overnight to get 2.2 mg of the title compound as an orange solid.
Reaction SMILES: [C:1]([C:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][C:10]=1[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24]([Br:28])=[C:23]([O:29][CH2:30][C:31]#[N:32])[CH:22]=[CH:21]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:33]=[N+:34]=[N-:35].[Na+].[NH4+].[Cl-]>CN(C=O)C>[Br:28][C:24]1[C:23]([O:29][CH2:30][C:31]2[NH:35][N:34]=[N:33][N:32]=2)=[CH:22][CH:21]=[C:20]2[C:25]=1[CH:26]=[CH:27][C:18]([C:10]1[O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:9]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:8])=[CH:19]2
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCOc1ccc2cc(-c3oc4ccccc4c3C(=O)c3ccccc3)ccc2c1Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1c(-c2ccc3c(Br)c(OCc4nnn[nH]4)ccc3c2)oc2ccccc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a stirred solution of {[6-(3-benzoyl-1-benzofuran-2-yl)-1-bromo-2-naphthyl]oxy} acetonitrile (0.174 g, 0.361 mmol) in DMF (10 mL) at room temperature was added NaN3 (0.117 g, 1.81 mmol) followed by NH4Cl (0.097 g, 1.81 mmol). The reaction was heated to 100° C. for 2 h. After this time, it was concentrated and diluted with 2 N HCl (˜5 mL). This mixture was stirred at room temperature for 1 h. The solid was filtered and washed with excess water and hexane then dried under high vacuum to afford the product (0.190 g, 99%) as a light. brown solid, mp>183° C. (dec.). Mass spectrum (+APCl, [M+NH4]+) m/z 542. 1HNMR (500 MHz, DMSO-d6): δ14.75-17.75 (br s, 1H), 8.28 (d, 1H, J=2.0 Hz), 8.03 (d, 1H, J=9.0 Hz), 8.00 (d, 1H, J=8.8 Hz), 7.78-7.83 (m, 3H), 7.76 (dd, 1H, J=1.7, 8.8 Hz), 7.67 (d, 1H, J=9.0 Hz), 755 (d, J=7.6 Hz, 1H), 7.32-7.38 (m, 3H), 7.45-7.52 (m, 2H), and 5.71 ppm (s, 2H). Elemental analysis for C27H17BrN4O3.1.0H2O: Calculated: C, 59.68; H, 3.52; N, 10.31. Found: C, 59.72; H, 3.23; N, 10.51.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2C=O.[N+:15]([C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[NH:27][NH2:28])([O-:17])=[O:16].O>C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=[N:28][NH:27][C:19]3[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=3[N+:15]([O-:17])=[O:16])[CH:7]([Cl:12])[CH:8]=[CH:9][C:10]=2[CH:11]=1
Reactant: NNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: O=Cc1c(Cl)ccc2cc(Cl)cnc12
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(NN=C2c3ncc(Cl)cc3C=CC2Cl)c([N+](=O)[O-])c1
Yield: 85.5 %

Procedure:
23 g of 3,7-dichloroquinoline-8-carbaldehyde and 20 g of 2,4-dinitrophenylhydrazine in 500 ml of ethanol were heated at 80° C. for 5 hours. Water was added to the reaction mixture, and the precipitated solid was filtered off under suction and recrystallized from dimethylformamide to give 34 g (85% of theory) of 3,7-dichloro-8-(2,4-dinitrophenylhydrazono)-quinoline of melting point >280° C.
Reaction SMILES: C1(N=C=O)C=CC=CC=1.C(N)CC.NC(N)=O.C(CC(O)=O)#N.N([O-])=O.[Na+].N[C:29]1[N:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:33](=[O:41])[N:32](CCC)[C:31](=O)[CH:30]=1.[H][H].NC1C(=O)N(CCC)C(=O)N(C2C=CC=CC=2)C=1N>>[CH2:31]([NH:32][C:33]([NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:41])[CH2:30][CH3:29]
Reactant: [H][H]
Reactant: CCCn1c(=O)cc(N)n(-c2ccccc2)c1=O
Agent: CCCn1c(=O)c(N)c(N)n(-c2ccccc2)c1=O
Agent: N#CCC(=O)O
Agent: NC(N)=O
Solvent: CCCN
Solvent: O=C=Nc1ccccc1
Product: CCCNC(=O)Nc1ccccc1

Procedure:
N-Propyl-N'-phenylurea was prepared preliminarily from phenyl isocyanate and propylamine by the same procedure as in Reference Example 1. The urea compound as the starting material was reacted with cyanoacetic acid to form a uracil ring. Using sodium nitrite a nitroso group was introduced into the 5-position of the uracil ring in the obtained 6-amino-1-phenyl-3-propyluracil and then reduced with hydrogen gas to prepare 5,6-diamino-1-phenyl-3-propyluracil.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18])=O)(C)(C)C.[CH2:27](O)[CH3:28].[ClH:30]>>[ClH:30].[NH2:8][CH2:9][CH2:10][C:11]1[CH:23]=[CH:22][C:21]([CH:24]([CH3:25])[CH3:26])=[CH:20][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:27][CH3:28])=[O:18]
Reactant: CCO
Reactant: CC(C)c1ccc(CCNC(=O)OC(C)(C)C)c(OCCCC(=O)[O-])c1
Agent: Cl
Product: CCOC(=O)CCCOc1cc(C(C)C)ccc1CCN
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-[2-(2-tert-Butoxycarbonylaminoethyl)-5-isopropyl-phenoxy]butyrate (0.283 g) was deissolved in 10 mL of 35% hydrogen chloride ethanol solution, and the mixture was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure to give 0.235 g of ethyl 4-[2-(2-aminoethyl)-5-isopropylphenoxy]butyrate hydrochloride.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9](=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>C1C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9](=[S:21])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1cc(-c2ccccc2)cc(-c2ccccc2)o1
Solvent: c1ccccc1
Product: S=c1cc(-c2ccccc2)cc(-c2ccccc2)o1
Yield: 134.2 %

Procedure:
Under an inert atmosphere, 2.1 g of the product of Step A 45 ml of benzene and 7.5 g of phosphorus pentasulfide were mixed together and refluxed under inert atmosphere for 5 hours. Then the supernatant solution was decanted hot and concentrated to dryness by distilling under reduced pressure. This operation was repeated hot on the reaction medium four times, each time with 30 ml of benzene. The concentrates were put together and dried under a good vacuum to obtain 3 g of product which was chromatographed on silica and eluted with methylene chloride to obtain 2 g of the product sought melting at 122°-123° C.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[NH:4]1)(=[O:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:14]>>[Cl:14][C:5]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[S:1](=[O:3])(=[O:2])[N:4]=1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: O=S1(=O)N=C(Cl)c2ccccc21
Yield: 28 %

Procedure:
Following the procedure of Stephen et al., J. Chem. Soc., 1957, 490-92, 1 mol of saccharin (1,2-benzisothiazol-3(2H)-one 1,1-dioxide) is heated with 1.1 mol phosphorus pentachloride at 170° C. for 1.5 hours. Phosphorus oxychloride is removed at 60°/30 mm and the yellow crystalline residue of ψ-saccharin chloride and o-cyanobenzene sulfonyl chloride is treated with ether in which the latter is soluble. The sparingly soluble ψ-saccharin chloride in a yield of 28% is collected and crystallized from ether as white needles, m.p. 132°-137° C.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH:15]1([C:18]2[CH:23]=[CH:22][C:21]([C:24]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][C:27]=3[OH:32])=[O:25])=[CH:20][CH:19]=2)[CH2:17][CH2:16]1.[CH2:33]([O:40][C@@H:41]1[C@@H:46]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@H:45]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@@H:44]([CH2:63][O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[CH2:43][C@@H:42]1O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH:15]1([C:18]2[CH:19]=[CH:20][C:21]([C:24]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][C:27]=3[O:32][C@@H:42]3[CH2:43][C@H:44]([CH2:63][O:64][CH2:65][C:66]4[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=4)[C@@H:45]([O:55][CH2:56][C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[C@H:46]([O:47][CH2:48][C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)[C@H:41]3[O:40][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:25])=[CH:22][CH:23]=2)[CH2:16][CH2:17]1
Reactant: O=C(c1ccc(C2CC2)cc1)c1ccncc1O
Reactant: O[C@H]1C[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(C2CC2)cc1)c1ccncc1O[C@@H]1C[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
In a nitrogen stream, diisopropylazodicarboxylate (0.14 mL, 0.72 mmol) was slowly added dropwise to a mixture of (4-cyclopropylphenyl)-(3-hydroxypyridin-4-yl)methanone (0.18 g, 0.74 mmol), (1S,2S,3S,4R,5R)-2,3,4-trisbenzyloxy-5-benzyloxymethylcyclohexanol (0.20 g, 0.37 mmol), triphenylphosphine (0.19 g, 0.74 mmol) and toluene (1.3 mL) under cooling with ice. The reaction mixture was stirred at room temperature for three hours, and then the solvent was distilled under reduced pressure and the obtained residue was purified by silica gel flash column chromatography [developing solution=n-hexane:ethyl acetate (2:3)] to obtain the title product (0.20 g, 71%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH:45]([C:47]#[N:48])[CH2:44][N:43]6C(=O)C(NC(OC)=O)C6C=CC=CC=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].COC(NC(C1C=CC=CC=1)C(O)=O)=O.[CH3:79][N:80]([CH:82]([C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1)[C:83]([OH:85])=O)[CH3:81]>>[CH3:1][O:2][C:3](=[O:63])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH:45]([C:47]#[N:48])[CH2:44][N:43]6[C:83](=[O:85])[CH:82]([N:80]([CH3:79])[CH3:81])[C:86]6[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: CN(C)C(C(=O)O)c1ccccc1
Reactant: COC(=O)NC(C(=O)N1CC(C#N)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Agent: COC(=O)NC(C(=O)O)c1ccccc1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(C#N)CN6C(=O)C(c6ccccc6)N(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C

Procedure:
Synthesized similar to [1-(2-{5-[6-(4-{2-[4-Cyano-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester replacing the methoxycarbonylamino-phenyl-acetic acid with dimethylamino-phenyl-acetic acid.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19]C)=[O:18])=[C:15]([O:21][CH2:22][CH2:23][NH:24]C(OC(C)(C)C)=O)[C:14]([CH2:32][CH3:33])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:34].[Li+]>O1CCOCC1.O>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:21][CH2:22][CH2:23][NH:24][O:34][C:11]([CH3:16])([CH3:12])[CH3:10])[C:14]([CH2:32][CH3:33])=[CH:13][CH:12]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OC)c1OCCNC(=O)OC(C)(C)C
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)O)c1OCCNOC(C)(C)C
Temperature: 130 °C
Yield: 131.6 %

Procedure:
A mixture of methyl 6-(benzenesulphonylmethyl)-2-(2-t-butoxycarbonylaminoethoxy)-3-ethylbenzoate (Intermediate 108, 0.125 g), and lithium hydroxide (0.066 g) in dioxane (1.4 ml) and water (0.4 ml) was stirred and heated in the microwave at 130° C. for 45 minutes. The mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The aqueous layer was acidified with hydrochloric acid (1M) and extracted with ethyl acetate, washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give 6-(benzenesulphonylmethyl)-2-(2-t-butoxyaminoethoxy)-3-ethylbenzoic acid (0.075 g) as a colourless gum.