Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10](Cl)(Cl)Cl)[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-:28].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:28])[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1
Reactant: C1CCNC1
Reactant: O=C([O-])[O-]
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1nccc(-n2c(C(=O)N3CCCC3)nc3ccc(Br)cc32)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
A mixture of 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (500 mg, 1.23 mmol), pyrrolidine (1 mL) and cesium carbonate (2 g, 6.14 mmol) in N,N-dimethylformamide (5 mL) was stirred for 24 h at room temperature. The reaction mixture was purified on a C18 column (acetonitrile/water, 5:95-80:20) to give 240 mg (51%) of 4-[6-bromo-2-[(pyrrolidin-1-yl)carbonyl]-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine as a white solid: 1H NMR (300 MHz, DMSO) delta 8.42 (d, J=5.1 Hz, 1H), 8.11 (d, J=1.8 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.57-7.53 (m, 1H), 7.07 (s, 2H), 6.71 (d, J=5.4 Hz, 1H), 3.60 (d, J=6.3 Hz, 2H), 3.50 (t, J=6.6 Hz, 2H), 1.92 (s, 4H); LC-MS: m/z=+387 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)=[O:5].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:2][CH2:3][C:4]([C:6]2[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=2)=[O:5])=[O:23])=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ccc(C(=O)CN)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Product: CCOC(=O)c1ccc(C(=O)CNC(=O)c2ccc(Cl)cc2)cc1
Yield: 54 %

Procedure:
In the same manner as in Reference Example 6, ethyl 4-(2-amino-1-oxoethyl)benzoate hydrochloride and 4-chlorobenzoyl chloride were condensed to obtain ethyl 4-[2-(4-chlorobenzoylamino)-1-oxoethyl]benzoate. Yield: 54%. NMR (CDCl3) δ 1.41 (3H, t, J=7 Hz), 4.43 (2H, q, J=7 Hz), 4.99 (2H, d, J=4 Hz), 7.23 (1H, brs), 7.46 (2H, d, J=8.5 Hz), 7.84 (2H, d, J=8.5 Hz), 8.09 (2H, d, J=8.5 Hz), 8.21 (2H, d, J=8.5 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:11][C:12]1[CH:17]=[C:16]([N:4]2[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]2)[CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COC(=O)c1c[nH]nc1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cn(-c2cccc(Cl)c2)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
Methyl 3-methyl-1H-pyrazole-4-carboxylate (1.6 g) synthesized in Example 1(3) was dissolved in N,N-dimethylacetamide (30 mL), 3-chlorophenylboronic acid (3.58 g), copper acetate (5.0 g) and pyridine (4.0 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (50 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (1.9 g, 67%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:5]([NH:7][C@H:8]([C:12]([N:14]([C@@H:16]([C@@H:48]([CH3:51])[CH2:49][CH3:50])[C@H:17]([O:46][CH3:47])[CH2:18][C:19](N1CCC[C@H]1[C@H](OC)[C@@H](C)C(N[C@@H](CC1C=CC=CC=1)C(OC)=O)=O)=[O:20])[CH3:15])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:6])([CH3:4])[NH2:3].C1C2C(COC(NC(C)(C(N[C@H](C(N([C@@H]([C@@H](C)CC)[C@H](OC)CC([N:88]3[CH2:92][CH2:91][CH2:90][C@H:89]3[C@H:93]([O:111][CH3:112])[C@@H:94]([CH3:110])[C:95]([NH:97][C@@H:98]([CH2:103][C:104]3[CH:109]=[CH:108][CH:107]=[CH:106][CH:105]=3)C(OC)=O)=[O:96])=O)C)=O)C(C)C)=O)C)=O)C3C(=CC=CC=3)C=2C=CC=1.[CH2:120](NCC)C.CO>ClCCl>[CH3:1][C:2]([C:5]([NH:7][C@H:8]([C:12]([N:14]([C@@H:16]([C@@H:48]([CH3:51])[CH2:49][CH3:50])[C@H:17]([O:46][CH3:47])[CH2:18][C:19]([N:88]1[CH2:92][CH2:91][CH2:90][C@H:89]1[C@H:93]([O:111][CH3:112])[C@@H:94]([CH3:110])[C:95]([NH:97][CH2:98][CH2:103][CH:104]1[CH:109]=[CH:108][CH:107]=[CH:106][CH:105]=[CH:120]1)=[O:96])=[O:20])[CH3:15])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:6])([CH3:4])[NH2:3]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N)C(C)C
Reactant: CCNCC
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N)C(C)C

Procedure:
Synthesis of 2-methylalanyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-3-{[(2S)-1-methoxy-1-oxo-3-phenylpropan-2-yl]amino}-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (#70). According to general procedure A, from #68 (240 mg, 0.255 mmol, 1 eq.), dichloromethane (10 mL, 0.026 M) and diethylamine (10 mL) was synthesized #70 (120 mg, 65%) as a white solid/glass mix after silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane). HPLC (Protocol A at 45° C.): m/z 762.7 [M+H+], 740.4 [M+Na+], retention time=6.903 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [8.26 (d, J=8.1 Hz) and 8.49 (d, J=8.3 Hz), total 1H], [8.03 (d, J=9.5 Hz) and 8.07 (d, J=9.5 Hz), total 1H], 7.14-7.27 (m, 5H), 3.63 and 3.67 (2 s, total 3H), 3.16, 3.18, 3.20 and 3.25 (4 s, total 6H), 2.92 and 3.01 (2 br s, total 3H), 1.20 and 1.22 (2 s, total 3H), 1.12 and 1.13 (2 s, total 3H), [1.02 (d, J=6.8 Hz) and 1.06 (d, J=6.7 Hz), total 3H], 0.74-0.80 (m, 3H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.O1CCOCC1.[CH:32]1([N:35]2[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH2:43][O:44][C:45]3[CH:53]=[CH:52][C:48]([C:49]([OH:51])=O)=[CH:47][C:46]=3[F:54])[CH2:37][CH2:36]2)[CH2:34][CH2:33]1.[CH3:55][N:56]1[C:65]2[NH:64][C:63]3[CH:66]=[CH:67][CH:68]=[CH:69][C:62]=3[NH:61][CH2:60][C:59]=2[CH:58]=[N:57]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:32]1([N:35]2[CH2:36][CH2:37][N:38]([CH2:41][CH2:42][CH2:43][O:44][C:45]3[CH:53]=[CH:52][C:48]([C:49]([N:61]4[CH2:60][C:59]5[CH:58]=[N:57][N:56]([CH3:55])[C:65]=5[NH:64][C:63]5[CH:66]=[CH:67][CH:68]=[CH:69][C:62]4=5)=[O:51])=[CH:47][C:46]=3[F:54])[CH2:39][CH2:40]2)[CH2:33][CH2:34]1
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Reactant: O=C(O)c1ccc(OCCCN2CCN(C3CC3)CC2)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(OCCCN3CCN(C4CC4)CC3)c(F)c1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
HBTU (325 mg, 0.9 mmol) and 4M HCl in dioxan (0.45 ml, 1.8 mmol) were added to a solution of 4-[3-(4-cyclopropyl-piperazin-1-yl)-propoxy]-3-fluoro-benzoic acid from Example E48.3 (230 mg, 0.7 mmol) in DMF (5 ml). The mixture was stirred at room temperature for 30 min. 3-Methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E65 (186 mg, 0.9 mmol) and DIEA (pH=9) were added and the mixture was stirred at room temperature for 18 h. The mixture was heated at 60° C. for 3 h then HBTU (300 mg, 0.8 mmol) was added. The mixture was heated at 60° C. for 2 days then solvents were removed in vacuo and azeotroped with toluene. The residue was redissolved in EtOAc, washed with saturated Na—HCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a brown solid identified as the title compound (55 mg, 15%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[CH:4][CH:3]=1.[F:11][C:12]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:13]=1[NH2:14].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:12]=2[F:11])=[O:10])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(O)c1cnccc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1F)c1cnccc1Cl
Temperature: 25 °C
Reaction time: 255 h
Yield: 42.8 %

Procedure:
To a mixture of 4-chloronicotinic acid (Lancaster Synthesis, 0.31 g, 2.0 mmol) and 2,4-difluoroaniline (Aldrich, 0.20 mL, 2.0 mmol) in anhydrous dichloromethane (5 mL) was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP®, Novabiochem, 1.4 g, 3.0 mmol) followed by diisopropylethylamine (1.1 mL, 6.4 mmol). Anhydrous DMF (2 mL) was added to the mixture and the reaction stirred at ambient temperature. After 255 hours, the reaction mixture was partitioned between chloroform and 10% LiCl (aq). The organic layer was washed three times with 10% LiCl (aq), dried over anhydrous MgSO4, then concentrated in vacuo. Purification of the residue by flash column chromatography (SiO2, eluting with 1:1 hexane/EtOAc) afforded the desired compound (0.23 g, 42%). 1H NMR (DMSO-d6) δ 10.58 (s, 1H), 8.78 (s, 1H), 8.66 (d, 1H, J=5.4 Hz), 7.82-7.88 (m, 1H), 7.71 (d, 1H, J=5.4 Hz), 7.37-7.43 (m, 1H), 7.14-7.19 (m, 1H);
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]=[CH:14][CH:15]([OH:20])[CH2:16][C:17](=[O:19])[CH3:18]>N1C=CC=CC=1>[C:1]([O:20][CH:15]([CH:14]=[CH:13][C:7]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:6]=1[Cl:5])[CH2:16][C:17](=[O:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)CC(O)C=Cc1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Product: CC(=O)CC(C=Cc1ccc(Cl)cc1Cl)OC(C)=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
Acetyl chloride (1.2 ml, 16.5 mmole) was added dropwise to a stirred solution of 6-(2,4-dichlorophenyl)-4-hydroxy-5-hexene-2-one (3.9 g, 15 mmole) in pyridine (60 ml) at 0° C. The ice bath was removed, and the reaction mixture was stirred at 20° C. for 2 hours and then diluted with ether (300 ml). The ether solution was washed with 1 N HCl (3×300 ml) and saturated NaHCO3, dried over MgSO4, filtered and evaporated. The residual pale amber oil (4.1 g) was chromatographed on a 50 mm column with 15 cm of silica gel (230-400 mesh). Elution with methylene chloride (2 L) provided the title compound as a pale yellow oil (3.95 g, 87%): pmr (CDCl3) δ2.03 (3H, s), 2.17 (3H, s), 2.83 (2H, dd).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:19](OC1C=CC([N+]([O-])=O)=CC=1)=[O:20].C(N(CC)CC)C.[N:38]1([C:44]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][NH:15][C:19]([N:41]2[CH2:42][CH2:43][N:38]([C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])[CH2:39][CH2:40]2)=[O:20])=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(CNC(=O)N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reaction time: 0.17 h
Yield: 81.5 %

Procedure:
At 0° C., 25.0 g (106 mmol) of 4-(tert-butyloxycarbonylaminomethyl)benzylamine in 150 ml of dichloromethane are added dropwise to a solution of 22.4 g (111 mmol) of 4-nitrophenyl chloroformate in 200 ml of dichloromethane, and the mixture is stirred for 10 min. 15.6 ml (111 mmol) of triethylamine are then added dropwise, and the mixture is stirred at RT for 1.5 h. At 0° C., initially 24.5 g (111 mmol) of benzyl piperazine-1-carboxylate in 80 ml of dichloromethane and then 15.6 ml (111 mmol) of triethylamine are added dropwise. The mixture is stirred at RT for 16 h. The solvent is removed from the reaction mixture and the crude product is chromatographed over silica gel (toluene/ethyl acetate=1:1). Crystallization from diisopropyl ether gives 41.7 g of the title compound as a colorless solid of m.p. 108-112° C.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([CH3:48])[CH3:47])=[CH:41][CH:40]=1)([CH3:38])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH:32]1[S:37][CH2:36][CH2:35][CH2:34][S:33]1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=1)([CH3:21])[C:16](OCC)=[O:17])C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:45]([C:42]1[CH:43]=[CH:44][C:39]([C:5]([CH3:38])([CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH:32]2[S:33][CH2:34][CH2:35][CH2:36][S:37]2)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=2)([CH3:21])[CH2:16][OH:17])[CH2:4][OH:3])=[CH:40][CH:41]=1)[CH:46]([CH3:48])[CH3:47]
Reactant: CCOC(=O)C(C)(CCCCC(CCCCC(C)(C(=O)OCC)c1ccc(CC(C)C)cc1)C1SCCCS1)c1ccc(CC(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(C(C)(CO)CCCCC(CCCCC(C)(CO)c2ccc(CC(C)C)cc2)C2SCCCS2)cc1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
A solution of 212f (5.81 g, 8.33 mmol) in freshly distilled THF (50 mL) was added dropwise to a suspension of LiAlH4 (1.0 g, 26.4 mmol) in THF (50 mL) at −78° C. under a nitrogen atmosphere. The solution was warmed to room temperature over 4 h, then cooled back to −78° C., and quenched with ethyl acetate (5.0 mL). After warming to room temperature, water (100 mL) was added and the product was extracted with Et2O (2×100 mL). The ether extracts were combined, dried with sodium sulfate, filtered, and concentrated. After drying under high vacuum for 4 h, 213f (4.80 g, 94%) was obtained as a colorless oil. 1H NMR (CDCl3): δ 7.20 (d, 4H, J=8.0), 7.09 (d, 4H, J=8.0), 3.64 (d, 2H, J=10.7), 3.48 (d, 2H, J=10.7), 2.71 (t, 4H, J=5.1), 2.50-2.35 (m br., 2H), 2.43 (d, 4H, J=7.0), 1.90-1.80 (m, 4H), 1.80-1.68 (m, 6H), 1.58-1.42 (m, 2H), 1.38-1.25 (m, 4H), 1.30 (s, 6H), 1.26-1.10 (m, 2H), 1.10-0.95 (m, 2H), 0.89 (d, 12H, J=6.6). 13C NMR (CDCl3): δ 141.94, 139.39, 129.20, 126.44, 72.48, 53.30, 44.97, 43.09, 38.45, 38.18, 30.21, 26.01, 25.64, 24.84, 24.09, 22.55, 21.64. HRMS (LSIMS, nba): Calcd for C38H61O2S2 (MH+): 613.4113. found: 613.4075. HPLC: 97.6% pure.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:15](Br)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.ClCCl>[CH2:17]([O:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)[CH:16]=[CH2:15]
Reactant: O=[N+]([O-])c1cccc2c(O)ccnc12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCOc1ccnc2c([N+](=O)[O-])cccc12
Temperature: 50 °C
Reaction time: 6 h
Yield: 49.6 %

Procedure:
To a solution of 4-hydroxy-8-nitroquinoline (200 mg) and allyl bromide (140 mg) in dimethylformamide (2 ml) was added potassium carbonate (290 mg) at 0° C., and the mixture was stirred for 6 hours at 50° C. The mixture was diluted with dichloromethane and washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved into hot ethyl acetate (2 ml), and the solution was stirred at ambient temperature. The resulting precipitate was collected by filtration to give 4-allyloxy-8-nitroquinoline (120 mg).
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4].S(Cl)([Cl:18])=O>>[ClH:18].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([Cl:1])=[O:15])[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: N=C(N)NC[C@H]1CC[C@H](C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride (1.2 g) and thionyl chloride (15 ml) was stirred at room temperature for 3 hours. Thereafter, excess thionyl chloride was removed by distillation under reduced pressure. The residue was washed with anhydrous ethyl ether to obtain trans-4-guanidinomethylcyclohexanecarboxylic acid chloride hydrochloride (1.2 g) as colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C=O.[Br:17]N1C(=O)CCC1=O>O>[NH2:1][C:2]1[C:10]([Br:17])=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(Br)cc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 10 h
Yield: 44.3 %

Procedure:
To a mixture of 1.7 g of 2-amino-5-chlorobenzoic acid and 100 ml of N,N-dimethylformamide was added 1.8 g of N-bromosuccinimide at room temperature, and the mixture was stirred at room temperature for 10 hours. Water was poured into the reaction mixture, and a deposited precipitate was collected by filtration to obtain 1.1 g of 2-amino-3-bromo-5-chlorobenzoic acid of the formula:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][C:7](=O)[CH2:8]Br.[C:12]([NH:19][C:20]([NH2:22])=[NH:21])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>CN(C=O)C>[C:15]([O:14][C:12]([N:19]1[CH:8]=[C:7]([CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:11])[N:21]=[C:20]1[NH2:22])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC(=N)N
Reactant: COC(=O)CCCC(=O)CBr
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Solvent: CN(C)C=O
Product: COC(=O)CCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
6-bromo-5-oxo-hexanoic acid methyl ester (2.30 g, 10.3 mmol), Boc-guanidine (4.92 g, 30.9 mmol),32 and Nal (3.07 g, 20.6 mmol) were dissolved in DMF (30 mL) and allowed to stir at room temperature. After 24 h the DMF was removed under reduced pressure and the residue was taken up in ethyl acetate (100 mL) and washed with water (3×50 mL) and brine (50 mL) before being dried (Na2SO4), filtered and evaporated to dryness. The resulting oil was purified by flash column chromatography (50-100% EtOAc/Hexanes) to obtain a yellow oil. Trituration of the viscous oil with cold hexanes (20 mL) produced a precipitate, which upon filtration yielded 18 (1.89 g, 65%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 6.53 (s, 1H), 5.6 (br s, 2H), 2.41 (t, 2H, J=7.2 Hz), 2.37 (t, 2H, J=7.2 Hz), 1.93 (quint., 2H, J=7.2 Hz), 1.58 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 174.09, 150.11, 149.61, 138.39, 107.15, 84.81, 51.56, 33.65, 28.18, 27.68, 23.82; HRMS (ESI) calcd for C13H22N3O4 (MH)+284.1604, found 284.1606.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][O:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([Br:18])=[CH:8][C:7]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[K+].[Br-]>>[Br:18][C:9]1[CH:8]=[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]([O:5][CH2:4][C:3]([OH:25])=[O:2])=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:10]=1
Reactant: COC(=O)COc1c(-c2ccccc2)cc(Br)cc1-c1ccccc1
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1c(-c2ccccc2)cc(Br)cc1-c1ccccc1

Procedure:
The title compound was prepared as a white solid (0.062 g, 83%) from (5′-bromo-[1,1′;3′,1″]terphenyl-2′-yloxy)acetic acid methyl ester using a procedure similar to step 2 of Example 36, mp>50° C. (decomp.); 1H NMR (CDCl3) δ 3.81 (s, 2H), 7.38-7.50 (m, 7H), 7.52-7.56 (m, 5H); IR (KBr) 3400, 3050, 2900, 1730, 1565, 1495, 1460, 1420, 1210, 1060, 875, 735, 700, and 610 cm−1; mass spectrum [(+) FAB], m/z 382 (M)+, 405 (M+Na)+; Anal. Calcd. for C20H15BrO3: C, 62.68; H, 3.95; N, 0.00, Found: C, 62.25; H, 4.01; N, 0.01.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH:8][CH:9]([CH2:20][N:21]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:22][CH:23]([OH:34])[CH2:24][NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[S:43]([O-:46])([O-:45])=[O:44].[Na+:47].[Na+]>C(Cl)(Cl)Cl.O>[C:4]([CH:3]([S:43]([O-:46])(=[O:45])=[O:44])[CH2:2][C:1](=[O:7])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24][CH:23]([OH:34])[CH2:22][N:21]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:20][CH:9]([OH:8])[CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:4](=[O:5])[CH2:3][CH:2]([C:1]([OH:6])=[O:7])[S:43]([O-:46])(=[O:45])=[O:44])([OH:6])=[O:5].[Na+:47].[Na+:47]
Reactant: CCCCCCCCNCC(O)CN(CCCCCCCC)CC(O)CNCCCCCCCC
Reactant: O=S([O-])[O-]
Reactant: O=C1C=CC(=O)O1
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCN(CC(O)CN(CCCCCCCC)C(=O)CC(C(=O)O)S(=O)(=O)[O-])CC(O)CN(CCCCCCCC)C(=O)CC(C(=O)O)S(=O)(=O)[O-]
Reaction time: 6 h
Yield: 73.3 %

Procedure:
A solution with 3.2 g (0.032 mole) of maleic anhydride dissolved in chloroform was added dropwise over 1 hour to 8 g (0.016 mole) of 11,15-dihydroxy-13-octyl-9,13,17-triazapentacosane in a reactor. The resultant mixture was heated to 50° C. and stirred for 6 hours. Thereafter, the solvent was distilled off under reduced pressure, and a solution with 6.0 g (0.048 mole) of sodium sulfite dissolved in 150 ml of water was added to the residue to react them at 60° C. for 7 hours. After completion of the reaction, the reaction mixture was added with 100 ml of additional water and adjusted to pH 7. The thus-adjusted reaction mixture was then desalted by electrodialysis and lyophilized, thereby obtaining 10.6 g (isolation yield: 71%) of sodium 1,15-dicarboxy-6,10-dihydroxy-3,13-dioxo-4,8,12-trioctyl-4,8,12-triaza-1,15-pentadecanedisulfonate.
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]2[CH2:25][NH:24][CH2:23][CH:22]2[CH:26]([O:28][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][N:30]=2)[CH3:27])[CH:17]=[CH:18][C:19]=1[Cl:20].N1C=CC=CC=1.CCOC(C)=O>C(Cl)Cl>[C:33]([C:32]1[CH:35]=[CH:36][C:29]([O:28][CH:26]([CH:22]2[CH:21]([C:16]3[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=3)[CH2:25][N:24]([C:7]([Cl:10])=[O:6])[CH2:23]2)[CH3:27])=[N:30][CH:31]=1)#[N:34]
Reactant: CC(Oc1ccc(C#N)cn1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 154.1 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (67 mg, 0.22 mmol) in CH2Cl2 (14 ml) at −78° C., was added a solution of 6-{(SR)-1-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile (intermediate XV-B-4) (210 mg, 0.56 mmol) and pyridine (0.10 ml, 1.23 mmol) in CH2Cl2 (7 mL) over 30 minutes. The temperature was raised to RT, and stirring was continued over night. The organic phase was washed with H2O, dried over Na2SO4. Concentration under vacuo yielded and column chromatography (SiO2, EtOAc/H, 1:1) yielded 144 mg (57%) of the title compound as a viscous colorless oil.