Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.O1CCOCC1.C(OC([N:15]1[C@H:19]([C:20]2[NH:21][CH:22]=[C:23]([C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH:31]=[C:30]([C:35]3[CH:40]=[CH:39][C:38]([C:41]5[N:42]=[C:43]([C@H:46]6[N:50](C(OC(C)(C)C)=O)[C@H:49]7[CH2:58][CH2:59][CH2:60][C@H:48]7[CH2:47]6)[NH:44][CH:45]=5)=[CH:37][CH:36]=3)[CH:29]=[CH:28]4)[N:24]=2)[CH2:18][C@@H:17]2[CH2:61][CH2:62][CH2:63][C@H:16]12)=O)(C)(C)C.C(Cl)Cl>C1(C)C=CC=CC=1>[NH:15]1[C@H:19]([C:20]2[NH:21][CH:22]=[C:23]([C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH:31]=[C:30]([C:35]3[CH:40]=[CH:39][C:38]([C:41]5[N:42]=[C:43]([C@H:46]6[NH:50][C@H:49]7[CH2:58][CH2:59][CH2:60][C@H:48]7[CH2:47]6)[NH:44][CH:45]=5)=[CH:37][CH:36]=3)[CH:29]=[CH:28]4)[N:24]=2)[CH2:18][C@@H:17]2[CH2:61][CH2:62][CH2:63][C@H:16]12
Reactant: CC(C)(C)OC(=O)N1[C@H](c2nc(-c3ccc(-c4ccc5cc(-c6c[nH]c([C@@H]7C[C@@H]8CCC[C@@H]8N7C(=O)OC(C)(C)C)n6)ccc5c4)cc3)c[nH]2)C[C@@H]2CCC[C@@H]21
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: c1cc(-c2c[nH]c([C@@H]3C[C@@H]4CCC[C@@H]4N3)n2)ccc1-c1ccc2cc(-c3c[nH]c([C@@H]4C[C@@H]5CCC[C@@H]5N4)n3)ccc2c1

Procedure:
4N HCl in dioxane (20 equiv) was added to a solution of (2S,3aS,6aS)-tert-butyl 2-(4-(4-(6-(2-((2S,3aS,6aS)-1-(tert-butoxycarbonyl)-octahydrocyclopenta[b]pyrrol-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)hexahydrocyclopenta[b]pyrrole-1(2H)-carboxylate in an. DCM and the mixture was stirred at rt for 2-3 h Anhydrous toluene was added to the resultant yellow suspension and then evaporated to dryness to an HCl salt of (2S,3aS,6aS)-2-(4-(4-(6-(2-((2S,3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)octahydrocyclopenta[b]pyrrole as a beige solid: LC-MS retention time: 2.343 min; m/z 555 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[CH:16][C:15]3[N:14]=[CH:13][C:12]4[N:18]([CH3:29])[C:19](=[O:28])[N:20]([C:21]5[C:22]([CH3:27])=[N:23][N:24]([CH3:26])[CH:25]=5)[C:11]=4[C:10]=3[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[CH:30](=O)[CH3:31].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:26][N:24]1[CH:25]=[C:21]([N:20]2[C:11]3[C:10]4[CH:9]=[C:8]([C:4]5[CH:5]=[N:6][CH:7]=[C:2]([NH:1][CH2:30][CH3:31])[CH:3]=5)[CH:17]=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:18]([CH3:29])[C:19]2=[O:28])[C:22]([CH3:27])=[N:23]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(N)c4)cc3c21
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCNc1cncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 8-(5-amino-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 45, 38 mg, 0.099 mmol), acetaldehyde (Fluka, Buchs, Switzerland, 4.8 mg, 0.108 mmol) in DCM (2 ml) was stirred for 1.5 h at rt in presence of acetic acid (0.02 ml, 3.54 mmol). Was added sodium triacetoxyborohydride (52.2 mg, 0.246 mmol) and the RM was stirred 1.5 h at rt, before being quenched with aqueous saturated NaHCO3 and extracted with DCM (2×). The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by Prep.HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 60:40). The fractions containing products were collected together and basified with NaHCO3 (0.3 g), before being concentrated, saturated with NaCl and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and evaporated to give the title compound as an off-white solid. (HPLC: tR 2.13 min (Method A); M+H=414 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.13-8.08 (m, 2H), 7.97-7.95 (m, 1H), 7.92-7.88 (m, 2H), 7.60-7.58 (m, 1H), 6.88-6.85 (m, 1H), 6.01 (t, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 3.15-3.06 (m, 2H), 1.95 (s, 3H), 1.21 (t, 3H))
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[C:10]2=[O:21])[CH:6]=[CH:7][CH:8]=1.O.[C:23]1([CH3:33])C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=[O:35].[Na+]>C(CC([O-])=O)(C)=C>[C:23]([O:21][C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=2)[CH2:17][CH2:18][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:35])[CH3:33]
Reactant: O=C([O-])O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1cccc(C2CCc3cc(OC)ccc3C2=O)c1
Agent: C=C(C)CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: COc1cccc(C2=C(OC(C)=O)c3ccc(OC)cc3CC2)c1

Procedure:
A suspension was prepared of 47 g (167 mmol) of 2-(3-methoxyphenyl)-6-methoxy-1-tetralone and 4.7 g of p-toluenesulfonic acid mono-hydrate in 470 mL of isopropenylacetate. The reaction mixture was refluxed for forty-eight hours under a nitrogen atmosphere. The reaction was allowed to cool and 10 g of NaHCO3 was added′ the solution was poured into 500 mL of an aqueous solution of NaHCO3. The aqueous solution was extracted three times with 200 mL portions of EtOAc. The combined organic extract was washed with brine, dried with Na2SO4, and evaporated to a dark oil. This yielded 52.7 g of the title compound.
Reaction SMILES: [CH2:1]([C:8]1[N:9]([CH2:19][C:20]([OH:22])=O)[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)(O)O.[NH2:39][C:40]([NH2:42])=[NH:41].C(N(CC)CC)C>CN(C=O)C>[NH2:41][C:40](=[NH:39])[NH:42][C:20](=[O:22])[CH2:19][N:9]1[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:12]=[C:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1c(Cc2ccccc2)ccc1-c1ccccc1
Reactant: N=C(N)N
Agent: O=C(O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N=C(N)NC(=O)Cn1c(Cc2ccccc2)ccc1-c1ccccc1
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a stirred solution of (2-benzyl-5-phenyl-1H-pyrrol-1-yl)acetic acid (155 mg, 0.53 mmol) in DMF (1.0 ml) was added 1,1′-carbonyldiimidazole (172 mg, 1.06 mmol) at room temperature. After 1 h stirring, the reaction mixture was treated with a solution of guanidine carbonate (286 mg, 1.59 mmol) in DMF (2.0 ml) and triethylamine (0.22 ml, 1.59 mmol). After stirring for 18 h, the reaction mixture was quenched with H2O (10 ml). The aqueous was extracted with EtOAc (3×30 ml). The combined organic extracts were washed with H2O (2×30 ml), brine (30 ml), dried (Na2SO4), filtered and concentrated. The crude material was purified by chromatography (silica gel; EtOAc/2M NH3 in MeOH: 97/3) to give the titled compound (130 mg, 74%) as a solid: mp 155-158° C.; MS (+) ES, 333 (M+H)+.
Reaction SMILES: [Br-].[CH2:2]1[CH2:29][O:28][C:4]([CH3:27])([CH2:5][CH2:6][CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:3]1.C([Li])CCC.CCCCCC.C([O:43][CH:44](OCC)[C:45](=O)[CH2:46][CH2:47][CH:48]=[C:49]([CH3:51])[CH3:50])C.CCCCCC>O1CCCC1.C(O)(=O)C>[CH2:29]1[CH2:2][O:3][C:4]([CH2:5][CH2:6][CH:7]=[C:45]([CH:44]=[O:43])[CH2:46][CH2:47][CH:48]=[C:49]([CH3:51])[CH3:50])([CH3:27])[O:28]1
Reactant: CCOC(OCC)C(=O)CCC=C(C)C
Reactant: CC1(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)OCCO1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CC(C)=CCCC(C=O)=CCCC1(C)OCCO1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
In 160 ml of anhydrous tetrahydrofuran was suspended 38.5 g of 4,4-ethylenedioxypentan-1-yltriphenylphosphonium bromide, and to this was added the equimolar amount of a n-butyl-lithium-hexane solution at -20° C in a stream of nitrogen. The reaction mixture was stirred for 1 hour and cooled to -60° C. To this was added 14.5 g of 1,1-diethoxy-6-methyl-5-hepten-2-one, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was, after addition of ice-water, extracted with n-hexane and from the extract was obtained an oil. The oil was suspended in 250 ml of 50 % acetic acid and stirred at room temperature for one hour. 2,2-Ethylenedioxy-6-formyl-10-methyl-5,9-undecadiene obtained by the n-hexane extraction, not purified, was reduced in 100 ml of ethanol by using 500 mg of sodium borohydride. The product thus obtained was chromatographed on the silica gel (100 g) column to yield 7.3 g of 2,2-ethylenedioxy-6-hydroxymethyl-10-methyl-5,9-undecadien.
Reaction SMILES: [Br:1][CH:2]([N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[N+:10]([O-:12])=[O:11])[CH2:3]Br.CC[O-].[Na+]>CO>[Br:1][C:2]([N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[N+:10]([O-:12])=[O:11])=[CH2:3]
Reactant: O=[N+]([O-])c1nccn1C(Br)CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CO
Product: C=C(Br)n1ccnc1[N+](=O)[O-]
Yield: 55.9 %

Procedure:
20.1 g of 1-(1,2-dibromoethyl)-2-nitroimidazole were heated under reflux for 1 hour in 132 ml of a 0.51 N solution of sodium ethylate in methanol. The mixture was evaporated and the residue was taken up with 250 ml of ethyl acetate and 100 ml of water. The organic phase was washed with 100 ml of 10% sodium chloride solution and evaporated, and the residue was chromatographed on 300 g of silica gel using ethyl acetate/cyclohexane (4:1, v/v). After a forerun of 420 ml, there were isolated from 270 ml of further eluate 8.2 g of 1-(1-bromovinyl)-2-nitroimidazole; yield 4.6 g; m.p. 80°-82° C. (from isopropanol).
Reaction SMILES: [CH:1](N1CCCCC1)=[CH:2][CH2:3][CH2:4][CH2:5]CCCCCCC.[Cl:19]([OH:23])(=[O:22])(=[O:21])=[O:20]>>[Cl:19]([O-:23])(=[O:22])(=[O:21])=[O:20].[O+:20]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: CCCCCCCCCCC=CN1CCCCC1
Reactant: [O-][Cl+3]([O-])([O-])O
Product: [O-][Cl+3]([O-])([O-])[O-]
Product: c1cc[o+]cc1

Procedure:
Using sodium hydride (2.0 g), p-(5-dlecyl-2-pyridinyl)-phenol (m.p. 90.4-91.8° C.) (9 g) and 2S-2-(2'-tetrahydropyranyloxy)-4-methyl-pentyl-p-toluenesulfonate (10 g) obtained in Example 1-(2), and in the same manner as in Example 1-(3), the objective compound, S-1-(4-(5-decyl-2-pyridinyl)-phenoxy)-4-methyl-pentane-2-ol ([α]D24 +6.4 (C 0.5, CHCl3)) (8.5 g) was obtained. In addition, the above-mentioned p-(5-decyl-2-pyridinyl)-phenol is obtained according to the process disclosed in Japanese patent application No. Sho 60-293934/1985 wherein p-methoxyphenyl-β-chlorovinyl ketone and N-dodecenylpiperidine as known substances are reacted together, followed by reacting the reaction product with perchloric acid to obtain pyrylium perchlorate, reacting this compound with ammonium acetate to obtain 5-decyl-2-(p-methoxyphenyl)-pyridine, and further reacting this compound with aqueous hydrogen bromide in acetic acid for demethylation.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10]CN.CSC(SC)=[CH:16][N+:17]([O-])=O.[N+:22]([CH:25]=[C:26](SC)[NH:27][CH2:28][CH2:29][CH2:30]SCC1NC=NC=1C)([O-:24])=[O:23].C(N)C#C>>[N+:22]([CH:25]=[C:26]([NH:27][CH2:28][C:29]#[CH:30])[NH:17][CH2:16][CH:9]([S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])[CH3:10])([O-:24])=[O:23]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CSC(=C[N+](=O)[O-])NCCCSCc1[nH]cnc1C
Reactant: Cc1nc[nH]c1CSCCCN
Agent: C#CCN
Product: C#CCNC(=C[N+](=O)[O-])NCC(C)SCc1[nH]cnc1C

Procedure:
When 3-[(4-methyl-1H-imidazol-5-yl)methylthio]propylamine [prepared according to the procedure described in Belgian Pat. No. 804,144] is reacted with 1,1-bis(methylthio)-2-nitroethylene according to the procedure of Example 6, Step A, and the resultant 1-nitro-2-methylthio-2-{3-[(4-methyl-1H-imidazol-5-yl)methylthio]propylamino}ethylene is treated with propargylamine by the procedure of Example 6, Step B, the title compound is produced.
Reaction SMILES: C(OC1N(CC2C=CC(C3C=CC=CC=3C3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)=CC=2)C2C(C(O)=O)=CC=CC=2N=1)C.[C:53]([N:59]([CH2:67][C:68]1[CH:73]=[CH:72][C:71]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=2[C:80]2[N:84](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:83]=[N:82][N:81]=2)=[CH:70][CH:69]=1)[C@H:60]([C:64]([OH:66])=[O:65])[CH:61]([CH3:63])[CH3:62])(=[O:58])[CH2:54][CH2:55][CH2:56][CH3:57].[CH3:104][O:105][C@@H:106]1[C@@H:110]([O:111][N+:112]([O-:114])=[O:113])[CH2:109][C@H:108]([C:115]([O:117][CH:118](Cl)[CH3:119])=[O:116])[CH2:107]1.CO[C@@H]1[C@@H](O[N+]([O-])=O)C[C@H](C(O[C@@H](Cl)C)=O)C1>>[C:53]([N:59]([CH2:67][C:68]1[CH:73]=[CH:72][C:71]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=2[C:80]2[NH:84][N:83]=[N:82][N:81]=2)=[CH:70][CH:69]=1)[C@H:60]([C:64]([O:66][C@@H:118]([O:117][C:115]([C@H:108]1[CH2:109][C@H:110]([O:111][N+:112]([O-:114])=[O:113])[C@@H:106]([O:105][CH3:104])[CH2:107]1)=[O:116])[CH3:119])=[O:65])[CH:61]([CH3:63])[CH3:62])(=[O:58])[CH2:54][CH2:55][CH2:56][CH3:57]
Reactant: CO[C@H]1C[C@@H](C(=O)OC(C)Cl)C[C@@H]1O[N+](=O)[O-]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)[C@H](C(=O)O)C(C)C
Agent: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CO[C@H]1C[C@@H](C(=O)O[C@H](C)Cl)C[C@@H]1O[N+](=O)[O-]
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O[C@H](C)OC(=O)[C@@H]1C[C@H](OC)[C@@H](O[N+](=O)[O-])C1)C(C)C

Procedure:
The title compound was prepared by following the procedure for example 2, except that the reagent 2-ethoxy-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid was replaced by N-pentanoyl-N-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-L-valine and 1-chloroethyl (1R,3S,4S)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylate (intermediate 2) was replaced by (1S)-1-chloroethyl (1R,3S,4S)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylate (intermediate 3). LC-MS: m/z 667.3 (M+H).
Reaction SMILES: [C:1]([NH:5][C:6]1[N:11]=[C:10]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([NH2:21])=[CH:20][C:15]=3[N:14]=[CH:13]2)[CH:9]=[N:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl.[C:41](O)(=[O:44])[CH:42]=[CH2:43]>ClCCl.O>[C:1]([NH:5][C:6]1[N:11]=[C:10]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([NH:21][C:41](=[O:44])[CH:42]=[CH2:43])=[CH:20][C:15]=3[N:14]=[CH:13]2)[CH:9]=[N:8][CH:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=O)O
Reactant: CC(C)(C)Nc1cncc(-n2cnc3cc(N)ccc32)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc2c(c1)ncn2-c1cncc(NC(C)(C)C)n1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-[6-(tert-butylamino)pyrazin-2-yl]-1H-benzimidazol-5-amine (20 mg, 0.08 mmol) in anhydrous dichloromethane (2 mL) under N2 was added triethylamine (33 μL, 0.24 mmol), EDAC.HCl (22 mg, 0.12 mmol), 4-(1-pyrrolidino)pyridine (cat.) and acrylic acid (8 μL, 0.12 mmol). The resulting mixture then stirred at RT for 3 clays and was the diluted with H2O (10 mL), the organic phase separated and the aqueous phase extracted with CH2Cl2 (10 mL). The combined organic layers were dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by column chromatography using dichloromethane-methanol (98:2-92:8) as eluant to separate the pure product (10 mg).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[O:13]1[C:17]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>CN1C(=O)CCC1>[O:13]1[C:17]2([CH2:22][CH2:21][N:20]([C:2]3[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=3)[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 150 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 4-fluorobenzoate (6.0 mL, 41 mmol), 1,4-dioxa-8-azaspiro(4,5)decane (13.5 mL, 102 mmol), and K2CO3 (5.7g, 41 mmol) in NMP (35 mL) was stirred at 150° C. for 4 hours, cooled to room temperature, treated with water (0.5 L) and filtered. The filter cake was washed with water and dried briefly. The crude product was triturated with hexane, filtered, and dried under vacuum to provide the desired product. MS (DCI) m/e 292 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH2:10][CH2:11][NH2:12].O1CCCC1.[Br:18][C:19]1[C:20](Cl)=[N:21][CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=1>O>[Br:18][C:19]1[C:20]([NH:12][CH2:11][CH2:10][O:9][CH3:8])=[N:21][CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Reactant: COCCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COCCNc1ncc([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 134 %

Procedure:
Triethylamine (53 μl) and 2-methoxyethylamine (23 mg) were added to a tetrahydrofuran (2 ml) solution containing 3-bromo-2-chloro-5-nitropyridine (60 mg), followed by stirring at room temperature for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=6:1 to 3:1), and a light yellow solid of 3-bromo-N-(2-methoxyethyl)-5-nitropyridin-2-amine (93.5 mg) was thus obtained.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Br:11][CH2:12][C:13]([OH:15])=[O:14]>C(OCC)(=O)C>[Br-:11].[C:13]([CH2:12][N+:6]1[CH:7]=[CH:8][C:3]([C:2]([F:10])([F:9])[F:1])=[CH:4][CH:5]=1)([OH:15])=[O:14]
Reactant: FC(F)(F)c1ccncc1
Reactant: O=C(O)CBr
Solvent: CCOC(C)=O
Product: O=C(O)C[n+]1ccc(C(F)(F)F)cc1
Product: [Br-]
Temperature: 25 °C
Yield: 34.7 %

Procedure:
To a solution of 4-trifluoromethylpyridine (2.0 g) in ethyl acetate (10 mL) was added bromoacetic acid (1.4 g) at room temperature, and the mixture was heated under reflux overnight. After the reaction mixture was cooled to room temperature, the precipitated solid was collected by filtration, and dried under reduced pressure to give 1-carboxymethyl-4-trifluoromethylpyridinium bromide (1.0 g). To a solution of the obtained compound (1.0 g) in toluene (10 mL) were added acrylonitrile (0.93 g), manganese dioxide (0.91 g) and triethylamine (0.42 g), and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.31 g).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([C:21]1[O:26][C:25](=[O:27])[C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=2[N:22]=1)[C:10]1[O:15][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]=1.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH:5]1[CH:6]=[CH:7][C:2]([CH:1]=[C:9]([C:10]2[O:15][C:14](=[O:16])[C:13]3[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:11]=2)[C:21]2[O:26][C:25](=[O:27])[C:24]3[C:23](=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:22]=2)=[CH:3][CH:4]=1
Reactant: O=c1oc(Cc2nc3ccccc3c(=O)o2)nc2ccccc12
Reactant: O=Cc1ccccc1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=c1oc(C(=Cc2ccccc2)c2nc3ccccc3c(=O)o2)nc2ccccc12

Procedure:
Benzaldehyde (259 mg, 2.45 mmol), Compound (2,2'-methylenebis(3,1-benzoxazine-4-one) (500 mg, 1.63 mmol), and BF3.(C2H5)2O (0.045 ml, 0.163 mmol) were heated under reflux in dry toluene (20 ml) for 20 hours. After the reaction, the solvent was removed under reduced pressure from the reaction mixture, the residue was treated with water, extracted with benzene, and the organic layer was separated, washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in the developing solvent and adsorbed on silica gel, and was purified by column chromatography to give the desired compound 52. The obtained product was crystallized from isopropylether to give the desired compound 52 in white solid in a good yield. m.p., IR, and NMR spectra of the product fully agreed with those of the one obtained in Example 19.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].CCN(CC)CC.FC(F)(F)C(O[C:36]1[C:41]([F:42])=[C:40]([F:43])[C:39]([F:44])=[C:38]([F:45])[C:37]=1[F:46])=O.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23][C:36]2[C:37]([F:46])=[C:38]([F:45])[C:39]([F:44])=[C:40]([F:43])[C:41]=2[F:42])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a stirred mixture of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (1.30 g, 4.136 mmol), Et3N (0.63 mL, 4.549 mmol) in DMF (20 mL) was added pentafluorophenyl trifluoroacetate at 0° C. The resulting mixture was stirred at room temp for 1 hr. The mixture was poured into water (60 mL) and precipitate was collected with suction. The crude solid was washed with 0.1N HCl, H2O, n-hexane, and dried at 40° C. to afford 1.91 g (96%) pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate as a pale brownish crystalline powder. IR (KBr) 1785, 1224, 1216 cm−1; 1H-NMR (400 MHz, CDCl3) δ2.29 (s, 3H), 3.76 (s, 3H), 3.90 (s, 2H), 6.49 (s, 1H), 6.81 (d, J=1.5 Hz, 1H), 6.91 (dd, J=1.5, 8.3 Hz, 1H), 7.15 (t, J=7.3 Hz, 3H), 7.24 (m, 1H), 7.50 (d, J=7.8 Hz, 1H), 8.17 (d, J=7.8 Hz, 1H); MS (FAB) m/z 481 (M++1); Anal. Calcd. for C30H33N3O5S.1/4H2O: C, 57.51; H, 3.57; N, 5.83. Found: C, 57.40; H, 3.75; N, 5.68.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1.[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[CH2:24]Br)[CH3:21].C(OCC)(=O)C>CN(C=O)C.O>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:17][CH2:24][CH:23]([O:26][CH2:27][CH3:28])[O:22][CH2:20][CH3:21])=[CH:14][CH:13]=1
Reactant: CCOC(CBr)OCC
Reactant: OCc1ccc(Br)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(COCc1ccc(Br)cc1)OCC
Reaction time: 0.08 h
Yield: 55.8 %

Procedure:
Sodium bis(trimethylsilyl)amide (12.1 mL, 1 N in THF) is added to a stirred solution of 4-bromo-benzylalcohol (2.05 g, 11.0 mmol) in dry DMF (7 mL) at ambient temperature. The mixture is stirred for 5 min before it is treated with bromoacetaldehyde diethyl acetal (1.99 mL, 13.2 mmol). The resultant mixture is allowed to stir at ambient temperature for 20 hours. Ethyl acetate (60 mL) and water (60 mL) are added to the mixture. The organic layer is separated, washed with half-saturated brine, dried, filtered and concentrated. After MPLC separation on silica (gradient 0-8% ethyl acetate in hexane), 1.86 g (56% yield) title compound is obtained as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:67]=[CH:66][C:52]([CH2:53][NH:54][CH2:55][CH:56]([C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[C:60]([Cl:65])[CH:59]=2)[OH:57])=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:67]=[CH:66][C:52]([CH2:53][N:54]([CH2:55][CH:56]([C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[C:60]([Cl:65])[CH:59]=2)[OH:57])[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCC(O)c2ccc(Cl)c(Cl)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(CN(CC(O)c2ccc(Cl)c(Cl)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44.8 %

Procedure:
To a solution of 31 mg (0.16 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 51 mg of TBTU (0.16 mmol) in 2 ml DMF, were added 0.14 ml (0.79 mmol) of N,N-diisopropyl-ethyl amine. After stirring for 5 min at rt, 81 mg (0.16 mmol) of [rac]-(4-tert-butyl-benzyl)-[2-(3,4-dichloro-phenyl)-2-hydroxy-ethyl]-amine were added. After stirring for 17 h at rt, the reaction mixture was diluted with 20 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; heptane/EtOAc 2:1) to give 38 mg (44%) of a light yellow foam. MS: 528 (M).