Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:20]([O:23][CH:24]1[CH2:32][C:31]2[C:26](=[CH:27][C:28]([O:33][CH3:34])=[CH:29][CH:30]=2)[CH:25]1[NH2:35])[CH:21]=[CH2:22]>C(#N)C>[CH2:20]([O:23][C@H:24]1[CH2:32][C:31]2[C:26](=[CH:27][C:28]([O:33][CH3:34])=[CH:29][CH:30]=2)[C@H:25]1[NH:35][CH2:3][C@@H:2]([OH:1])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:21]=[CH2:22]
Reactant: C=CCOC1Cc2ccc(OC)cc2C1N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Solvent: CC#N
Product: C=CCO[C@H]1Cc2ccc(OC)cc2[C@H]1NC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 45 °C

Procedure:
Step AE (4): A solution of tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (298 mg) and LiClO4 (mg) in acetonitrile (3.0 mL) was stirred at rt for 10 min. To the above solution was added 1R,2S)-2-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-amine from Step AE (3) (137 mg) in acetonitrile (0.50 mL), and the reaction mixture was heated at 45° C. for 36 h. Solvents were removed in vacuo, and the residue was purified by HPLC to give tert-butyl (2S,3R)-4-((1R,2S)-2-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate as an oil (77 mg). retention time: 1.85 min (method B). MS (ESI) (M+H)+ 483.30.
Reaction SMILES: C([O-])=O.[NH4+:4].[Br:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)=[CH:8][CH:7]=1>>[Br:5][C:6]1[CH:19]=[CH:18][C:9]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH2:4])=[CH:8][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Reactant: [NH4+]
Agent: O=C[O-]
Product: NC(c1ccccc1)c1ccc(Br)cc1
Temperature: 150 °C
Yield: 72.5 %

Procedure:
Ammonium formate (20.1 g, 0.318 mol) was placed in a 3-neck flask equipped with temperature controller, mechanical stirrer and a condenser and heated at 150° C. 4-bromobenzophenone (7.2 g, 0.0276 mol) was added at once, the temperature was raised to 165° C. and the mixture was stirred at reflux for twnety-four hours. The reaction mixture was cooled to ambient temperature, triturated in ethyl acetate (350 mL), treated with charcoal and filtered through a Celite pad. The filtrate was concentrated, suspended in concentrated hydrochloric acid (120 mL) and heated at reflux for 8 hours. The reaction mixture was cooled to ambient temperature and the precipitate was collected by filtration. It was triturated in water (120 mL), basified with saturated solution of sodium bicarbonate in water and extracted with ethyl acetate (2×250 mL). The combined organic extracts were dried with magnesium sulfate and concentrated under reduced pressure to yield (4-bromophenyl)(phenyl)methanamine (5.25 g, 0.02 mol) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[F:1][C:2]1[C:3]([N:25]2[CH2:26][CH2:27][CH:22]([OH:21])[CH2:23][CH2:24]2)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: OC1CCNCC1
Solvent: CS(C)=O
Product: CC1COc2c(N3CCC(O)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reaction time: 5.5 h
Yield: 36.6 %

Procedure:
140 mg of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid and 404 mg of 4-hydroxypiperidine were added to 2 ml of dimethylsulfoxide. The mixture was stirred at a temperature of from about 100° to 110° C. (bath temperature) for 5.5 hours and the reaction mixture was concentrated to dryness in vacuo. Water was added to the residue and the mixture was neutralized with diluted hydrochloric acid to yield precipitate. The precipitate was collected by filtration, washed with water, and then recrystallized from ethanol to provide 66 mg of 9-fluoro-10-(4-hydroxy-1-piperidinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid with m.p. 220°-240° C. (with decomposition).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[O:13][C:12](=[O:14])[CH:11]=[CH:10]1)[C:2]1C=CC=CC=1.[Br:15]Br>C(Cl)(Cl)(Cl)Cl>[Br:15][C:10]1[CH:9]([O:8][CH2:1][CH3:2])[O:13][C:12](=[O:14])[CH:11]=1
Reactant: BrBr
Reactant: O=C1C=CC(OCc2ccccc2)O1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC1OC(=O)C=C1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
This procedure was carried out in a manner similar to that described by C. Escobar, et al., Ann. Quim. (1971), 67, 43-57.). To a solution of 5-ethoxy-5H-furan-2-one (II, R1=Et) (10.0 g, 78.0 mmol) in carbon tetrachloride (50 mL) at 0° C. was added over 0.5 h a solution of bromine (4.05 mL, 78.2 mmol) in carbon tetrachloride (25 mL). The reaction was stirred 1 h at 0° C., then 2 h at room temperature. The solvents were removed under reduced pressure and the residue was short-path distilled at pump vacuum (about 0.5 mm). The fraction collected at 100° C.-120° C. provided 4-bromo-5-ethoxy-5H-furan-2-one (13.2 g, 82% yield) as a yellow oil. 1H-NMR (500 MHz, CDCl3) δ 6.24 (s, 1H), 5.63 (s, 1H), 3.71 (m, 1H), 3.63 (m, 1H), 1.14 (t, J=7.1 Hz, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=2)=[C:6]([NH:8][S:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[CH:16]=2)(=[O:11])=[O:10])[CH:7]=1.[NH4+].[Cl-]>CO.[Zn]>[NH2:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][S:21][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[NH:8][S:9]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[CH:16]=1)(=[O:11])=[O:10]
Reactant: O=[N+]([O-])c1cccc(CSc2ccc(F)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1cccc(CSc2ccc(F)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
N-(5-fluoro-2-((3-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide (91 mg, 0.199 mmol) was dissolved in MeOH (2 ml). Zn (322 mg, 4.967 mmol) and NH4Cl (1 ml) was added to the solution. After the mixture was stirred for 30 min at room temperature, the solid was filtered and the filtrate was concentrated in vacuo and then the crude residue was purified by column chromatography (0˜30% EtOAc in hexane) to afford the title product (50 mg, 59%).
Reaction SMILES: O([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])S(C(F)(F)F)(=O)=O.[Cl:15][C:16]1[CH:23]=[C:20]([CH:21]=[O:22])[C:19](O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:12][C:11]([F:14])([F:13])[CH2:10][O:9][C:19]1[CH:18]=[CH:17][C:16]([Cl:15])=[CH:23][C:20]=1[CH:21]=[O:22]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: O=S(=O)(OOCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using a small volume of DMF, the trifluorethoxy triflate thus prepared was added to a mixture of 5-chlorosalicylaldehyde (5 g, 32 mmol) and cesium carbonate (21 g, 64 mmol) in DMF (50 mL) at room temperature. After stirring at room temperature overnight the solids were filtered off and the filtrate concentrated under reduced pressure. The residue was diluted with ether and washed well with water. Drying (Na2SO4) and concentration yielded the title compound as an oil: 1H NMR (CDCl3) δ10.42 (s, 1H), 7.84 (dd, J=2.6 Hz, 1H), 7.54 (m, 1H), 6.93 (d, J=8.8 Hz, 1H), 4.48 (qd, J=1.5, 7.8 Hz, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:10]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)=[O:12]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: NCCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCCO)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
2-Benzofurancarboxylic acid (5.0 g, 30.8 mmol) and 4-amino-1-butanol (3.4 ml, 37 mmol) were dissolved in DMF (45 ml). 1-hydroxybenzotriazole (5.0 g, 37 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.7 g, 40 mmol), and diisopropylethylamine (10.7 ml, 61.7 mmol) were added sequentially to the solution and allowed to stir at room temperature overnight. After removing excess solvent in vacuo, the residue was taken up in water and the product was extracted into dichloromethane. The organics were combined, washed with brine, dried over Na2SO4, and solvent removed in vacuo to give a solid which was purified by column chromatography (100% ethyl acetate) to give 3.5 g (50% yield) of a white solid. 1H NMR (DMSO-d6): δ1.35-1.62 (m, CH2, CH2), 3.29 (q, CH2), 3.41 (q, CH2), 4.3 (t, NH), 7.78 (d, 1 Ar H), 7.63 (d, 1 Ar H), 7.51 (s, 1 Ar H), 7.46 (t, 1 Ar H), 7.35 (t, 1 Ar H), 8.71 (t, NH) Electrospray Mass Spec: m/z 234.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.C.O.NN>CO>[NH2:1][C:4]1[CH:18]=[CH:17][C:7]([CH2:8][N:9]2[CH2:10][CH2:11][S:12](=[O:16])(=[O:15])[CH2:13][CH2:14]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCS(=O)(=O)CC2)cc1
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Reaction time: 4 h

Procedure:
4-(4-Nitro-benzyl)-thiomorpholine 1,1-dioxide (110 mg, 0.41 mmol) is dissolved in MeOH (7 mL). To this solution is added FeCl3.6H2O (−20 mg, 0.07 mmol) and active Charcoal (12 mg, 1.0 mmol). The suspension is heated to reflux. Hydrazine hydrate (0.5 mL) is added, and reflux is continued for 4 h until full conversion, the active Charcoal is filtered off through Celite, and the MeOH is removed under reduced pressure. The residue (85 mg, 86%) is directly used in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([C:22](OC)=[O:23])[C:9]=2[C:26](OC)=[O:27])[N:3]=1.[BH4-].[Li+].CO>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([CH2:22][OH:23])[C:9]=2[CH2:26][OH:27])[N:3]=1
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2cccc(Br)n2)c1C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2cc(CO)c(CO)c(-c3cccc(Br)n3)c2cc1OC
Yield: 80.4 %

Procedure:
To a suspension of 1-(2-bromo-6-pyridyl)-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene (715 mg) in tetrahydrofuran (20 ml) is added lithium borohydride (174 mg), and the mixture is refluxed. To the mixture is added dropwise a mixture of methanol (2.2 ml) and tetrahydrofuran (10 ml) under reflux over a period of two hours. After the reaction is complete, the mixture is concentrated under reduced pressure to remove the solvent, and ethyl acetate and water are added to the residue. The ethyl acetate layer is separated, washed, dried, and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=15:1) to give 1-(2-bromo-6-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (505 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:12]=[C:13]([CH:26]=[C:27]([O:29][CH2:30][CH2:31][C:32]2[S:36][CH:35]=[N:34][C:33]=2[CH3:37])[CH:28]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][N:18]=1)=[O:15].C([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:10][C:11]1[CH:12]=[C:13]([CH:26]=[C:27]([O:29][CH2:30][CH2:31][C:32]2[S:36][CH:35]=[N:34][C:33]=2[CH3:37])[CH:28]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][N:18]=1)=[O:15]
Reactant: Cc1ncsc1CCOc1cc(N)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1
Reactant: Cc1ccccc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1ccccc1CNc1cc(OCCc2scnc2C)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1
Reaction time: 40 h
Yield: 96 %

Procedure:
2-Methylbenzaldehyde (0.035 ml, 0.3 mM) was added to a solution of 2-[3-amino-5-(4-methyl-thiazol-5-yl) ethoxy benzoyl]amino-5-pyridine carboxylic acid (0.10 g 0.25 mM) and 4A molecular sieves (0.25 g) in methanol (15 ml), under an inert atmosphere at room temperature. After 1 hr sodium cyanoborohydride (0.019 g, 0.3 mM) was added and the reaction mixture stirred for 40 hrs. The reaction mixture was filtered, concentrated in vacuo, 2M NaOH added to pH=11–12 then acidified with 2M HCl to precipitate a colourless solid. The solid was filtered, washed with water to give the title compound as a colourless solid (0.12 g, 96%); 1H NMR δ (d6-DMSO): 2.33 (m, 6H), 3.19 (dd, 2H), 4.13 (dd, 2H), 4.26 (s, 2H), 6.33 (s, 1H), 6.83 (s, 1H), 6.90 (s, 1H), 7.09–7.19 (m, 3H), 7.26 (s, 1H), 8.28 (s, 2H), 8.83 (s, 1H), 8.88 (s, 1H), 10.87 (s, 1H), 13.09 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][O:3][P:4](OCCOC(N1C2C(=CC=CC=2)/C(=C/C2NC(C)=CC=2C)/C1=O)=O)([O:6][O:7][CH3:8])=[O:5].[OH:33][CH2:34][CH2:35][CH2:36][O:37][C:38]([N:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)/[C:42](=[CH:49]/[C:50]2[NH:51][C:52]([CH3:56])=[CH:53][C:54]=2[CH3:55])/[C:41]1=[O:57])=[O:39]>>[CH3:1][O:2][O:3][P:4]([O:33][CH2:34][CH2:35][CH2:36][O:37][C:38]([N:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)/[C:42](=[CH:49]/[C:50]2[NH:51][C:52]([CH3:56])=[CH:53][C:54]=2[CH3:55])/[C:41]1=[O:57])=[O:39])([O:6][O:7][CH3:8])=[O:5]
Reactant: COOP(=O)(OCCOC(=O)N1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21)OOC
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCCCO)c3ccccc32)[nH]1
Product: COOP(=O)(OCCCOC(=O)N1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21)OOC

Procedure:
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 3-(dimethoxy-phosphonooxy)-propyl ester was prepared using the same protocol for synthesizing 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-(dimethoxy-phosphonooxy)-ethyl ester by replacing 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-hydroxy-ethyl ester with 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 3-hydroxy-propyl ester with a yield of (31%). 1H NMR (400 MHz, CDCl3) δ 12.63 (s, br, 1H, NH-1′), 7.82–7.84 (m, 1H, H-4), 7.48–7.52 (m, 1H, H-7), 7.41 (s, 1H, H-vinyl), 7.17–7.24 (m, 2H, H-5, 6), 6.04 (s, br, 1H, H-4′), 4.61 (t, J=6.25 Hz, 2H, NCOOCH2CH2CH2OPO(OCH3)2-1), 4.31 (q, J=6.38, 10.94 Hz, 2H, NCOOCH2CH2CH2OPO(OCH3)2-1), 3.80 (s, 3H, NCOOCH2CH2CH2OPO(OCH3)2-1), 3.77 (s, 3H, NCOOCH2CH2CH2OPO(OCH3)2-1), 2.40 (s, 3H, CH3), 2.35 (s, 3H, CH3), and 2.23–2.29 (m, 2H, NCOOCH2CH2CH2OPO(OCH3)2-1). 13P NMR (162 MHz, CDCl3) δ 2.40.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:6][C:5]=1[O:15][CH3:16].[Li+].[OH-]>CO>[C:12]([NH:11][C:7]1[C:8]([Cl:10])=[CH:9][C:4]([C:3]([OH:17])=[O:2])=[C:5]([O:15][CH3:16])[CH:6]=1)(=[O:14])[CH3:13]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 47.2 %

Procedure:
4-Acetylamino-5-chloro-2-methoxy-benzoic acid methyl ester (2.09 g, 8.11 mmol) was dissolved in MeOH (110 ml) and LiOH solution (25.48 mmol in 30 ml, 1:1 MeOH:H2O) added and the solution stirred at room temperature for 6 hours. The solvent was concentrated in vacuo, EtOAc added and the organic phase was washed with 0.5N HCl then extracted with saturated NaHCO3 (2×). The aqueous phase was acidified with 12N HCl to pH 1 and the resulting precipitate extracted into CH2Cl2. The combined extracts were dried over anhydrous Na2SO4, filtered and evaporated to give the title compound as a white solid (0.933 g, 50% yield). 1H-NMR (500 MHz, CDCl3) δ 2.31 (s, 3H), 4.10 (s, 3H), 7.78-7.92 (br s, 1H), 8.17 (s, 1H), 8.45 (s, 1H). Analytical HPLC 5.62 min.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([NH2:26])[CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27]1([C:33]([C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=O)=O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:22](=[CH:23][CH:24]=2)[N:25]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:26]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(-c2nc3cc(C(=O)O)ccc3n2C2CCCCC2)cc1N
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)c(-c4ccccc4)nc3c1)n2C1CCCCC1

Procedure:
A solution of 100 mg (0.29 mmol) of Compound 406b and 74 mg (0.35 mmol) of benzil was stirred at room temperature overnight. The solvent was evaporated and the residue was purified on preparative HPLC yielding 10 mg.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:21])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:3][CH2:4][NH2:5].[CH3:22][O:23]C(OC)N(C)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:21])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:3][CH2:4][NH:5][CH:22]=[O:23]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCN
Reactant: COC(OC)N(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCNC=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.6 %

Procedure:
To a stirred solution of 580 mg (2 mmol) of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenylamine (hereinafter abbreviated as tetraprenylamine) II-1 in 20 ml of anhydrous tetrahydrofuran is added 953 mg (8 mmol) of N,N-dimethylformamide dimethylacetal. The mixture is heated under reflux for 3 hours, mixed with 15 ml of 10% aqueous sodium carbonate, and stirred at room temperature for 4 hours. The reaction mixture is concentrated, and the resulting residue is dissolved in 50 ml of CH2Cl2 and washed twice with 50 ml of water. The resulting mixture is dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is purified by silica-gel column chromatography and eluted with AcOEt to give 410 mg of the titled compound I-1 as colorless oil. Yield: 64.7%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:4]=1[NH2:5].[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22]C)C(O)=O>>[Cl:12][C:13]1[CH:14]=[C:15]([C:1]2[O:2][C:3]3[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:4]=3[N:5]=2)[CH:19]=[CH:20][C:21]=1[OH:22]
Reactant: COc1ccc(C(=O)O)cc1Cl
Reactant: COc1ccc(N)c(OC)c1
Product: Oc1ccc2nc(-c3ccc(O)c(Cl)c3)oc2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,4-dimethoxyaniline, and 3-chloro-4-methoxybenzoic acid and was obtained as an off-white solid, m.p. 254-256° C.; MS m/e 262 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].Cl[C:25]1[N:26]([CH2:33][C@:34]2([CH3:37])[CH2:36][O:35]2)[CH:27]=[C:28]([N+:30]([O-:32])=[O:31])[N:29]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:36][C@:34]2([CH3:37])[O:35][C:25]3=[N:29][C:28]([N+:30]([O-:32])=[O:31])=[CH:27][N:26]3[CH2:33]2)[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(OC[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2Cl)CC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 54.9 %

Procedure:
Tert-butyl 4-(2-chloro-4-hydroxyphenyl)-piperazine-1-carboxylate (2.7 g, 8.63 mmol) was dissolved in DMF (20 ml). To the solution, sodium hydride (397 mg, 9.92 mmol) was added at room temperature, and the solution was stirred for 20 minutes at 80° C. To the solution, (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (2.1 g, 9.50 mmol) was added with cooling on ice-bath, and the solution was stirred for further 20 minutes at 80° C. To the reaction mixture, ice-water was added, and the solution was stirred vigorously. The precipitates were filtered off, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1) and then crystallized from methylene chloride-ethyl acetate to afford tert-butyl (R)-4-[2-chloro-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)phenyl]piperazine-1-carboxylate (2.34 g, yield 55%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:27][CH3:28])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[C:12]1[N:13](COCC[Si](C)(C)C)[CH:14]=[CH:15][N:16]=1)=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([OH:39])([C:37]#[CH:38])[CH3:36]>>[NH2:1][C:2]1[N:3]([CH2:27][CH3:28])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[C:12]1[NH:16][CH:15]=[CH:14][N:13]=1)=[CH:8][CH:7]=[C:6]([C:38]#[C:37][C:35]([OH:39])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=1)[CH3:36])[N:5]=2
Reactant: C#CC(C)(O)c1ccccn1
Reactant: CCn1c(N)c(-c2nccn2COCC[Si](C)(C)C)c(=O)c2ccc(Cl)nc21
Product: CCn1c(N)c(-c2ncc[nH]2)c(=O)c2ccc(C#CC(C)(O)c3ccccn3)nc21

Procedure:
Using the intermediate described under 1.6 (2-amino-7-chloro-1-ethyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-1H-[1,8]naphthyridin-4-one) and coupling it to (±)-2-pyridin-2-yl-but-3-yn-2-ol following the detailed procedure outlined for example 1 in an analogous manner the title compound was accessed.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[C:13]([S:15][CH3:16])[N:12]=[C:11]([NH:17][C:18](=[O:20])[CH3:19])[CH:10]=2)[CH2:5][CH2:4]1.[Cl:21][C:22]1[C:26]([Cl:27])=[C:25]([CH3:28])[NH:24][C:23]=1[C:29](NC1CCN(C2C=C(C3N=CON=3)C=C(Cl)N=2)CC1)=[O:30]>>[C:18]([NH:17][C:11]1[N:12]=[C:13]([S:15][CH3:16])[N:14]=[C:9]([N:6]2[CH2:5][CH2:4][CH:3]([NH:2][C:29]([C:23]3[NH:24][C:25]([CH3:28])=[C:26]([Cl:27])[C:22]=3[Cl:21])=[O:30])[CH2:8][CH2:7]2)[CH:10]=1)(=[O:20])[CH3:19]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(-c4ncon4)cc(Cl)n3)CC2)c(Cl)c1Cl
Reactant: CSc1nc(NC(C)=O)cc(N2CCC(N)CC2)n1
Agent: Cl
Product: CSc1nc(NC(C)=O)cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1

Procedure:
The title compound was synthesised by an analogous method to Example 118 starting from N-[6-(4-aminopiperidin-1-yl)-2-(methylthio)pyrimidin-4-yl]acetamide hydrochloride (Intermediate 69) and 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3).