Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:17]([O:13][C:12](=[O:14])[CH:11]1[CH2:15][CH2:16][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Reaction time: 6 h

Procedure:
To a solution of N-t-butoxycarbonyl isonipecotic acid (12.0 g, 52.3 mmol) from example 3 step A, in anhydrous CH2Cl2 (100 ml), was added benzyl alcohol (6.0 ml, 58 mmol), followed by EDC (11.04 g, 57.6 mmol), and DMAP (642 mg, 5.25 mmol). The resulting mixture was stirred for 6 hrs, then diluted with CH2Cl2 (150 ml) and washed successively with water, 10% aqueous citric acid, saturated NaHCO3, and brine and dried (MgSO4). Concentration in vacuo afforded a colorless oil which was chromatographed (SiO2, 20% EtOAc in hexanes) to afford the product as a white solid.
Reaction SMILES: C1C(C=O)=CC=C(C=O)C=1.C(O)(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:26]1[CH:30]=[CH:29][O:28][CH:27]1[C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1.[CH2:39]([N:43]1[C:47](=[O:48])[CH2:46][NH:45][C:44]1=[O:49])[CH2:40][CH2:41][CH3:42]>C1C=CC=CC=1.O>[CH2:39]([N:43]1[C:47](=[O:48])[C:46](=[CH:35][C:34]2[CH:37]=[CH:38][C:31]([CH:27]3[O:28][CH:29]=[CH:30][O:26]3)=[CH:32][CH:33]=2)[NH:45][C:44]1=[O:49])[CH2:40][CH2:41][CH3:42]
Reactant: CCCCN1C(=O)CNC1=O
Reactant: O=Cc1ccc(C2OC=CO2)cc1
Agent: CC(O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=Cc1ccc(C=O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCN1C(=O)NC(=Cc2ccc(C3OC=CO3)cc2)C1=O

Procedure:
Terephthaldialdehyde (67 g; 0.5 mole), ethanediol (31 g, 0.5 mole) and p-toluenesulphonic acid (0.5 g) in benzene (400 ml.) were boiled under reflux for 2 hours, with the removal of the water formed via a Dean and Stark separator. After cooling, the mixture was washed with dilute sodium bicarbonate solution (100 ml, 2% W/V), then saturated sodium chloride solution (2×100 ml.) and dried over magnesium sulphate. After filtration, the benzene solution was evaporated in vacuo to give a straw-coloured oil containing ca 70% of the desired aldehyde, viz: 4-(1,3-dioxol-2-yl)benzaldehyde, which was reacted with 3-n-butylhydantoin as in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([NH:18][C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:27]([O:29]C)=[O:28])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]I>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH3:33])[C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:27]([OH:29])=[O:28])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N[C@@H](C)c3ccccc3)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 47.3 %

Procedure:
To a solution of (S)-methyl 2-(4-fluorophenyl)-3-(1-phenylethylamino)quinoxaline-6-carboxylate (100 mg, 0.25 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (30 mg, 0.75 mmol), and the reaction mixture was stirred for 10 minutes. CH3I (106 mg, 0.75 mmol) was added, and the resulting mixture was stirred overnight. The reaction was then quenched by the addition of NH4Cl solution (50 mL) and adjusted pH to 5 with hydrochloric acid (3N). The solids were collected by filtration to afford (S)-2-(4-fluorophenyl)-3-(methyl(1-phenylethyl)amino)quinoxaline-6-carboxylic acid as a yellow solid (47.5 mg, 48%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11](CS(N)(=O)=O)[CH:12]=[CH:13][CH:14]=2)[N:3]=1.ClC1N=C(Cl)N=CN=1.NC1C=C([S:35]([NH2:38])(=[O:37])=[O:36])C=CC=1>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Agent: Clc1ncnc(Cl)n1
Product: NS(=O)(=O)c1cccc(Nc2ncnc(Cl)n2)c1
Yield: 35 %

Procedure:
A2 was prepared following the general procedure reported for A1 using 2,4-dichloro-1,3,5-triazine and 3-aminobenzenesulfonamide as reacting agents. The crude product was purified by flash chromatography on silica gel (cHex/EtOAc=20:1 to 1:20) to yield the desired product A2 as a white solid (35%). 1H NMR (400 MHz, d6-DMSO, 300K) δ 7.41 (s, 2H), 7.59 (m, 2H), 7.85 (d, J=6.9 Hz, 1H), 8.21 (br.s, 1H), 8.69 (s, 1H), 11.02 (s, 1H). MS (ES) C9H8ClN5O2S requires: 285. found: 286 (M+H)+.
Reaction SMILES: BrC1C=CC(C(CCCCl)C(O)=O)=NC=1.[Br:16][C:17]1[CH:18]=[CH:19][C:20](I)=[N:21][CH:22]=1.[CH2:24]([O:26][C:27](=[O:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:25]>[Cu]>[CH2:24]([O:26][C:27](=[O:34])[CH:28]([C:20]1[CH:19]=[CH:18][C:17]([Br:16])=[CH:22][N:21]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:25]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Brc1ccc(I)nc1
Agent: [Cu]
Agent: O=C(O)C(CCCCl)c1ccc(Br)cn1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(Br)cn1

Procedure:
Key building block 2-(5-bromo-pyridin-2-yl)-5-chloro-pentanoic acid (XII) can be prepared according to Scheme 8. Starting with commercially available 5-bromo-2-iodo-pyridine (XXXV), copper-catalyzed reaction with malonic acid diethyl ester furnishes 2-(5-bromo-pyridin-2-yl)-malonic acid diethyl ester (XXXVI). Hydrolysis and decarboxylation under basic conditions gives (5-bromo-pyridin-2-yl)-acetic acid (XXXVII), which subsequently can undergo nucleophilic acyl substitution with thionyl chloride in methanol to provide (5-bromo-pyridin-2-yl)-acetic acid methyl ester (XXXVIII). Deprotonation of XXXVIII with strong base followed by alkylation with 1-bromo-3-chloropropane gives 2-(5-bromo-pyridin-2-yl)-5-chloro-pentanoic acid methyl ester (XXXIX), which can then be hydrolyzed under aqueous basic conditions to furnish key building block 2-(5-bromo-pyridin-2-yl)-5-chloro-pentanoic acid (XII).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH3:8][C:9]1([CH3:34])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19](O)=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:32][CH2:31][O:30][C:29]2=[O:33])[CH:23]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:8][C:9]1([CH3:34])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:32][CH2:31][O:30][C:29]2=[O:33])[CH:23]=1
Reactant: CS(N)(=O)=O
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CCOC2=O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cccc(N2CCOC2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a suspension of 60% sodium hydride (106 mg, 2.6 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (257 mg, 2.7 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-[3-(2-oxo-oxazolidin-3-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.27 mmol) and 1,1′-carbonyldiimidazole (87 mg, 0.55 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-{3,3-dimethyl-2-[3-(2-oxo-oxazolidin-3-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-methanesulfonamide (24 mg, 20%) as a white solid: LC/MS m/e calcd for C22H25N3O5S (M+H)+: 444.53, observed: 444.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][CH2:24]OS(C)(=O)=O)[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].[CH3:30][NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)P(=O)(N(C)C)N(C)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][CH2:24][N:31]([CH3:30])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: CNc1ccccc1
Reactant: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCCOS(C)(=O)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCCN(C)c1ccccc1

Procedure:
A solution of 4.36 g. of 5-chloro-2-{3-[(methylsulfonyl)oxy]propyl}-3-phenylisoindole-1-carboxylic acid ethyl ester in 25 ml. of hexamethylphosphoric acid triamide is treated with 25 ml. of N-methylaniline and heated at 80° C. for 24 hours. The mixture is then evaporated to dryness under reduced pressure, and the residue treated with 250 ml. of ice-water. The oily precipitate is taken up in methylene chloride and the extract washed with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. The resulting oil is purified by chromatography on 150 g. of aluminum oxide [neutral; Brockmann activityI]. By elution with methylene chloride and evaporation of the solvent, there is obtained 5-chloro-2-[3-(N-methylanilino)propyl]-3-phenylisoindole- 1-carboxylic acid ethyl ester; melting point 108°-110° C. Crystallization from ether/hexane gives almost colorless crystals of the same melting point.
Reaction SMILES: [C:1]([C:3](=[CH:9][C:10]1[C:15]2[CH:16]=[CH:17][CH2:18][O:19][C:14]=2[C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C(O)(=O)C.CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.C([BH3-])#N.[Na+]>C(O)C>[C:1]([CH:3]([CH2:9][C:10]1[C:15]2[CH:16]=[CH:17][CH2:18][O:19][C:14]=2[C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)=Cc1cc(OC)c(OC)c2c1C=CCO2
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)Cc1cc(OC)c(OC)c2c1C=CCO2
Reaction time: 2 h

Procedure:
A mixture of ethyl 2-cyano-3-(7,8-dimethoxy-2H-1-benzopyran-5-yl)propenoate (19.8 g, 0.63 mole) in ethanol (500 mL) under nitrogen was treated with acetic acid (4 mL) and a trace of bromocresol green and heated to reflux. Heating was discontinued and sodium cyanoborohydride (4.4 g, 0.07 mole) in ethanol (100 mL) was co-added with additional acetic acid (11 mL). The mixture was stirred under nitrogen for 2 hr, acetic acid (10 mL) added and the ethanol removed under reduced pressure. The resultant yellow solid was taken up in ethyl acetate (250 mL) and successively extracted with water (125 mL), saturated sodium bicarbonate (3×100 mL) and water (100 mL), then dried over magnesium sulfate. The volatiles were removed under reduced pressure to leave an amber oil, 18.22 g (91.4%) which was used without further purification.
Reaction SMILES: [CH:1]1([C:4]([CH:12]2[CH2:14][CH2:13]2)([OH:11])[C:5]#[C:6][Si](C)(C)C)[CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[CH:1]1([C:4]([CH:12]2[CH2:14][CH2:13]2)([OH:11])[C:5]#[CH:6])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C#CC(O)(C1CC1)C1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#CC(O)(C1CC1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1,1-dicyclopropyl-3-(trimethylsilyl)prop-2-yn-1-ol (2.25 g, 10.6 mmol) in THF (100 mL), a 1M solution of tetrabutyl ammonium fluoride in THF (37.2 mL, 37.2 mmol) was added. The reaction was then stirred 1 hour at room temperature. The reaction mixture was then poured into an aqueous 5% NH4OAc solution and diluted with ethyl acetate. The isolated organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude residue obtained was purified by column chromatography (ethyl acetate/hexanes, 20:80) to afford the title compound. 1H NMR (400 MHz, acetone-d6): 4.17 (s, 1H), 2.75 (s, 1H), 1.25-1.15 (m, 2H), 0.65-0.55 (m, 2H), 0.55-0.30 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)N)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:4][CH:3]=1
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(F)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(F)cc4)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 548.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([O:14]CC(C)C)=O.[F:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1.CCOCC.Cl>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([C:23]1[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=1)=[O:14]
Reactant: CC(C)COC(=O)c1cccc2c(Br)cccc12
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(c1ccc(F)cc1)c1cccc2c(Br)cccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
Step 1 A solution of 5-bromo-1-naphthoic acid (prepared according to the procedure of Hausamann, Chem. Ber., 1876, 9, 1519; 2.00 g, 7.97 mmol) in THF (50 mL) was treated with TEA (2.22 mL, 15.93 mmol), then with isobutyl chloroformate (1.088 g, 7.97 mmol) and the resulting suspension was stirred at rt. After 25 min, the mixture was treated with additional TEA (2.22 mL, 15.93 mmol), then with a solution of N,O-dimethylhydroxylamine hydrochloric acid salt (0.777 g, 7.97 mmol) in water (5 mL), and the mixture was stirred at rt. After 2.5 h, the mixture was concentrated and the residue was taken up in EtOAc and water. The mixture was filtered, the layers were separated, and the organic phase was washed with NaHCO3 (aq), dried and concentrated to provide 5-bromo-N-methoxy-N-methyl-1-naphthamide as a pasty solid (1.03 g, 30%) contaminated with ca. 30% isobutyl 5-bromo-1-naphthoate. Mass spectrum m/z 294, 296 (M+H)+. Without further purification, a solution of this material (1.01 g, 2.404 mmol) in THF (15 mL) was stirred on ice and treated with (4-fluorophenyl)magnesium bromide, 2M in ether (7.21 mL, 14.42 mmol). The solution was stirred on ice and allowed to slowly warm to rt. After 16 h, the mixture was treated with 1 M hydrochloric acid and extracted twice with EtOAc. The combined organic layers were dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from hexane to 85:15 hexane-EtOAc) to provide (5-bromonaphthalen-1-yl)(4-fluorophenyl)methanone as a pale yellow viscous oil (658 mg, 83%). 1H NMR (400 MHz, methanol-d4) δ 8.49 (1 H, d, J=8.6 Hz), 7.95 (1 H, d, J=8.6 Hz), 7.86-7.93 (3 H, m), 7.74 (1 H, dd, J=8.5, 7.2 Hz), 7.64-7.68 (1 H, m), 7.40 (1 H, dd, J=8.5, 7.6 Hz), 7.25 (2 H, t, J=8.8 Hz). Mass spectrum m/z 329, 331 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9](Br)/[CH:10]=[CH:11]/[CH3:12]>>[CH2:9]([S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])/[CH:10]=[CH:11]/[CH3:12]
Reactant: Oc1ccccc1S
Reactant: C/C=C/CBr
Product: C/C=C/CSc1ccccc1O
Yield: 97 %

Procedure:
This compound was prepared from 2-mercaptophenol and (E)-2-butenyl bromide in 97% yield according to the general procedure for 16p in Example VII. Colorless oil; 1H NMR (CDCl3): δ 1.61 (d, J=0.8 Hz, 3H), 3.26 (d, J=7.40 Hz, 2H), 5.26-5.33 (m, 1H), 5.43-5.50 (m, 1H), 6.73 (s, 1H), 6.87 (dt, J=1.35 Hz, J=7.40 Hz, 1H), 6.99 (dd, J=1.10 Hz, 8.25 Hz, 1H), 7.27 (dt, J=1.65 Hz, J=7.40 Hz, 1H), 7.43 (dd, J=1.65 Hz, J=7.70 Hz, 1H); 13C NMR (CDCl3): δ 17.79, 39.40, 114.69, 118.57, 120.59, 125.77, 128.88, 131.27, 136.65, 157.28.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[NH:8][C:9]2[C:10]([N:15]=1)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:5][CH3:6].[C:16]1([C:22]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:23]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=3)=[N:26][N:25]=[N:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:3]([CH:7]1[N:15]([CH2:40][C:37]2[CH:36]=[CH:35][C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[C:27]3[N:23]([C:22]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:24]=[N:25][N:26]=3)=[CH:39][CH:38]=2)[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[NH:8]1)[CH2:4][CH2:5][CH3:6]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1nc2ncccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC1Nc2cccnc2N1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 23.6 %

Procedure:
To a stirred suspension of NaH (102 mg of an 80% dispersion, 3.39 mmol) in dry dimethylformamide (6 mL) at rt was added 2-butylimidazo[4,5-b]pyridine (495 mg, 2.83 mmol) in one portion. After 20 minutes, the mixture was cooled to 0° C. and N-triphenylmethyl-5-(4'-bromomethylbiphenyl-2-yl)tetrazole (1.50 g, 2.70 mmol) was added in one portion. The resulting dark colored mixture was warmed to rt and stirred for 15 hours. The excess NaH was quenched with water (1 mL) and the bulk of the DMF was removed in vacuo at 40°-50° C. Extraction with EtOAc (4×20 mL) from brine (60 mL), drying (K2CO3), and concentration gave a thick dark oil. Purification by flash chromatography (SiO2, solvent gradient: 80% EtOAc/hexanes, 100% EtOAc) gave 417 mg (23%) of 2-butyl-3-(2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl)methyl-1H-imidazo[ 4,5-b]pyridine as a thick oil: Rf=0.75 (SiO2, 100% EtOAc).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:23][CH:24]([CH3:27])[CH2:25][NH2:26].Cl>CN(C)C=O>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:26][CH2:25][CH:24]([CH3:27])[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: CC(C)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 0 °C
Yield: 90 %

Procedure:
A mixture of 2,4-dichloro-3-nitroquinoline (100g) and N,N-dimethylformamide (180 mL) was stirred, and triethylamine (42 g, 4 eq) was added dropwise, followed by dropwise addition of 2-methylpropylamine (21.5 g, 0.7 eq). The mixture was stirred at room temperature until the reaction was completed as determined by gas chromatography. Aqueous hydrochloric acid (250 mL, 4N) was added with stirring. The resulting mixture was stirred and cooled to about 0° C. to precipitate the product. The precipitate was filtered, washed with water, and dried at reduced pressure to afford the product 2-chloro-N-(2-methylpropyl)-3-nitro-4-quinolinamine in about 90% yield.
Reaction SMILES: C(OC(=O)NC[C:9]1[CH:38]=[CH:37][C:12]2[N:13]([CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[C:14]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=[O:27])[N:19]([CH:28]4[CH2:30][CH2:29]4)[C:18]3=[O:31])=[N:15][C:11]=2[CH:10]=1)(C)(C)C.C1(N2C(=O)C3C(=CC=CC=3)NC2=O)CC1.[CH3:55][O:56][C:57](C1C=CC2N(CCC(C)C)C(CCl)=NC=2C=1)=[O:58].Cl>O>[CH3:55][O:56][C:57]([C:9]1[CH:38]=[CH:37][C:12]2[N:13]([CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[C:14]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=[O:27])[N:19]([CH:28]4[CH2:29][CH2:30]4)[C:18]3=[O:31])=[N:15][C:11]=2[CH:10]=1)=[O:58]
Reactant: COC(=O)c1ccc2c(c1)nc(CCl)n2CCC(C)C
Reactant: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c(=O)c3ccccc32)nc2cc(CNC(=O)OC(C)(C)C)ccc21
Agent: Cl
Agent: O=c1[nH]c2ccccc2c(=O)n1C1CC1
Solvent: O
Product: COC(=O)c1ccc2c(c1)nc(Cn1c(=O)n(C3CC3)c(=O)c3ccccc31)n2CCC(C)C
Yield: 90 %

Procedure:
The procedure for the preparation of [2-(3-cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester was followed starting from 3-cyclopropyl-1H-quinazoline-2,4-dione (309 mg, 1.53 mmol) and 2-chloromethyl-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxylic acid methyl ester; HCl salt (506 mg, 1.53 mmol). At the end of the reaction a precipitate had formed. The mixture was diluted with water, and the solid collected by filtration. After washing with water and diethyl ether and drying in vacuo, 2-(3-Cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxylic acid methyl ester (634 mg, 90%) was obtained as a white solid:
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[C:31]([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[N:46]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C:45]4[CH:53]=[CH:54][CH:55]=[CH:56][C:44]=4[N:43]=3)=[CH:38][CH:37]=2)=[CH:32][CH:33]=[CH:34][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[C:31]([C:36]5[CH:41]=[CH:40][C:39]([C:42]6[N:46]([C:47]7[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=7)[C:45]7[CH:53]=[CH:54][CH:55]=[CH:56][C:44]=7[N:43]=6)=[CH:38][CH:37]=5)=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccccc1-c1ccccc1-c1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Reactant: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(-n2c(-c3ccc(-c4ccccc4-c4ccccc4-c4ccc5c(c4)c4ccccc4n5-c4ccccc4)cc3)nc3ccccc32)cc1

Procedure:
Following the procedure for Host-1, (9-phenyl-9H-carbazol-3-yl)boronic acid (0.458 g, 1.60 mmol), Compound 3 (0.800 g, 1.60 mmol), tetrakis(triphenylphosphine)palladium(0) (73.7 mg, 63.8 μmol), Na2CO3 (0.530 g, 5.00 mmol), H2O (5 mL) and 1,4-dioxane (25 mL) provided Host-2 (0.78 g, 74%) as an off-white solid after flash chromatography (SiO2, 17:3-hexanes: acetone) and recrystallization from methanol (CH3OH): confirmed by LCMS (APCI): calculated for C49H33N3 (M+): 664; Found: 664.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[OH:11].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[K]>CC(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: COC(=O)c1cc(I)ccc1O
Reactant: CCOC(=O)CBr
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(I)cc1C(=O)OC
Yield: 96.1 %

Procedure:
Reflux a mixture of 2-hydroxy-5-iodo-benzoic acid methyl ester (TCI; 5.5 g, 20 mmol) and ethyl bromoacetate (Aldrich; 6.7 g, 40 mmol) in acetone (60 mL) in the presence of potassium (5.5 g, 40 mmol) for 3 h. Filter out the solid and evaporate acetone to give a white residue. Dissolve the residue in ethyl acetate and wash with brine. Evaporate the solvent in vacuum to give final product as a white solid (7 g, 96%). MS (electrospray, m/z) 365 (M+1). 1H NMR (400 MHz, CDCl3) δ 8.1 (d, J=2.0 Hz, 1H), 7.70 (dd, J=8.8, 2.8 Hz, 1H), 6.6 (d, J=8.8 Hz, 1H), 4.68 (s, 2H), 4.3 (q, J=6.8 Hz, 2H), 3.9 (s, 1H), 1.3 (t, J=6.8 Hz, 3H).