Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH3:30][O:31][C:32](=[O:46])[C@@H:33]([CH3:45])[C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[C:39]([OH:44])[CH:40]=2)[CH:35]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:30][O:31][C:32](=[O:46])[C@@H:33]([CH3:45])[C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[C:39]([O:44][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:9]=3[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:40]=2)[CH:35]=1
Reactant: BrCCCCCCc1cccc(OCc2ccccc2)c1OCc1ccccc1
Reactant: COC(=O)[C@@H](C)c1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COC(=O)[C@@H](C)c1ccc2cc(OCCCCCCc3cccc(OCc4ccccc4)c3OCc3ccccc3)ccc2c1
Yield: 82.7 %

Procedure:
A mixture of 3.25 g (7.17 mmol) of 1-(6-bromohexyl)-2,3-bis-(phenylmethoxy)benzene, 1.50 g (6.5 mmol) of (S)-alpha-methyl-6-hydroxy-2-naphthaleneacetic acid methyl ester, 1.08 g (7.17 mmol) of sodium iodide and 2.70 g (19.6 mmol) of potassium carbonate in 60 mL of acetone - 6 mL of dimethylformamide was stirred at reflux for 48 hours. The reaction mixture was filtered and the filtrate was concentrated at reduced pressure. The residue was purified by HPLC using 20% ethyl acetate-hexane to give 3.24 g (75% yield) of (S)-alpha-methyl-6-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]-2-naphthaleneacetic acid methyl ester as an oil. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22].O>CN(C)C=O>[CH3:20][N:21]([CH3:23])[CH:22]=[C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:10]([C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: COc1ccc(CC(=O)c2ccncc2)cc1
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=CN(C)C)C(=O)c2ccncc2)cc1

Procedure:
A solution of 2-(4-methoxyphenyl)-1-(pyridin-4-yl)ethanone (10.2 g) and dimethylformamide-dimethylacetal (20 cm3) in dry dimethylformamide (50 cm3) was stirred at 80° C. for 4 hours. The mixture was cooled, poured into water (500 cm3) and extracted with ethyl acetate (3×200 cm3). The combined extracts were washed with brine (100 cm3), dried (magnesium sulphate), filtered and concentrated to give a yellow solid. The material was washed well with diethyl ether-hexane (1:9; 2×100 cm3) and dried in vacuo to give 3-dimethylamino-2-(4-methoxyphenyl)-1-(pyridin-4-yl)propen-1-one as a beige solid (7.7 g; 60%). δH (250 MHz; CDCl3) 2.78 [6 H, broad s, N(CH3)2], 3.79 (3 H, s, OCH3), 6.79 (2 H, d, J 9, methoxyphenyl H-2), 7.04 (2 H, d, J 9, methoxyphenyl H-3), 7.24 (2 H, d, J 6, pyridyl H-3) 7.40 (1 H, s, C═CH) and 8.51 (2 H, d, J 6, pyridyl H-2).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](B(O)O)[CH:12]=1.C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.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>[N+:8]([C:4]1[CH:3]=[C:2]([C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: OB(O)c1cccnc1
Reactant: O=[N+]([O-])c1cccc(I)c1
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: COCCOC
Solvent: O
Product: O=[N+]([O-])c1cccc(-c2cccnc2)c1
Reaction time: 0.08 h
Yield: 78.5 %

Procedure:
To a degassed solution of 1-iodo-3-nitrobenzene (0.35 g, 1.4 mmol) in DME (5 mL) was added Pd(PPh3)4 (0.08 g, 10% mol). After stirring for 5 min, 3-pyridylboronic acid (0.2 g, 1.65 mmol) and 2M Na2CO3 (1 mL) solution were added. After refluxing for 16 h under an Ar atmosphere, the reaction mixture was poured into H2O (15 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine, dried (Na2SO4), concentrated and purified via column chromatography to yield 3-(3-nitrophenyl)pyridine (0.22 g, 78%) as a white solid. 1H NMR (CDCl3): δ 8.94 (brs, 1H), 8.73 (brs, 1H), 8.48 (t, J=1.6 Hz, 1H), 8.32-8.29 (m, 1H), 7.98-7.93 (m, 2H), 7.72-7.68 (m, 1H), 7.48 (brs, 1H); Exact mass: 200.0, Found: 201.0 (M+1)+.
Reaction SMILES: [CH3:1]I.[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[C:9](=[O:14])[NH:10][CH2:11][CH2:12][N:13]=1.O.Cl>C(OCC)C.O1CCCC1>[CH3:1][C:8]1([C:4]2[S:3][CH:7]=[CH:6][CH:5]=2)[NH:13][CH2:12][CH2:11][NH:10][C:9]1=[O:14]
Reactant: CI
Reactant: O=C1NCCN=C1c1cccs1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC1(c2cccs2)NCCNC1=O
Reaction time: 15 h

Procedure:
The Grignard solution prepared from 7.3 g of Mg and 42.6 g of methyl iodide in 150 ml of diethyl ether is added dropwise slowly at room temperature to a solution of 18 g of 3-(thien-2-yl)-5,6-dihydropyrazin-2-one in 150 ml of tetrahydrofuran. Stirring is continued for 15 hours at room temperature and the mixture is then hydrolyzed with 100 ml of water. The pH of the mixture is adjusted to 2 with concentrated HCl, the organic phase is separated off and the aqueous phase is extracted twice by shaking with diethyl ether and its pH is adjusted to 8 with potassium carbonate. The compound is then extracted with methylene chloride. The methylene chloride phase is dried and concentrated. The residual oil is purified by column chromatography over silica gel made by Merck, Darmstadt, type "0.04-0.06", the mobile phase being methylene chloride/methanol in a ratio by volume of 95:5. The fractions containing the compound are concentrated on a rotary evaporator and the residue is recrystallized from isopropanol.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.B1([C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:44][CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41][CH2:40]3)=[N:35][CH:34]=2)OC(C)(C)C(C)(C)O1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:33]5[CH:34]=[N:35][C:36]([N:39]6[CH2:40][CH2:41][NH:42][CH2:43][CH2:44]6)=[CH:37][CH:38]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(N5CCNCC5)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 118.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-(4-boc-piperazine)pyridine-5-boronic acid pinacol ester (Combi-Blocks, San Diego, USA) to give the title compound as a white solid. (HPLC: tR 1.97 min (Method A); M+H=455 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.91 (s, 1H), 8.30-8.25 (m, 1H), 8.14-8.11 (m, 1H), 8.07-8.01 (m, 1H), 7.90-7.84 (m, 1H), 7.62-7.56 (m, 1H), 7.46-7.41 (m, 1H), 6.95-6.89 (m, 1H), 3.92 (s, 3H), 3.57 (s, 3H), 3.53-3.46 (m, 4H), 2.86-2.76 (m, 4H), 1.95 (s, 3H))
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.[CH:14](=[N:21][CH:22]([CH2:27][CH2:28][CH2:29][CH2:30][N:31]=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:23]([O:25][CH3:26])=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl:39][CH:40](Br)C>O1CCCC1.CCCCCC.CN(C)P(N(C)C)(N(C)C)=O>[Cl:39][CH2:40][C:22]([N:21]=[CH:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([CH2:27][CH2:28][CH2:29][CH2:30][N:31]=[CH:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: CC(Cl)Br
Reactant: COC(=O)C(CCCCN=Cc1ccccc1)N=Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(CCl)(CCCCN=Cc1ccccc1)N=Cc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of lithium diisopropylamide (10 mmol) prepared in situ from a solution of 1N diisoproppylamine in tetrahydrofuran (THF) and a solution of butyl lithium (2N) in hexane and hexamethylphosphoramide (HMPA) (2.5 ml) in THF cooled to -78° C., magnetically stirred, and kept under nitrogen, is added slowly a solution of methyl 2,6-bis(benzylideneamino)hexanoate (3.365 g, 10 mmol) in dry THF (20 ml). The reaction mixture is stirred at -78° C. for 1/2 hour, and then a solution of chlorobromoethane (1.3 g, about 10 mmol) in dry THF (10 ml) is added rapidly. the temperature is allowed to rise slowly to room temperature, and the stirring is continued overnight. The reaction mixture is quenched with water and extracted with ether. The ether extract is washed with water and concentrated at reduced pressure to give methyl 2-chloromethyl-2,6-bis(benzylideneamino)hexanoate as an oily residue.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][N:38]=1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][N:38]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: COC(=O)c1ccc(Br)nc1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)nc1
Temperature: 110 °C
Yield: 99.8 %

Procedure:
To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (500 mg, 1.04 mmol) and methyl 6-bromonicotinate (292 mg, 1.35 mmol) in dry 1,4-dioxane (5 mL) was added CsCO3 (1 mL, 2 mmol) and Pd(PPh3)2Cl2 (50 mg). After addition, the mixture was warmed to 110° C. for 30 min under microwave. After TLC showed the starting material had disappeared, the solid was filtered off. Water (20 mL) and EtOAc (10 mL) was added, the layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give methyl 6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinate (507 mg, 89%), which was purified by preparative TLC. 1H NMR (CDCl3): 1.13 (s, 3H), 1.19 (s, 3H), 1.61 (d, 3H), 2.24 (m, 4H), 2.37 (m, 1H), 2.88 (m, 1H), 4.02 (s, 3H), 5.76 (q, 1H), 7.11 (d, 2H), 7.29-7.47 (m, 6H), 7.78 (m, 1H), 7.82 (m, 2H), 8.38 (d, 1H), 9.31 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[N:11]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24]C(=O)OC(C)(C)C)[C:10]2=[O:32])=[CH:5][C:4]=1[C:33]([F:36])([F:35])[F:34])#[N:2].[ClH:37]>C(OCC)(=O)C.C(OCC)C>[ClH:37].[NH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:11]1[C:12]([CH3:15])([CH3:16])[C:13](=[O:14])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:5]=2)[C:10]1=[O:32]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1ccccc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.369 g of compound 68.2 were dissolved in 3.7 ml of ethyl acetate and admixed with 1.47 ml of a 2 molar solution of HCl in diethyl ether, and stirred at room temperature for 24 h. 4 equivalents in each case of ethereal HCl solution were added twice more and the solution was left to stand for 24 h each time. For workup, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in acetonitrile/water and freeze-dried. 4-[3-(2-Aminobenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile hydrochloride was obtained in quantitative yield. Molecular weight (free base) 402.13 (C20H17F3N4O2); retention time Rt=1.59 min. [B]; MS (ESI): 403.14 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[NH:30]C(OC(C)(C)C)=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl.O1CCOCC1>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[NH2:30])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(OCC2Cc3ccccc3N(C(=O)OCc3ccccc3)C2)c(NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(OCC2Cc3ccccc3N(C(=O)OCc3ccccc3)C2)c(N)c1

Procedure:
A solution of the crude 3-(2-tert-Butoxycarbonylamino-4-methyl-phenoxymethyl)-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (crude, 0.35 mmol) in 4N HCl in dioxane (2 mL) at room temperature was stirred under a drying tube overnight. The suspension was concentrated by rotovap, diluted to 30 mL with CH2Cl2 and shaken with 10% Na2CO3 (30 mL). The organics were isolated, dried (MgSO4), filtered and concentrated to a brown oil corresponding to the crude aniline, which was used without purification in the urea forming reaction.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:21]([O-])(O)=O.[Na+].CI.C(OCC)(=O)C>CN(C=O)C>[CH3:21][O:19][C:18](=[O:20])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([I:17])=[CH:15][CH:16]=1)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(I)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 40 h
Yield: 111.8 %

Procedure:
To a solution of 5.02 g (12.8 mmol) of N-Boc-4-iodophenylalanine in 60 mL of DMF was added NaHCO3 (1.42 g, 16.9 mmol) followed by methyl iodide (3.0 mL, 48.2 mmol). The mixture was stirred under argon for 40 h at room temperature. After this time, 150 mL of ethyl acetate was added, and the mixture was washed with 3×100 mL of deionized water. The organic layer was separated, dried over Na2SO4, and concentrated under vacuum to yield 5.80 g of a yellow oily solid. The crude product was purified by flash chromatography (1:5 ethyl acetate:hexanes) to afford a white solid (4.72 g, 91%). mp 79-80° C.; 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9 H), 3.04 (2 dd, J=4.8 Hz, 12.8 Hz), 3.72 (s, 3 H), 4.58 (m, 1 H), 4.97 (brs, NH, 1 H), 6.88 (d, J=7.8 Hz, 2 H), 7.62 (d, J=7.8 Hz, 2 H); HRMS (ESI, M+1) calcd for C15H21INO4406.0510, found 406.0515.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.[CH3:22][O:23][N:24]([CH3:31])[C:25](N(OC)C)=[O:26].[Cl-].[NH4+]>C1COCC1>[CH:19]1([C:16]2[CH:17]=[CH:18][C:13]([C:25]([N:24]([O:23][CH3:22])[CH3:31])=[O:26])=[CH:14][CH:15]=2)[CH2:21][CH2:20]1
Reactant: CON(C)C(=O)N(C)OC
Reactant: Brc1ccc(C2CC2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CON(C)C(=O)c1ccc(C2CC2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 46.7 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.6 M, 6.0 mL, 9.59 mmol) was added dropwise to an solution of 1-bromo-4-cyclopropylbenzene (1.8 g, 9.13 mmol) in anhydrous THF (30 mL) at −78° C. over 15 minutes. This solution was stirred at −78° C. for 10 minutes, and a solution of N,N′-dimethoxy-N,N′-dimethylurea (1.42 g, 9.59 mmol) in THF (15 mL) was added dropwise thereto. The reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added a saturated ammonium chloride aqueous solution and the mixture was extracted with ether, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography [developing solution=n-hexane:ethyl acetate (4:1)] to obtain the title compound (875 mg, 95%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH:9]1[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>O1CCCC1.[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
A solution of 3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (13.29 g, 57.47 mmol) in tetrahydrofuran (130 mL) is treated with borane-methyl sulfide complex (16.06 mL, 172.41 mmol) dropwise and stirred overnight at room temperature. The mixture is cooled to 5° C. in a water ice bath and treated with 3 N aqueous hydrogen chloride solution (5 mL) dropwise until evolution of gas has ceased. The resulting suspension is stirred further for 30 min and diluted with 5 N aqueous sodium hydroxide solution until a white solid is dissolved. This is extracted with ethyl acetate (3×100 mL). The organic layer is washed with water (2×100 mL) and brine, dried over sodium sulfate, filtered, and concentrated to dryness. The resulting oil is dried under vacuum to give 10.03 g (80%) of the title compound. LC-ES/MS m/z 457.2 [2M+Na]+, TR=1.59 min.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[C:5]([CH3:27])[NH:4][C:3]=1[CH3:28].[H-].[Na+].[C:31](Cl)(=[O:33])[CH3:32].O>CN(C=O)C>[C:31]([O:8][C:7]1[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[C:5]([CH3:27])[N:4]=[C:3]([CH3:28])[C:2]=1[Cl:1])(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c(C)c(-c2ccc(Oc3ccc(OC(F)(F)F)cc3)cc2)c(=O)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1c(Cl)c(C)nc(C)c1-c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 3-Chloro-5-(4-(4-trifluoromethoxyphenoxy)phenyl)-2,6-dimethyl pyridin-4(1H)-one (0.41 g) in dry DMF, under nitrogen, was added all at once sodium hydride (0.05 g of a 60% dispersion in mineral oil). After stirring at rt for 30 min acetyl chloride (0.14 ml) was added. The mixture was stirred at rt for a further 2 hr, poured into iced water, extracted with ether, washed with water and satd. aq. sodium bicarbonate and dried over magnesium sulphate. Evaporation gave an oil which was triturated with hexane to give the title compound (0.2 g), m.p. 78°-80°, Nmr δH (CDCl3) 7.3-7.0 (8H, m), 2.68 (3H, s), 2.35 (3H, s), 2.05 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([NH2:20])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]([F:35])([F:34])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1>>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([NH:20][C:31](=[O:32])[CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:23]([F:34])([F:22])[F:35])=[CH:29][CH:28]=2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1nn(N)c(=O)c2ccccc12
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Product: CC(C)(C)OC(=O)NCc1nn(NC(=O)Cc2ccc(C(F)(F)F)cc2)c(=O)c2ccccc12

Procedure:
The product of Example 41B and 2-[4-(trifluoromethyl)phenyl]acetic acid were treated using a method similar to that described in Example 56 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.67 (s, 1H), 8.32 (dd, J=7.8, 1.4, 1H), 8.11 (d, J=8.0, 1H), 8.04-7.95 (m, 1H), 7.95-7.86 (m, 1H), 7.76-7.69 (m, 2H), 7.63-7.57 (m, 2H), 7.44-7.37 (m, 1H), 4.48-4.41 (m, 2H), 3.79 (bs, 2H), 1.37 (s, 9H); MS (ESI−) M/Z 475 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[N:11]=[N:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8]2)[S:4][C:3]=1[C:18]([O:20]CC)=[O:19].O1CCCC1.[OH-].[Li+]>O>[CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[N:11]=[N:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8]2)[S:4][C:3]=1[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)c1sc(-n2nnc(-c3ccccc3)n2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-n2nnc(-c3ccccc3)n2)sc1C(=O)O
Temperature: 25 °C
Yield: 82.2 %

Procedure:
To a solution of ethyl 3-methyl-5-(5-phenyl-2H-tetrazol-2-yl)thiophene-2-carboxylate (0.16 g, 0.51 mmol) in a 1:1 mixture of tetrahydrofuran:water (10 mL) was added lithium hydroxide (0.11 g, 2.55 mmol). The reaction mixture was refluxed for 18 hours and allowed to cool to ambient temperature. The organic solvent was removed in vacuo. The aqueous solution was acidified with 10% aqueous solution. The white solid was collected by filtration, washed with water and dried to afford the title compound as red colored solid (0.12 g, 82%): 1H NMR (300 MHz, DMSO-d6) δ 8.14-8.11 (m, 2H), 7.75 (s, 1H), 7.62-7.60 (m, 3H), 2.54 (s, 3H); MS (ES+) m/z 287.2 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[CH3:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([NH2:26])=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.CCOC(C)=O>CN(C)C(=O)C>[CH3:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]4=[N:26][S:4](=[O:6])(=[O:5])[CH2:3][CH2:2][N:22]4[CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)=[CH:27][CH:28]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1ccc(Oc2ccc(-c3cccnc3N)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
2-Chloroethanesulfonyl chloride (0.885 g) in N,N-dimethylacetoamide (7.0 mL) was added dropwise to a solution of 3-[4-(4-methylphenoxy)phenyl]pyridin-2-amine (1.00 g) in N,N-dimethylacetoamide (3.0 mL) at 0° C. The mixture was stirred at 70° C. under N2 overnight. EtOAc and IPE was added dropwise to the mixture at room temperature. The solid was isolated by filtration and washed with water, IPE and EtOAc to give the title compound (1.07 g) as a gray solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.[N+:9]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br)([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: OB(O)c1ccco1
Product: O=[N+]([O-])c1cccc(Cc2ccco2)c1
Yield: 92 %

Procedure:
Using the same method as in Example 19-(ii), 2-furanboronic acid was reacted with the 3-nitrobenzyl bromide to give 2-(3-nitrobenzyl)furan (yield: 92%).