Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[N:2]1([C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[N:13]([CH2:19][CH2:20][N:21]=4)[C:14]([NH2:18])=[N:15][C:16]=3[CH:17]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[C:22]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][N:27]=1)(=[O:24])[CH3:23].C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CN(C)C=O>[C:22]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:18][C:14]2[N:13]3[CH2:19][CH2:20][N:21]=[C:12]3[C:11]3[CH:10]=[CH:9][C:8]([N:2]4[CH2:7][CH2:6][O:5][CH2:4][CH2:3]4)=[CH:17][C:16]=3[N:15]=2)=[O:31])=[CH:28][N:27]=1)(=[O:24])[CH3:23]
Reactant: NC1=Nc2cc(N3CCOCC3)ccc2C2=NCCN12
Reactant: CC(=O)Nc1ccc(C(=O)O)cn1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)NC2=Nc3cc(N4CCOCC4)ccc3C3=NCCN23)cn1
Temperature: 90 °C
Reaction time: 16 h
Yield: 31.6 %

Procedure:
To a mixture of 8-(morpholin-4-yl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine hydrobromide 105.7 mg (0.30 mmol), 6-(acetamido)nicotinic acid 81.1 mg (0.45 mmol) and N,N-diisopropylethylamine 0.26 mL (1.50 mmol) in N,N-dimethylformamide 2 mL was added PyBOP((1H-1,2,3-benzotriazol-1-yloxy)(tripyrrolidin-1-yl)phosphonium hexafluorophosphate) 234.2 mg (0.45 mmol) and stirred at 90° C. for 16 hours. After cooling to room temperature, saturated NaHCO3 solution was added. The precipitate was collected and washed with water, methanol, and diethyl ether to give the title compound 41.1 mg as yellow solid. Yield 31.6%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][CH2:22][CH2:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:28][CH2:27]1)=O.C(OC(NCCCN1CCN(CCCC(OC)=O)CC1)=O)(C)(C)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][CH2:22][CH2:23][CH2:24][N:26]1[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:30][CH2:31]1
Reactant: O=C(O)CCCN1CCN(C(=O)CCNc2ccccn2)CC1
Agent: COC(=O)CCCN1CCN(CCCNC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCCN1CCN(CCCNc2ccccn2)CC1

Procedure:
Prepared in an analogous manner to 4-[4-(N-pyridin-2-yl-beta-alanyl)-piperazin-1-yl]butanoic acid bis(trifluoroacetate) using methyl 4-(4-{3-[(tertbutoxycarbonyl)amino]propyl}piperazin-1-yl)butanoate in the place of methyl 4-{4-[N-(tert-butoxycarbonyl)-beta-alanyl]piperazin-1-yl}butanoate. 1H NMR (400 MHz, CD3CN) δ 7.91 (dt, 1 H), 7.82 (d, 1 H), 6.97 (d, 1 H), 6.86 (m, 1H), 3.60–3.42 (m, 8 H), 3.19–3.03 (m, 6 H), 2.44 (t, 2 H), 2.08 (t, 2 H), 1.95 (d, 2 H); MS (ESI+) for m/z 307 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][S:5]([CH3:8])(=[O:7])=[O:6])[C:2]#[CH:3].[F:9][C:10]1[C:11](I)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>CN(C=O)C.CCN(CC)CC.CCOC(C)=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>[F:9][C:10]1[C:11]([C:3]#[C:2][CH2:1][NH:4][S:5]([CH3:8])(=[O:7])=[O:6])=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: C#CCNS(C)(=O)=O
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCNS(C)(=O)=O)c21

Procedure:
Using Method C above, N-(Prop-2-ynyl)-methanesulfonamide (80 mg, 0.62 mmol) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P)4Pd (24 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (Z)-N-[3-[5-Fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-2,3-dihydro-1H-indol-4-yl]-prop-2-ynyl]-methanesulfonamide was obtained after HPLC purification with 40% EtOAc in hexanes and precipitation out of THF with excess of pentane. (Yield 48 mg, 59%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:27])[O:8][C@H:7]([CH2:9][C@@H:10]2[C:16](=[O:17])[C:15]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:14]=3[CH2:13][C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]2=3)[CH2:6][O:5]1>C(O)(C)C.P([O-])([O-])([O-])=O>[CH3:3][C:4]1([CH3:27])[O:8][C@H:7]([CH2:9][C@@H:10]2[C@H:16]([OH:17])[C:15]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:14]=3[CH2:13][C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]2=3)[CH2:6][O:5]1
Reactant: CC1(C)OC[C@@H](C[C@@H]2C(=O)c3cc(F)ccc3Cc3ccccc32)O1
Agent: O=P([O-])([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC1(C)OC[C@@H](C[C@H]2c3ccccc3Cc3ccc(F)cc3[C@H]2O)O1
Yield: 34.9 %

Procedure:
Solid sodium borohydride (2.50 g, 66 mmol) was added in small portions within 15 min. into a magnetically stirred, ice-cooled solution of (11R) and (11S)-11-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-8-fluoro-5,11-dihydro-10H-dibenzo[a,d]cyclohepten-10-one (reaction mixture of intermediate 7 and 8 before separation) (65:35, 1278 mg, 3.75 mmol) in isopropanol (160 mL) and 0.5 M phosphate buffer (pH 7, 63 mL). Reaction mixture was stirred at 0° C. for additional 15 min., quenched with saturated aqueous NH4Cl (30 mL); organic phase was separated, aqueous solution extracted with ether (2×30 mL), combined organics washed with water (2×50 mL), then brine (50 mL), dried (MgSO4), evaporated in vacuo, to furnish crude mixture of two alcohols. HPLC separation (Waters 515 pump, 2 mL injection loop, Merck Hibar® 250×25 mm column LiChrosorb® SI 60 7 μm, Waters 2410 refractive index detector, EtOAc-hexane 30:70, 15 mL/min) gave pure intermediate 13 (10S,11S)-11-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-8-fluoro-10,11-dihydro-5H-diben-zo[a,d]cyclohepten-10-ol (449 mg, 1.31 mmol, 35%) as a colorless oil.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:8]=1[C:9]([C:11]1[CH:12]=[N:13][N:14]([CH3:17])[C:15]=1O)=[O:10]>>[Cl:6][C:7]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:8]=1[C:9]([C:11]1[CH:12]=[N:13][N:14]([CH3:17])[C:15]=1[Cl:3])=[O:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1ncc(C(=O)c2ccc(Cl)cc2Cl)c1O
Product: Cn1ncc(C(=O)c2ccc(Cl)cc2Cl)c1Cl
Temperature: 0 °C
Yield: 98 %

Procedure:
To 5 ml of phosphorus oxychloride was added 2.71 g (0.01 mol) of 4-(2,4-dichlorobenzoyl)-1-methyl-5-hydroxypyrazole and the resulting mixture was heated under reflux for 3 hours. After cooling, the reaction mixture was poured into ice water. Oily product was extracted with ethyl acetate, washed successively with 5% aqueous sodium bicarbonate and saturated brine and dried over anhydrous sodium sulfate. Then the solvent was distilled off therefrom under reduced pressure and the resulting oil was purified through silica gel column chromatography using benzene as an eluant to give 2.84 g of the title compound as pale yellow crystals, (yield: 98%), m.p. 81.0°-83.0° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[CH:19]=1)[C:5]([NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH3:9])=[O:6].[CH:26]([C:28]1[O:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].C(NC(C)C)(C)C>CN(C=O)C>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C@H:8]([NH:7][C:5](=[O:6])[C:4]2[CH:17]=[C:18]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[CH:19]=[C:2]([C:31]3[O:32][C:28]([CH:26]=[O:27])=[CH:29][CH:30]=3)[CH:3]=2)[CH3:9])=[CH:11][CH:12]=1
Reactant: C[C@@H](NC(=O)c1cc(Br)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Reactant: O=Cc1ccc(B(O)O)o1
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: C[C@@H](NC(=O)c1cc(-c2ccc(C=O)o2)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Reaction time: 15 h

Procedure:
To a solution of Intermediate X (0.280 g, 0.65 mmol) and (5-formyl-2-furyl)boronic acid (0.0912 g, 0.65 mmol) in 5 mL degassed DMF was added TPPTS (0.111 g, 0.20 mmol) Pd(OAc)2 (0.015 g, 0.07 mmol) and diisopropylamine (0.066 g, 0.65 mmol). After 15 h at rt, the reaction was diluted with satd. aqueous NaHCO3 and EtOAc, and the layers were separated. The organics were washed with brine, dried over Na2SO4, filtered and concentrated. Purification by normal phase chromatography (50->100% EtOAc/hexanes) afforded the desired coupled adduct. 1H NMR (400 MHz, CDCl3) δ 9.67 (s, 1H), 8.09 (m, 1H), 7.95 (m, 1H), 7.84 (m, 1H), 7.41-7.34 (m, 3H), 7.08 (m, 2H), 6.99 (d, J=5.9 Hz, 1H), 6.54 (d, J=7.5 Hz, 1H), 5.31 (m, 1H), 3.40 (s, 3H), 2.89 (s, 3H), 1.65 (d, J=7.0 Hz, 3H). LCMS [M+H]+=445.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1([C:16]2[O:17][CH:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]([OH:22])[CH2:20][N:21]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCCl>[C:10]1([C:16]2[O:17][CH:18]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:19]([O:22][C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:20][N:21]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OC1CN=C(c2ccccc2)OC1c1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCCl
Product: O=C(Nc1ccccc1)OC1CN=C(c2ccccc2)OC1c1ccccc1
Yield: 61.2 %

Procedure:
Phenyl isocyanate (0.33 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere of (5RS, 6SR)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (0.4 g) in 1,2-dichloroethane (10 cc). The solution obtained is stirred under reflux for 4 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on silica (0.063-0.2 mm; 50 g) contained in a column 2 cm in diameter, collecting 20-cc fractions. Fractions 5 to 11, eluted with a mixture of ethyl acetate and cyclohexane (3:7 by volume), are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in petroleum ether, (5RS, 6SR)-2,6-diphenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (0.36 g), m.p. 111° C., is obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[C:9][Sn:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:6][CH:5]=[CH:4][N:3]=1>C1COCC1.CCCCCC>[F:1][C:2]1[C:7](/[CH:8]=[CH:9]\[Sn:10]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCCC[Sn](C#Cc1cccnc1F)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](/C=C\c1cccnc1F)(CCCC)CCCC
Yield: 83.5 %

Procedure:
To a suspension of Cp2ZrHCl (2.58 g) in dry THF (50 mL) was added 2-fluoro-3-(tributylstannylethynyl)pyridine (2.05 g). After 2 hours the mixture was diluted with hexane and filtered through a short silica gel column. Evaporation of the solvents gave Z-2-fluoro-3-(2-tributylstannylethenyl)pyridine as an oil (1.72 g).
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Cl:25][CH2:26][CH2:27][CH2:28][CH:29]([C:33]1[C:38]([F:39])=[CH:37][C:36]([F:40])=[CH:35][C:34]=1[F:41])[C:30]([OH:32])=O.[C:42]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])(=[O:45])[NH:43][NH2:44].Cl>C(Cl)Cl.C(OCC)(=O)C>[Cl:25][CH2:26][CH2:27][CH2:28][CH:29]([C:33]1[C:38]([F:39])=[CH:37][C:36]([F:40])=[CH:35][C:34]=1[F:41])[C:30]([NH:44][NH:43][C:42]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[O:32]
Reactant: O=C(O)C(CCCCl)c1c(F)cc(F)cc1F
Reactant: CC(C)(C)OC(=O)NN
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NNC(=O)C(CCCCl)c1c(F)cc(F)cc1F
Yield: 41.9 %

Procedure:
IPEA (1.1 mL) and BOPCl (798 mg) were added to a solution of 5-chloro-2-(2,4,6-trifluorophenyl)pentanoic acid (560 mg) synthesized according to the method described in Tetrahedron Letters, 2003, vol. 44, p. 365 and tert-butyl carbazate (276 mg) in methylene chloride (5 mL), and the reaction solution was stirred at room temperature for one hour. Ethyl acetate and 1 N aqueous hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer washed with saturated sodium bicarbonate water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane->heptane:ethyl acetate=1:1) to obtain 333 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](O)=[O:15])([CH3:10])([CH3:9])[CH3:8].O.[OH-].[Na+]>CCOCC>[C:7]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[CH2:14][OH:15])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1cccc(C(=O)O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a suspension (40 ml) of lithium aluminum hydride (1.38 g, 36.2 mmol) in ether was added dropwise a solution of 3-tert-butylbenzoic acid (3.13 g, 17.6 mmol) in ether (40 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hrs. After completion of the reaction, water (1.38 ml), 15% aqueous sodium hydroxide solution (1.38 ml) and water (4.2 ml) were successively added dropwise slowly under ice-cooling. The obtained solid was filtered with celite, and washed with ethyl acetate. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1, 4:1) to give 3-tert-butylbenzyl alcohol (2.59 g, 90%) as a colorless transparent oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])C#N.CO.[CH3:13][O:14][CH:15](OC)[O:16][CH3:17]>[Ni].O.C(O)=O>[CH3:13][O:14][CH:15]([O:16][CH3:17])[C:4]1[CH:7]=[CH:8][C:9]([F:10])=[C:2]([Br:1])[CH:3]=1
Reactant: COC(OC)OC
Reactant: N#Cc1ccc(F)c(Br)c1
Agent: [Ni]
Solvent: O
Solvent: O=CO
Solvent: CO
Product: COC(OC)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.7 %

Procedure:
A mixture of 85 g of Raney nickel, which had been washed thoroughly with water, 500 ml of formic acid and 100 g (0.5 mole) of 3-bromo-4-fluoro-benzonitrile was stirred for 24 hours at 90°-100° C. under an atmosphere of a blanketing gas (nitrogen or argon). After cooling to room temperature, 1 liter of water was added and the mixture was extracted twice with 300 ml of toluene. The combined toluene solutions were washed with 200 ml of water, with 200 ml of saturated sodium bicarbonate solution and again with 200 ml of water and then dried by incipient distillation. 1.5 g of air-dried ion exchanger SPC 118, 16 g (0.5 mole) of methanol and 58.5 g (0.55 mole) of orthoformic acid trimethyl ester were then added to the solution, the mixture was stirred for a further 1 hour without a bath and was then warmed at 50° C. for 2 hours. The reaction mixture was cooled, filtered to remove the ion exchanger and washed with 200 ml of 5% strength potassium carbonate solution. The solvent was then stripped off and the residue was distilled in vacuo. 93 g (75% of theory) of 3-bromo-4-fluoro-benzaldehyde dimethyl acetal were obtained in this way, in the form of a colorless liquid with a boiling point of 67°-68° C./0.1 mm Hg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([CH2:13]O)[N:10]=[CH:9]2)=[N:6][CH:7]=1.O=S(Cl)Cl.[N-:19]=[N+:20]=[N-:21].[Na+].O>CC#N.CCOC(C)=O>[N:19]([CH2:13][C:11]1[N:10]=[CH:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH:12]=1)=[N+:20]=[N-:21]
Reactant: OCc1cn(-c2ccc(Br)cn2)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: [N-]=[N+]=NCc1cn(-c2ccc(Br)cn2)cn1
Reaction time: 0.17 h
Yield: 87.4 %

Procedure:
To a suspension of (1-(5-bromopyridin-2-yl)-1H-imidazol-4-yl)methanol (520 mg, 2.05 mmol) in CH3CN (5 mL) at room temperature was added SOCl2 (2.5 mL). With the addition, the suspension became clear. After 10 min of stirring, the mixture was concentrated in vacuo. The residue was dissolved in DMF (12 mL), and NaN3 (565 mg, 8.69 mmol) was added. The mixture was stirred at room temperature overnight. H2O and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 2-(4-(azidomethyl)-1H-imidazol-1-yl)-5-bromopyridine (500 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17](Cl)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2].[F:33][C:34]([F:43])([F:42])[C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38].NC1C=C(O)C(C)=CC=1>CO>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17]([NH:38][C:37]3[CH:39]=[CH:40][CH:41]=[C:35]([C:34]([F:33])([F:42])[F:43])[CH:36]=3)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: Cc1ccc(N)cc1O
Solvent: CO
Product: COc1ccc(Sc2ccc(C(=O)Nc3cccc(C(F)(F)F)c3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1

Procedure:
The product from Example 14B was reacted with 3-(trifluoromethyl)aniline according to the procedure from Example 14C substituting 3-(trifluoromethyl)aniline for 5-amino-o-cresol to provide the title compound as an off white solid after trituration of the reaction product from methanol (73 mg, 77%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 10.54 (s, 1 H), 8.93 (d, J=8.46 Hz, 1 H), 8.67 (s, 1 H), 8.22 (s, 1 H), 8.04 (d, J=8.09 Hz, 1 H), 7.99 (s, 1 H), 7.85 (d, J=7.72 Hz, 1 H), 7.74 (d, J=8.46 Hz, 1 H), 7.59 (t, J=8.09 Hz, 1 H), 7.45 (d, J=8.46 Hz, 1 H), 7.41 (d, J=8.82 Hz, 2 H), 6.92-7.11 (m, 4 H), 3.77 (s, 3 H), 3.20-3.31 (m, 1 H), 1.35 (d, J=6.62 Hz, 6 H); MS (ESI+) m/z 590.3 (M+H)+, (ESI−) m/z 588.1 (M−H)−.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+].[BH4-].[Na+]>ClCCl.CO>[N:5]1([CH2:4][CH2:3][CH2:2][NH:1][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: O=Cc1ccccc1
Reactant: NCCCn1ccnc1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: c1ccc(CNCCCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
A mixture of 1-(3-aminopropyl)imidazole (Aldrich, 37.1 g, 297 mmol), benzaldehyde (30 g, 283 mmol), 3 Å molecular sieves (50 g), sodium acetate (24.1 g, 283 mmol) and anhydrous methanol (700 mL) are stirred at room temperature under N2 overnight. The mixture is cooled to 0° C. and sodium borohydride (10.9 g, 288 mmol) is added portionwise over 1 hour. The mixture is stirred at room temperature for 3 hours. The mixture is filtered through celite, washed with methanol, and concentrated in vacuo to give a residue which is diluted with dichloromethane and washed with 10% aqueous sodium hydroxide. The organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a pale yellow oil (56.3 g, MH+=216).
Reaction SMILES: CCO.[CH3:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[CH:14][N:13]=2)[CH:8]=[CH:7][C:6]=1/[CH:27]=[CH:28]/[C:29]([O:31]CCCC)=[O:30].[OH-].[Na+]>O>[CH3:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[CH:14][N:13]=2)[CH:8]=[CH:7][C:6]=1/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]
Reactant: CCCCOC(=O)/C=C/c1ccc(Oc2ccc(OCc3ccc(C)cc3)cn2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(COc2ccc(Oc3ccc(/C=C/C(=O)O)c(C)c3)nc2)cc1
Reaction time: 14 h
Yield: 99.9 %

Procedure:
To an EtOH (50 mL) solution of butyl (E)-3-[2-methyl-4-({5-[(4-methylbenzyl)-oxy]pyridin-2-yl}oxy)phenyl]prop-2-enoate (4.67 g) was added 5 M NaOH (3.25 mL) at room temperature. After stirring for 14 hours, 5 M NaOH (1.08 mL) and water (25 mL) were added, and then the reaction mixture was refluxed for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in water, and neutralized with 6 M HCl at 0° C. The resulting precipitate was collected by filtration and dried to afford (E)-3-[2-methyl-4-({5-[(4-methylbenzyl)oxy]pyridin-2-yl}oxy)phenyl]prop-2-enoic acid as a colorless solid (4.06 g).
Reaction SMILES: Br[C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[CH:16][CH:15]=2)=[CH:21][CH:22]=1
Reactant: Oc1ccc(COc2ccc(Cl)cc2)cc1
Reactant: CC(C)(Br)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(CO)Oc1ccc(COc2ccc(Cl)cc2)cc1
Reaction time: 12 h

Procedure:
A solution of 15.3 g. of 2-bromo-2-methylpropanol in 50 ml. of acetone is added slowly to a stirred mixture consisting of 23.45 g. of 4-p-chlorophenoxymethyl-phenol, 13.8 g. of K2CO3 an 80 ml. of acetone. The mixture is boiled for 12 hours while stirring and then filtered and evaporated to give 2-[4-(4-chlorophenoxymethyl)-phenoxy]-2-methyl-propanol, m.p. 67°-70° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C@@H:10]12[CH2:15][C@@H:14]1[CH2:13][NH:12][CH:11]2[C:16]([OH:18])=[O:17].CCN(CC)CC>CCO>[Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5]([N:12]2[CH2:13][C@@H:14]3[C@@H:10]([CH2:15]3)[CH:11]2[C:16]([OH:18])=[O:17])=[N:6][CH:7]=1
Reactant: Cc1nc(Cl)ncc1Br
Reactant: O=C(O)C1NC[C@H]2C[C@@H]12
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc(N2C[C@H]3C[C@H]3C2C(=O)O)ncc1Br
Temperature: 75 °C
Reaction time: 72 h

Procedure:
In a 40 mL vial were mixed 5-bromo-2-chloro-4-methylpyrimidine (438 mg, 2.109 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (295 mg, 2.320 mmol), and Et3N (0.882 mL, 6.33 mmol) in EtOH (90 mL). The resulting yellow solution was stirred at 75° C. for 3 days. The reaction mixture was subsequently partitioned between 1N HCl (40 mL) and EtOAc (40 mL). The phases were separated and the aqueous layer was back-extracted with EtOAc (75 mL). The organic layers were combined, washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated to give the title compound as a white solid, which was used without further purification (660 mg).