Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Br[C:9]([F:21])([F:20])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[C:22]([NH:32][CH2:33][C:34](=[O:40])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(#N)C>[C:22]([NH:32][CH2:33][C:34](=[O:40])[CH2:35][CH2:36][C:37]([O:39][C:9]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([F:21])[F:20])=[O:38])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]
Reactant: O=C(O)CCC(=O)CNC(=O)OCc1ccccc1
Reactant: O=C(OCc1ccccc1)C(F)(F)Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(CCC(=O)OC(F)(F)C(=O)OCc1ccccc1)CNC(=O)OCc1ccccc1
Yield: 74.5 %

Procedure:
Triethylamine (3.5 mL; 2.5 g; 25 mmol) was added using a syringe to a stirred mixture of the crude product of 3a (8.6 g; 20 mmol) and 5-(Cbz-amino)-4-oxopentanoic acid (6.63 g; 25 mmol) in dry acetonitrile (100 mL). The mixture was refluxed for 18 h, then the solvent was evaporated and the dark red residue was dissolved in diethyl ether (100 mL) and 0.5 M HCl (100 mL). After mixing thoroughly, the ether layer was washed with water (2×15 mL), saturated NaHCO3 (2×15 mL), and saturated NaCl solution (1×15 mL), then dried (MgSO4). After filtration and evaporation, the residue was purified by flash chromatography on a 60×55 mm silica gel 60 column eluted with dichloromethane-diethyl ether (9:1) (1000 mL), collecting 10×75 mL fractions. After evaporation of fractions 2-5 and vacuum-drying (0.02 mm Hg), 6.7 g (74%) product was obtained (red-orange solid mp 48-50° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:23]2[CH2:24][CH2:25][N:26]([CH2:28][C:29]#[CH:30])[CH2:27][C:22]=2[C:5]2[C:6]([OH:21])=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:16]([CH3:20])[CH2:17][CH2:18][CH3:19])=[CH:9][C:4]=2[O:3]1.C1(N=[C:39]=[N:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43]C2)CCCCC1.C(Cl)[Cl:48]>>[ClH:48].[CH3:31][C:2]1([CH3:1])[C:23]2[CH2:24][CH2:25][N:26]([CH2:28][C:29]#[CH:30])[CH2:27][C:22]=2[C:5]2[C:6]([O:21][C:2](=[O:3])[CH2:23][CH2:22][CH2:39][N:40]3[CH2:41][CH2:46][CH2:45][CH2:44][CH2:43]3)=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:16]([CH3:20])[CH2:17][CH2:18][CH3:19])=[CH:9][C:4]=2[O:3]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: ClCCl
Reactant: C#CCN1CCC2=C(C1)c1c(O)cc(-c3ccccc3C(C)CCC)cc1OC2(C)C
Product: C#CCN1CCC2=C(C1)c1c(OC(=O)CCCN3CCCCC3)cc(-c3ccccc3C(C)CCC)cc1OC2(C)C
Product: Cl
Reaction time: 16 h

Procedure:
A mixture of 1.45 g. (4.26 mm) of 5,5-dimethyl-10-hydroxy-2-(2-propynyl)-8-(1-methylbutylphenyl)-1,2,3,4-tetrahydro-5H[1]benzopyrano[3,4-d]pyridine, 0.89 g. (4.28 mm.) of Δ-piperidinobutyric acid hydrochloride and 0.93 g. (4.50 mm.) of dicyclohexylcarbodiimide in 200 ml. of methylene chloride are stirred at room temperature for 18 hours. After cooling the reaction mixture for 11/2 hours, the by-product of dicyclohexylurea is removed by suction filtration. A rotary evaporator is used to remove the methylene chloride, and a mixture of 25 ml. of methylene chloride and 50 ml. of cyclohexane is added. After standing at room temperature for 2 hours and a 5° C. for 16 hours, gravity filtration is used to separate the resulting solid. This material is generally a mixture of the starting acid hydrochloride and the hydrochloride salt of the starting benzopyran. The mother liquid is evaporated and the residue crystallized from a mixture of 2 ml. of methylene chloride and 15 ml. of diethyl ether. After filtration and drying, the pure product is obtained.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17]Cl>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH2:17][O:16][CH2:15][CH2:14][Si:13]([CH3:20])([CH3:19])[CH3:12])[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=c1[nH]nc(Cl)cc1Br
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(Cl)cc(Br)c1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
A 500-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with anhydrous DMF (150 mL) and 4-bromo-6-chloropyridazin-3(2H)-one (10.0 g, 47.8 mmol). The reaction mixture was cooled to 0° C. and sodium hydride was added. The reaction was stirred at 0° C. for 20 min. After this time, 2-(trimethylsilyl)ethoxymethyl chloride (11.9 g, 71.6 mmol) was added and the cooling bath was removed, and the reaction was stirred at room temperature for 3 h. The reaction was then quenched with saturated aqueous sodium bicarbonate (30 mL). The mixture was extracted with ethyl acetate (2×300 mL). The extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 110a in a 56% yield (9.00 g) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.02 (s, 1H), 5.42 (s, 2H), 3.79 (t, 2H, J=5.4 Hz), 0.96 (t, 2H, J=5.4 Hz), 0.01 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.I[CH3:10]>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[CH3:10][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1
Reactant: CI
Reactant: Cc1ccnc(O)c1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1cc(C)ccn1
Reaction time: 48 h
Yield: 70.6 %

Procedure:
To a stirred solution of 2-hydroxy-4-methylpyridine (10 g, 92 mmol) in chloroform (350 mL) was added at room temperature silver carbonate (34.2 g, 124 mmol) and iodomethane (130 g, 920 mmol). The reaction mixture was stirred in the dark for 48 h, and then filtered through Celite and washed with ether. The filtrate was concentrated below 20° C., and the residue was purified by chromatography with pentane/ether (5:1) to afford 2-methoxy-4-methylpyridine as a colorless oil (8.0 g, 71%). 1H NMR (CDCl3) δ 8.02 (d, 1H, J=5.4 Hz), 6.69 (d, 1H, J=5.4 Hz), 6.55 (s, 1H), 3.91 (s, 3H), 2.28 (s, 3H); 13C NMR (CDCl3) δ 164.40, 149.72, 146.31, 118.21, 110.88, 53.17, 20.81. MS m/z (%): 123 (M+, 76), 122 (100).
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[CH2:4][C:3](=[O:8])[CH2:2]1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Br:18])[CH:13]=O.[NH2:19][C:20]1[N:24]([CH3:25])[NH:23][C:22](=[O:26])[CH:21]=1>>[Br:18][C:17]1[CH:16]=[CH:15][C:12]([CH:13]2[C:21]3[C:22](=[O:26])[NH:23][N:24]([CH3:25])[C:20]=3[NH:19][C:5]3[CH2:6][O:1][CH2:2][C:3](=[O:8])[C:4]2=3)=[CH:11][C:10]=1[Cl:9]
Reactant: Cn1[nH]c(=O)cc1N
Reactant: O=Cc1ccc(Br)c(Cl)c1
Reactant: O=C1COCC(=O)C1
Product: Cn1[nH]c(=O)c2c1NC1=C(C(=O)COC1)C2c1ccc(Br)c(Cl)c1
Yield: 70.7 %

Procedure:
2H-Pyran-3,5(4H,6H)-dione (0.057 g, 05 mmol), 3-chloro4-bromo-benzaldehyde (0.11 g, 0.5 mmol), and 5-amino-1-methyl-1,2-dihydropyrazol-3-one (0.056g, 0.5 mmol) were processed as described in Example 26C to provide 0.145 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 3.5 (s, 3H), 4.0 (s, 2H), 4.52 (q, 2H), 4.92 (s, 1H), 7.03 (dt, 1H), 7.32(t, 1H), 7.6 (dd, 1H), 9.62 (s, 1H), 10.1 (s, 1H); MS (ESI−) m/z 410 (M−H:) Anal. calcd for C16H13N3BrClO3: C, 46.80;H,3.19; N, 10.23. Found: C, 46.77;H, 3.43; N, 10.27.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](OS(C(F)(F)F)(=O)=O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:31])=[N:5]1)([CH3:3])[CH3:2].[NH2:32][CH2:33][C:34]([NH2:36])=[O:35].CN1C(=O)CCC1>O>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([NH:32][CH2:33][C:34]([NH2:36])=[O:35])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:31])=[N:5]1)([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(OS(=O)(=O)C(F)(F)F)cc2OCC3)n(C(C)C)n1
Reactant: NCC(N)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nc(-c2cn3c(n2)-c2cnc(NCC(N)=O)cc2OCC3)n(C(C)C)n1
Temperature: 85 °C
Yield: 16.5 %

Procedure:
A mixture of trifluoro-methanesulphonic acid 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yl ester (174 mg, 0.38 mmol), 2-amino-acetamide (281 mg, 3.8 mmol) and NMP (2 mL) was heated at 85° C. for 18 hours. The reaction mixture was treated with water and stirred, the precipitate formed collected by filtration. The aqueous filtrate was passed down an Isolute SCX-2 cartridge washing with methanol and eluting with 2M ammonia in methanol. Appropriate fractions were combined and concentrated in vacuo, the resultant residue subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 458 (24 mg, 17%). LCMS: RT=2.18 min, [M+H]+=383. 1H NMR 400 MHz (DMSO-d6) δ: 9.00 (1H, s), 7.78 (1H, s), 7.31 (1H, br, s), 7.00 (1H, br, s), 6.94 (1H, br, t), 6.10 (1H, s), 5.85 (1H, m), 4.47 (4H, m), 3.83 (2H, d, J=5.85 Hz), 2.25 (3H, s), 1.45 (6H, d, J=6.61 Hz)
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:34])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=3)=[CH:4][C:3]=2[O:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:41]([O:43][C:44](=[O:47])[CH2:45]Br)[CH3:42].C(Cl)Cl.CO>CN(C=O)C>[O:34]=[C:23]([N:11]1[CH2:12][CH2:13][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:21][C:22]=2[CH:10]1[C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)/[CH:24]=[CH:25]/[C:26]1[CH:27]=[CH:28][C:29]([CH2:32][O:33][CH2:45][C:44]([O:43][CH2:41][CH3:42])=[O:47])=[CH:30][CH:31]=1
Reactant: O=C(/C=C/c1ccc(CO)cc1)N1CCc2c([nH]c3ccccc23)C1c1ccc2c(c1)OCO2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)COCc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Yield: 11 %

Procedure:
To a solution of Example 39 (0.7 g, 1.5 mmol) in 50 mL of DMF was added K2CO3 (0.25 g, 1.2 equiv.) and ethylbromoacetate (0.2 mL, 1.1 equiv.). The resulting mixture was heated at 60° C. for 16 hours until disappearance of the starting material (tlc monitoring, DCM:MeOH (95:5)). A new compound was formed (Rf=0.8). After evaporation of DMF, the residue was taken up in 150 mL of DCM, washed with 2×50 mL of water, dried over Na2SO4 and purified via radial chromatography with DCM to give the title compound (0.85 g, 11%) as a white powder.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([C@:7]2([CH3:15])[O:11][C:10](=[O:12])[C:9]([OH:13])=[C:8]2[OH:14])=[CH:3][CH:2]=1.C1(C2C=CC=CC=2)C=CC([C@](O)(C)C(O)=O)=CC=1.C1C=CC([C@H](N)CO)=CC=1>>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([CH3:15])[O:11][C:10](=[O:12])[C:9]([OH:13])=[C:8]2[OH:14])=[CH:3][CH:2]=1
Reactant: C[C@@]1(c2ccc(-c3ccccc3)cc2)OC(=O)C(O)=C1O
Agent: C[C@](O)(C(=O)O)c1ccc(-c2ccccc2)cc1
Agent: N[C@H](CO)c1ccccc1
Product: C[C@]1(c2ccc(-c3ccccc3)cc2)OC(=O)C(O)=C1O

Procedure:
(R)-(−)-5-[(1,1′-Biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone was prepared in an analogous manner as described for (S)-(+)-5-[(1,1′-biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone starting with 1.9 g (5.0 mmol) of the diastereomerically pure salt of (R)-(−)-2-[(1,1′-biphenyl)-4-yl]-2-hydroxypropionic acid and (S)-(+)-phenylglycinol to provide 280 mg (19% yield) of(R)-(−)-5-[(1,1′-biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone as a white crystalline material: mp 197-199° C. dec. (CHCl3/hexanes); [α]25D−182° (c=1.42; MeOH); 1H NMR (acetone-d6) δ 7.65-7.41 (m, 9H), 1.89 (s, 3H). Anal Calcd for C17H14O4+0.25 H2O: C, 71.20; H, 5.10. Found: C, 71.19; H, 4.74.
Reaction SMILES: Cl.[CH:2]([NH:5][OH:6])([CH3:4])[CH3:3].C(OCC)C.[OH-].[Na+].[CH3:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1>O.C(OCC)(=O)C>[OH:6][N:5]([CH:2]([CH3:4])[CH3:3])[C:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([S:15][CH3:14])=[CH:17][CH:18]=1)=[O:24]
Reactant: CC(C)NO
Reactant: CSc1ccc(N=C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1ccc(NC(=O)N(O)C(C)C)cc1
Yield: 55 %

Procedure:
N-Isopropylhydroxylamine hydrochloride (1.35 g, 12.1 mnmol) was dissolved in water (2 mL) then combined with diethyl ether (25 mL) followed by the addition of a solution of sodium hydroxide (0.48 g, 12.1 mmol) in water (2 mL). The reaction mixture was allowed to stir for several minutes then 4-(methylthio)phenyl isocyanate (2.0 g, 12.1 mmol) was added via pipette. A white precipitate formed. The reaction mixture was allowed to stir at ambient temperature overnight. The solid was isolated by filtration then dissolved in hot ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate then concentrated under vacuum. The precipitate was collected and dried to afford 1.60 g of the desired product as a crystalline solid, m.p. 150.0°-150.3° C. Analysis: Calculated for C11H16N2O2S: %C, 54.98; %H, 6.71; %N, 11.66; Found: %C, 54.96; %H, 6.53; %N, 11.61.
Reaction SMILES: [Si]([CH2:17][CH2:18][NH2:19])(OCCOC)(OCCOC)OCCOC.[Si:20]([CH2:30][CH2:31][CH2:32][NH2:33])([O:27][CH2:28]C)([O:24][CH2:25]C)[O:21][CH2:22]C.[Si](CCCN)(OCCOC)(OCCOC)OCCOC.[Si](CCCOCCCN)(OCC)(OCC)OCC.[Si](COCCN)(OCC)(OCC)OCC>>[Si:20]([CH2:30][CH2:31][CH2:32][NH:33][CH2:17][CH2:18][NH2:19])([O:27][CH3:28])([O:24][CH3:25])[O:21][CH3:22]
Reactant: COCCO[Si](CCN)(OCCOC)OCCOC
Reactant: CCO[Si](CCCN)(OCC)OCC
Agent: CCO[Si](CCCOCCCN)(OCC)OCC
Agent: CCO[Si](COCCN)(OCC)OCC
Agent: COCCO[Si](CCCN)(OCCOC)OCCOC
Product: CO[Si](CCCNCCN)(OC)OC

Procedure:
(CH3OCH2CH2O)3Si(CH2)2NH2 ; (C2H5O)3Si(CH2)3NH2 ; (CH3OCH2CH2O)3Si(CH2)3NH2 ; (C2H5O)3Si(CH2)3O(CH2)3NH2 ; (C2H5O)2C6H5Si(CH2)3O(CH2)3NH2 ; (C2H5O)3SiCH2O(CH2)2NH2 ; C2H5)Si(CH)0 (CH)NH(C2H5O)2CH3Si(CH2)3NH2 .
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23](Cl)=[O:24])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][OH:31].N1C=CC=CC=1>O1CCCC1>[OH:31][CH2:30][C:29]1[CH:28]=[C:27]([NH:26][C:23](=[O:24])[CH2:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:17]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: Nc1cccc(CO)c1
Reactant: CCCCCCCCCCCCCCOc1cccc(CC(=O)Cl)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1cccc(CC(=O)Nc2cccc(CO)c2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 10.5 g of 3-(tetradecyloxy)benzeneacetyl chloride in 110 ml of tetrahydrofuran is added a solution of m-aminobenzyl alcohol in 110 ml of tetrahydrofuran containing 9.05 g of pyridine followed by stirring at ambient temperature for 4 hours and storing in a refrigerator over the weekend. The solvent is evaporated and the residue is poured into water and extracted with tetrahydrofuran:ether. The organic layer is washed with dilute hydrochloric acid, dried and filtered through a pad of magnesium silicate. The filtrate is evaporated and the residue purified by high pressure liquid chromatography using 2:1 hexane:ethyl acetate to give 3.6 g of the desired product as a white powder, m.p. 108°-110° C. and 5.8 g of a white powder, m.p. 86°-90° C. found to be 3-(tetradecyloxy)-[3-[[[3-(tetradecyloxy)phenyl]acetyl]amino]phenyl]benzeneacetic acid methyl ester.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:17]([F:20])([F:19])[F:18])=[C:7]([NH:9]C(=O)OC(C)(C)C)[CH:8]=1.[F:21][C:22]([F:30])([F:29])[C:23]1([C:26](O)=[O:27])[CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[NH2:9][C:7]1[CH:8]=[C:3]([CH:4]=[CH:5][C:6]=1[C:17]([F:18])([F:19])[F:20])[CH2:2][NH:1][C:26]([C:23]1([C:22]([F:30])([F:29])[F:21])[CH2:25][CH2:24]1)=[O:27]
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1cc(CN)ccc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(CNC(=O)C2(C(F)(F)F)CC2)ccc1C(F)(F)F

Procedure:
The sub-title compound was prepared in accordance with the procedures in Example 72, step (c) and Example 72, step (d) using tert-butyl N-[5-(aminomethyl)-2-(trifluoromethyl)phenyl]-carbamate (2.09 g; 7.20 mmol), 1-(trifluoromethyl)-cyclopropanecarboxylic acid (1.11 g; 7.20 mmol), HBTU (2.73 g; 7.20 mmol), TEA (2.19 g; 21.6 mmol), DMF (25 mL), TFA (10 mL) and DCM (50 mL). Yield: 1.8 g (77%).
Reaction SMILES: [Br:1]Br.[C:3]1([C:9]2[N:10]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:11]1[N:10]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[N:13][C:12]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccncc2)nc1-c1ccccc1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c(-c2ccccc2)nc(-c2ccncc2)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.2 %

Procedure:
Bromine (0.2 mL, 3.8 mmol) was added slowly to a solution of 4-(2-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyridine (1.2 g, 3.41 mmol; Example 1, Step 2) in dry DCM at 0° C., followed by saturated aqueous Na2CO3 solution (40 mL). The reaction mixture was then stirred at rt for 16 h. The reaction was then allowed to partition and the layers separated. The aqueous phase was extracted with EtOAc (2×20 mL) and the combined organic phases were dried (Na2SO4). The resulting residue was purified by flash chromatography (SiO2, 100:0-90:10 DCM-MeOH) to furnish 1.06 g (72%) of 4-(5-bromo-2-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyridine: 1H NMR (400 MHz, CDCl3) δ 8.62-8.70 (m, 2H), 7.78-8.05 (m, 2H), 7.77-7.86 (m, 2H), 7.45-7.54 (m, 3H), 5.37 (s, 2H), 3.60-3.70 (m, 2H), 0.92-1.02 (m, 2H), 0.003 (s, 9H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10](OC1C=CC([N+]([O-])=O)=CC=1)=[O:11].C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([C:36]([N:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)=[CH:37][CH:38]=[N:39]2)=[CH:34][CH:33]=1>C(Cl)Cl.CO>[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([C:36]([N:42]3[CH2:47][CH2:46][N:45]([C:10]([NH:8][C@H:5]4[CH2:6][CH2:7][C@@H:2]([CH3:1])[CH2:3][CH2:4]4)=[O:11])[CH2:44][CH2:43]3)=[CH:37][CH:38]=[N:39]2)=[CH:34][CH:33]=1
Reactant: C[C@H]1CC[C@@H](N)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[C@H]1CC[C@@H](NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)CC1

Procedure:
As described for example 78, cis-4-methyl-1-cyclohexanamine (170 mg, 1.5 mmol), 4-nitrophenyl chloroformate (302 mg, 1.5 mmol), diisopropyl(ethyl)amine (258 mg, 2 mmol), and 7-chloro-4-(piperazin-1-yl)quinoline (248 mg, 1 mmol) are reacted affording the title product after flash chromatography with CH2Cl2-MeOH. 1H NMR (DSMO-d6) δ 0.92 (d, 3H), 1.2 (m, 2H), 1.55–1.7 (m, 8H), 3.22 (m, 4H), 3.65 (m, 4H), 4.02 (br. s, 1H), 4.6 (m, 1H), 6.82 (d, 1H), 7.44 (d, 1H), 7.98 (d, 1H), 8.06 (s, 1), 8.78 (d, 1H).
Reaction SMILES: BrC(C1C=C(Cl)C=C(Cl)C=1)[C:3]([F:6])([F:5])[F:4].Cl[C:16]1[CH:17]=[C:18]([CH:23]([OH:28])[C:24]([F:27])([F:26])[F:25])[CH:19]=[C:20](Cl)[CH:21]=1.C1C(=O)N(Br)C(=O)C1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(Cl)Cl>[F:25][C:24]([F:27])([F:26])[CH:23]([C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:3]([F:6])([F:5])[F:4])[CH:17]=1)[OH:28]
Reactant: OC(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: FC(F)(F)C(Br)c1cc(Cl)cc(Cl)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: ClCCl
Product: OC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C
Yield: 40 %

Procedure:
1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (AI1). To a stirred solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanol (4.0 g, 16.3 mmol) in CH2Cl2 (50 mL), were added NBS (2.9 g, 16.3 mmol) and triphenyl phosphite (5.06 g, 16.3 mmol), and the resultant reaction mixture was heated at reflux for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to 25° C. and was concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 100% pentane) afforded the title compound as a liquid (2.0 g, 40%): 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 3H), 5.00 (m, 1H); EIMS m/z 306 ([M]+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=4[O:19][CH:20]([CH3:23])[CH:21]=O)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:28].[CH3:29][NH:30][CH3:31].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=4[O:19][CH:20]([CH3:23])[CH2:21][N:30]([CH3:31])[CH3:29])=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:28]
Reactant: CNC
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC(C)C=O)C3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC(C)CN(C)C)C3
Product: Cl
Yield: 20 %

Procedure:
A mixture of 2-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-phenoxy]-propionaldehyde (170 mg; 0.43 mmol; 1 eq.), a 1M solution of dimethyl-amine in THF (2.1 mL; 2.1 mmol; 5 eq.) and sodium triacetoxyborohydride (117 mg; 0.55 mmol; 1.3 eq.) in DCE (10 mL) was stirred at 70° C. for 16 hours. The solution was diluted with DCM, washed with sat. aq. NaHCO3 then brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (DCM to 20% MeOH in DCM) followed by hydrochloride formation with a 4M solution of HCl in 1,4-dioxane and crystallization from hot MTBE afforded the title compound (40 mg, 20%) as a pale yellow solid. 1H NMR (DMSO-d6) δ 9.83 (br s, 1H), 7.54-7.45 (m, 1H), 7.41 (ddd, J=7.6, 3.9, 1.7 Hz, 1H), 7.26 (d, J=8.5 Hz, 1H), 7.13 (t, J=7.4 Hz, 1H), 5.04-4.91 (m, 1H), 4.90-4.80 (d, J=7.9 Hz, 2H), 4.71-4.41 (m, 2H), 2.85 (s, 1.5H), 2.82 (s, 1.5H), 2.75 (br s, 6H), 2.63 (s, 1.5H), 2.56 (s, 1.5H), 1.30-1.22 (m, 3H). HPLC (max plot) 98.7%, Rt 2.79 min. UPLC/MS: (MS+) 428.3 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.[BH3-]C#[N:15].[Na+]>C(O)(C)C>[CH3:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH2:15])=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1C)C(=O)CC2
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1ccc2c(c1C)C(N)CC2

Procedure:
6,7-Dimethyl-1-indanone (2.50 g, 15.60 mmol), NaBH3CN (6.90 g, 0.11 mol) and NH4OAc (36.00 g, 0.47 mol) in isopropanol were reacted according to the protocols as outlined in general procedure E to afford the title indanamine. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ 1.6 (br s, 2H), 1.83-1.96 (m, 1H), 2.01-2.11 (m, 1H), 2.26 (s, 3H), 2.31 (s, 3H), 2.72-2.87 (m, 1H), 3.05-3.18 (m, 1H), 4.42-4.50 (m, 1H), 6.95-7.09 (m, 2H).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16]>C1COCC1>[C:15](=[O:16])([O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)[O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCCCC1
Reaction time: 0.08 h
Yield: 90.5 %

Procedure:
To a solution of cyclohexanol (1.0 g, 10 mmol) in THF (20 mL) at 0° C. was added pyridine (0.97 mL, 12 mmol). After 5 min stirring under N2, a solution of 4-nitrophenyl chloroformate (2.2 g, 11 mmol) in THF (15 mL) was added slowly. After addition, the reaction mixture was stirred at 0° C. for 30 min, and then at RT for 3 h. The precipitate was filtered, the filtrate was concentrated. The resulting residue was chromatographed (40 g silica gel) eluting with EtOAc (0-20%) in hexanes to give the title compound (2.4 g, 91%) as a white solid.