Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:26][C@H:25]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[C@H:24]4[C@@H:15]([CH2:16][CH:17]=[C:18]5[C@@H:23]4[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C(=O)([O-])[OH:36].[Na+]>CC(C)=O.Cl>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C@H:25]2[CH2:26][C@@:4]3([CH3:5])[C@@H:6]([CH2:7][CH2:8][C:3]3=[O:2])[C@H:15]3[C@H:24]2[C@@H:23]2[C:18]([CH2:17][CH2:16]3)=[CH:19][C:20](=[O:36])[CH2:21][CH2:22]2)=[CH:28][CH:29]=1
Reactant: COc1ccc([C@H]2C[C@@]3(C)[C@@H](CC45OCCOC43OCCO5)[C@@H]3CC=C4CCCC[C@@H]4[C@H]32)cc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc([C@H]2C[C@]3(C)C(=O)CC[C@H]3[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]32)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
17,17-bis-(ethylenedioxy)-11β-(4-methoxyphenyl)-5-oestrene are dissolved in 500 ml of acetone and, under an inert gas, 12.5 ml of 4N aqueous hydrochloric acid are added. The reaction mixture is stirred for 2 hours at 40° C. and then poured onto cold saturated sodium hydrogen carbonate solution, and the aqueous phase is extracted repeatedly with methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated in vacuo. The residue is chromatographed on silica gel with a mixture of ethyl acetate/hexane. 12.94 g of 11β-(4-methoxyphenyl)-4-oestrene-3,17-dione are obtained in the form of a white foam.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:27]=[CH:26][C:11]([CH:12]=[CH:13][C:14]([O:16]CC2C=CC(OC)=CC=2)=[O:15])=[CH:10][CH:9]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[OH:1][CH:2]([C:8]1[CH:27]=[CH:26][C:11]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(O)c1ccc(C=CC(=O)OCc2ccc(OC)cc2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CC(O)c1ccc(C=CC(=O)O)cc1
Yield: 90.8 %

Procedure:
44 mg of p-anisyl 4-[1-hydroxy-2-(methoxycarbonyl)ethyl]cinnamate was dissolved in 0.1 ml anisole, and then treated with 0.1 ml trifluoroacetic acid on ice for 30 minutes to give 4-[1-hydroxy-2-(methoxycarbonyl)ethyl]cinnamic acid (27 mg, 91%) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[O:15][CH3:16].[I-].[Na+].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>COCCOC>[CH3:16][O:15][C:7]1[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1
Reactant: CN1CCNCC1
Reactant: COc1ccc([N+](=O)[O-])cc1OCCCCl
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc([N+](=O)[O-])cc1OCCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2(3-chloropropoxy)-1-methoxy-4-nitrobenzene, (100 g, 0.407 mol) and sodium iodide (9.2 g, 0.614 mol) was added to 520 mL of dry 1,2-dimethoxyethane. To the mixture was then added N-methylpiperazine (82 g, 0.814 mol). Stirred and heated the reaction to reflux. The reaction was monitored by HPLC. After 8 hours, the heating mantle was removed and the reaction was allowed to cool to ambient temperature. The reaction mixture was then drowned in 1 L of ethyl acetate and stirred for a minimum of 1 hour. Bright yellow solids precipitated. The mixture was filtered and rinsed and the salts collected with ethyl acetate. The filtrate was washed once with 400 mL of 0.5 N NaOH. The layers were separated and the organic layer was washed with water (3×390 mL). The combined organic layers were concentrated under vacuum at 35-40° C. to obtain 97.8 g (light orange oil) (77%); 1H NMR (300 MHz, CDCl3) δ 7.91 (dd, J=2.6, 9 Hz, 1H), 7.77 (d, J=2.6 Hz, 1H), 6.90 (d, J=9 Hz, 1H), 4.14 (t, J=7 Hz, 2H), 3.96 (s, 3H) 2.54 (t, J=7 Hz, 2H), 2.48 (m, 8H), 2.30 (s, 3H), 2.06 (m, 2H); MS (ES) m/z310.1 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[C:11]([NH:13][C:14](=[N:17][CH3:18])SC)#[N:12]>>[C:11]([NH:13][C:14]([NH:17][CH3:18])=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)#[N:12]
Reactant: CN=C(NC#N)SC
Reactant: NCCSCc1nccs1
Product: CNC(=NCCSCc1nccs1)NC#N

Procedure:
Reaction of [(2-aminoethyl)thiomethyl]thiazole (from the dihydrobromide 20.2 g.) with N-cyano-N',S-dimethylisothiourea (7.75 g.) by a procedure similar to that described in Example 3(a) afforded N-cyano-N'-methyl-N"-[2-(2-thiazolylmethylthio)ethyl]guanidine, m.p. 120°-122.5°, following chromatography on silica gel with acetonitrile as eluant, and recrystallisation from isopropyl alcohol. (Found: C, 42.3; H, 5.1; N, 27.2; S, 25.3. C9H13N5S2 requires: C, 42.3; H, 5.1; N, 27.4; S, 25.1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[CH:19](I)([CH3:21])[CH3:20].O>C(#N)C>[Cl:1][C:2]1[C:3]([O:12][CH:19]([CH3:21])[CH3:20])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 25 °C
Yield: 57.9 %

Procedure:
To a solution of 2-chloro-4-fluoro-5-nitrophenol (19.1 g) in acetonitrile (100 ml), there was added anhydrous potassium carbonate (8 g). After stirring at room temperature for several minutes, isopropyl iodide (25 g) was added thereto, and the resultant mixture was heated under reflux for 3 hours. After being allowed to cool to room temperature, water was added thereto, and the reaction mixture was extracted with ether. The ether extract was washed with a 5% aqueous sodium hydroxide solution and water in this order, dried over anhydrous magnesium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol to obtain 13.5 g of 4-chloro-2-fluoro-5-isopropoxynitrobenzene. M.P., 61.3°-62.4° C.
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][C:12]([CH3:32])([CH3:31])[C:13](=[O:30])[N:14]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[N:9][CH:8]=1.[Br:33]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(OCC)C>[Br:33][CH:11]1[C:10]2[C:15](=[CH:16][C:7]([Cl:6])=[CH:8][N:9]=2)[N:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]2)[C:13](=[O:30])[C:12]1([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)Cc3ncc(Cl)cc32)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)C(Br)c3ncc(Cl)cc32)CC1
Temperature: 0 °C
Yield: 41 %

Procedure:
A carbon tetrachloride solution (25 ml) of tert-butyl 4-(7-chloro-3,3-dimethyl-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (Reference Example 10-2) (1.0 g), N-bromosuccinimide (903 mg) and 2,2′-azobisisobutyronitrile (43.2 mg) was heated at reflux for 40 minutes. After the reaction solution was cooled to 0° C., diethylether was added, and filtered through Celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to afford tert-butyl 4-(4-bromo-7-chloro-3,3-dimethyl-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (492 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][C:9]([S@@:12]([NH2:14])=[O:13])([CH3:11])[CH3:10]>C1COCC1.C(OCC)(=O)C.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[N:14]/[S@:12]([C:9]([CH3:11])([CH3:10])[CH3:8])=[O:13]
Reactant: O=Cc1ccco1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[S@](=O)/N=C/c1ccco1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.2 %

Procedure:
In a round-bottomed flask, furan-2-carbaldehyde (800 mg, 8.33 mmol) was dissolved in THF (20 ml) and (S)-2-methylpropane-2-sulfinamide (1.21 g, 10.0 mmol) and titanium(IV) ethoxide (3.5 ml, 16.7 mmol) were added. The reaction mixture was stirred at room temperature for 5 h then slowly quenched by dropwise addition of brine (5 ml) which resulted in the formation of a thick precipitate. The reaction mixture was diluted with ethyl acetate and stirred vigorously at room temperature for 15 min. The suspension was filtered over Celite and rinsed with ethyl acetate. The filtrate was concentrated and the residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-25% EtOAc) to give 1.48 g (89%) of (S)-2-methyl-propane-2-sulfinic acid 1-furan-2-yl-meth-(E)-ylideneamide as a light yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]2[C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[C:6]=2[N:7]=1)[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:23][C:24]1[C:28]([NH2:29])=[C:27]([CH3:30])[O:26][N:25]=1.C(N(CC)CC)C>ClCCl>[CH3:23][C:24]1[C:28]([NH:29][C:12]([C:11]2[C:5]3[S:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=3[C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)=[O:14])=[C:27]([CH3:30])[O:26][N:25]=1
Reactant: CCc1nc2c(OC)ccc(C(=O)O)c2s1
Reactant: Cc1noc(C)c1N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(OC)ccc(C(=O)Nc3c(C)noc3C)c2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.5 %

Procedure:
To a suspension of 2-ethyl-4-methoxybenzothiazole-7-carboxylic acid (0.1 g) in dichloromethane (10 ml) was added oxalyl chloride (0.08 ml) and dimethylformanide (1 drop). The reaction was stirred at room temperature for 16 hrs, and then the solvent was removed in vacuo to yield a brown solid residue. This was taken up in dichloromethane is (30 ml) and 3,5-dimethylisoxazol-4-amine (0.05 g) was added followed by triethylamine (0.15 ml) and the reaction stirred at room temperature for 16 hrs. The solvent was removed in vacuo and the product purified by flash chromatography (eluent ethyl acetate) to yield the title compound as an off-white solid (0.016 g). TLC Rf 0.38 (ethyl acetate); Mpt 85-87° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29](F)(F)F)[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC([C:49]3N(CCNC(C)C)[CH:51]=[C:52]([C:54]4C=CC(F)=C(C)C=4)[N:53]=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:49][NH:53][CH:52]([CH3:54])[CH3:51])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH3:29])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2cn(CCNC(C)C)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Product: Cc1cc(-c2cn(CCNC(C)C)c(C3CCN(c4ncnc(N)c4C(N)=O)CC3)n2)ccc1F

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-isopropylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=481, obsd.=481).
Reaction SMILES: [C:1]([C:8]1[NH:9][CH:10]=[CH:11]N=1)([C:3]1NC=CN=1)=O.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].N1CCCCC1>C(OCC)(=O)C>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:9]2[CH2:8][CH2:1][CH2:3][CH2:11][CH2:10]2)=[O:20])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)N1CCCCC1
Reaction time: 1.5 h
Yield: 96.9 %

Procedure:
A 5-L flask was charged with ethyl acetate (2.3 L) and carbonyl diimidazole (500.0 g, 2.48 mol) to which 4-chloro-3-nitrobenzoic acid (402.5 g, 2.48 mol) was added in portions over 1 hour. The solution was stirred for an additional 1.5 hours. Piperidine (222.2 g, 2.60 mol) was added dropwise over 2 hours and the resulting solution was stirred for an additional 4 hours. The reaction mixture was washed sequentially, twice with 6N HCl solution (600 mL), twice with saturated NaHCO3 (250 mL), and finally with saturated NaCl (250 mL). The organic solution was dried over anhydrous Na2SO4 and filtered, and the solvent was removed in vacuo to yield 646 g (97%) of 4-chloro-3-nitrobenzoyl-piperidine as a yellow crystalline solid with m.p. =76—78 ° C. IR: 1633, 1535, and 1440 cm31 1. 1H NMR (500 MHz, CDCl3): δ 7.92 (1H, d, J 1.5 Hz), 7.60 (1H, d, J=8.1 Hz), 7.56 (1H, dd, J═8.1 and 1.5 Hz), 3.70 (2H, br s), 3.35 (2H, br s), 1.70 (4H, br s), and 1.56 ppm (2H, br s).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3](SC)=[CH:4][C:5]#[N:6].O.[NH2:11][NH2:12]>C(O)C>[CH3:1][N:2]([CH3:9])[C:3]1[NH:12][N:11]=[C:5]([NH2:6])[CH:4]=1
Reactant: NN
Reactant: CSC(=CC#N)N(C)C
Solvent: CCO
Solvent: O
Product: CN(C)c1cc(N)n[nH]1
Temperature: 85 °C
Yield: 68.6 %

Procedure:
A mixture of (2E or Z)-3-(dimethylamino)-3-(methylthio)acrylonitrile (Method 33, 9.525 g, 67 mmol) and hydrazine hydrate (10.06 g, 201 mmol) in ethanol (70 ml) was heated at 85° C. overnight. Solvent was removed. The residue was purified by silica gel column chromatography (by ISCO Combiflash with a gradient of 0-10% methanol in methylenechloride with 1% NH4OH). 5.8 g (69%) product as obtained brownish thick oil. LC-MS, 127 (M+1). NMR (DMSO, 400 MHz) δ9.51 (br, 1H), 4.67 (s, 1H), 2.62 (s, 6H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH:5]([C:7]([O:9][CH2:10][CH:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[NH2:6]>ClCCl.C([O-])(O)=O.[Na+]>[CH:13]1[C:12]2[CH:11]([CH2:10][O:9][C:7]3[O:8][C:1](=[O:2])[NH:6][N:5]=3)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: NNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1[nH]nc(OCC2c3ccccc3-c3ccccc32)o1
Reaction time: 0.25 h

Procedure:
Two equivalents of phosgene (1.89 M in toluene; 4.2 ml) are added to a solution of 995 mg of 9H-fluoren-9-yl-methyl hydrazinecarboxylate in 40 ml of dichloromethane and 40 ml of saturated aqueous NaHCO3 solution. The mixture is stirred for 15 minutes and then worked up as usual, giving 5-(9H-fluoren-9-ylmethoxy)-3H-[1,3,4]oxadiazol-2-one (“A”).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:27])([F:26])[C:9]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:10]=1>C1COCC1>[F:27][C:8]([F:7])([F:26])[C:9]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]([C:18]2[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=2)[N:10]=1
Reactant: N#Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Lithium aluminium hydride (12.44 ml, 2 M in THF solution, 24.88 mmol) and THF (30 ml) were stirred in an ice bath under argon. A solution of 4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzonitrile (1.812 g, 6.22 mmol) in THF (30 ml) was added dropwise over 15 mins. Then the ice bath was removed and the reaction mixture was allowed to stir at room temperature for 1.5 hrs. Then the reaction mixture was cooled using an ice bath and quenched with water dropwise, solvent was removed under vacuo (i.e reduced pressure). Residual material was diluted with DCM and water. Insoluble solid filtered off and organic layer separated, washed with brine, dried over sodium sulphate. The solvent was removed by rotary evaporation. The desired product was isolated using a 25 g SCX column initially washed with DCM (30 ml), DCM/MeOH (60 ml), MeOH (30 ml) and then the desired product was eluted with 1M ammonia in MeOH (25 ml). Solvent evaporated off under reduced pressure to give the title compound as a brown oil (1.563 g, 85%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2.[OH:23][C:24]1[N:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+].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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:3]3[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=3[C:27]3[CH:26]=[CH:25][C:24]([OH:23])=[N:29][CH:28]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1
Reactant: CC1(C)OB(c2ccc(O)nc2)OC1(C)C
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: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2ccccc2-c2ccc(O)nc2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 6-hydroxypyridine-3-boronic acid pinacol ester (124 mg, 0.562 mmol) and K2CO3 (120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure to dryness. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-(2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)pyridin-2-ol. 1H NMR (TFA salt, CD3OD) d (ppm): 7.59-7.68 (m, 3H), 7.4 (s, 1H), 7.3 (s, 1H), 6.98-7.18 (m, 3H), 6.82 (d, 1H), 6.23 (d, 1H), 4.7 (d, 1H), 4.37 (d, 1H), 3.7 (m, 1H), 3.4 (m, 1H), 3.0 (m, 4H), 2.8 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][O+](C)C.[CH3:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1>ClCCCl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:10][N+:11]1[CH:15]=[CH:14][N:13]([CH3:6])[CH:12]=1
Reactant: Cn1ccnc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCCl
Product: Cn1cc[n+](C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The procedure of Example 2 was followed. 3.9 g of trimethyloxonium tetrafluoroborate in suspension in 20 ml of 1,2-dichloroethane was added to 2.1 ml (2.16 g) of N-methylimidazole in 5 ml of 1,2-dichloroethane. The mixture was stirred for 4 hours at room temperature. A salt was formed (lower phase) which was non miscible with the solvent and was separated by decanting. The remaining solvent was evaporated off under vacuum using a vane pump. A colorless liquid was obtained.
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20]([C@@H:22]([O:24][C:25](=[O:32])[NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH3:23])=[O:21])[C:15]2[CH:33]=[CH:34][CH:35]=[CH:36][C:14]=2[C:13]2[CH:37]=[CH:38][CH:39]=[CH:40][C:12]1=2)C1C=CC=CC=1.C(OCC)(=O)C>CCCCCCC>[OH:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20]([C@@H:22]([O:24][C:25](=[O:32])[NH:26][CH2:27][C:28]([F:29])([F:30])[F:31])[CH3:23])=[O:21])[C:15]2[CH:33]=[CH:34][CH:35]=[CH:36][C:14]=2[C:13]2[CH:37]=[CH:38][CH:39]=[CH:40][C:12]1=2
Reactant: C[C@H](OC(=O)NCC(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: C[C@H](OC(=O)NCC(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCO)c2ccccc2-c2ccccc21
Yield: 70 %

Procedure:
Using (2,2,2-trifluoro-ethyl)-carbamic acid (S)-1-[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl]-ethyl ester, the title compound was prepared in the same manner as example 3. Final chromatography (silica, gradient of ethyl acetate in heptane 5-90%) afforded the title compound as white solid (70%). MS: m/e=466(M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.Br[CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([OH:16])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([OH:16])=[O:15])=[N:7][C:6]=2[CH:11]=1
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: Sc1nc2cc(Cl)ccc2s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C(Sc1nc2cc(Cl)ccc2s1)c1ccccc1
Yield: 69.1 %

Procedure:
To a solution of 5-chloro-2-mercaptobenzothiazole (38 g, 0.188 mol) in methylene chloride (750 mL) was added α-bromophenylacetic acid (38 g, 0.177 L mol) and triethylamine (38.5 g, 53 mL, 0.38 mol). The mixture was heated to reflux overnight. The clear solution was evaporated in vacuo and the residue was taken up in ethyl acetate, washed with dilute hydrochloric acid solution, then with water and finally dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to a small volume and treated with n-hexane whereby the product crystallized out. Filtration yielded the product as a beige crystalline compound (41 g, 70%), m.p. 184°-185° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+]([O-])=O)[CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[O:16]([CH3:18])[Li]>CO>[CH3:18][O:16][C:11]1[CH:10]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: [Li]OC
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: CO
Product: COc1cc(C(=O)O)cc([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
3,5-Dinitrobenzoic acid (866 mg) was dissolved in 1 M LiOMe in MeOH (1.3 mL), then evaporated to dryness. The resulting solid was dissolved in 30 mL of hexamethyl phosphoramide and heated at 80° C. for 16 h. The mixture was then cooled and poured onto a mixture of crushed ice (250 g) and 6NH2SO4 (42 mL). The mixture was extracted with ether, and the extract was washed with water and brine, then dried over MgSO4, filtered and evaporated to yield an orange solid. Filtration through silica gel using 9:1 CH2Cl2/MeOH followed by evaporation provided 624 mg of product. 1H-NMR (d6-acetone): δ 8.36 (1H, dd, J=1.6, 2.0 Hz), 7.97 (1H, t, J=2.0 Hz), 7.91 (1H, dd, J=1.6, 2.0 Hz), 4.03 (3H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH2:15]([Sn](CCCC)(CCCC)CCCC)[CH:16]=[CH2:17].[Cl-].[Li+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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:5]1[CH:6]=[CH:7][C:2]([CH2:17][CH:16]=[CH2:15])=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=[N+]([O-])c1ccc(Br)c(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1ccc([N+](=O)[O-])cc1C(F)(F)F

Procedure:
A mixture of 1-bromo-4-nitro-2-(trifluoromethyl)benzene (1.0 g, 3.7 mmol), Allyl Tri-n-butyltin (1.4 mL, 4.4 mmol), Lithium Chloride (470 mg, 11 mmol), and Palladium Tetrakis (210 mg, 0.18 mmol) in toluene (30 mL) was heated to reflux for 16 hours under nitrogen. TLC showed complete reaction at that point. The reaction was diluted with ethyl acetate, adsorbed onto silica gel, and purified by silica gel chromatography to afford the title product.